WO2024030437A1 - Functionalized and crosslinked polymer methods and compositions - Google Patents
Functionalized and crosslinked polymer methods and compositions Download PDFInfo
- Publication number
- WO2024030437A1 WO2024030437A1 PCT/US2023/029224 US2023029224W WO2024030437A1 WO 2024030437 A1 WO2024030437 A1 WO 2024030437A1 US 2023029224 W US2023029224 W US 2023029224W WO 2024030437 A1 WO2024030437 A1 WO 2024030437A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- polymer
- derivatized
- solution
- groups
- group
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims description 309
- 238000000034 method Methods 0.000 title description 81
- 229920006037 cross link polymer Polymers 0.000 title description 13
- 229920000642 polymer Polymers 0.000 claims abstract description 505
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 466
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 400
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 400
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 124
- 150000002632 lipids Chemical group 0.000 claims description 69
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical group C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 68
- 239000013543 active substance Substances 0.000 claims description 58
- 150000003839 salts Chemical class 0.000 claims description 52
- 235000012000 cholesterol Nutrition 0.000 claims description 34
- 229910052717 sulfur Inorganic materials 0.000 claims description 28
- 229920001223 polyethylene glycol Polymers 0.000 claims description 27
- 125000003277 amino group Chemical group 0.000 claims description 26
- 239000002202 Polyethylene glycol Substances 0.000 claims description 25
- 150000002148 esters Chemical class 0.000 claims description 25
- 125000000542 sulfonic acid group Chemical group 0.000 claims description 24
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 125000001931 aliphatic group Chemical group 0.000 claims description 18
- 239000002502 liposome Substances 0.000 claims description 8
- 239000002105 nanoparticle Substances 0.000 claims description 7
- 229940127089 cytotoxic agent Drugs 0.000 claims description 6
- 150000003904 phospholipids Chemical class 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 125000003827 glycol group Chemical group 0.000 claims 1
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 abstract description 146
- 238000006243 chemical reaction Methods 0.000 abstract description 79
- -1 described above Chemical class 0.000 description 108
- 239000000243 solution Substances 0.000 description 75
- 150000001875 compounds Chemical class 0.000 description 66
- 150000003573 thiols Chemical class 0.000 description 57
- 238000004132 cross linking Methods 0.000 description 44
- 150000004804 polysaccharides Chemical class 0.000 description 44
- 235000002639 sodium chloride Nutrition 0.000 description 40
- 239000010408 film Substances 0.000 description 39
- 229920001282 polysaccharide Polymers 0.000 description 37
- 239000005017 polysaccharide Substances 0.000 description 37
- 125000003118 aryl group Chemical group 0.000 description 36
- 239000000835 fiber Substances 0.000 description 36
- 239000002904 solvent Substances 0.000 description 32
- 239000002245 particle Substances 0.000 description 30
- 239000003431 cross linking reagent Substances 0.000 description 29
- 239000000499 gel Substances 0.000 description 29
- 239000003795 chemical substances by application Substances 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 239000000546 pharmaceutical excipient Substances 0.000 description 27
- 230000008569 process Effects 0.000 description 27
- 210000001519 tissue Anatomy 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 238000006467 substitution reaction Methods 0.000 description 22
- 239000003112 inhibitor Substances 0.000 description 21
- 102000004169 proteins and genes Human genes 0.000 description 19
- 108090000623 proteins and genes Proteins 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 210000003101 oviduct Anatomy 0.000 description 18
- 235000018102 proteins Nutrition 0.000 description 18
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 17
- 108090000765 processed proteins & peptides Proteins 0.000 description 17
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 17
- 238000009472 formulation Methods 0.000 description 16
- 238000001356 surgical procedure Methods 0.000 description 16
- 239000007787 solid Substances 0.000 description 15
- 125000001424 substituent group Chemical group 0.000 description 15
- 239000004971 Cross linker Substances 0.000 description 14
- 125000003396 thiol group Chemical group [H]S* 0.000 description 14
- 229920001661 Chitosan Polymers 0.000 description 13
- 229910052751 metal Inorganic materials 0.000 description 13
- 239000002184 metal Substances 0.000 description 13
- 239000003814 drug Substances 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- 239000005557 antagonist Substances 0.000 description 11
- 239000011248 coating agent Substances 0.000 description 11
- 238000000576 coating method Methods 0.000 description 11
- 102000004196 processed proteins & peptides Human genes 0.000 description 11
- 230000035484 reaction time Effects 0.000 description 11
- 230000001954 sterilising effect Effects 0.000 description 11
- 238000004659 sterilization and disinfection Methods 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- 125000000217 alkyl group Chemical group 0.000 description 10
- 239000003102 growth factor Substances 0.000 description 10
- 239000000017 hydrogel Substances 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- 238000003801 milling Methods 0.000 description 10
- 230000000269 nucleophilic effect Effects 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- 239000003246 corticosteroid Substances 0.000 description 9
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 9
- 235000018417 cysteine Nutrition 0.000 description 9
- 230000002500 effect on skin Effects 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 9
- 229960004756 ethanol Drugs 0.000 description 9
- 229920000139 polyethylene terephthalate Polymers 0.000 description 9
- 239000005020 polyethylene terephthalate Substances 0.000 description 9
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 208000027418 Wounds and injury Diseases 0.000 description 8
- 239000003242 anti bacterial agent Substances 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 229920001577 copolymer Polymers 0.000 description 8
- 238000009826 distribution Methods 0.000 description 8
- 125000001072 heteroaryl group Chemical group 0.000 description 8
- 238000002156 mixing Methods 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 229920002307 Dextran Polymers 0.000 description 7
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 7
- 108091007433 antigens Proteins 0.000 description 7
- 102000036639 antigens Human genes 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 238000001523 electrospinning Methods 0.000 description 7
- 239000000839 emulsion Substances 0.000 description 7
- 239000000945 filler Substances 0.000 description 7
- 150000004676 glycans Polymers 0.000 description 7
- 235000011187 glycerol Nutrition 0.000 description 7
- 239000011159 matrix material Substances 0.000 description 7
- 239000003755 preservative agent Substances 0.000 description 7
- 229910001220 stainless steel Inorganic materials 0.000 description 7
- 150000003568 thioethers Chemical class 0.000 description 7
- SHKUUQIDMUMQQK-UHFFFAOYSA-N 2-[4-(oxiran-2-ylmethoxy)butoxymethyl]oxirane Chemical compound C1OC1COCCCCOCC1CO1 SHKUUQIDMUMQQK-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 6
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000006845 Michael addition reaction Methods 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 239000004677 Nylon Substances 0.000 description 6
- 208000002193 Pain Diseases 0.000 description 6
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 239000004698 Polyethylene Substances 0.000 description 6
- 239000004743 Polypropylene Substances 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 206010052428 Wound Diseases 0.000 description 6
- 239000000556 agonist Substances 0.000 description 6
- 239000000427 antigen Substances 0.000 description 6
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 239000001506 calcium phosphate Substances 0.000 description 6
- 229960001747 cinchocaine Drugs 0.000 description 6
- PUFQVTATUTYEAL-UHFFFAOYSA-N cinchocaine Chemical compound C1=CC=CC2=NC(OCCCC)=CC(C(=O)NCCN(CC)CC)=C21 PUFQVTATUTYEAL-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 6
- 239000002131 composite material Substances 0.000 description 6
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 6
- 238000013467 fragmentation Methods 0.000 description 6
- 238000006062 fragmentation reaction Methods 0.000 description 6
- 238000000227 grinding Methods 0.000 description 6
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 6
- 239000011261 inert gas Substances 0.000 description 6
- 230000000977 initiatory effect Effects 0.000 description 6
- 229940043355 kinase inhibitor Drugs 0.000 description 6
- 229960004194 lidocaine Drugs 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- FEKRFYZGYUTGRY-UHFFFAOYSA-N n'-ethylmethanediimine Chemical compound CCN=C=N FEKRFYZGYUTGRY-UHFFFAOYSA-N 0.000 description 6
- 229920001778 nylon Polymers 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 230000036407 pain Effects 0.000 description 6
- 229920000728 polyester Polymers 0.000 description 6
- 229920000573 polyethylene Polymers 0.000 description 6
- 229920001155 polypropylene Polymers 0.000 description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 6
- 239000010935 stainless steel Substances 0.000 description 6
- 239000004094 surface-active agent Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 6
- 230000029663 wound healing Effects 0.000 description 6
- WJOHZNCJWYWUJD-IUGZLZTKSA-N Fluocinonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)C)[C@@]2(C)C[C@@H]1O WJOHZNCJWYWUJD-IUGZLZTKSA-N 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 5
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 5
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 5
- 239000000654 additive Substances 0.000 description 5
- 230000000996 additive effect Effects 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 230000003110 anti-inflammatory effect Effects 0.000 description 5
- 229960002537 betamethasone Drugs 0.000 description 5
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 239000002537 cosmetic Substances 0.000 description 5
- 229920006237 degradable polymer Polymers 0.000 description 5
- 238000001212 derivatisation Methods 0.000 description 5
- 229960003957 dexamethasone Drugs 0.000 description 5
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 5
- 239000003889 eye drop Substances 0.000 description 5
- 229960000785 fluocinonide Drugs 0.000 description 5
- 239000011888 foil Substances 0.000 description 5
- 230000033001 locomotion Effects 0.000 description 5
- 239000012038 nucleophile Substances 0.000 description 5
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 5
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 5
- 229920002635 polyurethane Polymers 0.000 description 5
- 239000004814 polyurethane Substances 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 230000002335 preservative effect Effects 0.000 description 5
- 239000007921 spray Substances 0.000 description 5
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 5
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 4
- QGVQZRDQPDLHHV-DPAQBDIFSA-N (3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthrene-3-thiol Chemical compound C1C=C2C[C@@H](S)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 QGVQZRDQPDLHHV-DPAQBDIFSA-N 0.000 description 4
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 4
- PMBXCGGQNSVESQ-UHFFFAOYSA-N 1-Hexanethiol Chemical compound CCCCCCS PMBXCGGQNSVESQ-UHFFFAOYSA-N 0.000 description 4
- ZRKMQKLGEQPLNS-UHFFFAOYSA-N 1-Pentanethiol Chemical compound CCCCCS ZRKMQKLGEQPLNS-UHFFFAOYSA-N 0.000 description 4
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 108010035532 Collagen Proteins 0.000 description 4
- 102000008186 Collagen Human genes 0.000 description 4
- 102400001368 Epidermal growth factor Human genes 0.000 description 4
- 101800003838 Epidermal growth factor Proteins 0.000 description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 229930012538 Paclitaxel Natural products 0.000 description 4
- 239000004696 Poly ether ether ketone Substances 0.000 description 4
- 241000083513 Punctum Species 0.000 description 4
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 4
- NGCGMRBZPXEPOZ-HBBGHHHDSA-N acetic acid;(2s)-n-[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[2-[[(2s)-1-[[(2s)-1-[(2s)-2-[(2-amino-2-oxoethyl)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-3-(4-hydroxyphenyl)- Chemical compound CC(O)=O.C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 NGCGMRBZPXEPOZ-HBBGHHHDSA-N 0.000 description 4
- 229960001138 acetylsalicylic acid Drugs 0.000 description 4
- 239000000853 adhesive Substances 0.000 description 4
- 230000001070 adhesive effect Effects 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 230000001028 anti-proliverative effect Effects 0.000 description 4
- 229940121375 antifungal agent Drugs 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 239000002249 anxiolytic agent Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 229920002988 biodegradable polymer Polymers 0.000 description 4
- 239000004621 biodegradable polymer Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 238000005266 casting Methods 0.000 description 4
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 4
- 229920001436 collagen Polymers 0.000 description 4
- 229960001334 corticosteroids Drugs 0.000 description 4
- 238000009646 cryomilling Methods 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 239000002934 diuretic Substances 0.000 description 4
- 229940030606 diuretics Drugs 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229940116977 epidermal growth factor Drugs 0.000 description 4
- 229960003276 erythromycin Drugs 0.000 description 4
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 4
- 229940012356 eye drops Drugs 0.000 description 4
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 239000007972 injectable composition Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 229910010272 inorganic material Inorganic materials 0.000 description 4
- 238000010902 jet-milling Methods 0.000 description 4
- 239000003589 local anesthetic agent Substances 0.000 description 4
- 238000003701 mechanical milling Methods 0.000 description 4
- 229960000282 metronidazole Drugs 0.000 description 4
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 4
- 229910001000 nickel titanium Inorganic materials 0.000 description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 4
- QJAOYSPHSNGHNC-UHFFFAOYSA-N octadecane-1-thiol Chemical compound CCCCCCCCCCCCCCCCCCS QJAOYSPHSNGHNC-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000001301 oxygen Chemical group 0.000 description 4
- 229960001592 paclitaxel Drugs 0.000 description 4
- 229920006260 polyaryletherketone Polymers 0.000 description 4
- 229920002530 polyetherether ketone Polymers 0.000 description 4
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 4
- 229960005205 prednisolone Drugs 0.000 description 4
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 4
- 229940071643 prefilled syringe Drugs 0.000 description 4
- 230000005855 radiation Effects 0.000 description 4
- 229940044551 receptor antagonist Drugs 0.000 description 4
- 239000002464 receptor antagonist Substances 0.000 description 4
- 229910052709 silver Inorganic materials 0.000 description 4
- 239000004332 silver Substances 0.000 description 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 4
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000000935 solvent evaporation Methods 0.000 description 4
- 238000001694 spray drying Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 210000002435 tendon Anatomy 0.000 description 4
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical class O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 4
- 229910052719 titanium Inorganic materials 0.000 description 4
- 239000010936 titanium Substances 0.000 description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 4
- 229940078499 tricalcium phosphate Drugs 0.000 description 4
- 235000019731 tricalcium phosphate Nutrition 0.000 description 4
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 4
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 4
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 3
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 description 3
- LVNGJLRDBYCPGB-UHFFFAOYSA-N 1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-UHFFFAOYSA-N 0.000 description 3
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- YYFLDZZDOUDZQM-UHFFFAOYSA-N 3-[1-[[4-(3-phenylquinolin-2-yl)phenyl]methyl]piperidin-4-yl]-1h-benzimidazol-2-one Chemical compound O=C1NC2=CC=CC=C2N1C(CC1)CCN1CC(C=C1)=CC=C1C1=NC2=CC=CC=C2C=C1C1=CC=CC=C1 YYFLDZZDOUDZQM-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229940127291 Calcium channel antagonist Drugs 0.000 description 3
- 229920002101 Chitin Polymers 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VTUSIVBDOCDNHS-UHFFFAOYSA-N Etidocaine Chemical compound CCCN(CC)C(CC)C(=O)NC1=C(C)C=CC=C1C VTUSIVBDOCDNHS-UHFFFAOYSA-N 0.000 description 3
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- 102000003886 Glycoproteins Human genes 0.000 description 3
- 108090000288 Glycoproteins Proteins 0.000 description 3
- 229920002683 Glycosaminoglycan Polymers 0.000 description 3
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 3
- 108010025020 Nerve Growth Factor Proteins 0.000 description 3
- 108091034117 Oligonucleotide Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229920002732 Polyanhydride Polymers 0.000 description 3
- 229920000331 Polyhydroxybutyrate Polymers 0.000 description 3
- 229920001710 Polyorthoester Polymers 0.000 description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- BGNVBNJYBVCBJH-UHFFFAOYSA-N SM-102 Chemical compound OCCN(CCCCCCCC(=O)OC(CCCCCCCC)CCCCCCCC)CCCCCC(OCCCCCCCCCCC)=O BGNVBNJYBVCBJH-UHFFFAOYSA-N 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 3
- 239000004809 Teflon Substances 0.000 description 3
- 229920006362 Teflon® Polymers 0.000 description 3
- 239000004098 Tetracycline Substances 0.000 description 3
- ZJCCRDAZUWHFQH-UHFFFAOYSA-N Trimethylolpropane Chemical compound CCC(CO)(CO)CO ZJCCRDAZUWHFQH-UHFFFAOYSA-N 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- FVECELJHCSPHKY-UHFFFAOYSA-N Veratridine Natural products C1=C(OC)C(OC)=CC=C1C(=O)OC1C2(O)OC34CC5(O)C(CN6C(CCC(C)C6)C6(C)O)C6(O)C(O)CC5(O)C4CCC2C3(C)CC1 FVECELJHCSPHKY-UHFFFAOYSA-N 0.000 description 3
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 3
- 238000007259 addition reaction Methods 0.000 description 3
- 230000001800 adrenalinergic effect Effects 0.000 description 3
- 239000013566 allergen Substances 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 229960003022 amoxicillin Drugs 0.000 description 3
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 3
- 239000004037 angiogenesis inhibitor Substances 0.000 description 3
- 229940045799 anthracyclines and related substance Drugs 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 239000000935 antidepressant agent Substances 0.000 description 3
- 229940005513 antidepressants Drugs 0.000 description 3
- 239000000739 antihistaminic agent Substances 0.000 description 3
- 229940125715 antihistaminic agent Drugs 0.000 description 3
- 239000004599 antimicrobial Substances 0.000 description 3
- 239000000164 antipsychotic agent Substances 0.000 description 3
- 239000004019 antithrombin Substances 0.000 description 3
- 150000005840 aryl radicals Chemical class 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 229960005274 benzocaine Drugs 0.000 description 3
- 239000002876 beta blocker Substances 0.000 description 3
- 238000001574 biopsy Methods 0.000 description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- 235000010338 boric acid Nutrition 0.000 description 3
- 239000004067 bulking agent Substances 0.000 description 3
- 229960003150 bupivacaine Drugs 0.000 description 3
- 239000000480 calcium channel blocker Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 3
- 229960000830 captopril Drugs 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 125000002091 cationic group Chemical group 0.000 description 3
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 3
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 3
- 229960003920 cocaine Drugs 0.000 description 3
- 239000008139 complexing agent Substances 0.000 description 3
- 150000001944 cysteine derivatives Chemical class 0.000 description 3
- 239000000824 cytostatic agent Substances 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 229960003662 desonide Drugs 0.000 description 3
- WBGKWQHBNHJJPZ-LECWWXJVSA-N desonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O WBGKWQHBNHJJPZ-LECWWXJVSA-N 0.000 description 3
- 229960003722 doxycycline Drugs 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 229960003976 etidocaine Drugs 0.000 description 3
- 229960005167 everolimus Drugs 0.000 description 3
- 239000003527 fibrinolytic agent Substances 0.000 description 3
- 229960002011 fludrocortisone Drugs 0.000 description 3
- AAXVEMMRQDVLJB-BULBTXNYSA-N fludrocortisone Chemical compound O=C1CC[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 AAXVEMMRQDVLJB-BULBTXNYSA-N 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 229960003469 flumetasone Drugs 0.000 description 3
- WXURHACBFYSXBI-GQKYHHCASA-N flumethasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O WXURHACBFYSXBI-GQKYHHCASA-N 0.000 description 3
- 229960003973 fluocortolone Drugs 0.000 description 3
- GAKMQHDJQHZUTJ-ULHLPKEOSA-N fluocortolone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)CO)[C@@]2(C)C[C@@H]1O GAKMQHDJQHZUTJ-ULHLPKEOSA-N 0.000 description 3
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthene Chemical group C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 229960005150 glycerol Drugs 0.000 description 3
- 229960002897 heparin Drugs 0.000 description 3
- 229920000669 heparin Polymers 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 229960000890 hydrocortisone Drugs 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229960003444 immunosuppressant agent Drugs 0.000 description 3
- 239000003018 immunosuppressive agent Substances 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 150000002484 inorganic compounds Chemical class 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 229960002409 mepivacaine Drugs 0.000 description 3
- INWLQCZOYSRPNW-UHFFFAOYSA-N mepivacaine Chemical compound CN1CCCCC1C(=O)NC1=C(C)C=CC=C1C INWLQCZOYSRPNW-UHFFFAOYSA-N 0.000 description 3
- 150000002739 metals Chemical class 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 229960004023 minocycline Drugs 0.000 description 3
- 239000003607 modifier Substances 0.000 description 3
- MENOBBYDZHOWLE-UHFFFAOYSA-N morpholine-2,3-dione Chemical compound O=C1NCCOC1=O MENOBBYDZHOWLE-UHFFFAOYSA-N 0.000 description 3
- HLXZNVUGXRDIFK-UHFFFAOYSA-N nickel titanium Chemical compound [Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni] HLXZNVUGXRDIFK-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Chemical group 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 235000016709 nutrition Nutrition 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 3
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 3
- 239000003002 pH adjusting agent Substances 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- 230000000149 penetrating effect Effects 0.000 description 3
- 235000019371 penicillin G benzathine Nutrition 0.000 description 3
- 229940056360 penicillin g Drugs 0.000 description 3
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 3
- 229940059574 pentaerithrityl Drugs 0.000 description 3
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphonic acid group Chemical group P(O)(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- 229920001432 poly(L-lactide) Polymers 0.000 description 3
- 239000005015 poly(hydroxybutyrate) Substances 0.000 description 3
- 239000004417 polycarbonate Substances 0.000 description 3
- 229920000515 polycarbonate Polymers 0.000 description 3
- 229920001296 polysiloxane Polymers 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 3
- 229960001807 prilocaine Drugs 0.000 description 3
- MVFGUOIZUNYYSO-UHFFFAOYSA-N prilocaine Chemical compound CCCNC(C)C(=O)NC1=CC=CC=C1C MVFGUOIZUNYYSO-UHFFFAOYSA-N 0.000 description 3
- 229960004919 procaine Drugs 0.000 description 3
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 150000003180 prostaglandins Chemical class 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 230000008439 repair process Effects 0.000 description 3
- 230000000717 retained effect Effects 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 229960004889 salicylic acid Drugs 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 229960002930 sirolimus Drugs 0.000 description 3
- 239000000021 stimulant Substances 0.000 description 3
- 208000003265 stomatitis Diseases 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 229920001059 synthetic polymer Polymers 0.000 description 3
- 229960001967 tacrolimus Drugs 0.000 description 3
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 3
- 229960002372 tetracaine Drugs 0.000 description 3
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 description 3
- 235000019364 tetracycline Nutrition 0.000 description 3
- 150000003522 tetracyclines Chemical class 0.000 description 3
- 239000004753 textile Substances 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 229960002117 triamcinolone acetonide Drugs 0.000 description 3
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 3
- 102000003390 tumor necrosis factor Human genes 0.000 description 3
- FVECELJHCSPHKY-JLSHOZRYSA-N veratridine Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)O[C@@H]1[C@@]2(O)O[C@]34C[C@@]5(O)[C@H](CN6[C@@H](CC[C@H](C)C6)[C@@]6(C)O)[C@]6(O)[C@@H](O)C[C@@]5(O)[C@@H]4CC[C@H]2[C@]3(C)CC1 FVECELJHCSPHKY-JLSHOZRYSA-N 0.000 description 3
- 229940088594 vitamin Drugs 0.000 description 3
- 229930003231 vitamin Natural products 0.000 description 3
- 235000013343 vitamin Nutrition 0.000 description 3
- 239000011782 vitamin Substances 0.000 description 3
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 2
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 2
- FDBQLLMYSACLPB-UHFFFAOYSA-N (+/-)-4-Mercapto-4-methyl-2-pentanol Chemical compound CC(O)CC(C)(C)S FDBQLLMYSACLPB-UHFFFAOYSA-N 0.000 description 2
- PROQIPRRNZUXQM-UHFFFAOYSA-N (16alpha,17betaOH)-Estra-1,3,5(10)-triene-3,16,17-triol Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)O)C4C3CCC2=C1 PROQIPRRNZUXQM-UHFFFAOYSA-N 0.000 description 2
- RDEIXVOBVLKYNT-VQBXQJRRSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(1-aminoethyl)oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol;(2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(aminomethyl)oxan-2-yl]o Chemical compound OS(O)(=O)=O.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@@H](CN)O2)N)[C@@H](N)C[C@H]1N.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@H](O2)C(C)N)N)[C@@H](N)C[C@H]1N.O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N RDEIXVOBVLKYNT-VQBXQJRRSA-N 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 2
- MASIZQYHVMQQKI-OIIXUNCGSA-N (2r,3r,4s,5s,6r)-2-[(2r,3s,4r,5r,6r)-4,5-dihydroxy-2-(hydroxymethyl)-6-octoxyoxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](OCCCCCCCC)O[C@H](CO)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 MASIZQYHVMQQKI-OIIXUNCGSA-N 0.000 description 2
- JVAZJLFFSJARQM-RMPHRYRLSA-N (2r,3r,4s,5s,6r)-2-hexoxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound CCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O JVAZJLFFSJARQM-RMPHRYRLSA-N 0.000 description 2
- OPCHFPHZPIURNA-MFERNQICSA-N (2s)-2,5-bis(3-aminopropylamino)-n-[2-(dioctadecylamino)acetyl]pentanamide Chemical compound CCCCCCCCCCCCCCCCCCN(CC(=O)NC(=O)[C@H](CCCNCCCN)NCCCN)CCCCCCCCCCCCCCCCCC OPCHFPHZPIURNA-MFERNQICSA-N 0.000 description 2
- ZEUUPKVZFKBXPW-TWDWGCDDSA-N (2s,3r,4s,5s,6r)-4-amino-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,5s,6r)-3-amino-6-(aminomethyl)-5-hydroxyoxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-6-(hydroxymethyl)oxane-3,5-diol;sulfuric acid Chemical compound OS(O)(=O)=O.N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N ZEUUPKVZFKBXPW-TWDWGCDDSA-N 0.000 description 2
- LJRDOKAZOAKLDU-UDXJMMFXSA-N (2s,3s,4r,5r,6r)-5-amino-2-(aminomethyl)-6-[(2r,3s,4r,5s)-5-[(1r,2r,3s,5r,6s)-3,5-diamino-2-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol;sulfuric ac Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO LJRDOKAZOAKLDU-UDXJMMFXSA-N 0.000 description 2
- NNRXCKZMQLFUPL-WBMZRJHASA-N (3r,4s,5s,6r,7r,9r,11r,12r,13s,14r)-6-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-7,12,13-trihydroxy-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione;(2r,3 Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O.O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 NNRXCKZMQLFUPL-WBMZRJHASA-N 0.000 description 2
- NNRFRJQMBSBXGO-CIUDSAMLSA-N (3s)-3-[[2-[[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-4-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-oxobutanoic acid Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O NNRFRJQMBSBXGO-CIUDSAMLSA-N 0.000 description 2
- PUDHBTGHUJUUFI-SCTWWAJVSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-p Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 PUDHBTGHUJUUFI-SCTWWAJVSA-N 0.000 description 2
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 description 2
- CZJXBZPJABCCRQ-BULBTXNYSA-N (8s,9r,10s,11s,13s,14s,17r)-9,11-dichloro-17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-3-one Chemical compound O=C1C=C[C@]2(C)[C@@]3(Cl)[C@@H](Cl)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 CZJXBZPJABCCRQ-BULBTXNYSA-N 0.000 description 2
- IZFHEQBZOYJLPK-SSDOTTSWSA-N (R)-dihydrolipoic acid Chemical compound OC(=O)CCCC[C@@H](S)CCS IZFHEQBZOYJLPK-SSDOTTSWSA-N 0.000 description 2
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 description 2
- WTBFLCSPLLEDEM-JIDRGYQWSA-N 1,2-dioleoyl-sn-glycero-3-phospho-L-serine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC WTBFLCSPLLEDEM-JIDRGYQWSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VPVXHAANQNHFSF-UHFFFAOYSA-N 1,4-dioxan-2-one Chemical compound O=C1COCCO1 VPVXHAANQNHFSF-UHFFFAOYSA-N 0.000 description 2
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 2
- KPQZUUQMTUIKBP-UHFFFAOYSA-N 1-(2-methyl-5-nitro-1-imidazolyl)-2-propanol Chemical compound CC(O)CN1C(C)=NC=C1[N+]([O-])=O KPQZUUQMTUIKBP-UHFFFAOYSA-N 0.000 description 2
- RVHYPUORVDKRTM-UHFFFAOYSA-N 1-[2-[bis(2-hydroxydodecyl)amino]ethyl-[2-[4-[2-[bis(2-hydroxydodecyl)amino]ethyl]piperazin-1-yl]ethyl]amino]dodecan-2-ol Chemical compound CCCCCCCCCCC(O)CN(CC(O)CCCCCCCCCC)CCN(CC(O)CCCCCCCCCC)CCN1CCN(CCN(CC(O)CCCCCCCCCC)CC(O)CCCCCCCCCC)CC1 RVHYPUORVDKRTM-UHFFFAOYSA-N 0.000 description 2
- KURBRAZBXURPCJ-QYCRHRGJSA-N 1-methyl-4,4-bis[(9z,12z)-octadeca-9,12-dienoxy]piperidine Chemical compound CCCCC\C=C/C\C=C/CCCCCCCCOC1(OCCCCCCCC\C=C/C\C=C/CCCCC)CCN(C)CC1 KURBRAZBXURPCJ-QYCRHRGJSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 2
- WHBHBVVOGNECLV-OBQKJFGGSA-N 11-deoxycortisol Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 WHBHBVVOGNECLV-OBQKJFGGSA-N 0.000 description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical group C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- IJFVSSZAOYLHEE-UHFFFAOYSA-N 2,3-di(dodecanoyloxy)propyl 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCC(=O)OCC(COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCC IJFVSSZAOYLHEE-UHFFFAOYSA-N 0.000 description 2
- WALUVDCNGPQPOD-UHFFFAOYSA-M 2,3-di(tetradecoxy)propyl-(2-hydroxyethyl)-dimethylazanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCOCC(C[N+](C)(C)CCO)OCCCCCCCCCCCCCC WALUVDCNGPQPOD-UHFFFAOYSA-M 0.000 description 2
- JLVSRWOIZZXQAD-UHFFFAOYSA-N 2,3-disulfanylpropane-1-sulfonic acid Chemical compound OS(=O)(=O)CC(S)CS JLVSRWOIZZXQAD-UHFFFAOYSA-N 0.000 description 2
- ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 description 2
- OIQOAYVCKAHSEJ-UHFFFAOYSA-N 2-[2,3-bis(2-hydroxyethoxy)propoxy]ethanol;hexadecanoic acid;octadecanoic acid Chemical compound OCCOCC(OCCO)COCCO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O OIQOAYVCKAHSEJ-UHFFFAOYSA-N 0.000 description 2
- FSVJFNAIGNNGKK-UHFFFAOYSA-N 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one Chemical compound C1C(C2=CC=CC=C2CC2)N2C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-UHFFFAOYSA-N 0.000 description 2
- NEZDNQCXEZDCBI-UHFFFAOYSA-N 2-azaniumylethyl 2,3-di(tetradecanoyloxy)propyl phosphate Chemical compound CCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCCCC NEZDNQCXEZDCBI-UHFFFAOYSA-N 0.000 description 2
- SPCKHVPPRJWQRZ-UHFFFAOYSA-N 2-benzhydryloxy-n,n-dimethylethanamine;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 SPCKHVPPRJWQRZ-UHFFFAOYSA-N 0.000 description 2
- BANXPJUEBPWEOT-UHFFFAOYSA-N 2-methyl-Pentadecane Chemical compound CCCCCCCCCCCCCC(C)C BANXPJUEBPWEOT-UHFFFAOYSA-N 0.000 description 2
- QYIGFZOHYGYBLX-UHFFFAOYSA-N 2-phenyl-2-sulfanylacetic acid Chemical compound OC(=O)C(S)C1=CC=CC=C1 QYIGFZOHYGYBLX-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- HNTKPUXXCNQLFR-KWXKLSQISA-N 3-[2,2-bis[(9z,12z)-octadeca-9,12-dienyl]-1,3-dioxolan-4-yl]-n,n-dimethylpropan-1-amine Chemical compound CCCCC\C=C/C\C=C/CCCCCCCCC1(CCCCCCCC\C=C/C\C=C/CCCCC)OCC(CCCN(C)C)O1 HNTKPUXXCNQLFR-KWXKLSQISA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- LSLYOANBFKQKPT-DIFFPNOSSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-hydroxyphenyl)propan-2-yl]amino]ethyl]benzene-1,3-diol Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(O)C=C(O)C=1)C1=CC=C(O)C=C1 LSLYOANBFKQKPT-DIFFPNOSSA-N 0.000 description 2
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 2
- HCKFPALGXKOOBK-NRYMJLQJSA-N 7332-27-6 Chemical compound C1([C@]2(O[C@]3([C@@]4(C)C[C@H](O)[C@]5(F)[C@@]6(C)C=CC(=O)C=C6CC[C@H]5[C@@H]4C[C@H]3O2)C(=O)CO)C)=CC=CC=C1 HCKFPALGXKOOBK-NRYMJLQJSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 2
- 239000005541 ACE inhibitor Substances 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 208000004926 Bacterial Vaginosis Diseases 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 108010049931 Bone Morphogenetic Protein 2 Proteins 0.000 description 2
- 102100024506 Bone morphogenetic protein 2 Human genes 0.000 description 2
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 2
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 2
- 208000009079 Bronchial Spasm Diseases 0.000 description 2
- 208000014181 Bronchial disease Diseases 0.000 description 2
- 206010006482 Bronchospasm Diseases 0.000 description 2
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 241000218645 Cedrus Species 0.000 description 2
- KEJCWVGMRLCZQQ-YJBYXUATSA-N Cefuroxime axetil Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(=O)OC(C)OC(C)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 KEJCWVGMRLCZQQ-YJBYXUATSA-N 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 2
- 229920001287 Chondroitin sulfate Polymers 0.000 description 2
- 102000011022 Chorionic Gonadotropin Human genes 0.000 description 2
- 108010062540 Chorionic Gonadotropin Proteins 0.000 description 2
- 235000001258 Cinchona calisaya Nutrition 0.000 description 2
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 2
- 102000015225 Connective Tissue Growth Factor Human genes 0.000 description 2
- 108010039419 Connective Tissue Growth Factor Proteins 0.000 description 2
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 2
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- BSHYASCHOGHGHW-PIQRJGQMSA-N Descinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)C)[C@@]1(C)C[C@@H]2O BSHYASCHOGHGHW-PIQRJGQMSA-N 0.000 description 2
- WYQPLTPSGFELIB-JTQPXKBDSA-N Difluprednate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2CC[C@@](C(=O)COC(C)=O)(OC(=O)CCC)[C@@]2(C)C[C@@H]1O WYQPLTPSGFELIB-JTQPXKBDSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 2
- 206010013774 Dry eye Diseases 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 102000002322 Egg Proteins Human genes 0.000 description 2
- 108010000912 Egg Proteins Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 2
- 229940122331 Fibrinogen antagonist Drugs 0.000 description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
- POPFMWWJOGLOIF-XWCQMRHXSA-N Flurandrenolide Chemical compound C1([C@@H](F)C2)=CC(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O POPFMWWJOGLOIF-XWCQMRHXSA-N 0.000 description 2
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 2
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 2
- 108700012941 GNRH1 Proteins 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- 102000014015 Growth Differentiation Factors Human genes 0.000 description 2
- 108010050777 Growth Differentiation Factors Proteins 0.000 description 2
- 229940118547 Guanylate cyclase stimulant Drugs 0.000 description 2
- MUQNGPZZQDCDFT-JNQJZLCISA-N Halcinonide Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CCl)[C@@]1(C)C[C@@H]2O MUQNGPZZQDCDFT-JNQJZLCISA-N 0.000 description 2
- YCISZOVUHXIOFY-HKXOFBAYSA-N Halopredone acetate Chemical compound C1([C@H](F)C2)=CC(=O)C(Br)=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2CC[C@](OC(C)=O)(C(=O)COC(=O)C)[C@@]2(C)C[C@@H]1O YCISZOVUHXIOFY-HKXOFBAYSA-N 0.000 description 2
- 241000893570 Hendra henipavirus Species 0.000 description 2
- VPIAKHNXCOTPAY-UHFFFAOYSA-N Heptane-1-thiol Chemical compound CCCCCCCS VPIAKHNXCOTPAY-UHFFFAOYSA-N 0.000 description 2
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 101001052035 Homo sapiens Fibroblast growth factor 2 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000037147 Hypercalcaemia Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 2
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- 108010002386 Interleukin-3 Proteins 0.000 description 2
- 102100021596 Interleukin-31 Human genes 0.000 description 2
- 101710181613 Interleukin-31 Proteins 0.000 description 2
- 108090000978 Interleukin-4 Proteins 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- GIJGXNFNUUFEGH-UHFFFAOYSA-N Isopentyl mercaptan Chemical compound CC(C)CCS GIJGXNFNUUFEGH-UHFFFAOYSA-N 0.000 description 2
- 102000015617 Janus Kinases Human genes 0.000 description 2
- 108010024121 Janus Kinases Proteins 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 2
- 102000009151 Luteinizing Hormone Human genes 0.000 description 2
- 108010073521 Luteinizing Hormone Proteins 0.000 description 2
- IPWKIXLWTCNBKN-UHFFFAOYSA-N Madelen Chemical compound CC1=NC=C([N+]([O-])=O)N1CC(O)CCl IPWKIXLWTCNBKN-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- GZENKSODFLBBHQ-ILSZZQPISA-N Medrysone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@H](C(C)=O)CC[C@H]21 GZENKSODFLBBHQ-ILSZZQPISA-N 0.000 description 2
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 2
- 206010028116 Mucosal inflammation Diseases 0.000 description 2
- 201000010927 Mucositis Diseases 0.000 description 2
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical group C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 102000015336 Nerve Growth Factor Human genes 0.000 description 2
- 108090000742 Neurotrophin 3 Proteins 0.000 description 2
- 102100029268 Neurotrophin-3 Human genes 0.000 description 2
- 102000003683 Neurotrophin-4 Human genes 0.000 description 2
- 108090000099 Neurotrophin-4 Proteins 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- JVAZJLFFSJARQM-UHFFFAOYSA-N O-n-hexyl beta-D-glucopyranoside Natural products CCCCCCOC1OC(CO)C(O)C(O)C1O JVAZJLFFSJARQM-UHFFFAOYSA-N 0.000 description 2
- 229940126033 PPAR agonist Drugs 0.000 description 2
- 235000021314 Palmitic acid Nutrition 0.000 description 2
- HYRKAAMZBDSJFJ-LFDBJOOHSA-N Paramethasone acetate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)COC(C)=O)(O)[C@@]2(C)C[C@@H]1O HYRKAAMZBDSJFJ-LFDBJOOHSA-N 0.000 description 2
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 2
- 239000000026 Pentaerythritol tetranitrate Substances 0.000 description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 102000015439 Phospholipases Human genes 0.000 description 2
- 108010064785 Phospholipases Proteins 0.000 description 2
- 108010047386 Pituitary Hormones Proteins 0.000 description 2
- 102000006877 Pituitary Hormones Human genes 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- 229920002873 Polyethylenimine Polymers 0.000 description 2
- 241001673669 Porcine circovirus 2 Species 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 108090000829 Ribosome Inactivating Proteins Proteins 0.000 description 2
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 description 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 2
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 2
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 2
- 108010023197 Streptokinase Proteins 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- HJLSLZFTEKNLFI-UHFFFAOYSA-N Tinidazole Chemical compound CCS(=O)(=O)CCN1C(C)=NC=C1[N+]([O-])=O HJLSLZFTEKNLFI-UHFFFAOYSA-N 0.000 description 2
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 2
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
- 241000960387 Torque teno virus Species 0.000 description 2
- TZIZWYVVGLXXFV-FLRHRWPCSA-N Triamcinolone hexacetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)CC(C)(C)C)[C@@]1(C)C[C@@H]2O TZIZWYVVGLXXFV-FLRHRWPCSA-N 0.000 description 2
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 2
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 2
- 208000032159 Vaginal inflammation Diseases 0.000 description 2
- 208000037009 Vaginitis bacterial Diseases 0.000 description 2
- 108010059993 Vancomycin Proteins 0.000 description 2
- 229930003427 Vitamin E Natural products 0.000 description 2
- 240000008042 Zea mays Species 0.000 description 2
- 235000016383 Zea mays subsp huehuetenangensis Nutrition 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- NRLNQCOGCKAESA-KWXKLSQISA-N [(6z,9z,28z,31z)-heptatriaconta-6,9,28,31-tetraen-19-yl] 4-(dimethylamino)butanoate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCCC(OC(=O)CCCN(C)C)CCCCCCCC\C=C/C\C=C/CCCCC NRLNQCOGCKAESA-KWXKLSQISA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229940022663 acetate Drugs 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 229960004150 aciclovir Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 2
- 150000001356 alkyl thiols Chemical class 0.000 description 2
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 2
- 229960003459 allopurinol Drugs 0.000 description 2
- 229910045601 alloy Inorganic materials 0.000 description 2
- 239000000956 alloy Substances 0.000 description 2
- 229960000711 alprostadil Drugs 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 229950003408 amcinafide Drugs 0.000 description 2
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- VIROVYVQCGLCII-UHFFFAOYSA-N amobarbital Chemical compound CC(C)CCC1(CC)C(=O)NC(=O)NC1=O VIROVYVQCGLCII-UHFFFAOYSA-N 0.000 description 2
- 239000003263 anabolic agent Substances 0.000 description 2
- 229940124325 anabolic agent Drugs 0.000 description 2
- 239000002269 analeptic agent Substances 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 229940030486 androgens Drugs 0.000 description 2
- 239000003945 anionic surfactant Substances 0.000 description 2
- 230000000954 anitussive effect Effects 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 230000000507 anthelmentic effect Effects 0.000 description 2
- 229940124339 anthelmintic agent Drugs 0.000 description 2
- 239000000921 anthelmintic agent Substances 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical group C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 230000007131 anti Alzheimer effect Effects 0.000 description 2
- 230000002280 anti-androgenic effect Effects 0.000 description 2
- 230000001142 anti-diarrhea Effects 0.000 description 2
- 230000002686 anti-diuretic effect Effects 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940044684 anti-microtubule agent Drugs 0.000 description 2
- 230000002927 anti-mitotic effect Effects 0.000 description 2
- 230000001139 anti-pruritic effect Effects 0.000 description 2
- 230000001754 anti-pyretic effect Effects 0.000 description 2
- 230000003356 anti-rheumatic effect Effects 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 239000000051 antiandrogen Substances 0.000 description 2
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 229940125681 anticonvulsant agent Drugs 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- 239000003793 antidiarrheal agent Substances 0.000 description 2
- 229940125714 antidiarrheal agent Drugs 0.000 description 2
- 229940124538 antidiuretic agent Drugs 0.000 description 2
- 229960001497 antiemetics and antinauseants Drugs 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 229940030225 antihemorrhagics Drugs 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 239000003430 antimalarial agent Substances 0.000 description 2
- 229940033495 antimalarials Drugs 0.000 description 2
- 239000003096 antiparasitic agent Substances 0.000 description 2
- 229940125688 antiparkinson agent Drugs 0.000 description 2
- 239000003908 antipruritic agent Substances 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- 229940125716 antipyretic agent Drugs 0.000 description 2
- VEQOALNAAJBPNY-UHFFFAOYSA-N antipyrine Chemical compound CN1C(C)=CC(=O)N1C1=CC=CC=C1 VEQOALNAAJBPNY-UHFFFAOYSA-N 0.000 description 2
- 239000003200 antithyroid agent Substances 0.000 description 2
- 229940043671 antithyroid preparations Drugs 0.000 description 2
- 239000003434 antitussive agent Substances 0.000 description 2
- 229940124584 antitussives Drugs 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 150000001504 aryl thiols Chemical class 0.000 description 2
- 230000003416 augmentation Effects 0.000 description 2
- AUJRCFUBUPVWSZ-XTZHGVARSA-M auranofin Chemical compound CCP(CC)(CC)=[Au]S[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O AUJRCFUBUPVWSZ-XTZHGVARSA-M 0.000 description 2
- 229960005207 auranofin Drugs 0.000 description 2
- CUFNKYGDVFVPHO-UHFFFAOYSA-N azulene Chemical group C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 229940030611 beta-adrenergic blocking agent Drugs 0.000 description 2
- 229960004311 betamethasone valerate Drugs 0.000 description 2
- SNHRLVCMMWUAJD-SUYDQAKGSA-N betamethasone valerate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(OC(=O)CCCC)[C@@]1(C)C[C@@H]2O SNHRLVCMMWUAJD-SUYDQAKGSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- LLEMOWNGBBNAJR-UHFFFAOYSA-N biphenyl-2-ol Chemical compound OC1=CC=CC=C1C1=CC=CC=C1 LLEMOWNGBBNAJR-UHFFFAOYSA-N 0.000 description 2
- 239000003114 blood coagulation factor Substances 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 229940077737 brain-derived neurotrophic factor Drugs 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 230000003177 cardiotonic effect Effects 0.000 description 2
- 239000003093 cationic surfactant Substances 0.000 description 2
- 229960002620 cefuroxime axetil Drugs 0.000 description 2
- 230000021164 cell adhesion Effects 0.000 description 2
- 229940106164 cephalexin Drugs 0.000 description 2
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 229940106189 ceramide Drugs 0.000 description 2
- 150000001783 ceramides Chemical class 0.000 description 2
- 229940081733 cetearyl alcohol Drugs 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229960005091 chloramphenicol Drugs 0.000 description 2
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 229940059329 chondroitin sulfate Drugs 0.000 description 2
- WDECIBYCCFPHNR-UHFFFAOYSA-N chrysene Chemical group C1=CC=CC2=CC=C3C4=CC=CC=C4C=CC3=C21 WDECIBYCCFPHNR-UHFFFAOYSA-N 0.000 description 2
- 229960003405 ciprofloxacin Drugs 0.000 description 2
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 2
- 229960002227 clindamycin Drugs 0.000 description 2
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 2
- 229960003608 clomifene Drugs 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- 229960001338 colchicine Drugs 0.000 description 2
- BMCQMVFGOVHVNG-TUFAYURCSA-N cortisol 17-butyrate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCC)[C@@]1(C)C[C@@H]2O BMCQMVFGOVHVNG-TUFAYURCSA-N 0.000 description 2
- FZCHYNWYXKICIO-FZNHGJLXSA-N cortisol 17-valerate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCCC)[C@@]1(C)C[C@@H]2O FZCHYNWYXKICIO-FZNHGJLXSA-N 0.000 description 2
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 description 2
- 229960004544 cortisone Drugs 0.000 description 2
- 229950002276 cortodoxone Drugs 0.000 description 2
- 229960000265 cromoglicic acid Drugs 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- VTXVGVNLYGSIAR-UHFFFAOYSA-N decane-1-thiol Chemical compound CCCCCCCCCCS VTXVGVNLYGSIAR-UHFFFAOYSA-N 0.000 description 2
- 239000000850 decongestant Substances 0.000 description 2
- 229940124581 decongestants Drugs 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000000151 deposition Methods 0.000 description 2
- 229940000033 dermatological agent Drugs 0.000 description 2
- 239000003241 dermatological agent Substances 0.000 description 2
- VQODGRNSFPNSQE-CXSFZGCWSA-N dexamethasone phosphate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COP(O)(O)=O)(O)[C@@]1(C)C[C@@H]2O VQODGRNSFPNSQE-CXSFZGCWSA-N 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 229960003529 diazepam Drugs 0.000 description 2
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 2
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical compound C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 description 2
- IYYZUPMFVPLQIF-UHFFFAOYSA-N dibenzothiophene Chemical compound C1=CC=C2C3=CC=CC=C3SC2=C1 IYYZUPMFVPLQIF-UHFFFAOYSA-N 0.000 description 2
- RNPXCFINMKSQPQ-UHFFFAOYSA-N dicetyl hydrogen phosphate Chemical compound CCCCCCCCCCCCCCCCOP(O)(=O)OCCCCCCCCCCCCCCCC RNPXCFINMKSQPQ-UHFFFAOYSA-N 0.000 description 2
- 229940093541 dicetylphosphate Drugs 0.000 description 2
- 229950009888 dichlorisone Drugs 0.000 description 2
- 229960004875 difluprednate Drugs 0.000 description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
- 229960000520 diphenhydramine Drugs 0.000 description 2
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 2
- 229960002768 dipyridamole Drugs 0.000 description 2
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- GRIXGZQULWMCLU-UHFFFAOYSA-L disodium;7-[[2-carboxylato-2-(4-hydroxyphenyl)acetyl]amino]-7-methoxy-3-[(1-methyltetrazol-5-yl)sulfanylmethyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].[Na+].C12OCC(CSC=3N(N=NN=3)C)=C(C([O-])=O)N2C(=O)C1(OC)NC(=O)C(C([O-])=O)C1=CC=C(O)C=C1 GRIXGZQULWMCLU-UHFFFAOYSA-L 0.000 description 2
- 150000004662 dithiols Chemical class 0.000 description 2
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 2
- WNAHIZMDSQCWRP-UHFFFAOYSA-N dodecane-1-thiol Chemical compound CCCCCCCCCCCCS WNAHIZMDSQCWRP-UHFFFAOYSA-N 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000001793 endectocide Effects 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229960000610 enoxaparin Drugs 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 229960002179 ephedrine Drugs 0.000 description 2
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 2
- 229960000741 erythromycin ethylsuccinate Drugs 0.000 description 2
- NSYZCCDSJNWWJL-YXOIYICCSA-N erythromycin ethylsuccinate Chemical compound O1[C@H](C)C[C@H](N(C)C)[C@@H](OC(=O)CCC(=O)OCC)[C@@H]1O[C@H]1[C@@](O)(C)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@](C)(O)[C@@H](CC)OC(=O)[C@H](C)[C@@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(OC)C2)[C@@H]1C NSYZCCDSJNWWJL-YXOIYICCSA-N 0.000 description 2
- 229960004213 erythromycin lactobionate Drugs 0.000 description 2
- 229960005309 estradiol Drugs 0.000 description 2
- 229930182833 estradiol Natural products 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 description 2
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 2
- 239000003172 expectorant agent Substances 0.000 description 2
- 230000003419 expectorant effect Effects 0.000 description 2
- 210000000416 exudates and transudate Anatomy 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229960001022 fenoterol Drugs 0.000 description 2
- NJNWEGFJCGYWQT-VSXGLTOVSA-N fluclorolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(Cl)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1Cl NJNWEGFJCGYWQT-VSXGLTOVSA-N 0.000 description 2
- 229940094766 flucloronide Drugs 0.000 description 2
- 229960004511 fludroxycortide Drugs 0.000 description 2
- 229940043075 fluocinolone Drugs 0.000 description 2
- 229960001347 fluocinolone acetonide Drugs 0.000 description 2
- FAOZLTXFLGPHNG-KNAQIMQKSA-N fluorometholone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@]2(F)[C@@H](O)C[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FAOZLTXFLGPHNG-KNAQIMQKSA-N 0.000 description 2
- 229920002313 fluoropolymer Polymers 0.000 description 2
- 229960003590 fluperolone Drugs 0.000 description 2
- HHPZZKDXAFJLOH-QZIXMDIESA-N fluperolone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@@](C(=O)[C@@H](OC(C)=O)C)(O)[C@@]1(C)C[C@@H]2O HHPZZKDXAFJLOH-QZIXMDIESA-N 0.000 description 2
- 229940028334 follicle stimulating hormone Drugs 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 239000001087 glyceryl triacetate Substances 0.000 description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 description 2
- 229960004275 glycolic acid Drugs 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 150000002338 glycosides Chemical class 0.000 description 2
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 2
- 229960002383 halcinonide Drugs 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- 229950008940 halopredone Drugs 0.000 description 2
- 239000002874 hemostatic agent Substances 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- ORTRWBYBJVGVQC-UHFFFAOYSA-N hexadecane-1-thiol Chemical compound CCCCCCCCCCCCCCCCS ORTRWBYBJVGVQC-UHFFFAOYSA-N 0.000 description 2
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 description 2
- 229940084986 human chorionic gonadotropin Drugs 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 229960001524 hydrocortisone butyrate Drugs 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- LFZGYTBWUHCAKF-DCNJEFSFSA-N hydron;(2s,4r)-n-[(1r,2r)-2-hydroxy-1-[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-methylsulfanyloxan-2-yl]propyl]-1-methyl-4-propylpyrrolidine-2-carboxamide;chloride;hydrate Chemical compound O.Cl.CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 LFZGYTBWUHCAKF-DCNJEFSFSA-N 0.000 description 2
- 229960000930 hydroxyzine Drugs 0.000 description 2
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 2
- 230000000148 hypercalcaemia Effects 0.000 description 2
- 229940126904 hypoglycaemic agent Drugs 0.000 description 2
- 239000000960 hypophysis hormone Substances 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical group C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000000411 inducer Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 239000002563 ionic surfactant Substances 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 229960000201 isosorbide dinitrate Drugs 0.000 description 2
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 2
- 229960000318 kanamycin Drugs 0.000 description 2
- 229930027917 kanamycin Natural products 0.000 description 2
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 2
- 229930182823 kanamycin A Natural products 0.000 description 2
- 210000003127 knee Anatomy 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 108010021336 lanreotide Proteins 0.000 description 2
- 229960002437 lanreotide Drugs 0.000 description 2
- PYIDGJJWBIBVIA-UYTYNIKBSA-N lauryl glucoside Chemical compound CCCCCCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O PYIDGJJWBIBVIA-UYTYNIKBSA-N 0.000 description 2
- 229960003376 levofloxacin Drugs 0.000 description 2
- 229960004400 levonorgestrel Drugs 0.000 description 2
- 229960001595 lincomycin hydrochloride Drugs 0.000 description 2
- 229960005015 local anesthetics Drugs 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 229940040129 luteinizing hormone Drugs 0.000 description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 235000009973 maize Nutrition 0.000 description 2
- 229960003439 mebendazole Drugs 0.000 description 2
- BAXLBXFAUKGCDY-UHFFFAOYSA-N mebendazole Chemical compound [CH]1C2=NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CC=C1 BAXLBXFAUKGCDY-UHFFFAOYSA-N 0.000 description 2
- 229960001011 medrysone Drugs 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- LMOINURANNBYCM-UHFFFAOYSA-N metaproterenol Chemical compound CC(C)NCC(O)C1=CC(O)=CC(O)=C1 LMOINURANNBYCM-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 229960004584 methylprednisolone Drugs 0.000 description 2
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 2
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 2
- 229910052750 molybdenum Inorganic materials 0.000 description 2
- WOFMFGQZHJDGCX-ZULDAHANSA-N mometasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(Cl)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)C(=O)CCl)C(=O)C1=CC=CO1 WOFMFGQZHJDGCX-ZULDAHANSA-N 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 230000000921 morphogenic effect Effects 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 229940035363 muscle relaxants Drugs 0.000 description 2
- 229960000951 mycophenolic acid Drugs 0.000 description 2
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 2
- 239000003158 myorelaxant agent Substances 0.000 description 2
- WIDKTXGNSOORHA-CJHXQPGBSA-N n,n'-dibenzylethane-1,2-diamine;(2s,5r,6r)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;tetrahydrate Chemical compound O.O.O.O.C=1C=CC=CC=1CNCCNCC1=CC=CC=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 WIDKTXGNSOORHA-CJHXQPGBSA-N 0.000 description 2
- GLGLUQVVDHRLQK-WRBBJXAJSA-N n,n-dimethyl-2,3-bis[(z)-octadec-9-enoxy]propan-1-amine Chemical compound CCCCCCCC\C=C/CCCCCCCCOCC(CN(C)C)OCCCCCCCC\C=C/CCCCCCCC GLGLUQVVDHRLQK-WRBBJXAJSA-N 0.000 description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 2
- 229950006780 n-acetylglucosamine Drugs 0.000 description 2
- HSUGDXPUFCVGES-UHFFFAOYSA-N n-tetradecyltetradecan-1-amine Chemical compound CCCCCCCCCCCCCCNCCCCCCCCCCCCCC HSUGDXPUFCVGES-UHFFFAOYSA-N 0.000 description 2
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 description 2
- 229960000210 nalidixic acid Drugs 0.000 description 2
- 229960002009 naproxen Drugs 0.000 description 2
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 229940053128 nerve growth factor Drugs 0.000 description 2
- 239000000842 neuromuscular blocking agent Substances 0.000 description 2
- 239000002581 neurotoxin Substances 0.000 description 2
- 231100000618 neurotoxin Toxicity 0.000 description 2
- 229940032018 neurotrophin 3 Drugs 0.000 description 2
- 229940097998 neurotrophin 4 Drugs 0.000 description 2
- 229960001920 niclosamide Drugs 0.000 description 2
- RJMUSRYZPJIFPJ-UHFFFAOYSA-N niclosamide Chemical compound OC1=CC=C(Cl)C=C1C(=O)NC1=CC=C([N+]([O-])=O)C=C1Cl RJMUSRYZPJIFPJ-UHFFFAOYSA-N 0.000 description 2
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 2
- 229960001597 nifedipine Drugs 0.000 description 2
- 229910052758 niobium Inorganic materials 0.000 description 2
- 229960000564 nitrofurantoin Drugs 0.000 description 2
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- ZVEZMVFBMOOHAT-UHFFFAOYSA-N nonane-1-thiol Chemical compound CCCCCCCCCS ZVEZMVFBMOOHAT-UHFFFAOYSA-N 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 229960001180 norfloxacin Drugs 0.000 description 2
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- KZCOBXFFBQJQHH-UHFFFAOYSA-N octane-1-thiol Chemical compound CCCCCCCCS KZCOBXFFBQJQHH-UHFFFAOYSA-N 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229960001699 ofloxacin Drugs 0.000 description 2
- 229940005483 opioid analgesics Drugs 0.000 description 2
- 229960002657 orciprenaline Drugs 0.000 description 2
- 229960002313 ornidazole Drugs 0.000 description 2
- 230000016087 ovulation Effects 0.000 description 2
- 210000004681 ovum Anatomy 0.000 description 2
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 2
- 229960001639 penicillamine Drugs 0.000 description 2
- 229960004321 pentaerithrityl tetranitrate Drugs 0.000 description 2
- 239000002307 peroxisome proliferator activated receptor agonist Substances 0.000 description 2
- 229960000482 pethidine Drugs 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical group C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical compound C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 description 2
- 229960005222 phenazone Drugs 0.000 description 2
- 150000002990 phenothiazines Chemical class 0.000 description 2
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 description 2
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- 229960002895 phenylbutazone Drugs 0.000 description 2
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 2
- 229960001802 phenylephrine Drugs 0.000 description 2
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 2
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 2
- 229960000395 phenylpropanolamine Drugs 0.000 description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 2
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 2
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 description 2
- 230000001817 pituitary effect Effects 0.000 description 2
- 229960001237 podophyllotoxin Drugs 0.000 description 2
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 2
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 2
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 2
- 239000002745 poly(ortho ester) Substances 0.000 description 2
- 229920002401 polyacrylamide Polymers 0.000 description 2
- 239000004926 polymethyl methacrylate Substances 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- 239000003361 porogen Substances 0.000 description 2
- 229960002957 praziquantel Drugs 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- JDOZJEUDSLGTLU-VWUMJDOOSA-N prednisolone phosphate Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COP(O)(O)=O)[C@@H]4[C@@H]3CCC2=C1 JDOZJEUDSLGTLU-VWUMJDOOSA-N 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000000583 progesterone congener Substances 0.000 description 2
- SUVIGLJNEAMWEG-UHFFFAOYSA-N propane-1-thiol Chemical compound CCCS SUVIGLJNEAMWEG-UHFFFAOYSA-N 0.000 description 2
- KJRCEJOSASVSRA-UHFFFAOYSA-N propane-2-thiol Chemical compound CC(C)S KJRCEJOSASVSRA-UHFFFAOYSA-N 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 2
- KAQKFAOMNZTLHT-OZUDYXHBSA-N prostaglandin I2 Chemical compound O1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-OZUDYXHBSA-N 0.000 description 2
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 2
- 229960003908 pseudoephedrine Drugs 0.000 description 2
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical group C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 229960000948 quinine Drugs 0.000 description 2
- 150000007660 quinolones Chemical class 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000011369 resultant mixture Substances 0.000 description 2
- 229960002052 salbutamol Drugs 0.000 description 2
- 229960004017 salmeterol Drugs 0.000 description 2
- WVYADZUPLLSGPU-UHFFFAOYSA-N salsalate Chemical compound OC(=O)C1=CC=CC=C1OC(=O)C1=CC=CC=C1O WVYADZUPLLSGPU-UHFFFAOYSA-N 0.000 description 2
- 231100000241 scar Toxicity 0.000 description 2
- 239000003229 sclerosing agent Substances 0.000 description 2
- LACQPOBCQQPVIT-SEYKEWMNSA-N scopolamine hydrobromide trihydrate Chemical compound O.O.O.Br.C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 LACQPOBCQQPVIT-SEYKEWMNSA-N 0.000 description 2
- 239000000565 sealant Substances 0.000 description 2
- 229960004076 secnidazole Drugs 0.000 description 2
- 229910001961 silver nitrate Inorganic materials 0.000 description 2
- 230000005586 smoking cessation Effects 0.000 description 2
- 229940083542 sodium Drugs 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229960005491 sodium morrhuate Drugs 0.000 description 2
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 229960000776 sodium tetradecyl sulfate Drugs 0.000 description 2
- LWBVAHQZGAKXPU-BOXHHOBZSA-M sodium;(4s)-4-amino-5-octadecoxy-5-oxopentanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)[C@@H](N)CCC([O-])=O LWBVAHQZGAKXPU-BOXHHOBZSA-M 0.000 description 2
- RMLUKZWYIKEASN-UHFFFAOYSA-M sodium;2-amino-9-(2-hydroxyethoxymethyl)purin-6-olate Chemical compound [Na+].O=C1[N-]C(N)=NC2=C1N=CN2COCCO RMLUKZWYIKEASN-UHFFFAOYSA-M 0.000 description 2
- UNFWWIHTNXNPBV-WXKVUWSESA-N spectinomycin Chemical compound O([C@@H]1[C@@H](NC)[C@@H](O)[C@H]([C@@H]([C@H]1O1)O)NC)[C@]2(O)[C@H]1O[C@H](C)CC2=O UNFWWIHTNXNPBV-WXKVUWSESA-N 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 230000003068 static effect Effects 0.000 description 2
- 239000002294 steroidal antiinflammatory agent Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 229960005202 streptokinase Drugs 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- ACTRVOBWPAIOHC-UHFFFAOYSA-N succimer Chemical compound OC(=O)C(S)C(S)C(O)=O ACTRVOBWPAIOHC-UHFFFAOYSA-N 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 229960005404 sulfamethoxazole Drugs 0.000 description 2
- 239000003774 sulfhydryl reagent Substances 0.000 description 2
- 125000001174 sulfone group Chemical group 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 229960000195 terbutaline Drugs 0.000 description 2
- 229960002180 tetracycline Drugs 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- 235000010296 thiabendazole Nutrition 0.000 description 2
- 239000004308 thiabendazole Substances 0.000 description 2
- 229960004546 thiabendazole Drugs 0.000 description 2
- WJCNZQLZVWNLKY-UHFFFAOYSA-N thiabendazole Chemical compound S1C=NC(C=2NC3=CC=CC=C3N=2)=C1 WJCNZQLZVWNLKY-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 229960000103 thrombolytic agent Drugs 0.000 description 2
- 239000005495 thyroid hormone Substances 0.000 description 2
- 229940036555 thyroid hormone Drugs 0.000 description 2
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 description 2
- 229960004605 timolol Drugs 0.000 description 2
- 229960005053 tinidazole Drugs 0.000 description 2
- 239000003106 tissue adhesive Substances 0.000 description 2
- 239000002407 tissue scaffold Substances 0.000 description 2
- 229960000707 tobramycin Drugs 0.000 description 2
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 2
- 229960004477 tobramycin sulfate Drugs 0.000 description 2
- 235000010384 tocopherol Nutrition 0.000 description 2
- 229930003799 tocopherol Natural products 0.000 description 2
- 229960001295 tocopherol Drugs 0.000 description 2
- 239000011732 tocopherol Substances 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- 229960002622 triacetin Drugs 0.000 description 2
- 229960005294 triamcinolone Drugs 0.000 description 2
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 2
- 229960004221 triamcinolone hexacetonide Drugs 0.000 description 2
- YFHICDDUDORKJB-UHFFFAOYSA-N trimethylene carbonate Chemical compound O=C1OCCCO1 YFHICDDUDORKJB-UHFFFAOYSA-N 0.000 description 2
- 238000007039 two-step reaction Methods 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- CCIDWXHLGNEQSL-UHFFFAOYSA-N undecane-1-thiol Chemical compound CCCCCCCCCCCS CCIDWXHLGNEQSL-UHFFFAOYSA-N 0.000 description 2
- 229960005356 urokinase Drugs 0.000 description 2
- 210000004291 uterus Anatomy 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- 229910052720 vanadium Inorganic materials 0.000 description 2
- 229940124549 vasodilator Drugs 0.000 description 2
- 239000003071 vasodilator agent Substances 0.000 description 2
- 239000004034 viscosity adjusting agent Substances 0.000 description 2
- 239000003932 viscosupplement Substances 0.000 description 2
- 235000019155 vitamin A Nutrition 0.000 description 2
- 239000011719 vitamin A Substances 0.000 description 2
- 235000019165 vitamin E Nutrition 0.000 description 2
- 239000011709 vitamin E Substances 0.000 description 2
- 229940046009 vitamin E Drugs 0.000 description 2
- 229960005080 warfarin Drugs 0.000 description 2
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 2
- 230000037303 wrinkles Effects 0.000 description 2
- 229920001285 xanthan gum Polymers 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 2
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 1
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 1
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 1
- DBGIVFWFUFKIQN-UHFFFAOYSA-N (+-)-Fenfluramine Chemical compound CCNC(C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-UHFFFAOYSA-N 0.000 description 1
- CEMAWMOMDPGJMB-UHFFFAOYSA-N (+-)-Oxprenolol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1OCC=C CEMAWMOMDPGJMB-UHFFFAOYSA-N 0.000 description 1
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 description 1
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 1
- CMRJPMODSSEAPL-UHFFFAOYSA-N (13-methyl-3-oxo-2,6,7,8,14,15,16,17-octahydro-1h-cyclopenta[a]phenanthren-17-yl) acetate Chemical compound C1CC2=CC(=O)CCC2=C2C1C1CCC(OC(=O)C)C1(C)C=C2 CMRJPMODSSEAPL-UHFFFAOYSA-N 0.000 description 1
- IGLYMJRIWWIQQE-QUOODJBBSA-N (1S,2R)-2-phenylcyclopropan-1-amine (1R,2S)-2-phenylcyclopropan-1-amine Chemical compound N[C@H]1C[C@@H]1C1=CC=CC=C1.N[C@@H]1C[C@H]1C1=CC=CC=C1 IGLYMJRIWWIQQE-QUOODJBBSA-N 0.000 description 1
- WYDUSKDSKCASEF-LJQANCHMSA-N (1s)-1-cyclohexyl-1-phenyl-3-pyrrolidin-1-ylpropan-1-ol Chemical compound C([C@](O)(C1CCCCC1)C=1C=CC=CC=1)CN1CCCC1 WYDUSKDSKCASEF-LJQANCHMSA-N 0.000 description 1
- PGEHZROVWYXBFH-DOPHYNLBSA-N (1s,15r,20s)-3-methyl-11,12,14,15,16,17,18,19,20,21-decahydro-1h-yohimban;hydrochloride Chemical compound Cl.C12=CC=CC=C2N(C)C2=C1CCN1C[C@@H]3CCCC[C@H]3C[C@H]12 PGEHZROVWYXBFH-DOPHYNLBSA-N 0.000 description 1
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
- MQHLMHIZUIDKOO-OKZBNKHCSA-N (2R,6S)-2,6-dimethyl-4-[(2S)-2-methyl-3-[4-(2-methylbutan-2-yl)phenyl]propyl]morpholine Chemical compound C1=CC(C(C)(C)CC)=CC=C1C[C@H](C)CN1C[C@@H](C)O[C@@H](C)C1 MQHLMHIZUIDKOO-OKZBNKHCSA-N 0.000 description 1
- BJFIDCADFRDPIO-DZCXQCEKSA-N (2S)-N-[(2S)-6-amino-1-[(2-amino-2-oxoethyl)amino]-1-oxohexan-2-yl]-1-[[(4R,7S,10S,13S,16S,19R)-19-amino-7-(2-amino-2-oxoethyl)-10-(3-amino-3-oxopropyl)-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-13-(phenylmethyl)-1,2-dithia-5,8,11,14,17-pentazacycloeicos-4-yl]-oxomethyl]-2-pyrrolidinecarboxamide Chemical compound NCCCC[C@@H](C(=O)NCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](N)CSSC1 BJFIDCADFRDPIO-DZCXQCEKSA-N 0.000 description 1
- CIDUJQMULVCIBT-MQDUPKMGSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4-amino-3-[[(2s,3r)-3-amino-6-(aminomethyl)-3,4-dihydro-2h-pyran-2-yl]oxy]-6-(ethylamino)-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](NC)[C@@](C)(O)CO1)O)NCC)[C@H]1OC(CN)=CC[C@H]1N CIDUJQMULVCIBT-MQDUPKMGSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 description 1
- XQQUSYWGKLRJRA-RABCQHRBSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-6-amino-2-[[(2s,3s)-2-amino-3-methylpentanoyl]amino]hexanoyl]amino]-3-methylbutanoyl]amino]propanoyl]amino]-3-methylbutanoic acid Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O XQQUSYWGKLRJRA-RABCQHRBSA-N 0.000 description 1
- YKFCISHFRZHKHY-NGQGLHOPSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid;trihydrate Chemical compound O.O.O.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 YKFCISHFRZHKHY-NGQGLHOPSA-N 0.000 description 1
- OMPCVMLFFSQFIX-CONSDPRKSA-N (2s,3s)-2-benzhydryl-n-[(5-tert-butyl-2-methoxyphenyl)methyl]-1-azabicyclo[2.2.2]octan-3-amine Chemical compound COC1=CC=C(C(C)(C)C)C=C1CN[C@@H]1[C@H](C(C=2C=CC=CC=2)C=2C=CC=CC=2)N2CCC1CC2 OMPCVMLFFSQFIX-CONSDPRKSA-N 0.000 description 1
- 239000001356 (3R)-3-sulfanylbutan-2-one Substances 0.000 description 1
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 1
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 1
- DIWRORZWFLOCLC-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound N([C@H](C(NC1=CC=C(Cl)C=C11)=O)O)=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-HNNXBMFYSA-N 0.000 description 1
- ZDHHGGFQZRPUSN-UHFFFAOYSA-N (4-chlorophenyl)-[3-(2h-tetrazol-5-ylmethyl)indol-1-yl]methanone Chemical compound C1=CC(Cl)=CC=C1C(=O)N1C2=CC=CC=C2C(CC2=NNN=N2)=C1 ZDHHGGFQZRPUSN-UHFFFAOYSA-N 0.000 description 1
- PTDVPWWJRCOIIO-UHFFFAOYSA-N (4-methoxyphenyl)methanethiol Chemical compound COC1=CC=C(CS)C=C1 PTDVPWWJRCOIIO-UHFFFAOYSA-N 0.000 description 1
- WQBIOEFDDDEARX-STQMWFEESA-N (4as,10bs)-8-chloro-4-methyl-1,2,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one Chemical compound C1CC2=CC(Cl)=CC=C2[C@H]2[C@H]1N(C)C(=O)CC2 WQBIOEFDDDEARX-STQMWFEESA-N 0.000 description 1
- LGFMXOTUSSVQJV-NEYUFSEYSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;(4r,4ar,7s,7ar,12bs)-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol;1-[(3,4-dimethoxyphenyl)methyl]-6 Chemical compound Cl.Cl.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 LGFMXOTUSSVQJV-NEYUFSEYSA-N 0.000 description 1
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- OFMQLVRLOGHAJI-FGHAYEPSSA-N (4r,7s,10s,13r,16s,19r)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-10-[3-(diaminomethylideneamino)propyl]-7-[(1r)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-3,3-dimethyl-6,9,12,15,18 Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(=O)N[C@@H](C(SSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=CC=CC=1)(C)C)C(=O)N[C@@H]([C@H](O)C)C(N)=O)[C@@H](C)O)C1=CC=C(O)C=C1 OFMQLVRLOGHAJI-FGHAYEPSSA-N 0.000 description 1
- XIYOPDCBBDCGOE-IWVLMIASSA-N (4s,4ar,5s,5ar,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methylidene-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C=C1C2=CC=CC(O)=C2C(O)=C2[C@@H]1[C@H](O)[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O XIYOPDCBBDCGOE-IWVLMIASSA-N 0.000 description 1
- UHHHTIKWXBRCLT-VDBOFHIQSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;ethanol;hydrate;dihydrochloride Chemical compound O.Cl.Cl.CCO.C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O.C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O UHHHTIKWXBRCLT-VDBOFHIQSA-N 0.000 description 1
- FZKWRPSUNUOXKJ-CVHRZJFOSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydrate Chemical compound O.C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O FZKWRPSUNUOXKJ-CVHRZJFOSA-N 0.000 description 1
- SOVUOXKZCCAWOJ-HJYUBDRYSA-N (4s,4as,5ar,12ar)-9-[[2-(tert-butylamino)acetyl]amino]-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=C(NC(=O)CNC(C)(C)C)C(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O SOVUOXKZCCAWOJ-HJYUBDRYSA-N 0.000 description 1
- GUXHBMASAHGULD-SEYHBJAFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O GUXHBMASAHGULD-SEYHBJAFSA-N 0.000 description 1
- OAPVUSSHCBRCOL-KBHRXELFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O OAPVUSSHCBRCOL-KBHRXELFSA-N 0.000 description 1
- JFTOCKFCHJCDDX-UVTDQMKNSA-N (4z)-4-benzylidene-5,6,7,8-tetrahydroisoquinoline-1,3-dione Chemical compound C1CCCC2=C1C(=O)NC(=O)\C2=C/C1=CC=CC=C1 JFTOCKFCHJCDDX-UVTDQMKNSA-N 0.000 description 1
- KPJZHOPZRAFDTN-ZRGWGRIASA-N (6aR,9R)-N-[(2S)-1-hydroxybutan-2-yl]-4,7-dimethyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@H](CO)CC)C2)=C3C2=CN(C)C3=C1 KPJZHOPZRAFDTN-ZRGWGRIASA-N 0.000 description 1
- DOEWDSDBFRHVAP-KRXBUXKQSA-N (E)-3-tosylacrylonitrile Chemical compound CC1=CC=C(S(=O)(=O)\C=C\C#N)C=C1 DOEWDSDBFRHVAP-KRXBUXKQSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- RXZBMPWDPOLZGW-XMRMVWPWSA-N (E)-roxithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 description 1
- WSWCOQWTEOXDQX-MQQKCMAXSA-M (E,E)-sorbate Chemical compound C\C=C\C=C\C([O-])=O WSWCOQWTEOXDQX-MQQKCMAXSA-M 0.000 description 1
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 description 1
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 1
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- MPIPASJGOJYODL-SFHVURJKSA-N (R)-isoconazole Chemical compound ClC1=CC(Cl)=CC=C1[C@@H](OCC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 MPIPASJGOJYODL-SFHVURJKSA-N 0.000 description 1
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 1
- RKUNBYITZUJHSG-FXUDXRNXSA-N (S)-atropine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@H]3CC[C@@H](C2)N3C)=CC=CC=C1 RKUNBYITZUJHSG-FXUDXRNXSA-N 0.000 description 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 description 1
- WLRMANUAADYWEA-NWASOUNVSA-N (S)-timolol maleate Chemical compound OC(=O)\C=C/C(O)=O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 WLRMANUAADYWEA-NWASOUNVSA-N 0.000 description 1
- GQGRDYWMOPRROR-ZIFKCHSBSA-N (e)-7-[(1r,2r,3s,5s)-3-hydroxy-5-[(4-phenylphenyl)methoxy]-2-piperidin-1-ylcyclopentyl]hept-4-enoic acid Chemical compound O([C@H]1C[C@@H]([C@@H]([C@H]1CC\C=C\CCC(O)=O)N1CCCCC1)O)CC(C=C1)=CC=C1C1=CC=CC=C1 GQGRDYWMOPRROR-ZIFKCHSBSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- ZFXBERJDEUDDMX-UHFFFAOYSA-N 1,2,3,5-tetrazine Chemical compound C1=NC=NN=N1 ZFXBERJDEUDDMX-UHFFFAOYSA-N 0.000 description 1
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical compound C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- HTJMXYRLEDBSLT-UHFFFAOYSA-N 1,2,4,5-tetrazine Chemical compound C1=NN=CN=N1 HTJMXYRLEDBSLT-UHFFFAOYSA-N 0.000 description 1
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 1
- JCIIKRHCWVHVFF-UHFFFAOYSA-N 1,2,4-thiadiazol-5-amine;hydrochloride Chemical compound Cl.NC1=NC=NS1 JCIIKRHCWVHVFF-UHFFFAOYSA-N 0.000 description 1
- YGTAZGSLCXNBQL-UHFFFAOYSA-N 1,2,4-thiadiazole Chemical compound C=1N=CSN=1 YGTAZGSLCXNBQL-UHFFFAOYSA-N 0.000 description 1
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 description 1
- UDGKZGLPXCRRAM-UHFFFAOYSA-N 1,2,5-thiadiazole Chemical compound C=1C=NSN=1 UDGKZGLPXCRRAM-UHFFFAOYSA-N 0.000 description 1
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- LFKLPJRVSHJZPL-UHFFFAOYSA-N 1,2:7,8-diepoxyoctane Chemical compound C1OC1CCCCC1CO1 LFKLPJRVSHJZPL-UHFFFAOYSA-N 0.000 description 1
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 description 1
- MBIZXFATKUQOOA-UHFFFAOYSA-N 1,3,4-thiadiazole Chemical compound C1=NN=CS1 MBIZXFATKUQOOA-UHFFFAOYSA-N 0.000 description 1
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical compound C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 1
- KBKGPMDADJLBEM-UHFFFAOYSA-N 1-(4-pentylphenyl)ethanone Chemical compound CCCCCC1=CC=C(C(C)=O)C=C1 KBKGPMDADJLBEM-UHFFFAOYSA-N 0.000 description 1
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 description 1
- WFNAKBGANONZEQ-UHFFFAOYSA-N 1-[(4-chlorophenyl)-phenylmethyl]-4-methylpiperazine Chemical compound C1CN(C)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 WFNAKBGANONZEQ-UHFFFAOYSA-N 0.000 description 1
- OZOMQRBLCMDCEG-CHHVJCJISA-N 1-[(z)-[5-(4-nitrophenyl)furan-2-yl]methylideneamino]imidazolidine-2,4-dione Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(O1)=CC=C1\C=N/N1C(=O)NC(=O)C1 OZOMQRBLCMDCEG-CHHVJCJISA-N 0.000 description 1
- OCAPBUJLXMYKEJ-UHFFFAOYSA-N 1-[biphenyl-4-yl(phenyl)methyl]imidazole Chemical compound C1=NC=CN1C(C=1C=CC(=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 OCAPBUJLXMYKEJ-UHFFFAOYSA-N 0.000 description 1
- FPHIGGMDBMWPDB-UHFFFAOYSA-N 1-benzyl-3-(2-pyridin-4-ylethyl)indole;hydrochloride Chemical compound [Cl-].C=1[NH+](CC=2C=CC=CC=2)C2=CC=CC=C2C=1CCC1=CC=NC=C1 FPHIGGMDBMWPDB-UHFFFAOYSA-N 0.000 description 1
- MBDUIEKYVPVZJH-UHFFFAOYSA-N 1-ethylsulfonylethane Chemical group CCS(=O)(=O)CC MBDUIEKYVPVZJH-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- ULIDRMKBVYYVIQ-UHFFFAOYSA-N 1-phenyltetrazol-5-amine Chemical compound NC1=NN=NN1C1=CC=CC=C1 ULIDRMKBVYYVIQ-UHFFFAOYSA-N 0.000 description 1
- LEZWWPYKPKIXLL-UHFFFAOYSA-N 1-{2-(4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound C1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 LEZWWPYKPKIXLL-UHFFFAOYSA-N 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 description 1
- GWOLZNVIRIHJHB-UHFFFAOYSA-N 11-mercaptoundecanoic acid Chemical compound OC(=O)CCCCCCCCCCS GWOLZNVIRIHJHB-UHFFFAOYSA-N 0.000 description 1
- ULGGZAVAARQJCS-UHFFFAOYSA-N 11-sulfanylundecan-1-ol Chemical compound OCCCCCCCCCCCS ULGGZAVAARQJCS-UHFFFAOYSA-N 0.000 description 1
- XPYXJSSCWCSOFO-UHFFFAOYSA-N 11-sulfanylundecyl dihydrogen phosphate Chemical compound OP(O)(=O)OCCCCCCCCCCCS XPYXJSSCWCSOFO-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- 101710175516 14 kDa zinc-binding protein Proteins 0.000 description 1
- INOAASCWQMFJQA-UHFFFAOYSA-N 16-sulfanylhexadecanoic acid Chemical compound OC(=O)CCCCCCCCCCCCCCCS INOAASCWQMFJQA-UHFFFAOYSA-N 0.000 description 1
- PROQIPRRNZUXQM-ZMSHIADSSA-N 16beta-hydroxyestradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZMSHIADSSA-N 0.000 description 1
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 1
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 1
- GCKMFJBGXUYNAG-UHFFFAOYSA-N 17alpha-methyltestosterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C)(O)C1(C)CC2 GCKMFJBGXUYNAG-UHFFFAOYSA-N 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- USYCQABRSUEURP-UHFFFAOYSA-N 1h-benzo[f]benzimidazole Chemical compound C1=CC=C2C=C(NC=N3)C3=CC2=C1 USYCQABRSUEURP-UHFFFAOYSA-N 0.000 description 1
- 229940043268 2,2,4,4,6,8,8-heptamethylnonane Drugs 0.000 description 1
- IMQFZQVZKBIPCQ-UHFFFAOYSA-N 2,2-bis(3-sulfanylpropanoyloxymethyl)butyl 3-sulfanylpropanoate Chemical compound SCCC(=O)OCC(CC)(COC(=O)CCS)COC(=O)CCS IMQFZQVZKBIPCQ-UHFFFAOYSA-N 0.000 description 1
- SRETXDDCKMOQNE-UHFFFAOYSA-N 2,3-bis(4-methoxyphenyl)-1h-indole Chemical compound C1=CC(OC)=CC=C1C1=C(C=2C=CC(OC)=CC=2)C2=CC=CC=C2N1 SRETXDDCKMOQNE-UHFFFAOYSA-N 0.000 description 1
- LDGWQMRUWMSZIU-LQDDAWAPSA-M 2,3-bis[(z)-octadec-9-enoxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCCOCC(C[N+](C)(C)C)OCCCCCCCC\C=C/CCCCCCCC LDGWQMRUWMSZIU-LQDDAWAPSA-M 0.000 description 1
- KWVJHCQQUFDPLU-YEUCEMRASA-N 2,3-bis[[(z)-octadec-9-enoyl]oxy]propyl-trimethylazanium Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC KWVJHCQQUFDPLU-YEUCEMRASA-N 0.000 description 1
- KSXTUUUQYQYKCR-LQDDAWAPSA-M 2,3-bis[[(z)-octadec-9-enoyl]oxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC KSXTUUUQYQYKCR-LQDDAWAPSA-M 0.000 description 1
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- KYBOCQHDFLVQIB-UHFFFAOYSA-N 2-(4-methyl-2-sulfanylidene-3h-1,3-thiazol-5-yl)acetic acid Chemical compound CC=1N=C(S)SC=1CC(O)=O KYBOCQHDFLVQIB-UHFFFAOYSA-N 0.000 description 1
- CTPDSKVQLSDPLC-UHFFFAOYSA-N 2-(oxolan-2-ylmethoxy)ethanol Chemical compound OCCOCC1CCCO1 CTPDSKVQLSDPLC-UHFFFAOYSA-N 0.000 description 1
- UCJMHYXRQZYNNL-UHFFFAOYSA-N 2-Ethyl-1-hexanethiol Chemical compound CCCCC(CC)CS UCJMHYXRQZYNNL-UHFFFAOYSA-N 0.000 description 1
- JVKUCNQGESRUCL-UHFFFAOYSA-N 2-Hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 description 1
- WGQKBCSACFQGQY-UHFFFAOYSA-N 2-Methyl-1-butanethiol Chemical compound CCC(C)CS WGQKBCSACFQGQY-UHFFFAOYSA-N 0.000 description 1
- XSLHNXBPPDZDAU-UHFFFAOYSA-M 2-[(e)-2-(2,5-dimethyl-1-phenylpyrrol-3-yl)ethenyl]-n,n,1-trimethylquinolin-1-ium-6-amine;hydroxide Chemical compound [OH-].C1=CC2=CC(N(C)C)=CC=C2[N+](C)=C1\C=C\C(=C1C)C=C(C)N1C1=CC=CC=C1 XSLHNXBPPDZDAU-UHFFFAOYSA-M 0.000 description 1
- GSHCNPAEDNETGJ-HKOLQMFGSA-N 2-[2,3-bis[[(z)-octadec-9-enoyl]oxy]propoxy-ethoxyphosphoryl]oxyethyl-trimethylazanium Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(=O)(OCC)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC GSHCNPAEDNETGJ-HKOLQMFGSA-N 0.000 description 1
- DWHIUNMOTRUVPG-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCO DWHIUNMOTRUVPG-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- TYCOFFBAZNSQOJ-UHFFFAOYSA-N 2-[4-(3-fluorophenyl)phenyl]propanoic acid Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC(F)=C1 TYCOFFBAZNSQOJ-UHFFFAOYSA-N 0.000 description 1
- YNZFUWZUGRBMHL-UHFFFAOYSA-N 2-[4-[3-(11-benzo[b][1]benzazepinyl)propyl]-1-piperazinyl]ethanol Chemical compound C1CN(CCO)CCN1CCCN1C2=CC=CC=C2C=CC2=CC=CC=C21 YNZFUWZUGRBMHL-UHFFFAOYSA-N 0.000 description 1
- PGYFLJKHWJVRMC-ZXRZDOCRSA-N 2-[4-[[(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]butoxy]-n,n-dimethyl-3-[(9z,12z)-octadeca-9,12-dienoxy]propan-1-amine Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OCCCCOC(CN(C)C)COCCCCCCCC\C=C/C\C=C/CCCCC)C1 PGYFLJKHWJVRMC-ZXRZDOCRSA-N 0.000 description 1
- YIYCUMYWGOOSNU-FMZZOXHWSA-N 2-[[(2s)-1-[(2s,3s)-2-[[(2s,3r)-2-[[2-[[(2s)-2-amino-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxybutanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbonyl]amino]acetic acid Chemical group CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O YIYCUMYWGOOSNU-FMZZOXHWSA-N 0.000 description 1
- LRYZPFWEZHSTHD-HEFFAWAOSA-O 2-[[(e,2s,3r)-2-formamido-3-hydroxyoctadec-4-enoxy]-hydroxyphosphoryl]oxyethyl-trimethylazanium Chemical class CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](NC=O)COP(O)(=O)OCC[N+](C)(C)C LRYZPFWEZHSTHD-HEFFAWAOSA-O 0.000 description 1
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 1
- XKSAJZSJKURQRX-UHFFFAOYSA-N 2-acetyloxy-5-(4-fluorophenyl)benzoic acid Chemical compound C1=C(C(O)=O)C(OC(=O)C)=CC=C1C1=CC=C(F)C=C1 XKSAJZSJKURQRX-UHFFFAOYSA-N 0.000 description 1
- VRVRGVPWCUEOGV-UHFFFAOYSA-N 2-aminothiophenol Chemical compound NC1=CC=CC=C1S VRVRGVPWCUEOGV-UHFFFAOYSA-N 0.000 description 1
- RTDXMJJSUVCSKB-UHFFFAOYSA-N 2-azanyl-4-sulfanyl-butanoic acid Chemical compound OC(=O)C(N)CCS.OC(=O)C(N)CCS RTDXMJJSUVCSKB-UHFFFAOYSA-N 0.000 description 1
- UXGVMFHEKMGWMA-UHFFFAOYSA-N 2-benzofuran Chemical compound C1=CC=CC2=COC=C21 UXGVMFHEKMGWMA-UHFFFAOYSA-N 0.000 description 1
- LYTMVABTDYMBQK-UHFFFAOYSA-N 2-benzothiophene Chemical compound C1=CC=CC2=CSC=C21 LYTMVABTDYMBQK-UHFFFAOYSA-N 0.000 description 1
- JIVPVXMEBJLZRO-CQSZACIVSA-N 2-chloro-5-[(1r)-1-hydroxy-3-oxo-2h-isoindol-1-yl]benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC([C@@]2(O)C3=CC=CC=C3C(=O)N2)=C1 JIVPVXMEBJLZRO-CQSZACIVSA-N 0.000 description 1
- JMOLZNNXZPAGBH-UHFFFAOYSA-M 2-hexyldecanoate Chemical compound CCCCCCCCC(C([O-])=O)CCCCCC JMOLZNNXZPAGBH-UHFFFAOYSA-M 0.000 description 1
- GNXFOGHNGIVQEH-UHFFFAOYSA-N 2-hydroxy-3-(2-methoxyphenoxy)propyl carbamate Chemical compound COC1=CC=CC=C1OCC(O)COC(N)=O GNXFOGHNGIVQEH-UHFFFAOYSA-N 0.000 description 1
- IXIGWKNBFPKCCD-UHFFFAOYSA-N 2-hydroxy-5-octanoylbenzoic acid Chemical compound CCCCCCCC(=O)C1=CC=C(O)C(C(O)=O)=C1 IXIGWKNBFPKCCD-UHFFFAOYSA-N 0.000 description 1
- SGUAFYQXFOLMHL-UHFFFAOYSA-N 2-hydroxy-5-{1-hydroxy-2-[(4-phenylbutan-2-yl)amino]ethyl}benzamide Chemical compound C=1C=C(O)C(C(N)=O)=CC=1C(O)CNC(C)CCC1=CC=CC=C1 SGUAFYQXFOLMHL-UHFFFAOYSA-N 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- SCNWTQPZTZMXBG-UHFFFAOYSA-N 2-methyloct-2-enoic acid Chemical compound CCCCCC=C(C)C(O)=O SCNWTQPZTZMXBG-UHFFFAOYSA-N 0.000 description 1
- YZEUHQHUFTYLPH-UHFFFAOYSA-N 2-nitroimidazole Chemical compound [O-][N+](=O)C1=NC=CN1 YZEUHQHUFTYLPH-UHFFFAOYSA-N 0.000 description 1
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 1
- YTRMTPPVNRALON-UHFFFAOYSA-N 2-phenyl-4-quinolinecarboxylic acid Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=CC=C1 YTRMTPPVNRALON-UHFFFAOYSA-N 0.000 description 1
- ZMRFRBHYXOQLDK-UHFFFAOYSA-N 2-phenylethanethiol Chemical compound SCCC1=CC=CC=C1 ZMRFRBHYXOQLDK-UHFFFAOYSA-N 0.000 description 1
- NLALYORXOGLYAQ-UHFFFAOYSA-N 2-sulfanylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1S.OC(=O)C1=CC=CC=C1S NLALYORXOGLYAQ-UHFFFAOYSA-N 0.000 description 1
- AZSNMRSAGSSBNP-UHFFFAOYSA-N 22,23-dihydroavermectin B1a Natural products C1CC(C)C(C(C)CC)OC21OC(CC=C(C)C(OC1OC(C)C(OC3OC(C)C(O)C(OC)C3)C(OC)C1)C(C)C=CC=C1C3(C(C(=O)O4)C=C(C)C(O)C3OC1)O)CC4C2 AZSNMRSAGSSBNP-UHFFFAOYSA-N 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- OKXBWVNLYDDCPX-UHFFFAOYSA-N 3,3-di(tetradecoxy)propan-1-amine Chemical compound CCCCCCCCCCCCCCOC(CCN)OCCCCCCCCCCCCCC OKXBWVNLYDDCPX-UHFFFAOYSA-N 0.000 description 1
- NCZPCONIKBICGS-UHFFFAOYSA-N 3-(2-ethylhexoxy)propane-1,2-diol Chemical compound CCCCC(CC)COCC(O)CO NCZPCONIKBICGS-UHFFFAOYSA-N 0.000 description 1
- NHUPEUMBGMETKD-UHFFFAOYSA-N 3-(4-methoxyphenyl)-4-methyl-1h-imidazol-2-one Chemical compound C1=CC(OC)=CC=C1N1C(=O)NC=C1C NHUPEUMBGMETKD-UHFFFAOYSA-N 0.000 description 1
- ACGSRAAAQJSWLC-UHFFFAOYSA-N 3-(trifluoromethyl)-1h-pyridine-2-thione Chemical compound FC(F)(F)C1=CC=CN=C1S ACGSRAAAQJSWLC-UHFFFAOYSA-N 0.000 description 1
- XLMPYCGSRHSSSX-UHFFFAOYSA-N 3-Mercapto-2-butanone Chemical compound CC(S)C(C)=O XLMPYCGSRHSSSX-UHFFFAOYSA-N 0.000 description 1
- FLNYCRJBCNNHRH-OIYLJQICSA-N 3-[(3ar,4r,5s,7as)-5-[(1r)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-fluorophenyl)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]cyclopent-2-en-1-one Chemical compound C1([C@H]2[C@@H]3CN(C[C@H]3CC[C@@H]2O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C=2CCC(=O)C=2)=CC=C(F)C=C1 FLNYCRJBCNNHRH-OIYLJQICSA-N 0.000 description 1
- QPFDPUCWRFYCFB-UHFFFAOYSA-N 3-[2-(diethylamino)ethyl]-1,3-benzoxazine-2,4-dione;hydrochloride Chemical compound Cl.C1=CC=C2C(=O)N(CCN(CC)CC)C(=O)OC2=C1 QPFDPUCWRFYCFB-UHFFFAOYSA-N 0.000 description 1
- IXOCGRPBILEGOX-UHFFFAOYSA-N 3-[3-(dodecanoylamino)propyl-dimethylazaniumyl]-2-hydroxypropane-1-sulfonate Chemical compound CCCCCCCCCCCC(=O)NCCC[N+](C)(C)CC(O)CS([O-])(=O)=O IXOCGRPBILEGOX-UHFFFAOYSA-N 0.000 description 1
- CDOUZKKFHVEKRI-UHFFFAOYSA-N 3-bromo-n-[(prop-2-enoylamino)methyl]propanamide Chemical compound BrCCC(=O)NCNC(=O)C=C CDOUZKKFHVEKRI-UHFFFAOYSA-N 0.000 description 1
- TYZFMFVWHZKYSE-UHFFFAOYSA-N 3-mercaptohexanol Chemical compound CCCC(S)CCO TYZFMFVWHZKYSE-UHFFFAOYSA-N 0.000 description 1
- DKIDEFUBRARXTE-UHFFFAOYSA-N 3-mercaptopropanoic acid Chemical compound OC(=O)CCS DKIDEFUBRARXTE-UHFFFAOYSA-N 0.000 description 1
- GBCGIJAYTBMFHI-UHFFFAOYSA-N 3-methyl-3-sulfanylbutan-1-ol Chemical compound CC(C)(S)CCO GBCGIJAYTBMFHI-UHFFFAOYSA-N 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- MVQVNTPHUGQQHK-UHFFFAOYSA-N 3-pyridinemethanol Chemical compound OCC1=CC=CN=C1 MVQVNTPHUGQQHK-UHFFFAOYSA-N 0.000 description 1
- SHLSSLVZXJBVHE-UHFFFAOYSA-N 3-sulfanylpropan-1-ol Chemical compound OCCCS SHLSSLVZXJBVHE-UHFFFAOYSA-N 0.000 description 1
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 description 1
- WTJXVDPDEQKTCV-UHFFFAOYSA-N 4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydron;chloride Chemical compound Cl.C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2C1CC1C(N(C)C)C(=O)C(C(N)=O)=C(O)C1(O)C2=O WTJXVDPDEQKTCV-UHFFFAOYSA-N 0.000 description 1
- BMUKKTUHUDJSNZ-UHFFFAOYSA-N 4-[1-hydroxy-2-(1-phenoxypropan-2-ylamino)propyl]phenol Chemical compound C=1C=C(O)C=CC=1C(O)C(C)NC(C)COC1=CC=CC=C1 BMUKKTUHUDJSNZ-UHFFFAOYSA-N 0.000 description 1
- BVPWJMCABCPUQY-UHFFFAOYSA-N 4-amino-5-chloro-2-methoxy-N-[1-(phenylmethyl)-4-piperidinyl]benzamide Chemical compound COC1=CC(N)=C(Cl)C=C1C(=O)NC1CCN(CC=2C=CC=CC=2)CC1 BVPWJMCABCPUQY-UHFFFAOYSA-N 0.000 description 1
- WZRJTRPJURQBRM-UHFFFAOYSA-N 4-amino-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide;5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1.COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 WZRJTRPJURQBRM-UHFFFAOYSA-N 0.000 description 1
- WCDSVWRUXWCYFN-UHFFFAOYSA-N 4-aminobenzenethiol Chemical compound NC1=CC=C(S)C=C1 WCDSVWRUXWCYFN-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- BYDNGJQDDNBAHI-UHFFFAOYSA-N 4-methyl-7-sulfanylchromen-2-one Chemical compound C1=C(S)C=CC2=C1OC(=O)C=C2C BYDNGJQDDNBAHI-UHFFFAOYSA-N 0.000 description 1
- WLHCBQAPPJAULW-UHFFFAOYSA-N 4-methylbenzenethiol Chemical compound CC1=CC=C(S)C=C1 WLHCBQAPPJAULW-UHFFFAOYSA-N 0.000 description 1
- AXBVSRMHOPMXBA-UHFFFAOYSA-N 4-nitrothiophenol Chemical compound [O-][N+](=O)C1=CC=C(S)C=C1 AXBVSRMHOPMXBA-UHFFFAOYSA-N 0.000 description 1
- LMJXSOYPAOSIPZ-UHFFFAOYSA-N 4-sulfanylbenzoic acid Chemical compound OC(=O)C1=CC=C(S)C=C1 LMJXSOYPAOSIPZ-UHFFFAOYSA-N 0.000 description 1
- NEJMTSWXTZREOC-UHFFFAOYSA-N 4-sulfanylbutan-1-ol Chemical compound OCCCCS NEJMTSWXTZREOC-UHFFFAOYSA-N 0.000 description 1
- GNXBFFHXJDZGEK-UHFFFAOYSA-N 4-tert-butylbenzenethiol Chemical compound CC(C)(C)C1=CC=C(S)C=C1 GNXBFFHXJDZGEK-UHFFFAOYSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- 229940124125 5 Lipoxygenase inhibitor Drugs 0.000 description 1
- PJJGZPJJTHBVMX-UHFFFAOYSA-N 5,7-Dihydroxyisoflavone Chemical compound C=1C(O)=CC(O)=C(C2=O)C=1OC=C2C1=CC=CC=C1 PJJGZPJJTHBVMX-UHFFFAOYSA-N 0.000 description 1
- 102000035037 5-HT3 receptors Human genes 0.000 description 1
- 108091005477 5-HT3 receptors Proteins 0.000 description 1
- YLCCEQZHUHUYPA-UHFFFAOYSA-N 5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine;hydrochloride Chemical compound Cl.COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 YLCCEQZHUHUYPA-UHFFFAOYSA-N 0.000 description 1
- 239000002677 5-alpha reductase inhibitor Substances 0.000 description 1
- XKFPYPQQHFEXRZ-UHFFFAOYSA-N 5-methyl-N'-(phenylmethyl)-3-isoxazolecarbohydrazide Chemical compound O1C(C)=CC(C(=O)NNCC=2C=CC=CC=2)=N1 XKFPYPQQHFEXRZ-UHFFFAOYSA-N 0.000 description 1
- YPXQSGWOGQPLQO-UHFFFAOYSA-N 5-nitro-1,3-dihydrobenzimidazole-2-thione Chemical compound [O-][N+](=O)C1=CC=C2N=C(S)NC2=C1 YPXQSGWOGQPLQO-UHFFFAOYSA-N 0.000 description 1
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 description 1
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- BKYKPTRYDKTTJY-UHFFFAOYSA-N 6-chloro-3-(cyclopentylmethyl)-1,1-dioxo-3,4-dihydro-2H-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1CCCC1 BKYKPTRYDKTTJY-UHFFFAOYSA-N 0.000 description 1
- IGZZHADAOWGUEI-UHFFFAOYSA-N 6-methyl-1h-pyridine-2-thione Chemical compound CC1=CC=CC(S)=N1 IGZZHADAOWGUEI-UHFFFAOYSA-N 0.000 description 1
- UQJLPBLXSJWAKG-UHFFFAOYSA-N 6-methyl-1h-pyrimidin-3-ium-2-thione;chloride Chemical compound Cl.CC1=CC=NC(=S)N1 UQJLPBLXSJWAKG-UHFFFAOYSA-N 0.000 description 1
- UGZAJZLUKVKCBM-UHFFFAOYSA-N 6-sulfanylhexan-1-ol Chemical compound OCCCCCCS UGZAJZLUKVKCBM-UHFFFAOYSA-N 0.000 description 1
- CMNQZZPAVNBESS-UHFFFAOYSA-N 6-sulfanylhexanoic acid Chemical compound OC(=O)CCCCCS CMNQZZPAVNBESS-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- KFQYTPMOWPVWEJ-UHFFFAOYSA-N 6-{propyl[2-(thiophen-2-yl)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound C1CC2=C(O)C=CC=C2CC1N(CCC)CCC1=CC=CS1 KFQYTPMOWPVWEJ-UHFFFAOYSA-N 0.000 description 1
- MYYIMZRZXIQBGI-HVIRSNARSA-N 6alpha-Fluoroprednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3C[C@H](F)C2=C1 MYYIMZRZXIQBGI-HVIRSNARSA-N 0.000 description 1
- DSFGXPJYDCSWTA-UHFFFAOYSA-N 7-[2-hydroxy-3-[2-hydroxyethyl(methyl)amino]propyl]-1,3-dimethylpurine-2,6-dione Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2CC(O)CN(CCO)C DSFGXPJYDCSWTA-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WXIGSVFQTLVMQM-UHFFFAOYSA-N 8-(trifluoromethyl)-10h-phenothiazine-1-carboxylic acid Chemical compound S1C2=CC=C(C(F)(F)F)C=C2NC2=C1C=CC=C2C(=O)O WXIGSVFQTLVMQM-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- XJTWZETUWHTBTG-UHFFFAOYSA-N 8-sulfanyloctan-1-ol Chemical compound OCCCCCCCCS XJTWZETUWHTBTG-UHFFFAOYSA-N 0.000 description 1
- FYEMIKRWWMYBFG-UHFFFAOYSA-N 8-sulfanyloctanoic acid Chemical compound OC(=O)CCCCCCCS FYEMIKRWWMYBFG-UHFFFAOYSA-N 0.000 description 1
- SPBDXSGPUHCETR-JFUDTMANSA-N 8883yp2r6d Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)CC4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1C[C@H](C)[C@@H]([C@@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 SPBDXSGPUHCETR-JFUDTMANSA-N 0.000 description 1
- FXFJFNVBVKPAPL-UHFFFAOYSA-N 9-sulfanylnonan-1-ol Chemical compound OCCCCCCCCCS FXFJFNVBVKPAPL-UHFFFAOYSA-N 0.000 description 1
- BPMFPOGUJAAYHL-UHFFFAOYSA-N 9H-Pyrido[2,3-b]indole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=N1 BPMFPOGUJAAYHL-UHFFFAOYSA-N 0.000 description 1
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- 206010000050 Abdominal adhesions Diseases 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 239000000275 Adrenocorticotropic Hormone Substances 0.000 description 1
- 241000607525 Aeromonas salmonicida Species 0.000 description 1
- 241000122170 Aliivibrio salmonicida Species 0.000 description 1
- ATXHVCQZZJYMCF-XUDSTZEESA-N Allylestrenol Chemical compound C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)CC=C)[C@@H]4[C@@H]3CCC2=C1 ATXHVCQZZJYMCF-XUDSTZEESA-N 0.000 description 1
- 229940121947 Alpha 2 adrenoreceptor agonist Drugs 0.000 description 1
- XYLJNLCSTIOKRM-UHFFFAOYSA-N Alphagan Chemical compound C1=CC2=NC=CN=C2C(Br)=C1NC1=NCCN1 XYLJNLCSTIOKRM-UHFFFAOYSA-N 0.000 description 1
- RLFWWDJHLFCNIJ-UHFFFAOYSA-N Aminoantipyrine Natural products CN1C(C)=C(N)C(=O)N1C1=CC=CC=C1 RLFWWDJHLFCNIJ-UHFFFAOYSA-N 0.000 description 1
- RMMXTBMQSGEXHJ-UHFFFAOYSA-N Aminophenazone Chemical compound O=C1C(N(C)C)=C(C)N(C)N1C1=CC=CC=C1 RMMXTBMQSGEXHJ-UHFFFAOYSA-N 0.000 description 1
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 229930183010 Amphotericin Natural products 0.000 description 1
- QGGFZZLFKABGNL-UHFFFAOYSA-N Amphotericin A Natural products OC1C(N)C(O)C(C)OC1OC1C=CC=CC=CC=CCCC=CC=CC(C)C(O)C(C)C(C)OC(=O)CC(O)CC(O)CCC(O)C(O)CC(O)CC(O)(CC(O)C2C(O)=O)OC2C1 QGGFZZLFKABGNL-UHFFFAOYSA-N 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 102400000068 Angiostatin Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- 229940086440 Angiotensin I converting enzyme inhibitor Drugs 0.000 description 1
- 229940123413 Angiotensin II antagonist Drugs 0.000 description 1
- 108050008874 Annexin Proteins 0.000 description 1
- 102000000412 Annexin Human genes 0.000 description 1
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- YXSLJKQTIDHPOT-UHFFFAOYSA-N Atracurium Dibesylate Chemical compound C1=C(OC)C(OC)=CC=C1CC1[N+](CCC(=O)OCCCCCOC(=O)CC[N+]2(C)C(C3=CC(OC)=C(OC)C=C3CC2)CC=2C=C(OC)C(OC)=CC=2)(C)CCC2=CC(OC)=C(OC)C=C21 YXSLJKQTIDHPOT-UHFFFAOYSA-N 0.000 description 1
- XHVAWZZCDCWGBK-WYRLRVFGSA-M Aurothioglucose Chemical compound OC[C@H]1O[C@H](S[Au])[C@H](O)[C@@H](O)[C@@H]1O XHVAWZZCDCWGBK-WYRLRVFGSA-M 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 description 1
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 1
- 208000012639 Balance disease Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- HNNIWKQLJSNAEQ-UHFFFAOYSA-N Benzydamine hydrochloride Chemical compound Cl.C12=CC=CC=C2C(OCCCN(C)C)=NN1CC1=CC=CC=C1 HNNIWKQLJSNAEQ-UHFFFAOYSA-N 0.000 description 1
- 229940122361 Bisphosphonate Drugs 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical group OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 108030001720 Bontoxilysin Proteins 0.000 description 1
- VMIYHDSEFNYJSL-UHFFFAOYSA-N Bromazepam Chemical compound C12=CC(Br)=CC=C2NC(=O)CN=C1C1=CC=CC=N1 VMIYHDSEFNYJSL-UHFFFAOYSA-N 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- 102100028990 C-X-C chemokine receptor type 3 Human genes 0.000 description 1
- DTPVYWHLQLAXFT-SMCUOGPFSA-N CC(O)=O.CC(O)=O.C([C@@H](C(=O)N[C@H](CCCNC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 Chemical compound CC(O)=O.CC(O)=O.C([C@@H](C(=O)N[C@H](CCCNC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 DTPVYWHLQLAXFT-SMCUOGPFSA-N 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 241001264766 Callistemon Species 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 244000284152 Carapichea ipecacuanha Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 229940123003 Cathepsin inhibitor Drugs 0.000 description 1
- NCFTXMQPRQZFMZ-WERGMSTESA-M Cefoperazone sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C([O-])=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 NCFTXMQPRQZFMZ-WERGMSTESA-M 0.000 description 1
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 description 1
- 229940123587 Cell cycle inhibitor Drugs 0.000 description 1
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 1
- CXRFDZFCGOPDTD-UHFFFAOYSA-M Cetrimide Chemical compound [Br-].CCCCCCCCCCCCCC[N+](C)(C)C CXRFDZFCGOPDTD-UHFFFAOYSA-M 0.000 description 1
- 229940122444 Chemokine receptor antagonist Drugs 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical class ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- PCLITLDOTJTVDJ-UHFFFAOYSA-N Chlormethiazole Chemical compound CC=1N=CSC=1CCCl PCLITLDOTJTVDJ-UHFFFAOYSA-N 0.000 description 1
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 1
- 239000004099 Chlortetracycline Substances 0.000 description 1
- 208000032544 Cicatrix Diseases 0.000 description 1
- KATBVKFXGKGUFE-UHFFFAOYSA-N Cintazone Chemical compound C12=CC=CC=C2N2C(=O)C(CCCCC)C(=O)N2C=C1C1=CC=CC=C1 KATBVKFXGKGUFE-UHFFFAOYSA-N 0.000 description 1
- GTNDZRUWKHDICY-DJHAJVGHSA-N Clindamycin palmitate hydrochloride Chemical compound Cl.O1[C@H](SC)[C@H](OC(=O)CCCCCCCCCCCCCCC)[C@@H](O)[C@@H](O)[C@H]1[C@@H]([C@H](C)Cl)NC(=O)[C@H]1N(C)C[C@H](CCC)C1 GTNDZRUWKHDICY-DJHAJVGHSA-N 0.000 description 1
- ARPLCFGLEYFDCN-CDACMRRYSA-N Clocortolone acetate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(Cl)[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)COC(C)=O)[C@@]2(C)C[C@@H]1O ARPLCFGLEYFDCN-CDACMRRYSA-N 0.000 description 1
- GDLIGKIOYRNHDA-UHFFFAOYSA-N Clomipramine Chemical compound C1CC2=CC=C(Cl)C=C2N(CCCN(C)C)C2=CC=CC=C21 GDLIGKIOYRNHDA-UHFFFAOYSA-N 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- XYGMEFJSKQEBTO-KUJXMBTLSA-N Clostebol acetate Chemical compound C1CC2=C(Cl)C(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)C)[C@@]1(C)CC2 XYGMEFJSKQEBTO-KUJXMBTLSA-N 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 1
- 206010010984 Corneal abrasion Diseases 0.000 description 1
- 208000028006 Corneal injury Diseases 0.000 description 1
- 101800000414 Corticotropin Proteins 0.000 description 1
- ITRJWOMZKQRYTA-RFZYENFJSA-N Cortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2=O ITRJWOMZKQRYTA-RFZYENFJSA-N 0.000 description 1
- WVDYBOADDMMFIY-UHFFFAOYSA-N Cyclopentanethiol Chemical compound SC1CCCC1 WVDYBOADDMMFIY-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 description 1
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- 239000012624 DNA alkylating agent Substances 0.000 description 1
- 229940126161 DNA alkylating agent Drugs 0.000 description 1
- 230000002112 DNA intercalation Effects 0.000 description 1
- XULFJDKZVHTRLG-JDVCJPALSA-N DOSPA trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.CCCCCCCC\C=C/CCCCCCCCOCC(C[N+](C)(C)CCNC(=O)C(CCCNCCCN)NCCCN)OCCCCCCCC\C=C/CCCCCCCC XULFJDKZVHTRLG-JDVCJPALSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- MQJKPEGWNLWLTK-UHFFFAOYSA-N Dapsone Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=C1 MQJKPEGWNLWLTK-UHFFFAOYSA-N 0.000 description 1
- 108010013198 Daptomycin Proteins 0.000 description 1
- 206010011891 Deafness neurosensory Diseases 0.000 description 1
- 108010000437 Deamino Arginine Vasopressin Proteins 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 229940124186 Dehydrogenase inhibitor Drugs 0.000 description 1
- NNJPGOLRFBJNIW-UHFFFAOYSA-N Demecolcine Natural products C1=C(OC)C(=O)C=C2C(NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-UHFFFAOYSA-N 0.000 description 1
- FMTDIUIBLCQGJB-UHFFFAOYSA-N Demethylchlortetracyclin Natural products C1C2C(O)C3=C(Cl)C=CC(O)=C3C(=O)C2=C(O)C2(O)C1C(N(C)C)C(O)=C(C(N)=O)C2=O FMTDIUIBLCQGJB-UHFFFAOYSA-N 0.000 description 1
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 1
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 1
- 206010056340 Diabetic ulcer Diseases 0.000 description 1
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 1
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 1
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 1
- JRWZLRBJNMZMFE-UHFFFAOYSA-N Dobutamine Chemical compound C=1C=C(O)C(O)=CC=1CCNC(C)CCC1=CC=C(O)C=C1 JRWZLRBJNMZMFE-UHFFFAOYSA-N 0.000 description 1
- 241001269524 Dura Species 0.000 description 1
- 229940122858 Elastase inhibitor Drugs 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- MBYXEBXZARTUSS-QLWBXOBMSA-N Emetamine Natural products O(C)c1c(OC)cc2c(c(C[C@@H]3[C@H](CC)CN4[C@H](c5c(cc(OC)c(OC)c5)CC4)C3)ncc2)c1 MBYXEBXZARTUSS-QLWBXOBMSA-N 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 102400001047 Endostatin Human genes 0.000 description 1
- 108010079505 Endostatins Proteins 0.000 description 1
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 1
- 229940122586 Enkephalinase inhibitor Drugs 0.000 description 1
- OBMLHUPNRURLOK-XGRAFVIBSA-N Epitiostanol Chemical compound C1[C@@H]2S[C@@H]2C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 OBMLHUPNRURLOK-XGRAFVIBSA-N 0.000 description 1
- 108010056764 Eptifibatide Proteins 0.000 description 1
- WVVSZNPYNCNODU-CJBNDPTMSA-N Ergometrine Natural products C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@@H](CO)C)C2)=C3C2=CNC3=C1 WVVSZNPYNCNODU-CJBNDPTMSA-N 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- YAVZHCFFUATPRK-YZPBMOCRSA-N Erythromycin stearate Chemical compound CCCCCCCCCCCCCCCCCC(O)=O.O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 YAVZHCFFUATPRK-YZPBMOCRSA-N 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- 102100038595 Estrogen receptor Human genes 0.000 description 1
- 102100029951 Estrogen receptor beta Human genes 0.000 description 1
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 1
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- OGDVEMNWJVYAJL-LEPYJNQMSA-N Ethyl morphine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OCC OGDVEMNWJVYAJL-LEPYJNQMSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- OGDVEMNWJVYAJL-UHFFFAOYSA-N Ethylmorphine Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OCC OGDVEMNWJVYAJL-UHFFFAOYSA-N 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- 208000034347 Faecal incontinence Diseases 0.000 description 1
- 229940124226 Farnesyltransferase inhibitor Drugs 0.000 description 1
- SRANDCPSMJNFCK-WOJGMQOQSA-N Fezatione Chemical compound C1=CC(C)=CC=C1\C=N\N1C(=S)SC=C1C1=CC=CC=C1 SRANDCPSMJNFCK-WOJGMQOQSA-N 0.000 description 1
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 1
- 102000003971 Fibroblast Growth Factor 1 Human genes 0.000 description 1
- 108090000569 Fibroblast Growth Factor-23 Proteins 0.000 description 1
- 102100024802 Fibroblast growth factor 23 Human genes 0.000 description 1
- DJBNUMBKLMJRSA-UHFFFAOYSA-N Flecainide Chemical compound FC(F)(F)COC1=CC=C(OCC(F)(F)F)C(C(=O)NCC2NCCCC2)=C1 DJBNUMBKLMJRSA-UHFFFAOYSA-N 0.000 description 1
- PLDUPXSUYLZYBN-UHFFFAOYSA-N Fluphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 PLDUPXSUYLZYBN-UHFFFAOYSA-N 0.000 description 1
- QZJIMDIBFFHQDW-LMLSDSMGSA-N Fosfomycin tromethamine Chemical compound C[C@@H]1O[C@@H]1P(O)([O-])=O.OCC([NH3+])(CO)CO QZJIMDIBFFHQDW-LMLSDSMGSA-N 0.000 description 1
- RGLLOUBXMOGLDQ-IVEVATEUSA-N Furazabol Chemical compound C([C@@H]1CC2)C3=NON=C3C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@](C)(O)[C@@]2(C)CC1 RGLLOUBXMOGLDQ-IVEVATEUSA-N 0.000 description 1
- IECPWNUMDGFDKC-UHFFFAOYSA-N Fusicsaeure Natural products C12C(O)CC3C(=C(CCC=C(C)C)C(O)=O)C(OC(C)=O)CC3(C)C1(C)CCC1C2(C)CCC(O)C1C IECPWNUMDGFDKC-UHFFFAOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 102100033299 Glia-derived nexin Human genes 0.000 description 1
- 101710183811 Glia-derived nexin Proteins 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 1
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- FOHHNHSLJDZUGQ-VWLOTQADSA-N Halofantrine Chemical compound FC(F)(F)C1=CC=C2C([C@@H](O)CCN(CCCC)CCCC)=CC3=C(Cl)C=C(Cl)C=C3C2=C1 FOHHNHSLJDZUGQ-VWLOTQADSA-N 0.000 description 1
- 229940123034 Heat shock protein 90 antagonist Drugs 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 102000007625 Hirudins Human genes 0.000 description 1
- 108010007267 Hirudins Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000916050 Homo sapiens C-X-C chemokine receptor type 3 Proteins 0.000 description 1
- 101000746367 Homo sapiens Granulocyte colony-stimulating factor Proteins 0.000 description 1
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 1
- 101000829980 Homo sapiens Ral guanine nucleotide dissociation stimulator Proteins 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
- 102000001974 Hyaluronidases Human genes 0.000 description 1
- DLVOSEUFIRPIRM-KAQKJVHQSA-N Hydrocortisone cypionate Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(CCC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCC1CCCC1 DLVOSEUFIRPIRM-KAQKJVHQSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 229940122296 IKK2 inhibitor Drugs 0.000 description 1
- GRSZFWQUAKGDAV-KQYNXXCUSA-N IMP Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(NC=NC2=O)=C2N=C1 GRSZFWQUAKGDAV-KQYNXXCUSA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 229940122355 Insulin sensitizer Drugs 0.000 description 1
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 1
- 102100025306 Integrin alpha-IIb Human genes 0.000 description 1
- 101710149643 Integrin alpha-IIb Proteins 0.000 description 1
- 108010008212 Integrin alpha4beta1 Proteins 0.000 description 1
- 229940123038 Integrin antagonist Drugs 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 206010058031 Joint adhesion Diseases 0.000 description 1
- 229940124091 Keratolytic Drugs 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 1
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 description 1
- 241001594303 Lepidoscia polymeres Species 0.000 description 1
- DUKURNFHYQXCJG-UHFFFAOYSA-N Lewis A pentasaccharide Natural products OC1C(O)C(O)C(C)OC1OC1C(OC2C(C(O)C(O)C(CO)O2)O)C(NC(C)=O)C(OC2C(C(OC3C(OC(O)C(O)C3O)CO)OC(CO)C2O)O)OC1CO DUKURNFHYQXCJG-UHFFFAOYSA-N 0.000 description 1
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 description 1
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 description 1
- YHBTXTFFTYXOFV-UHFFFAOYSA-N Liquid thiophthene Chemical compound C1=CSC2=C1C=CS2 YHBTXTFFTYXOFV-UHFFFAOYSA-N 0.000 description 1
- 108010007859 Lisinopril Proteins 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229920000161 Locust bean gum Polymers 0.000 description 1
- 108010074338 Lymphokines Proteins 0.000 description 1
- 102000008072 Lymphokines Human genes 0.000 description 1
- YNVGQYHLRCDXFQ-XGXHKTLJSA-N Lynestrenol Chemical compound C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 YNVGQYHLRCDXFQ-XGXHKTLJSA-N 0.000 description 1
- 108010048179 Lypressin Proteins 0.000 description 1
- WVVSZNPYNCNODU-XTQGRXLLSA-N Lysergic acid propanolamide Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@H](CO)C)C2)=C3C2=CNC3=C1 WVVSZNPYNCNODU-XTQGRXLLSA-N 0.000 description 1
- 229940122696 MAP kinase inhibitor Drugs 0.000 description 1
- 229940123313 MCP-1 antagonist Drugs 0.000 description 1
- 229940124761 MMP inhibitor Drugs 0.000 description 1
- 102100028123 Macrophage colony-stimulating factor 1 Human genes 0.000 description 1
- 101710127797 Macrophage colony-stimulating factor 1 Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- ZPXSCAKFGYXMGA-UHFFFAOYSA-N Mazindol Chemical compound N12CCN=C2C2=CC=CC=C2C1(O)C1=CC=C(Cl)C=C1 ZPXSCAKFGYXMGA-UHFFFAOYSA-N 0.000 description 1
- OCJYIGYOJCODJL-UHFFFAOYSA-N Meclizine Chemical compound CC1=CC=CC(CN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC(Cl)=CC=2)=C1 OCJYIGYOJCODJL-UHFFFAOYSA-N 0.000 description 1
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 description 1
- SMNOERSLNYGGOU-UHFFFAOYSA-N Mefruside Chemical compound C=1C=C(Cl)C(S(N)(=O)=O)=CC=1S(=O)(=O)N(C)CC1(C)CCCO1 SMNOERSLNYGGOU-UHFFFAOYSA-N 0.000 description 1
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 1
- 244000062730 Melissa officinalis Species 0.000 description 1
- 235000010654 Melissa officinalis Nutrition 0.000 description 1
- NPPQSCRMBWNHMW-UHFFFAOYSA-N Meprobamate Chemical compound NC(=O)OCC(C)(CCC)COC(N)=O NPPQSCRMBWNHMW-UHFFFAOYSA-N 0.000 description 1
- XOGTZOOQQBDUSI-UHFFFAOYSA-M Mesna Chemical compound [Na+].[O-]S(=O)(=O)CCS XOGTZOOQQBDUSI-UHFFFAOYSA-M 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- ROAIXOJGRFKICW-UHFFFAOYSA-N Methenamine hippurate Chemical compound C1N(C2)CN3CN1CN2C3.OC(=O)CNC(=O)C1=CC=CC=C1 ROAIXOJGRFKICW-UHFFFAOYSA-N 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- AJXPJJZHWIXJCJ-UHFFFAOYSA-N Methsuximide Chemical compound O=C1N(C)C(=O)CC1(C)C1=CC=CC=C1 AJXPJJZHWIXJCJ-UHFFFAOYSA-N 0.000 description 1
- MWCLLHOVUTZFKS-UHFFFAOYSA-N Methyl cyanoacrylate Chemical compound COC(=O)C(=C)C#N MWCLLHOVUTZFKS-UHFFFAOYSA-N 0.000 description 1
- GCKMFJBGXUYNAG-HLXURNFRSA-N Methyltestosterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GCKMFJBGXUYNAG-HLXURNFRSA-N 0.000 description 1
- UEQUQVLFIPOEMF-UHFFFAOYSA-N Mianserin Chemical compound C1C2=CC=CC=C2N2CCN(C)CC2C2=CC=CC=C21 UEQUQVLFIPOEMF-UHFFFAOYSA-N 0.000 description 1
- 108010021062 Micafungin Proteins 0.000 description 1
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 description 1
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 description 1
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 description 1
- 108010050619 Monokines Proteins 0.000 description 1
- 102000013967 Monokines Human genes 0.000 description 1
- 241000204045 Mycoplasma hyopneumoniae Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- IJHNSHDBIRRJRN-UHFFFAOYSA-N N,N-dimethyl-3-phenyl-3-(2-pyridinyl)-1-propanamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=CC=C1 IJHNSHDBIRRJRN-UHFFFAOYSA-N 0.000 description 1
- IDBPHNDTYPBSNI-UHFFFAOYSA-N N-(1-(2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl)-4-(methoxymethyl)-4-piperidyl)propionanilide Chemical compound C1CN(CCN2C(N(CC)N=N2)=O)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 IDBPHNDTYPBSNI-UHFFFAOYSA-N 0.000 description 1
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 1
- SBKRTALNRRAOJP-BWSIXKJUSA-N N-[(2S)-4-amino-1-[[(2S,3R)-1-[[(2S)-4-amino-1-oxo-1-[[(3S,6S,9S,12S,15R,18R,21S)-6,9,18-tris(2-aminoethyl)-15-benzyl-3-[(1R)-1-hydroxyethyl]-12-(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-6-methylheptanamide (6S)-N-[(2S)-4-amino-1-[[(2S,3R)-1-[[(2S)-4-amino-1-oxo-1-[[(3S,6S,9S,12S,15R,18R,21S)-6,9,18-tris(2-aminoethyl)-15-benzyl-3-[(1R)-1-hydroxyethyl]-12-(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-6-methyloctanamide sulfuric acid Polymers OS(O)(=O)=O.CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@@H](NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H](CCN)NC1=O)[C@@H](C)O.CC[C@H](C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@@H](NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H](CCN)NC1=O)[C@@H](C)O SBKRTALNRRAOJP-BWSIXKJUSA-N 0.000 description 1
- RRHONYZEMUNMJX-UHFFFAOYSA-N N-[5-[[5-[(4-acetyl-1-piperazinyl)-oxomethyl]-4-methoxy-2-methylphenyl]thio]-2-thiazolyl]-4-[(3-methylbutan-2-ylamino)methyl]benzamide Chemical compound C1=C(C(=O)N2CCN(CC2)C(C)=O)C(OC)=CC(C)=C1SC(S1)=CN=C1NC(=O)C1=CC=C(CNC(C)C(C)C)C=C1 RRHONYZEMUNMJX-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 1
- 241000526636 Nipah henipavirus Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229940123134 Nitric oxide inhibitor Drugs 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- IMONTRJLAWHYGT-ZCPXKWAGSA-N Norethindrone Acetate Chemical compound C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@](C#C)(OC(=O)C)[C@@]1(C)CC2 IMONTRJLAWHYGT-ZCPXKWAGSA-N 0.000 description 1
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 229940121682 Osteoclast inhibitor Drugs 0.000 description 1
- 102000008108 Osteoprotegerin Human genes 0.000 description 1
- 108010035042 Osteoprotegerin Proteins 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- QSLJIVKCVHQPLV-PEMPUTJUSA-N Oxandrin Chemical compound C([C@@H]1CC2)C(=O)OC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@](C)(O)[C@@]2(C)CC1 QSLJIVKCVHQPLV-PEMPUTJUSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 1
- 239000004100 Oxytetracycline Substances 0.000 description 1
- 102400000050 Oxytocin Human genes 0.000 description 1
- 101800000989 Oxytocin Proteins 0.000 description 1
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 description 1
- 108091008606 PDGF receptors Proteins 0.000 description 1
- 102100033337 PDZ and LIM domain protein 7 Human genes 0.000 description 1
- FVJZSBGHRPJMMA-IOLBBIBUSA-N PG(18:0/18:0) Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-IOLBBIBUSA-N 0.000 description 1
- UOZODPSAJZTQNH-UHFFFAOYSA-N Paromomycin II Natural products NC1C(O)C(O)C(CN)OC1OC1C(O)C(OC2C(C(N)CC(N)C2O)OC2C(C(O)C(O)C(CO)O2)N)OC1CO UOZODPSAJZTQNH-UHFFFAOYSA-N 0.000 description 1
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 1
- 206010034238 Pelvic adhesions Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 239000004186 Penicillin G benzathine Substances 0.000 description 1
- 239000004107 Penicillin G sodium Substances 0.000 description 1
- 229930195708 Penicillin V Natural products 0.000 description 1
- 229940080774 Peroxisome proliferator-activated receptor gamma agonist Drugs 0.000 description 1
- RGCVKNLCSQQDEP-UHFFFAOYSA-N Perphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 RGCVKNLCSQQDEP-UHFFFAOYSA-N 0.000 description 1
- WLWFNJKHKGIJNW-UHFFFAOYSA-N Phensuximide Chemical compound O=C1N(C)C(=O)CC1C1=CC=CC=C1 WLWFNJKHKGIJNW-UHFFFAOYSA-N 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 1
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 1
- 229940120646 Platelet-derived growth factor receptor kinase inhibitor Drugs 0.000 description 1
- 229920001363 Polidocanol Polymers 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 1
- 229920000362 Polyethylene-block-poly(ethylene glycol) Polymers 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 108010093965 Polymyxin B Proteins 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- 229920002690 Polyoxyl 40 HydrogenatedCastorOil Polymers 0.000 description 1
- 229920002700 Polyoxyl 60 hydrogenated castor oil Polymers 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229920001219 Polysorbate 40 Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 229920002642 Polysorbate 65 Polymers 0.000 description 1
- 229920002651 Polysorbate 85 Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 241001135989 Porcine reproductive and respiratory syndrome virus Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- ZGUGWUXLJSTTMA-UHFFFAOYSA-N Promazinum Chemical compound C1=CC=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZGUGWUXLJSTTMA-UHFFFAOYSA-N 0.000 description 1
- KNAHARQHSZJURB-UHFFFAOYSA-N Propylthiouracile Chemical compound CCCC1=CC(=O)NC(=S)N1 KNAHARQHSZJURB-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 229940123924 Protein kinase C inhibitor Drugs 0.000 description 1
- 108010067787 Proteoglycans Proteins 0.000 description 1
- 102000016611 Proteoglycans Human genes 0.000 description 1
- WFAULHLDTDDABL-UHFFFAOYSA-N Proxazole citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(CC)C1=NOC(CCN(CC)CC)=N1 WFAULHLDTDDABL-UHFFFAOYSA-N 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- AQXXZDYPVDOQEE-MXDQRGINSA-N Pyrantel pamoate Chemical compound CN1CCCN=C1\C=C\C1=CC=CS1.C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 AQXXZDYPVDOQEE-MXDQRGINSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 229940123752 RNA synthesis inhibitor Drugs 0.000 description 1
- 102100023320 Ral guanine nucleotide dissociation stimulator Human genes 0.000 description 1
- 101001000212 Rattus norvegicus Decorin Proteins 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- 229940122756 Retinoic acid receptor antagonist Drugs 0.000 description 1
- 229930189077 Rifamycin Natural products 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- PPTYJKAXVCCBDU-UHFFFAOYSA-N Rohypnol Chemical compound N=1CC(=O)N(C)C2=CC=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1F PPTYJKAXVCCBDU-UHFFFAOYSA-N 0.000 description 1
- AUVVAXYIELKVAI-UHFFFAOYSA-N SJ000285215 Natural products N1CCC2=CC(OC)=C(OC)C=C2C1CC1CC2C3=CC(OC)=C(OC)C=C3CCN2CC1CC AUVVAXYIELKVAI-UHFFFAOYSA-N 0.000 description 1
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 1
- 208000009966 Sensorineural Hearing Loss Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920001304 Solutol HS 15 Polymers 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- LKAJKIOFIWVMDJ-IYRCEVNGSA-N Stanazolol Chemical compound C([C@@H]1CC[C@H]2[C@@H]3CC[C@@]([C@]3(CC[C@@H]2[C@@]1(C)C1)C)(O)C)C2=C1C=NN2 LKAJKIOFIWVMDJ-IYRCEVNGSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 206010066218 Stress Urinary Incontinence Diseases 0.000 description 1
- 102100037346 Substance-P receptor Human genes 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- PJSFRIWCGOHTNF-UHFFFAOYSA-N Sulphormetoxin Chemical compound COC1=NC=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1OC PJSFRIWCGOHTNF-UHFFFAOYSA-N 0.000 description 1
- HMHVCUVYZFYAJI-UHFFFAOYSA-N Sultiame Chemical compound C1=CC(S(=O)(=O)N)=CC=C1N1S(=O)(=O)CCCC1 HMHVCUVYZFYAJI-UHFFFAOYSA-N 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- SEQDDYPDSLOBDC-UHFFFAOYSA-N Temazepam Chemical compound N=1C(O)C(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 SEQDDYPDSLOBDC-UHFFFAOYSA-N 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- BGNXCDMCOKJUMV-UHFFFAOYSA-N Tert-Butylhydroquinone Chemical compound CC(C)(C)C1=CC(O)=CC=C1O BGNXCDMCOKJUMV-UHFFFAOYSA-N 0.000 description 1
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 1
- KLBQZWRITKRQQV-UHFFFAOYSA-N Thioridazine Chemical compound C12=CC(SC)=CC=C2SC2=CC=CC=C2N1CCC1CCCCN1C KLBQZWRITKRQQV-UHFFFAOYSA-N 0.000 description 1
- 108010036928 Thiorphan Proteins 0.000 description 1
- GFBKORZTTCHDGY-UWVJOHFNSA-N Thiothixene Chemical compound C12=CC(S(=O)(=O)N(C)C)=CC=C2SC2=CC=CC=C2\C1=C\CCN1CCN(C)CC1 GFBKORZTTCHDGY-UWVJOHFNSA-N 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical compound IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- 102000011923 Thyrotropin Human genes 0.000 description 1
- 108010061174 Thyrotropin Proteins 0.000 description 1
- 208000009205 Tinnitus Diseases 0.000 description 1
- YTGJWQPHMWSCST-UHFFFAOYSA-N Tiopronin Chemical compound CC(S)C(=O)NCC(O)=O YTGJWQPHMWSCST-UHFFFAOYSA-N 0.000 description 1
- 108010058907 Tiopronin Proteins 0.000 description 1
- 208000031737 Tissue Adhesions Diseases 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 108020004566 Transfer RNA Proteins 0.000 description 1
- 108010009583 Transforming Growth Factors Proteins 0.000 description 1
- 102000009618 Transforming Growth Factors Human genes 0.000 description 1
- FNYLWPVRPXGIIP-UHFFFAOYSA-N Triamterene Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=CC=C1 FNYLWPVRPXGIIP-UHFFFAOYSA-N 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- SLGBZMMZGDRARJ-UHFFFAOYSA-N Triphenylene Chemical group C1=CC=C2C3=CC=CC=C3C3=CC=CC=C3C2=C1 SLGBZMMZGDRARJ-UHFFFAOYSA-N 0.000 description 1
- 101000623262 Trypanosoma brucei brucei Uncharacterized 22 kDa protein in aldolase locus Proteins 0.000 description 1
- GUARTUJKFNAVIK-QPTWMBCESA-N Tulathromycin A Chemical compound C1[C@](OC)(C)[C@@](CNCCC)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](C)C(=O)O[C@H](CC)[C@@](C)(O)[C@H](O)[C@@H](C)NC[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C GUARTUJKFNAVIK-QPTWMBCESA-N 0.000 description 1
- 108010057266 Type A Botulinum Toxins Proteins 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 229940122435 VCAM-1 antagonist Drugs 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 108010034265 Vascular Endothelial Growth Factor Receptors Proteins 0.000 description 1
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 description 1
- 108010004977 Vasopressins Proteins 0.000 description 1
- 102000002852 Vasopressins Human genes 0.000 description 1
- 241000544286 Vibrio anguillarum Species 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 235000018936 Vitellaria paradoxa Nutrition 0.000 description 1
- 241001135917 Vitellaria paradoxa Species 0.000 description 1
- 108010031318 Vitronectin Proteins 0.000 description 1
- 102100035140 Vitronectin Human genes 0.000 description 1
- VOXIUXZAOFEFBL-UHFFFAOYSA-N Voacangin Natural products CCC1CC2CN3CC1C(C2)(OC(=O)C)c4[nH]c5ccc(OC)cc5c4C3 VOXIUXZAOFEFBL-UHFFFAOYSA-N 0.000 description 1
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 1
- 241001441550 Zeiformes Species 0.000 description 1
- JLPULHDHAOZNQI-JLOPVYAASA-N [(2r)-3-hexadecanoyloxy-2-[(9e,12e)-octadeca-9,12-dienoyl]oxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC JLPULHDHAOZNQI-JLOPVYAASA-N 0.000 description 1
- UFUVLHLTWXBHGZ-MGZQPHGTSA-N [(2r,3r,4s,5r,6r)-6-[(1s,2s)-2-chloro-1-[[(2s,4r)-1-methyl-4-propylpyrrolidine-2-carbonyl]amino]propyl]-4,5-dihydroxy-2-methylsulfanyloxan-3-yl] dihydrogen phosphate Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](OP(O)(O)=O)[C@@H](SC)O1 UFUVLHLTWXBHGZ-MGZQPHGTSA-N 0.000 description 1
- BSUQCLSFQSUNED-PPPRQHODSA-N [(2s,3r,4s,6r)-4-(dimethylamino)-2-[[(3r,4s,5s,6r,7r,9r,11r,12r,13s,14r)-14-ethyl-7,12,13-trihydroxy-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-oxacyclotetradec-6-yl]oxy]-6-methyloxan-3-yl] ethyl car Chemical compound O1[C@H](C)C[C@H](N(C)C)[C@@H](OC(=O)OCC)[C@@H]1O[C@H]1[C@@](O)(C)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@](C)(O)[C@@H](CC)OC(=O)[C@H](C)[C@@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(OC)C2)[C@@H]1C BSUQCLSFQSUNED-PPPRQHODSA-N 0.000 description 1
- ZSYULWHBPBAOKV-TXEJJXNPSA-N [(3ar,6as)-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl]-phenylmethanone Chemical compound C([C@H]1COC[C@H]1C1)N1C(=O)C1=CC=CC=C1 ZSYULWHBPBAOKV-TXEJJXNPSA-N 0.000 description 1
- JXWVQHSDWAODPY-HHJIKABBSA-N [(6s,8s,9s,10r,11s,13s,14s,17r)-6-fluoro-11-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-17-yl] pentanoate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@](C(=O)CO)(OC(=O)CCCC)[C@@]2(C)C[C@@H]1O JXWVQHSDWAODPY-HHJIKABBSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- MJDIWCQJUPYRAF-UHFFFAOYSA-N [1-[1-(dimethylamino)propan-2-yl]-2-phenylcyclohexyl] acetate;hydrochloride Chemical compound Cl.CN(C)CC(C)C1(OC(C)=O)CCCCC1C1=CC=CC=C1 MJDIWCQJUPYRAF-UHFFFAOYSA-N 0.000 description 1
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 description 1
- HVUMOYIDDBPOLL-XGKPLOKHSA-N [2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XGKPLOKHSA-N 0.000 description 1
- RACDDTQBAFEERP-PLTZVPCUSA-N [2-[(6s,8s,9s,10r,13s,14s,17r)-6-chloro-17-hydroxy-10,13-dimethyl-3,11-dioxo-6,7,8,9,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl]-2-oxoethyl] acetate Chemical compound C1([C@@H](Cl)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@](C(=O)COC(=O)C)(O)[C@@]2(C)CC1=O RACDDTQBAFEERP-PLTZVPCUSA-N 0.000 description 1
- LVBMFPUTQOHXQE-UHFFFAOYSA-N [2-[6-(diaminomethylideneamino)hexylamino]-2-oxoethyl] n-[4-(3-aminopropylamino)butyl]carbamate Chemical compound NCCCNCCCCNC(=O)OCC(=O)NCCCCCCN=C(N)N LVBMFPUTQOHXQE-UHFFFAOYSA-N 0.000 description 1
- HCAJCMUKLZSPFT-KWXKLSQISA-N [3-(dimethylamino)-2-[(9z,12z)-octadeca-9,12-dienoyl]oxypropyl] (9z,12z)-octadeca-9,12-dienoate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OCC(CN(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC HCAJCMUKLZSPFT-KWXKLSQISA-N 0.000 description 1
- NYDLOCKCVISJKK-WRBBJXAJSA-N [3-(dimethylamino)-2-[(z)-octadec-9-enoyl]oxypropyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(CN(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC NYDLOCKCVISJKK-WRBBJXAJSA-N 0.000 description 1
- HZEWFHLRYVTOIW-UHFFFAOYSA-N [Ti].[Ni] Chemical compound [Ti].[Ni] HZEWFHLRYVTOIW-UHFFFAOYSA-N 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000012084 abdominal surgery Methods 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- JDPAVWAQGBGGHD-UHFFFAOYSA-N aceanthrylene Chemical group C1=CC=C2C(C=CC3=CC=C4)=C3C4=CC2=C1 JDPAVWAQGBGGHD-UHFFFAOYSA-N 0.000 description 1
- 125000004054 acenaphthylenyl group Chemical group C1(=CC2=CC=CC3=CC=CC1=C23)* 0.000 description 1
- SQFPKRNUGBRTAR-UHFFFAOYSA-N acephenanthrylene Chemical group C1=CC(C=C2)=C3C2=CC2=CC=CC=C2C3=C1 SQFPKRNUGBRTAR-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- LYCYLGFSIXIXAB-NUZRHMIVSA-N acetic acid;(2s)-n-[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2r)-1-[[(2s)-1-[[(2s)-5-(diaminomethylideneamino)-1-[(2s)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1h-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(4-h Chemical compound CC(O)=O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CNC2=CC=CC=C12 LYCYLGFSIXIXAB-NUZRHMIVSA-N 0.000 description 1
- HXGDTGSAIMULJN-UHFFFAOYSA-N acetnaphthylene Chemical group C1=CC(C=C2)=C3C2=CC=CC3=C1 HXGDTGSAIMULJN-UHFFFAOYSA-N 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 210000001361 achilles tendon Anatomy 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 208000026231 acute otitis externa Diseases 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000002313 adhesive film Substances 0.000 description 1
- 239000000695 adrenergic alpha-agonist Substances 0.000 description 1
- 229960002669 albendazole Drugs 0.000 description 1
- HXHWSAZORRCQMX-UHFFFAOYSA-N albendazole Chemical compound CCCSC1=CC=C2NC(NC(=O)OC)=NC2=C1 HXHWSAZORRCQMX-UHFFFAOYSA-N 0.000 description 1
- 229960005142 alclofenac Drugs 0.000 description 1
- ARHWPKZXBHOEEE-UHFFFAOYSA-N alclofenac Chemical compound OC(=O)CC1=CC=C(OCC=C)C(Cl)=C1 ARHWPKZXBHOEEE-UHFFFAOYSA-N 0.000 description 1
- MUQUYTSLDVKIOF-CHJKCJHBSA-N alcuronium Chemical compound C/1([C@@H]23)=C\N([C@H]4\5)C6=CC=CC=C6[C@]4(CC[N@@+]4(CC=C)C\C6=C\CO)[C@@H]4C[C@@H]6C/5=C/N3C3=CC=CC=C3[C@@]22CC[N@@+]3(CC=C)C/C(=C/CO)[C@@H]\1C[C@H]32 MUQUYTSLDVKIOF-CHJKCJHBSA-N 0.000 description 1
- 229960004322 alcuronium Drugs 0.000 description 1
- 229960001391 alfentanil Drugs 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 229960002692 allylestrenol Drugs 0.000 description 1
- 229960004685 aloxiprin Drugs 0.000 description 1
- MANKSFVECICGLK-UHFFFAOYSA-K aloxiprin Chemical compound [OH-].[Al+3].CC(=O)OC1=CC=CC=C1C([O-])=O.CC(=O)OC1=CC=CC=C1C([O-])=O MANKSFVECICGLK-UHFFFAOYSA-K 0.000 description 1
- 229940061720 alpha hydroxy acid Drugs 0.000 description 1
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 1
- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 description 1
- FPQFYIAXQDXNOR-QDKLYSGJSA-N alpha-Zearalenol Chemical compound O=C1O[C@@H](C)CCC[C@H](O)CCC\C=C\C2=CC(O)=CC(O)=C21 FPQFYIAXQDXNOR-QDKLYSGJSA-N 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 229960004538 alprazolam Drugs 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 229960002213 alprenolol Drugs 0.000 description 1
- PAZJSJFMUHDSTF-UHFFFAOYSA-N alprenolol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1CC=C PAZJSJFMUHDSTF-UHFFFAOYSA-N 0.000 description 1
- DIZPMCHEQGEION-UHFFFAOYSA-H aluminium sulfate (anhydrous) Chemical compound [Al+3].[Al+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O DIZPMCHEQGEION-UHFFFAOYSA-H 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- 229960004821 amikacin Drugs 0.000 description 1
- 229960002576 amiloride Drugs 0.000 description 1
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 229960000212 aminophenazone Drugs 0.000 description 1
- 229960005260 amiodarone Drugs 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229960001301 amobarbital Drugs 0.000 description 1
- 229960003204 amorolfine Drugs 0.000 description 1
- 229940009444 amphotericin Drugs 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960003473 androstanolone Drugs 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 210000003423 ankle Anatomy 0.000 description 1
- 238000000137 annealing Methods 0.000 description 1
- 229940125709 anorectic agent Drugs 0.000 description 1
- 230000001539 anorectic effect Effects 0.000 description 1
- 230000000578 anorexic effect Effects 0.000 description 1
- 210000002159 anterior chamber Anatomy 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 229940125713 antianxiety drug Drugs 0.000 description 1
- 229940127090 anticoagulant agent Drugs 0.000 description 1
- 239000000504 antifibrinolytic agent Substances 0.000 description 1
- 229940006133 antiglaucoma drug and miotics carbonic anhydrase inhibitors Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940124433 antimigraine drug Drugs 0.000 description 1
- 229940005486 antimigraine preparations Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229940125687 antiparasitic agent Drugs 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000002830 appetite depressant Substances 0.000 description 1
- 229960002610 apraclonidine Drugs 0.000 description 1
- IEJXVRYNEISIKR-UHFFFAOYSA-N apraclonidine Chemical compound ClC1=CC(N)=CC(Cl)=C1NC1=NCCN1 IEJXVRYNEISIKR-UHFFFAOYSA-N 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 description 1
- 229960003856 argatroban Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 description 1
- 108010089975 arginyl-glycyl-aspartyl-serine Proteins 0.000 description 1
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- KNNXFYIMEYKHBZ-UHFFFAOYSA-N as-indacene Chemical group C1=CC2=CC=CC2=C2C=CC=C21 KNNXFYIMEYKHBZ-UHFFFAOYSA-N 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- GXDALQBWZGODGZ-UHFFFAOYSA-N astemizole Chemical compound C1=CC(OC)=CC=C1CCN1CCC(NC=2N(C3=CC=CC=C3N=2)CC=2C=CC(F)=CC=2)CC1 GXDALQBWZGODGZ-UHFFFAOYSA-N 0.000 description 1
- 229960002274 atenolol Drugs 0.000 description 1
- 229960001862 atracurium Drugs 0.000 description 1
- 229960001799 aurothioglucose Drugs 0.000 description 1
- 229960002379 avibactam Drugs 0.000 description 1
- NDCUAPJVLWFHHB-UHNVWZDZSA-N avibactam Chemical compound C1N2[C@H](C(N)=O)CC[C@@]1([H])N(OS(O)(=O)=O)C2=O NDCUAPJVLWFHHB-UHNVWZDZSA-N 0.000 description 1
- YEESUBCSWGVPCE-UHFFFAOYSA-N azanylidyneoxidanium iron(2+) pentacyanide Chemical compound [Fe++].[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.N#[O+] YEESUBCSWGVPCE-UHFFFAOYSA-N 0.000 description 1
- 229960001671 azapropazone Drugs 0.000 description 1
- WOIIIUDZSOLAIW-NSHDSACASA-N azapropazone Chemical compound C1=C(C)C=C2N3C(=O)[C@H](CC=C)C(=O)N3C(N(C)C)=NC2=C1 WOIIIUDZSOLAIW-NSHDSACASA-N 0.000 description 1
- 229960000383 azatadine Drugs 0.000 description 1
- SEBMTIQKRHYNIT-UHFFFAOYSA-N azatadine Chemical compound C1CN(C)CCC1=C1C2=NC=CC=C2CCC2=CC=CC=C21 SEBMTIQKRHYNIT-UHFFFAOYSA-N 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- JTWOMNBEOCYFNV-NFFDBFGFSA-N azlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCNC1=O JTWOMNBEOCYFNV-NFFDBFGFSA-N 0.000 description 1
- 229960003623 azlocillin Drugs 0.000 description 1
- 229960003644 aztreonam Drugs 0.000 description 1
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 description 1
- PFOLLRNADZZWEX-FFGRCDKISA-N bacampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)[C@H](C(S3)(C)C)C(=O)OC(C)OC(=O)OCC)=CC=CC=C1 PFOLLRNADZZWEX-FFGRCDKISA-N 0.000 description 1
- 229960002699 bacampicillin Drugs 0.000 description 1
- 229960000794 baclofen Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 229960003515 bendroflumethiazide Drugs 0.000 description 1
- HDWIHXWEUNVBIY-UHFFFAOYSA-N bendroflumethiazidum Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1=CC=CC=C1 HDWIHXWEUNVBIY-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- BNQDCRGUHNALGH-UHFFFAOYSA-N benserazide Chemical compound OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O BNQDCRGUHNALGH-UHFFFAOYSA-N 0.000 description 1
- 229960000911 benserazide Drugs 0.000 description 1
- 229960001716 benzalkonium Drugs 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- GIJXKZJWITVLHI-PMOLBWCYSA-N benzatropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(C=1C=CC=CC=1)C1=CC=CC=C1 GIJXKZJWITVLHI-PMOLBWCYSA-N 0.000 description 1
- 229960001081 benzatropine Drugs 0.000 description 1
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N benzo-alpha-pyrone Natural products C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 1
- WMUIZUWOEIQJEH-UHFFFAOYSA-N benzo[e][1,3]benzoxazole Chemical compound C1=CC=C2C(N=CO3)=C3C=CC2=C1 WMUIZUWOEIQJEH-UHFFFAOYSA-N 0.000 description 1
- FZICDBOJOMQACG-UHFFFAOYSA-N benzo[h]isoquinoline Chemical compound C1=NC=C2C3=CC=CC=C3C=CC2=C1 FZICDBOJOMQACG-UHFFFAOYSA-N 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- CYDRXTMLKJDRQH-UHFFFAOYSA-N benzododecinium Chemical compound CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 CYDRXTMLKJDRQH-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 229960001689 benzydamine hydrochloride Drugs 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- SOQJPQZCPBDOMF-YCUXZELOSA-N betamethasone benzoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(F)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@@H]1C)C(=O)CO)C(=O)C1=CC=CC=C1 SOQJPQZCPBDOMF-YCUXZELOSA-N 0.000 description 1
- 229960000870 betamethasone benzoate Drugs 0.000 description 1
- 229960004324 betaxolol Drugs 0.000 description 1
- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 229960002206 bifonazole Drugs 0.000 description 1
- 229960002470 bimatoprost Drugs 0.000 description 1
- AQOKCDNYWBIDND-FTOWTWDKSA-N bimatoprost Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-FTOWTWDKSA-N 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000033558 biomineral tissue development Effects 0.000 description 1
- YSXKPIUOCJLQIE-UHFFFAOYSA-N biperiden Chemical compound C1C(C=C2)CC2C1C(C=1C=CC=CC=1)(O)CCN1CCCCC1 YSXKPIUOCJLQIE-UHFFFAOYSA-N 0.000 description 1
- 229960003003 biperiden Drugs 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 150000004663 bisphosphonates Chemical class 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 229940019700 blood coagulation factors Drugs 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 229960002645 boric acid Drugs 0.000 description 1
- 229940089093 botox Drugs 0.000 description 1
- 229940053031 botulinum toxin Drugs 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 229960003679 brimonidine Drugs 0.000 description 1
- HCRKCZRJWPKOAR-JTQLQIEISA-N brinzolamide Chemical compound CCN[C@H]1CN(CCCOC)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 HCRKCZRJWPKOAR-JTQLQIEISA-N 0.000 description 1
- 229960000722 brinzolamide Drugs 0.000 description 1
- 229960002729 bromazepam Drugs 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- 229960002802 bromocriptine Drugs 0.000 description 1
- ZDIGNSYAACHWNL-UHFFFAOYSA-N brompheniramine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Br)C=C1 ZDIGNSYAACHWNL-UHFFFAOYSA-N 0.000 description 1
- 229960000725 brompheniramine Drugs 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 description 1
- 229960004064 bumetanide Drugs 0.000 description 1
- 229960000330 bupranolol Drugs 0.000 description 1
- HQIRNZOQPUAHHV-UHFFFAOYSA-N bupranolol Chemical compound CC1=CC=C(Cl)C(OCC(O)CNC(C)(C)C)=C1 HQIRNZOQPUAHHV-UHFFFAOYSA-N 0.000 description 1
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 1
- 229960001736 buprenorphine Drugs 0.000 description 1
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 description 1
- 229960001058 bupropion Drugs 0.000 description 1
- 229960003874 butobarbital Drugs 0.000 description 1
- STDBAQMTJLUMFW-UHFFFAOYSA-N butobarbital Chemical compound CCCCC1(CC)C(=O)NC(=O)NC1=O STDBAQMTJLUMFW-UHFFFAOYSA-N 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 229940067596 butylparaben Drugs 0.000 description 1
- FFSAXUULYPJSKH-UHFFFAOYSA-N butyrophenone Chemical compound CCCC(=O)C1=CC=CC=C1 FFSAXUULYPJSKH-UHFFFAOYSA-N 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 229960005084 calcitriol Drugs 0.000 description 1
- 235000020964 calcitriol Nutrition 0.000 description 1
- 239000011612 calcitriol Substances 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 235000010410 calcium alginate Nutrition 0.000 description 1
- 239000000648 calcium alginate Substances 0.000 description 1
- 229960002681 calcium alginate Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001175 calcium sulphate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229960002504 capsaicin Drugs 0.000 description 1
- 235000017663 capsaicin Nutrition 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 description 1
- 229960003669 carbenicillin Drugs 0.000 description 1
- QTAOMKOIBXZKND-PPHPATTJSA-N carbidopa Chemical compound O.NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 QTAOMKOIBXZKND-PPHPATTJSA-N 0.000 description 1
- 229960004205 carbidopa Drugs 0.000 description 1
- CFOYWRHIYXMDOT-UHFFFAOYSA-N carbimazole Chemical compound CCOC(=O)N1C=CN(C)C1=S CFOYWRHIYXMDOT-UHFFFAOYSA-N 0.000 description 1
- 229960001704 carbimazole Drugs 0.000 description 1
- VPKDCDLSJZCGKE-UHFFFAOYSA-N carbodiimide group Chemical group N=C=N VPKDCDLSJZCGKE-UHFFFAOYSA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- IVUMCTKHWDRRMH-UHFFFAOYSA-N carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 description 1
- 229960003184 carprofen Drugs 0.000 description 1
- 229960001222 carteolol Drugs 0.000 description 1
- LWAFSWPYPHEXKX-UHFFFAOYSA-N carteolol Chemical compound N1C(=O)CCC2=C1C=CC=C2OCC(O)CNC(C)(C)C LWAFSWPYPHEXKX-UHFFFAOYSA-N 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 229960005361 cefaclor Drugs 0.000 description 1
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 1
- 229960004841 cefadroxil Drugs 0.000 description 1
- NBFNMSULHIODTC-CYJZLJNKSA-N cefadroxil monohydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=C(O)C=C1 NBFNMSULHIODTC-CYJZLJNKSA-N 0.000 description 1
- 229960000603 cefalotin Drugs 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 1
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 description 1
- 229960003719 cefdinir Drugs 0.000 description 1
- LRAJHPGSGBRUJN-OMIVUECESA-N cefepime hydrochloride Chemical compound O.Cl.[Cl-].S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 LRAJHPGSGBRUJN-OMIVUECESA-N 0.000 description 1
- 229960000927 cefepime hydrochloride Drugs 0.000 description 1
- 229960002417 cefoperazone sodium Drugs 0.000 description 1
- 229960001846 cefovecin sodium Drugs 0.000 description 1
- 229960004828 ceftaroline fosamil Drugs 0.000 description 1
- KRWPPVCZNGQQHZ-IINIBMQSSA-N ceftaroline fosamil acetate monohydrate Chemical compound O.CC(O)=O.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OCC)C=2N=C(NP(O)(O)=O)SN=2)CC=1SC(SC=1)=NC=1C1=CC=[N+](C)C=C1 KRWPPVCZNGQQHZ-IINIBMQSSA-N 0.000 description 1
- 229960002940 ceftazidime sodium Drugs 0.000 description 1
- JEEWDSDYUSEQML-ROMZVAKDSA-M ceftazidime sodium Chemical compound [Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C([O-])=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 JEEWDSDYUSEQML-ROMZVAKDSA-M 0.000 description 1
- UNJFKXSSGBWRBZ-BJCIPQKHSA-N ceftibuten Chemical compound S1C(N)=NC(C(=C\CC(O)=O)\C(=O)N[C@@H]2C(N3C(=CCS[C@@H]32)C(O)=O)=O)=C1 UNJFKXSSGBWRBZ-BJCIPQKHSA-N 0.000 description 1
- 229960004086 ceftibuten Drugs 0.000 description 1
- 229960005229 ceftiofur Drugs 0.000 description 1
- ZBHXIWJRIFEVQY-IHMPYVIRSA-N ceftiofur Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC(=O)C1=CC=CO1 ZBHXIWJRIFEVQY-IHMPYVIRSA-N 0.000 description 1
- 229960004755 ceftriaxone Drugs 0.000 description 1
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 description 1
- 229960001668 cefuroxime Drugs 0.000 description 1
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229940083181 centrally acting adntiadrenergic agent methyldopa Drugs 0.000 description 1
- VUFGUVLLDPOSBC-XRZFDKQNSA-M cephalothin sodium Chemical compound [Na+].N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C([O-])=O)C(=O)CC1=CC=CS1 VUFGUVLLDPOSBC-XRZFDKQNSA-M 0.000 description 1
- 229960001803 cetirizine Drugs 0.000 description 1
- 229960002798 cetrimide Drugs 0.000 description 1
- 229960000800 cetrimonium bromide Drugs 0.000 description 1
- 108700008462 cetrorelix Proteins 0.000 description 1
- 229960001865 cetrorelix acetate Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 1
- NFCRBQADEGXVDL-UHFFFAOYSA-M cetylpyridinium chloride monohydrate Chemical compound O.[Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 NFCRBQADEGXVDL-UHFFFAOYSA-M 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- JQXXHWHPUNPDRT-YOPQJBRCSA-N chembl1332716 Chemical compound O([C@](C1=O)(C)O\C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)/C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CCN(C)CC1 JQXXHWHPUNPDRT-YOPQJBRCSA-N 0.000 description 1
- VQIGDTLRBSNOBV-VQIYXBGXSA-N chembl2105739 Chemical compound OC(=O)\C=C/C(O)=O.C1C[C@@H](CS(=O)(=O)NC)CC[C@@H]1N(C)C1=NC=NC2=C1C=CN2 VQIGDTLRBSNOBV-VQIYXBGXSA-N 0.000 description 1
- GJPGCACMCURAKH-YQCFNCLSSA-L chembl2364574 Chemical compound [Ca+2].O=C1C2=C([O-])C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O.O=C1C2=C([O-])C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O GJPGCACMCURAKH-YQCFNCLSSA-L 0.000 description 1
- XMEVHPAGJVLHIG-FMZCEJRJSA-N chembl454950 Chemical compound [Cl-].C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H]([NH+](C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O XMEVHPAGJVLHIG-FMZCEJRJSA-N 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000002559 chemokine receptor antagonist Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 229960004831 chlorcyclizine Drugs 0.000 description 1
- 229960004782 chlordiazepoxide Drugs 0.000 description 1
- ANTSCNMPPGJYLG-UHFFFAOYSA-N chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 description 1
- 229960003260 chlorhexidine Drugs 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 229960002242 chlorocresol Drugs 0.000 description 1
- NPSLCOWKFFNQKK-ZPSUVKRCSA-N chloroprednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3C[C@H](Cl)C2=C1 NPSLCOWKFFNQKK-ZPSUVKRCSA-N 0.000 description 1
- 229950006229 chloroprednisone Drugs 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- CYDMQBQPVICBEU-UHFFFAOYSA-N chlorotetracycline Natural products C1=CC(Cl)=C2C(O)(C)C3CC4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-UHFFFAOYSA-N 0.000 description 1
- 229960002155 chlorothiazide Drugs 0.000 description 1
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- 229960001761 chlorpropamide Drugs 0.000 description 1
- 229960001523 chlortalidone Drugs 0.000 description 1
- 229960004475 chlortetracycline Drugs 0.000 description 1
- CYDMQBQPVICBEU-XRNKAMNCSA-N chlortetracycline Chemical compound C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-XRNKAMNCSA-N 0.000 description 1
- 235000019365 chlortetracycline Nutrition 0.000 description 1
- 150000001841 cholesterols Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- GRWVQDDAKZFPFI-UHFFFAOYSA-H chromium(III) sulfate Chemical compound [Cr+3].[Cr+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O GRWVQDDAKZFPFI-UHFFFAOYSA-H 0.000 description 1
- HHHKFGXWKKUNCY-FHWLQOOXSA-N cilazapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N2[C@@H](CCCN2CCC1)C(O)=O)=O)CC1=CC=CC=C1 HHHKFGXWKKUNCY-FHWLQOOXSA-N 0.000 description 1
- 229960005025 cilazapril Drugs 0.000 description 1
- 229960002468 cinchophen Drugs 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 229960004621 cinoxacin Drugs 0.000 description 1
- VDUWPHTZYNWKRN-UHFFFAOYSA-N cinoxacin Chemical compound C1=C2N(CC)N=C(C(O)=O)C(=O)C2=CC2=C1OCO2 VDUWPHTZYNWKRN-UHFFFAOYSA-N 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 229960001653 citalopram Drugs 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 229940090805 clavulanate Drugs 0.000 description 1
- 229960003324 clavulanic acid Drugs 0.000 description 1
- 229960001791 clebopride Drugs 0.000 description 1
- YNNUSGIPVFPVBX-NHCUHLMSSA-N clemastine Chemical compound CN1CCC[C@@H]1CCO[C@@](C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 YNNUSGIPVFPVBX-NHCUHLMSSA-N 0.000 description 1
- 229960002881 clemastine Drugs 0.000 description 1
- 229960001200 clindamycin hydrochloride Drugs 0.000 description 1
- 229960000792 clindamycin palmitate hydrochloride Drugs 0.000 description 1
- 229960002291 clindamycin phosphate Drugs 0.000 description 1
- 229960001403 clobazam Drugs 0.000 description 1
- CXOXHMZGEKVPMT-UHFFFAOYSA-N clobazam Chemical compound O=C1CC(=O)N(C)C2=CC=C(Cl)C=C2N1C1=CC=CC=C1 CXOXHMZGEKVPMT-UHFFFAOYSA-N 0.000 description 1
- 229960004287 clofazimine Drugs 0.000 description 1
- WDQPAMHFFCXSNU-BGABXYSRSA-N clofazimine Chemical compound C12=CC=CC=C2N=C2C=C(NC=3C=CC(Cl)=CC=3)C(=N/C(C)C)/C=C2N1C1=CC=C(Cl)C=C1 WDQPAMHFFCXSNU-BGABXYSRSA-N 0.000 description 1
- 229960004414 clomethiazole Drugs 0.000 description 1
- 229960004606 clomipramine Drugs 0.000 description 1
- 229960003120 clonazepam Drugs 0.000 description 1
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 229960001209 clonixin Drugs 0.000 description 1
- CLOMYZFHNHFSIQ-UHFFFAOYSA-N clonixin Chemical compound CC1=C(Cl)C=CC=C1NC1=NC=CC=C1C(O)=O CLOMYZFHNHFSIQ-UHFFFAOYSA-N 0.000 description 1
- 229960004362 clorazepate Drugs 0.000 description 1
- XDDJGVMJFWAHJX-UHFFFAOYSA-N clorazepic acid Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(C(=O)O)N=C1C1=CC=CC=C1 XDDJGVMJFWAHJX-UHFFFAOYSA-N 0.000 description 1
- 229960002039 clostebol acetate Drugs 0.000 description 1
- 229960004022 clotrimazole Drugs 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 229960003326 cloxacillin Drugs 0.000 description 1
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 description 1
- 229940047766 co-trimoxazole Drugs 0.000 description 1
- MRUAUOIMASANKQ-UHFFFAOYSA-N cocamidopropyl betaine Chemical compound CCCCCCCCCCCC(=O)NCCC[N+](C)(C)CC([O-])=O MRUAUOIMASANKQ-UHFFFAOYSA-N 0.000 description 1
- 229940073507 cocamidopropyl betaine Drugs 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 1
- XDJYMJULXQKGMM-RVYUQJQSSA-N colistin A Chemical compound CC[C@@H](C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O XDJYMJULXQKGMM-RVYUQJQSSA-N 0.000 description 1
- 229940047120 colony stimulating factors Drugs 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 229960000258 corticotropin Drugs 0.000 description 1
- 229960003290 cortisone acetate Drugs 0.000 description 1
- 229960003840 cortivazol Drugs 0.000 description 1
- RKHQGWMMUURILY-UHRZLXHJSA-N cortivazol Chemical compound C([C@H]1[C@@H]2C[C@H]([C@]([C@@]2(C)C[C@H](O)[C@@H]1[C@@]1(C)C2)(O)C(=O)COC(C)=O)C)=C(C)C1=CC1=C2C=NN1C1=CC=CC=C1 RKHQGWMMUURILY-UHRZLXHJSA-N 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 150000004775 coumarins Chemical class 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 229960000729 cyclandelate Drugs 0.000 description 1
- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 description 1
- UVKZSORBKUEBAZ-UHFFFAOYSA-N cyclizine Chemical compound C1CN(C)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 UVKZSORBKUEBAZ-UHFFFAOYSA-N 0.000 description 1
- 229960003564 cyclizine Drugs 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 229960000500 cyclobenzaprine hydrochloride Drugs 0.000 description 1
- VXEAYBOGHINOKW-UHFFFAOYSA-N cyclobenzaprine hydrochloride Chemical compound Cl.C1=CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 VXEAYBOGHINOKW-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- CMKBCTPCXZNQKX-UHFFFAOYSA-N cyclohexanethiol Chemical compound SC1CCCCC1 CMKBCTPCXZNQKX-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 229960003206 cyclopenthiazide Drugs 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- JJCFRYNCJDLXIK-UHFFFAOYSA-N cyproheptadine Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2C=CC2=CC=CC=C21 JJCFRYNCJDLXIK-UHFFFAOYSA-N 0.000 description 1
- 229960001140 cyproheptadine Drugs 0.000 description 1
- 229960000978 cyproterone acetate Drugs 0.000 description 1
- UWFYSQMTEOIJJG-FDTZYFLXSA-N cyproterone acetate Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 UWFYSQMTEOIJJG-FDTZYFLXSA-N 0.000 description 1
- 229960002433 cysteine Drugs 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical class O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 229960002321 dalbavancin hydrochloride Drugs 0.000 description 1
- 229960002615 dalfopristin Drugs 0.000 description 1
- SUYRLXYYZQTJHF-VMBLUXKRSA-N dalfopristin Chemical compound O=C([C@@H]1N(C2=O)CC[C@H]1S(=O)(=O)CCN(CC)CC)O[C@H](C(C)C)[C@H](C)\C=C\C(=O)NC\C=C\C(\C)=C\[C@@H](O)CC(=O)CC1=NC2=CO1 SUYRLXYYZQTJHF-VMBLUXKRSA-N 0.000 description 1
- 108700028430 dalfopristin Proteins 0.000 description 1
- 229960004969 dalteparin Drugs 0.000 description 1
- POZRVZJJTULAOH-LHZXLZLDSA-N danazol Chemical compound C1[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=CC2=C1C=NO2 POZRVZJJTULAOH-LHZXLZLDSA-N 0.000 description 1
- 229960000766 danazol Drugs 0.000 description 1
- 229960001987 dantrolene Drugs 0.000 description 1
- 229960000860 dapsone Drugs 0.000 description 1
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical compound C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 description 1
- 229960005484 daptomycin Drugs 0.000 description 1
- JWPGJSVJDAJRLW-UHFFFAOYSA-N debrisoquin Chemical compound C1=CC=C2CN(C(=N)N)CCC2=C1 JWPGJSVJDAJRLW-UHFFFAOYSA-N 0.000 description 1
- 229960004096 debrisoquine Drugs 0.000 description 1
- 125000004855 decalinyl group Chemical group C1(CCCC2CCCCC12)* 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- WOQQAWHSKSSAGF-WXFJLFHKSA-N decyl beta-D-maltopyranoside Chemical compound O[C@@H]1[C@@H](O)[C@H](OCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 WOQQAWHSKSSAGF-WXFJLFHKSA-N 0.000 description 1
- JDRSMPFHFNXQRB-IBEHDNSVSA-N decyl glucoside Chemical compound CCCCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O JDRSMPFHFNXQRB-IBEHDNSVSA-N 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 1
- 229960002398 demeclocycline Drugs 0.000 description 1
- 229960005104 demeclocycline hydrochloride Drugs 0.000 description 1
- 229960005052 demecolcine Drugs 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 229950004709 descinolone Drugs 0.000 description 1
- 238000000586 desensitisation Methods 0.000 description 1
- 229960003914 desipramine Drugs 0.000 description 1
- 108700025485 deslorelin Proteins 0.000 description 1
- 229960004165 deslorelin acetate Drugs 0.000 description 1
- 229960004281 desmopressin Drugs 0.000 description 1
- NFLWUMRGJYTJIN-NXBWRCJVSA-N desmopressin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSCCC(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(N)=O)=O)CCC(=O)N)C1=CC=CC=C1 NFLWUMRGJYTJIN-NXBWRCJVSA-N 0.000 description 1
- 229960002593 desoximetasone Drugs 0.000 description 1
- VWVSBHGCDBMOOT-IIEHVVJPSA-N desoximetasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@H](C(=O)CO)[C@@]1(C)C[C@@H]2O VWVSBHGCDBMOOT-IIEHVVJPSA-N 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- SOYKEARSMXGVTM-HNNXBMFYSA-N dexchlorpheniramine Chemical compound C1([C@H](CCN(C)C)C=2N=CC=CC=2)=CC=C(Cl)C=C1 SOYKEARSMXGVTM-HNNXBMFYSA-N 0.000 description 1
- 229960001882 dexchlorpheniramine Drugs 0.000 description 1
- VPNGEIHDPSLNMU-MERQFXBCSA-N dexmedetomidine hydrochloride Chemical compound Cl.C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CNC=N1 VPNGEIHDPSLNMU-MERQFXBCSA-N 0.000 description 1
- 229960002746 dexmedetomidine hydrochloride Drugs 0.000 description 1
- 229960002086 dextran Drugs 0.000 description 1
- 229960001985 dextromethorphan Drugs 0.000 description 1
- INUNXTSAACVKJS-OAQYLSRUSA-N dextromoramide Chemical compound C([C@@H](C)C(C(=O)N1CCCC1)(C=1C=CC=CC=1)C=1C=CC=CC=1)N1CCOCC1 INUNXTSAACVKJS-OAQYLSRUSA-N 0.000 description 1
- 229960003701 dextromoramide Drugs 0.000 description 1
- 229960004193 dextropropoxyphene Drugs 0.000 description 1
- QMQBBUPJKANITL-MYXGOWFTSA-N dextropropoxyphene hydrochloride Chemical compound [H+].[Cl-].C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 QMQBBUPJKANITL-MYXGOWFTSA-N 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 229960004042 diazoxide Drugs 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- YFAGHNZHGGCZAX-JKIFEVAISA-N dicloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(Cl)C=CC=C1Cl YFAGHNZHGGCZAX-JKIFEVAISA-N 0.000 description 1
- 229960001585 dicloxacillin Drugs 0.000 description 1
- DOBMPNYZJYQDGZ-UHFFFAOYSA-N dicoumarol Chemical compound C1=CC=CC2=C1OC(=O)C(CC=1C(OC3=CC=CC=C3C=1O)=O)=C2O DOBMPNYZJYQDGZ-UHFFFAOYSA-N 0.000 description 1
- 229960001912 dicoumarol Drugs 0.000 description 1
- 229960002656 didanosine Drugs 0.000 description 1
- UMGXUWVIJIQANV-UHFFFAOYSA-M didecyl(dimethyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCC[N+](C)(C)CCCCCCCCCC UMGXUWVIJIQANV-UHFFFAOYSA-M 0.000 description 1
- 229960003839 dienestrol Drugs 0.000 description 1
- NFDFQCUYFHCNBW-SCGPFSFSSA-N dienestrol Chemical compound C=1C=C(O)C=CC=1\C(=C/C)\C(=C\C)\C1=CC=C(O)C=C1 NFDFQCUYFHCNBW-SCGPFSFSSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229960003974 diethylcarbamazine Drugs 0.000 description 1
- RCKMWOKWVGPNJF-UHFFFAOYSA-N diethylcarbamazine Chemical compound CCN(CC)C(=O)N1CCN(C)CC1 RCKMWOKWVGPNJF-UHFFFAOYSA-N 0.000 description 1
- XXEPPPIWZFICOJ-UHFFFAOYSA-N diethylpropion Chemical compound CCN(CC)C(C)C(=O)C1=CC=CC=C1 XXEPPPIWZFICOJ-UHFFFAOYSA-N 0.000 description 1
- 229960004890 diethylpropion Drugs 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 229960000452 diethylstilbestrol Drugs 0.000 description 1
- 229960000616 diflunisal Drugs 0.000 description 1
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 description 1
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 1
- 229960005156 digoxin Drugs 0.000 description 1
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 1
- 229960000920 dihydrocodeine Drugs 0.000 description 1
- RBOXVHNMENFORY-DNJOTXNNSA-N dihydrocodeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC RBOXVHNMENFORY-DNJOTXNNSA-N 0.000 description 1
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 description 1
- HESHRHUZIWVEAJ-JGRZULCMSA-N dihydroergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2[C@@H](C3=CC=CC4=NC=C([C]34)C2)C1)C)C1=CC=CC=C1 HESHRHUZIWVEAJ-JGRZULCMSA-N 0.000 description 1
- 229960004704 dihydroergotamine Drugs 0.000 description 1
- ILYCWAKSDCYMBB-OPCMSESCSA-N dihydrotachysterol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1/C[C@@H](O)CC[C@@H]1C ILYCWAKSDCYMBB-OPCMSESCSA-N 0.000 description 1
- 229960000465 dihydrotachysterol Drugs 0.000 description 1
- 229960000691 diiodohydroxyquinoline Drugs 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- GAVBHVRHVQMWEI-UHFFFAOYSA-N dimefadane Chemical compound C12=CC=CC=C2C(N(C)C)CC1C1=CC=CC=C1 GAVBHVRHVQMWEI-UHFFFAOYSA-N 0.000 description 1
- 229950010893 dimefadane Drugs 0.000 description 1
- MZDOIJOUFRQXHC-UHFFFAOYSA-N dimenhydrinate Chemical compound O=C1N(C)C(=O)N(C)C2=NC(Cl)=N[C]21.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 MZDOIJOUFRQXHC-UHFFFAOYSA-N 0.000 description 1
- 229960004993 dimenhydrinate Drugs 0.000 description 1
- 229940008099 dimethicone Drugs 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- REZZEXDLIUJMMS-UHFFFAOYSA-M dimethyldioctadecylammonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC REZZEXDLIUJMMS-UHFFFAOYSA-M 0.000 description 1
- 229960005160 dimyristoylphosphatidylglycerol Drugs 0.000 description 1
- 229960001342 dinoprost Drugs 0.000 description 1
- PKPOVTYZGGYDIJ-UHFFFAOYSA-N dioctyl carbonate Chemical compound CCCCCCCCOC(=O)OCCCCCCCC PKPOVTYZGGYDIJ-UHFFFAOYSA-N 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- HYPPXZBJBPSRLK-UHFFFAOYSA-N diphenoxylate Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 HYPPXZBJBPSRLK-UHFFFAOYSA-N 0.000 description 1
- 229960004192 diphenoxylate Drugs 0.000 description 1
- 229940035422 diphenylamine Drugs 0.000 description 1
- OWQUZNMMYNAXSL-UHFFFAOYSA-N diphenylpyraline Chemical compound C1CN(C)CCC1OC(C=1C=CC=CC=1)C1=CC=CC=C1 OWQUZNMMYNAXSL-UHFFFAOYSA-N 0.000 description 1
- 229960000879 diphenylpyraline Drugs 0.000 description 1
- 229960003983 diphtheria toxoid Drugs 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- VXIHRIQNJCRFQX-UHFFFAOYSA-K disodium aurothiomalate Chemical compound [Na+].[Na+].[O-]C(=O)CC(S[Au])C([O-])=O VXIHRIQNJCRFQX-UHFFFAOYSA-K 0.000 description 1
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- KMVRATCHVMUJHM-SHZCTIMHSA-L disodium;(4r,5s,6s)-3-[(3s,5s)-5-[(3-carboxylatophenyl)carbamoyl]pyrrolidin-3-yl]sulfanyl-6-[(1r)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Chemical compound [Na+].[Na+].O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C([O-])=O)=O)[C@H](O)C)NC1=CC=CC(C([O-])=O)=C1 KMVRATCHVMUJHM-SHZCTIMHSA-L 0.000 description 1
- UVTNFZQICZKOEM-UHFFFAOYSA-N disopyramide Chemical compound C=1C=CC=NC=1C(C(N)=O)(CCN(C(C)C)C(C)C)C1=CC=CC=C1 UVTNFZQICZKOEM-UHFFFAOYSA-N 0.000 description 1
- 229960001066 disopyramide Drugs 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- FVJZSBGHRPJMMA-UHFFFAOYSA-N distearoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-UHFFFAOYSA-N 0.000 description 1
- HKNRNTYTYUWGLN-UHFFFAOYSA-N dithieno[3,2-a:2',3'-d]thiophene Chemical compound C1=CSC2=C1SC1=C2C=CS1 HKNRNTYTYUWGLN-UHFFFAOYSA-N 0.000 description 1
- VHJLVAABSRFDPM-ZXZARUISSA-N dithioerythritol Chemical compound SC[C@H](O)[C@H](O)CS VHJLVAABSRFDPM-ZXZARUISSA-N 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960001089 dobutamine Drugs 0.000 description 1
- NOPFSRXAKWQILS-UHFFFAOYSA-N docosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCO NOPFSRXAKWQILS-UHFFFAOYSA-N 0.000 description 1
- FGXWKSZFVQUSTL-UHFFFAOYSA-N domperidone Chemical compound C12=CC=CC=C2NC(=O)N1CCCN(CC1)CCC1N1C2=CC=C(Cl)C=C2NC1=O FGXWKSZFVQUSTL-UHFFFAOYSA-N 0.000 description 1
- 229960001253 domperidone Drugs 0.000 description 1
- 229960000895 doripenem Drugs 0.000 description 1
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 description 1
- IAVUPMFITXYVAF-XPUUQOCRSA-N dorzolamide Chemical compound CCN[C@H]1C[C@H](C)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 IAVUPMFITXYVAF-XPUUQOCRSA-N 0.000 description 1
- 229960003933 dorzolamide Drugs 0.000 description 1
- 229960001393 dosulepin Drugs 0.000 description 1
- 229960005426 doxepin Drugs 0.000 description 1
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229960003788 doxycycline calcium Drugs 0.000 description 1
- 229960001172 doxycycline hyclate Drugs 0.000 description 1
- 229960004434 doxycycline monohydrate Drugs 0.000 description 1
- HCFDWZZGGLSKEP-UHFFFAOYSA-N doxylamine Chemical compound C=1C=CC=NC=1C(C)(OCCN(C)C)C1=CC=CC=C1 HCFDWZZGGLSKEP-UHFFFAOYSA-N 0.000 description 1
- 229960005178 doxylamine Drugs 0.000 description 1
- RMEDXOLNCUSCGS-UHFFFAOYSA-N droperidol Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CC=C(N2C(NC3=CC=CC=C32)=O)CC1 RMEDXOLNCUSCGS-UHFFFAOYSA-N 0.000 description 1
- 229960000394 droperidol Drugs 0.000 description 1
- 229950005101 drostanolone Drugs 0.000 description 1
- 229940072185 drug for treatment of tuberculosis Drugs 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 229960003913 econazole Drugs 0.000 description 1
- 239000003602 elastase inhibitor Substances 0.000 description 1
- 210000001513 elbow Anatomy 0.000 description 1
- AUVVAXYIELKVAI-CKBKHPSWSA-N emetine Chemical compound N1CCC2=CC(OC)=C(OC)C=C2[C@H]1C[C@H]1C[C@H]2C3=CC(OC)=C(OC)C=C3CCN2C[C@@H]1CC AUVVAXYIELKVAI-CKBKHPSWSA-N 0.000 description 1
- 229960002694 emetine Drugs 0.000 description 1
- AUVVAXYIELKVAI-UWBTVBNJSA-N emetine Natural products N1CCC2=CC(OC)=C(OC)C=C2[C@H]1C[C@H]1C[C@H]2C3=CC(OC)=C(OC)C=C3CCN2C[C@H]1CC AUVVAXYIELKVAI-UWBTVBNJSA-N 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000002792 enkephalinase inhibitor Substances 0.000 description 1
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 description 1
- 229960002549 enoxacin Drugs 0.000 description 1
- 229950007315 epiestriol Drugs 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 229950002973 epitiostanol Drugs 0.000 description 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- 229960004468 eptifibatide Drugs 0.000 description 1
- GLGOPUHVAZCPRB-LROMGURASA-N eptifibatide Chemical compound N1C(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCCNC(=N)N)NC(=O)CCSSC[C@@H](C(N)=O)NC(=O)[C@@H]2CCCN2C(=O)[C@@H]1CC1=CN=C2[C]1C=CC=C2 GLGOPUHVAZCPRB-LROMGURASA-N 0.000 description 1
- 229960001405 ergometrine Drugs 0.000 description 1
- 229960005450 eritrityl tetranitrate Drugs 0.000 description 1
- 229960002818 ertapenem sodium Drugs 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- SNFOERUNNSHUGP-ZXZARUISSA-N erythrityl tetranitrate Chemical compound [O-][N+](=O)OC[C@@H](O[N+]([O-])=O)[C@@H](O[N+]([O-])=O)CO[N+]([O-])=O SNFOERUNNSHUGP-ZXZARUISSA-N 0.000 description 1
- 229960003203 erythromycin estolate Drugs 0.000 description 1
- AWMFUEJKWXESNL-JZBHMOKNSA-N erythromycin estolate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O.O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)OC(=O)CC)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AWMFUEJKWXESNL-JZBHMOKNSA-N 0.000 description 1
- 229960004142 erythromycin stearate Drugs 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- PROQIPRRNZUXQM-ZXXIGWHRSA-N estriol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 229960003399 estrone Drugs 0.000 description 1
- 229940081345 estropipate Drugs 0.000 description 1
- HZEQBCVBILBTEP-ZFINNJDLSA-N estropipate Chemical compound C1CNCCN1.OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 HZEQBCVBILBTEP-ZFINNJDLSA-N 0.000 description 1
- 229960003199 etacrynic acid Drugs 0.000 description 1
- AVOLMBLBETYQHX-UHFFFAOYSA-N etacrynic acid Chemical compound CCC(=C)C(=O)C1=CC=C(OCC(O)=O)C(Cl)=C1Cl AVOLMBLBETYQHX-UHFFFAOYSA-N 0.000 description 1
- 229960000285 ethambutol Drugs 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- 229960002767 ethosuximide Drugs 0.000 description 1
- HAPOVYFOVVWLRS-UHFFFAOYSA-N ethosuximide Chemical compound CCC1(C)CC(=O)NC1=O HAPOVYFOVVWLRS-UHFFFAOYSA-N 0.000 description 1
- BUDBHJPMAKXMLD-UHFFFAOYSA-N ethyl 6-methyl-2-phenylquinoline-4-carboxylate Chemical compound N=1C2=CC=C(C)C=C2C(C(=O)OCC)=CC=1C1=CC=CC=C1 BUDBHJPMAKXMLD-UHFFFAOYSA-N 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 1
- 229940116333 ethyl lactate Drugs 0.000 description 1
- ULANGSAJTINEBA-UHFFFAOYSA-N ethyl n-(3-benzoylphenyl)-n-(trifluoromethylsulfonyl)carbamate Chemical compound CCOC(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 ULANGSAJTINEBA-UHFFFAOYSA-N 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 229940100524 ethylhexylglycerin Drugs 0.000 description 1
- 229960004578 ethylmorphine Drugs 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- ZXUMUPVQYAFTLF-UHFFFAOYSA-N etryptamine Chemical compound C1=CC=C2C(CC(N)CC)=CNC2=C1 ZXUMUPVQYAFTLF-UHFFFAOYSA-N 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 229940066493 expectorants Drugs 0.000 description 1
- 229960004396 famciclovir Drugs 0.000 description 1
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 229960003580 felodipine Drugs 0.000 description 1
- 229950003579 fenamole Drugs 0.000 description 1
- ZPAKPRAICRBAOD-UHFFFAOYSA-N fenbufen Chemical compound C1=CC(C(=O)CCC(=O)O)=CC=C1C1=CC=CC=C1 ZPAKPRAICRBAOD-UHFFFAOYSA-N 0.000 description 1
- 229960001395 fenbufen Drugs 0.000 description 1
- 229960001582 fenfluramine Drugs 0.000 description 1
- 229960001419 fenoprofen Drugs 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 description 1
- 229950002557 fezatione Drugs 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 229940126864 fibroblast growth factor Drugs 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 210000001145 finger joint Anatomy 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 229960000449 flecainide Drugs 0.000 description 1
- 229960004500 flubendazole Drugs 0.000 description 1
- CPEUVMUXAHMANV-UHFFFAOYSA-N flubendazole Chemical compound C1=C2NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=C(F)C=C1 CPEUVMUXAHMANV-UHFFFAOYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 description 1
- 229960004413 flucytosine Drugs 0.000 description 1
- SYWHXTATXSMDSB-GSLJADNHSA-N fludrocortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O SYWHXTATXSMDSB-GSLJADNHSA-N 0.000 description 1
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 1
- 229960004369 flufenamic acid Drugs 0.000 description 1
- 229950007979 flufenisal Drugs 0.000 description 1
- 229940042902 flumethasone pivalate Drugs 0.000 description 1
- JWRMHDSINXPDHB-OJAGFMMFSA-N flumethasone pivalate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)COC(=O)C(C)(C)C)(O)[C@@]2(C)C[C@@H]1O JWRMHDSINXPDHB-OJAGFMMFSA-N 0.000 description 1
- 229960000676 flunisolide Drugs 0.000 description 1
- WEGNFRKBIKYVLC-XTLNBZDDSA-N flunisolide acetate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)C)[C@@]2(C)C[C@@H]1O WEGNFRKBIKYVLC-XTLNBZDDSA-N 0.000 description 1
- 229960002200 flunitrazepam Drugs 0.000 description 1
- NOOCSNJCXJYGPE-UHFFFAOYSA-N flunixin Chemical compound C1=CC=C(C(F)(F)F)C(C)=C1NC1=NC=CC=C1C(O)=O NOOCSNJCXJYGPE-UHFFFAOYSA-N 0.000 description 1
- 229960000588 flunixin Drugs 0.000 description 1
- MGCCHNLNRBULBU-WZTVWXICSA-N flunixin meglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.C1=CC=C(C(F)(F)F)C(C)=C1NC1=NC=CC=C1C(O)=O MGCCHNLNRBULBU-WZTVWXICSA-N 0.000 description 1
- 229960000469 flunixin meglumine Drugs 0.000 description 1
- RMBPEFMHABBEKP-UHFFFAOYSA-N fluorene Chemical group C1=CC=C2C3=C[CH]C=CC3=CC2=C1 RMBPEFMHABBEKP-UHFFFAOYSA-N 0.000 description 1
- 229960003336 fluorocortisol acetate Drugs 0.000 description 1
- 150000005699 fluoropyrimidines Chemical class 0.000 description 1
- 238000002594 fluoroscopy Methods 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 229960001751 fluoxymesterone Drugs 0.000 description 1
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 description 1
- 229960002690 fluphenazine Drugs 0.000 description 1
- 229960000618 fluprednisolone Drugs 0.000 description 1
- 229950001284 fluprofen Drugs 0.000 description 1
- 229960003528 flurazepam Drugs 0.000 description 1
- SAADBVWGJQAEFS-UHFFFAOYSA-N flurazepam Chemical compound N=1CC(=O)N(CCN(CC)CC)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1F SAADBVWGJQAEFS-UHFFFAOYSA-N 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 229950003654 flutiazin Drugs 0.000 description 1
- 229960004038 fluvoxamine Drugs 0.000 description 1
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 210000001061 forehead Anatomy 0.000 description 1
- IYWCBYFJFZCCGV-UHFFFAOYSA-N formamide;hydrate Chemical compound O.NC=O IYWCBYFJFZCCGV-UHFFFAOYSA-N 0.000 description 1
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 1
- 229960000671 formocortal Drugs 0.000 description 1
- QNXUUBBKHBYRFW-QWAPGEGQSA-N formocortal Chemical compound C1C(C=O)=C2C=C(OCCCl)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)C)[C@@]1(C)C[C@@H]2O QNXUUBBKHBYRFW-QWAPGEGQSA-N 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229960000308 fosfomycin Drugs 0.000 description 1
- PGBHMTALBVVCIT-VCIWKGPPSA-N framycetin Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CN)O2)N)O[C@@H]1CO PGBHMTALBVVCIT-VCIWKGPPSA-N 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229950010710 furazabol Drugs 0.000 description 1
- JKFAIQOWCVVSKC-UHFFFAOYSA-N furazan Chemical compound C=1C=NON=1 JKFAIQOWCVVSKC-UHFFFAOYSA-N 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 229960004675 fusidic acid Drugs 0.000 description 1
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical compound O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 description 1
- ICLWTJIMXVISSR-UHFFFAOYSA-N gallamine Chemical compound CCN(CC)CCOC1=CC=CC(OCCN(CC)CC)=C1OCCN(CC)CC ICLWTJIMXVISSR-UHFFFAOYSA-N 0.000 description 1
- 229960003054 gallamine Drugs 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 description 1
- 229960003480 gemeprost Drugs 0.000 description 1
- KYBOHGVERHWSSV-VNIVIJDLSA-N gemeprost Chemical compound CCCCC(C)(C)[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCC\C=C\C(=O)OC KYBOHGVERHWSSV-VNIVIJDLSA-N 0.000 description 1
- JIYMVSQRGZEYAX-CWUUNJJBSA-N gemifloxacin mesylate Chemical compound CS(O)(=O)=O.C1C(CN)C(=N/OC)/CN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1CC1 JIYMVSQRGZEYAX-CWUUNJJBSA-N 0.000 description 1
- 229960001151 gemifloxacin mesylate Drugs 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 229960005352 gestodene Drugs 0.000 description 1
- SIGSPDASOTUPFS-XUDSTZEESA-N gestodene Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](C=C4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 SIGSPDASOTUPFS-XUDSTZEESA-N 0.000 description 1
- 229960004580 glibenclamide Drugs 0.000 description 1
- 229960000346 gliclazide Drugs 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 235000003969 glutathione Nutrition 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- 150000002314 glycerols Chemical class 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 102000035122 glycosylated proteins Human genes 0.000 description 1
- 108091005608 glycosylated proteins Proteins 0.000 description 1
- 229960005122 gonadorelin acetate Drugs 0.000 description 1
- MFWNKCLOYSRHCJ-BTTYYORXSA-N granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 description 1
- 229960003727 granisetron Drugs 0.000 description 1
- 239000008169 grapeseed oil Substances 0.000 description 1
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 1
- 229960002867 griseofulvin Drugs 0.000 description 1
- ACGDKVXYNVEAGU-UHFFFAOYSA-N guanethidine Chemical compound NC(N)=NCCN1CCCCCCC1 ACGDKVXYNVEAGU-UHFFFAOYSA-N 0.000 description 1
- 229960003602 guanethidine Drugs 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- IDINUJSAMVOPCM-UHFFFAOYSA-N gusperimus Chemical compound NCCCNCCCCNC(=O)C(O)NC(=O)CCCCCCN=C(N)N IDINUJSAMVOPCM-UHFFFAOYSA-N 0.000 description 1
- 229960002706 gusperimus Drugs 0.000 description 1
- 229960003242 halofantrine Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- ACGUYXCXAPNIKK-UHFFFAOYSA-N hexachlorophene Chemical compound OC1=C(Cl)C=C(Cl)C(Cl)=C1CC1=C(O)C(Cl)=CC(Cl)=C1Cl ACGUYXCXAPNIKK-UHFFFAOYSA-N 0.000 description 1
- 229960004068 hexachlorophene Drugs 0.000 description 1
- 210000001624 hip Anatomy 0.000 description 1
- 229940006607 hirudin Drugs 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 239000003395 histamine H3 receptor antagonist Substances 0.000 description 1
- 239000002944 hormone and hormone analog Substances 0.000 description 1
- 229960002773 hyaluronidase Drugs 0.000 description 1
- 229960002474 hydralazine Drugs 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 229960003331 hydrocortisone cypionate Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 description 1
- 229960001410 hydromorphone Drugs 0.000 description 1
- CEXBONHIOKGWNU-NTISSMGPSA-N hydron;(6s)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol;chloride Chemical compound [Cl-].CCC[NH+]([C@@H]1CC2=CC=CC(O)=C2CC1)CCC1=CC=CS1 CEXBONHIOKGWNU-NTISSMGPSA-N 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 1
- 229960004171 hydroxychloroquine Drugs 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 229940124512 hyoscine hydrobromide Drugs 0.000 description 1
- KXPXJGYSEPEXMF-WYHSTMEOSA-N hyoscine hydrochloride Chemical compound Cl.C1([C@@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 KXPXJGYSEPEXMF-WYHSTMEOSA-N 0.000 description 1
- 229960003210 hyoscyamine Drugs 0.000 description 1
- 229930005342 hyoscyamine Natural products 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 229940005535 hypnotics and sedatives Drugs 0.000 description 1
- 239000005554 hypnotics and sedatives Substances 0.000 description 1
- HSIBGVUMFOSJPD-CFDPKNGZSA-N ibogaine Chemical compound N1([C@@H]2[C@H]3C[C@H](C1)C[C@@H]2CC)CCC1=C3NC2=CC=C(OC)C=C12 HSIBGVUMFOSJPD-CFDPKNGZSA-N 0.000 description 1
- OLOCMRXSJQJJPL-UHFFFAOYSA-N ibogaine Natural products CCC1CC2CC3C1N(C2)C=Cc4c3[nH]c5ccc(OC)cc45 OLOCMRXSJQJJPL-UHFFFAOYSA-N 0.000 description 1
- AREITJMUSRHSBK-UHFFFAOYSA-N ibogamine Natural products CCC1CC2C3CC1CN2CCc4c3[nH]c5ccccc45 AREITJMUSRHSBK-UHFFFAOYSA-N 0.000 description 1
- CYWFCPPBTWOZSF-UHFFFAOYSA-N ibufenac Chemical compound CC(C)CC1=CC=C(CC(O)=O)C=C1 CYWFCPPBTWOZSF-UHFFFAOYSA-N 0.000 description 1
- 229950009183 ibufenac Drugs 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229960004716 idoxuridine Drugs 0.000 description 1
- 229960002182 imipenem Drugs 0.000 description 1
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- NDDAHWYSQHTHNT-UHFFFAOYSA-N indapamide Chemical compound CC1CC2=CC=CC=C2N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NDDAHWYSQHTHNT-UHFFFAOYSA-N 0.000 description 1
- 229960004569 indapamide Drugs 0.000 description 1
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 1
- 229960001936 indinavir Drugs 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 229950008443 indoxole Drugs 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 235000013902 inosinic acid Nutrition 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 229950004204 intrazole Drugs 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002497 iodine compounds Chemical class 0.000 description 1
- UXZFQZANDVDGMM-UHFFFAOYSA-N iodoquinol Chemical compound C1=CN=C2C(O)=C(I)C=C(I)C2=C1 UXZFQZANDVDGMM-UHFFFAOYSA-N 0.000 description 1
- 229960005208 ipecacuanha Drugs 0.000 description 1
- 229960001361 ipratropium bromide Drugs 0.000 description 1
- KEWHKYJURDBRMN-ZEODDXGYSA-M ipratropium bromide hydrate Chemical compound O.[Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 KEWHKYJURDBRMN-ZEODDXGYSA-M 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 229960002672 isocarboxazid Drugs 0.000 description 1
- 229960004849 isoconazole Drugs 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 108010088381 isoleucyl-lysyl-valyl-alanyl-valine Proteins 0.000 description 1
- 229960003350 isoniazid Drugs 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- KUVMKLCGXIYSNH-UHFFFAOYSA-N isopentadecane Natural products CCCCCCCCCCCCC(C)C KUVMKLCGXIYSNH-UHFFFAOYSA-N 0.000 description 1
- 229960001317 isoprenaline Drugs 0.000 description 1
- 229940093629 isopropyl isostearate Drugs 0.000 description 1
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- 229940075495 isopropyl palmitate Drugs 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 229960004819 isoxsuprine Drugs 0.000 description 1
- 229960002418 ivermectin Drugs 0.000 description 1
- 230000001530 keratinolytic effect Effects 0.000 description 1
- 239000003410 keratolytic agent Substances 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 1
- 238000009940 knitting Methods 0.000 description 1
- 229960001632 labetalol Drugs 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- 229960001160 latanoprost Drugs 0.000 description 1
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 description 1
- 229940031674 laureth-7 Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000003199 leukotriene receptor blocking agent Substances 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 1
- 229960005287 lincomycin Drugs 0.000 description 1
- 229960003907 linezolid Drugs 0.000 description 1
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 229960002394 lisinopril Drugs 0.000 description 1
- CZRQXSDBMCMPNJ-ZUIPZQNBSA-N lisinopril dihydrate Chemical compound O.O.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 CZRQXSDBMCMPNJ-ZUIPZQNBSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229960001078 lithium Drugs 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 235000010420 locust bean gum Nutrition 0.000 description 1
- 239000000711 locust bean gum Substances 0.000 description 1
- 229950000359 lokivetmab Drugs 0.000 description 1
- 239000002171 loop diuretic Substances 0.000 description 1
- 229960001571 loperamide Drugs 0.000 description 1
- RDOIQAHITMMDAJ-UHFFFAOYSA-N loperamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)CCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 RDOIQAHITMMDAJ-UHFFFAOYSA-N 0.000 description 1
- 229960003088 loratadine Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 229960004391 lorazepam Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229940127215 low-molecular weight heparin Drugs 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 229960001910 lynestrenol Drugs 0.000 description 1
- 229960003837 lypressin Drugs 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 125000003588 lysine group Chemical class [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- DGMJZELBSFOPHH-KVTDHHQDSA-N mannite hexanitrate Chemical compound [O-][N+](=O)OC[C@@H](O[N+]([O-])=O)[C@@H](O[N+]([O-])=O)[C@H](O[N+]([O-])=O)[C@H](O[N+]([O-])=O)CO[N+]([O-])=O DGMJZELBSFOPHH-KVTDHHQDSA-N 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 229960001765 mannitol hexanitrate Drugs 0.000 description 1
- 229960002505 maropitant Drugs 0.000 description 1
- 210000001595 mastoid Anatomy 0.000 description 1
- 229960000299 mazindol Drugs 0.000 description 1
- FQQIIPAOSKSOJM-UHFFFAOYSA-N mebhydrolin Chemical compound C1N(C)CCC2=C1C1=CC=CC=C1N2CC1=CC=CC=C1 FQQIIPAOSKSOJM-UHFFFAOYSA-N 0.000 description 1
- 229960004934 mebhydrolin Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- 229960003803 meclofenamic acid Drugs 0.000 description 1
- 229960001474 meclozine Drugs 0.000 description 1
- 229960004616 medroxyprogesterone Drugs 0.000 description 1
- FRQMUZJSZHZSGN-HBNHAYAOSA-N medroxyprogesterone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FRQMUZJSZHZSGN-HBNHAYAOSA-N 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- 229960001962 mefloquine Drugs 0.000 description 1
- 229960004678 mefruside Drugs 0.000 description 1
- 229960001786 megestrol Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960003987 melatonin Drugs 0.000 description 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
- 229960000901 mepacrine Drugs 0.000 description 1
- ALARQZQTBTVLJV-UHFFFAOYSA-N mephobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)N(C)C1=O ALARQZQTBTVLJV-UHFFFAOYSA-N 0.000 description 1
- 229960001810 meprednisone Drugs 0.000 description 1
- PIDANAQULIKBQS-RNUIGHNZSA-N meprednisone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)CC2=O PIDANAQULIKBQS-RNUIGHNZSA-N 0.000 description 1
- 229960004815 meprobamate Drugs 0.000 description 1
- 229960003151 mercaptamine Drugs 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 229960002260 meropenem Drugs 0.000 description 1
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 1
- IMSSROKUHAOUJS-MJCUULBUSA-N mestranol Chemical compound C1C[C@]2(C)[C@@](C#C)(O)CC[C@H]2[C@@H]2CCC3=CC(OC)=CC=C3[C@H]21 IMSSROKUHAOUJS-MJCUULBUSA-N 0.000 description 1
- 229960001390 mestranol Drugs 0.000 description 1
- 229960003729 mesuximide Drugs 0.000 description 1
- 229950010581 metazamide Drugs 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229940042016 methacycline Drugs 0.000 description 1
- 229960001797 methadone Drugs 0.000 description 1
- 229960004056 methdilazine Drugs 0.000 description 1
- HTMIBDQKFHUPSX-UHFFFAOYSA-N methdilazine Chemical compound C1N(C)CCC1CN1C2=CC=CC=C2SC2=CC=CC=C21 HTMIBDQKFHUPSX-UHFFFAOYSA-N 0.000 description 1
- 229960003900 methenamine hippurate Drugs 0.000 description 1
- PMRYVIKBURPHAH-UHFFFAOYSA-N methimazole Chemical compound CN1C=CNC1=S PMRYVIKBURPHAH-UHFFFAOYSA-N 0.000 description 1
- 229960002330 methocarbamol Drugs 0.000 description 1
- IKXILDNPCZPPRV-RFMGOVQKSA-N metholone Chemical compound C1C[C@@H]2[C@@]3(C)C[C@@H](C)C(=O)C[C@@H]3CC[C@H]2[C@@H]2CC[C@H](O)[C@]21C IKXILDNPCZPPRV-RFMGOVQKSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- OJLOPKGSLYJEMD-URPKTTJQSA-N methyl 7-[(1r,2r,3r)-3-hydroxy-2-[(1e)-4-hydroxy-4-methyloct-1-en-1-yl]-5-oxocyclopentyl]heptanoate Chemical compound CCCCC(C)(O)C\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC OJLOPKGSLYJEMD-URPKTTJQSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229960001703 methylphenobarbital Drugs 0.000 description 1
- 229960001566 methyltestosterone Drugs 0.000 description 1
- 229960001186 methysergide Drugs 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- 229960002817 metolazone Drugs 0.000 description 1
- AQCHWTWZEMGIFD-UHFFFAOYSA-N metolazone Chemical compound CC1NC2=CC(Cl)=C(S(N)(=O)=O)C=C2C(=O)N1C1=CC=CC=C1C AQCHWTWZEMGIFD-UHFFFAOYSA-N 0.000 description 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 1
- 229960002237 metoprolol Drugs 0.000 description 1
- 229960003955 mianserin Drugs 0.000 description 1
- KOOAFHGJVIVFMZ-WZPXRXMFSA-M micafungin sodium Chemical compound [Na+].C1=CC(OCCCCC)=CC=C1C1=CC(C=2C=CC(=CC=2)C(=O)N[C@@H]2C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C2)[C@H](O)CC(N)=O)[C@H](O)[C@@H](O)C=2C=C(OS([O-])(=O)=O)C(O)=CC=2)[C@@H](C)O)=O)=NO1 KOOAFHGJVIVFMZ-WZPXRXMFSA-M 0.000 description 1
- 229960004806 micafungin sodium Drugs 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 229960002509 miconazole Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 229960002421 minocycline hydrochloride Drugs 0.000 description 1
- 229960003632 minoxidil Drugs 0.000 description 1
- 229960005249 misoprostol Drugs 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- YHXISWVBGDMDLQ-UHFFFAOYSA-N moclobemide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCCN1CCOCC1 YHXISWVBGDMDLQ-UHFFFAOYSA-N 0.000 description 1
- 229960004644 moclobemide Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- XLFWDASMENKTKL-UHFFFAOYSA-N molsidomine Chemical compound O1C(N=C([O-])OCC)=C[N+](N2CCOCC2)=N1 XLFWDASMENKTKL-UHFFFAOYSA-N 0.000 description 1
- 229960004027 molsidomine Drugs 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 229940051866 mouthwash Drugs 0.000 description 1
- YZBLFMPOMVTDJY-CBYMMZEQSA-N moxidectin Chemical compound O1[C@H](C(\C)=C\C(C)C)[C@@H](C)C(=N/OC)\C[C@@]11O[C@H](C\C=C(C)\C[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 YZBLFMPOMVTDJY-CBYMMZEQSA-N 0.000 description 1
- 229960004816 moxidectin Drugs 0.000 description 1
- IDIIJJHBXUESQI-DFIJPDEKSA-N moxifloxacin hydrochloride Chemical compound Cl.COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 IDIIJJHBXUESQI-DFIJPDEKSA-N 0.000 description 1
- 229960005112 moxifloxacin hydrochloride Drugs 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- NKDJNEGDJVXHKM-UHFFFAOYSA-N n,2-dimethyl-4,5,6,7-tetrahydroindazol-3-amine Chemical compound C1CCCC2=NN(C)C(NC)=C21 NKDJNEGDJVXHKM-UHFFFAOYSA-N 0.000 description 1
- NFQBIAXADRDUGK-KWXKLSQISA-N n,n-dimethyl-2,3-bis[(9z,12z)-octadeca-9,12-dienoxy]propan-1-amine Chemical compound CCCCC\C=C/C\C=C/CCCCCCCCOCC(CN(C)C)OCCCCCCCC\C=C/C\C=C/CCCCC NFQBIAXADRDUGK-KWXKLSQISA-N 0.000 description 1
- DTIAYBYJXZBQDD-UHFFFAOYSA-N n-(3-methylphenyl)-2-sulfanylacetamide Chemical compound CC1=CC=CC(NC(=O)CS)=C1 DTIAYBYJXZBQDD-UHFFFAOYSA-N 0.000 description 1
- HWCORKBTTGTRDY-UHFFFAOYSA-N n-(4-chlorophenyl)-1,3-dioxo-4h-isoquinoline-4-carboxamide Chemical compound C1=CC(Cl)=CC=C1NC(=O)C1C2=CC=CC=C2C(=O)NC1=O HWCORKBTTGTRDY-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XFCDCTAQNWXTKT-UHFFFAOYSA-N n-ethyl-n'-[10-(ethyliminomethylideneamino)decyl]methanediimine Chemical compound CCN=C=NCCCCCCCCCCN=C=NCC XFCDCTAQNWXTKT-UHFFFAOYSA-N 0.000 description 1
- SIUPPTRKFWMXIE-UHFFFAOYSA-N n-ethyl-n'-propylmethanediimine Chemical compound CCCN=C=NCC SIUPPTRKFWMXIE-UHFFFAOYSA-N 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- NQYKSVOHDVVDOR-UHFFFAOYSA-N n-hexadecylhexadecan-1-amine Chemical compound CCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCC NQYKSVOHDVVDOR-UHFFFAOYSA-N 0.000 description 1
- CKRXZOZYQYDWIQ-UHFFFAOYSA-N n-nonyl-3-sulfanylpropanamide Chemical compound CCCCCCCCCNC(=O)CCS CKRXZOZYQYDWIQ-UHFFFAOYSA-N 0.000 description 1
- HKUFIYBZNQSHQS-UHFFFAOYSA-N n-octadecyloctadecan-1-amine Chemical compound CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC HKUFIYBZNQSHQS-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960004255 nadolol Drugs 0.000 description 1
- VWPOSFSPZNDTMJ-UCWKZMIHSA-N nadolol Chemical compound C1[C@@H](O)[C@@H](O)CC2=C1C=CC=C2OCC(O)CNC(C)(C)C VWPOSFSPZNDTMJ-UCWKZMIHSA-N 0.000 description 1
- UPZVYDSBLFNMLK-UHFFFAOYSA-N nadoxolol Chemical compound C1=CC=C2C(OCC(O)CC(/N)=N/O)=CC=CC2=C1 UPZVYDSBLFNMLK-UHFFFAOYSA-N 0.000 description 1
- 229960004501 nadoxolol Drugs 0.000 description 1
- GPXLMGHLHQJAGZ-JTDSTZFVSA-N nafcillin Chemical compound C1=CC=CC2=C(C(=O)N[C@@H]3C(N4[C@H](C(C)(C)S[C@@H]43)C(O)=O)=O)C(OCC)=CC=C21 GPXLMGHLHQJAGZ-JTDSTZFVSA-N 0.000 description 1
- 229960000515 nafcillin Drugs 0.000 description 1
- 229960004719 nandrolone Drugs 0.000 description 1
- NPAGDVCDWIYMMC-IZPLOLCNSA-N nandrolone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 NPAGDVCDWIYMMC-IZPLOLCNSA-N 0.000 description 1
- LTRANDSQVZFZDG-SNVBAGLBSA-N naproxol Chemical compound C1=C([C@H](C)CO)C=CC2=CC(OC)=CC=C21 LTRANDSQVZFZDG-SNVBAGLBSA-N 0.000 description 1
- 229950006890 naproxol Drugs 0.000 description 1
- 229960003255 natamycin Drugs 0.000 description 1
- 235000010298 natamycin Nutrition 0.000 description 1
- 239000004311 natamycin Substances 0.000 description 1
- NCXMLFZGDNKEPB-FFPOYIOWSA-N natamycin Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C[C@@H](C)OC(=O)/C=C/[C@H]2O[C@@H]2C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 NCXMLFZGDNKEPB-FFPOYIOWSA-N 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 229950003155 neocinchophen Drugs 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 229940053050 neomycin sulfate Drugs 0.000 description 1
- 229960000808 netilmicin Drugs 0.000 description 1
- 239000002742 neurokinin 1 receptor antagonist Substances 0.000 description 1
- 239000002740 neurokinin 3 receptor antagonist Substances 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- LBHIOVVIQHSOQN-UHFFFAOYSA-N nicorandil Chemical compound [O-][N+](=O)OCCNC(=O)C1=CC=CN=C1 LBHIOVVIQHSOQN-UHFFFAOYSA-N 0.000 description 1
- 229960002497 nicorandil Drugs 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960004738 nicotinyl alcohol Drugs 0.000 description 1
- 229960001454 nitrazepam Drugs 0.000 description 1
- KJONHKAYOJNZEC-UHFFFAOYSA-N nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 description 1
- 229960005425 nitrendipine Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- UEHLXXJAWYWUGI-UHFFFAOYSA-M nitromersol Chemical compound CC1=CC=C([N+]([O-])=O)C2=C1O[Hg]2 UEHLXXJAWYWUGI-UHFFFAOYSA-M 0.000 description 1
- 229940118238 nitromersol Drugs 0.000 description 1
- 229960002460 nitroprusside Drugs 0.000 description 1
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 1
- ZQLOAGFNRKBEAJ-BDPSOKNUSA-N nivazol Chemical compound C([C@@H]1[C@@H]([C@]2(C3)C)CC[C@]4([C@H]1CC[C@@]4(O)C#C)C)CC2=CC1=C3C=NN1C1=CC=C(F)C=C1 ZQLOAGFNRKBEAJ-BDPSOKNUSA-N 0.000 description 1
- 229920004918 nonoxynol-9 Polymers 0.000 description 1
- 229940087419 nonoxynol-9 Drugs 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 229940053934 norethindrone Drugs 0.000 description 1
- 229960001652 norethindrone acetate Drugs 0.000 description 1
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 1
- 229960001158 nortriptyline Drugs 0.000 description 1
- 239000002417 nutraceutical Substances 0.000 description 1
- 235000021436 nutraceutical agent Nutrition 0.000 description 1
- 229960000988 nystatin Drugs 0.000 description 1
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Chemical group C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 1
- 229960000393 oclacitinib maleate Drugs 0.000 description 1
- XXUPLYBCNPLTIW-UHFFFAOYSA-N octadec-7-ynoic acid Chemical compound CCCCCCCCCCC#CCCCCCC(O)=O XXUPLYBCNPLTIW-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- AEIJTFQOBWATKX-UHFFFAOYSA-N octane-1,2-diol Chemical compound CCCCCCC(O)CO AEIJTFQOBWATKX-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 229950005023 octazamide Drugs 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229940012843 omega-3 fatty acid Drugs 0.000 description 1
- 235000020660 omega-3 fatty acid Nutrition 0.000 description 1
- 229960005343 ondansetron Drugs 0.000 description 1
- 239000000014 opioid analgesic Substances 0.000 description 1
- 229960005290 opipramol Drugs 0.000 description 1
- 229920000620 organic polymer Polymers 0.000 description 1
- PWTROOMOPLCZHB-BHYQHFGMSA-N oritavancin bisphosphate Chemical compound OP(O)(O)=O.OP(O)(O)=O.O([C@@H]1C2=CC=C(C(=C2)Cl)OC=2C=C3C=C(C=2O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O[C@@H]2O[C@@H](C)[C@H](O)[C@@](C)(NCC=4C=CC(=CC=4)C=4C=CC(Cl)=CC=4)C2)OC2=CC=C(C=C2Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]2C(=O)N[C@@H]1C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@@H](O)[C@H](C)O1 PWTROOMOPLCZHB-BHYQHFGMSA-N 0.000 description 1
- 229960004959 oritavancin diphosphate Drugs 0.000 description 1
- 229960003941 orphenadrine Drugs 0.000 description 1
- QVYRGXJJSLMXQH-UHFFFAOYSA-N orphenadrine Chemical compound C=1C=CC=C(C)C=1C(OCCN(C)C)C1=CC=CC=C1 QVYRGXJJSLMXQH-UHFFFAOYSA-N 0.000 description 1
- 235000010292 orthophenyl phenol Nutrition 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 229940082663 other cardiac glycosides in atc Drugs 0.000 description 1
- 229940054001 other hypnotics and sedatives in atc Drugs 0.000 description 1
- UWYHMGVUTGAWSP-JKIFEVAISA-N oxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 UWYHMGVUTGAWSP-JKIFEVAISA-N 0.000 description 1
- 229960001019 oxacillin Drugs 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960000464 oxandrolone Drugs 0.000 description 1
- 229960004535 oxazepam Drugs 0.000 description 1
- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 description 1
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
- 229960004570 oxprenolol Drugs 0.000 description 1
- 229960002085 oxycodone Drugs 0.000 description 1
- 125000006353 oxyethylene group Chemical group 0.000 description 1
- 229960000649 oxyphenbutazone Drugs 0.000 description 1
- CNDQSXOVEQXJOE-UHFFFAOYSA-N oxyphenbutazone hydrate Chemical compound O.O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=C(O)C=C1 CNDQSXOVEQXJOE-UHFFFAOYSA-N 0.000 description 1
- HXNFUBHNUDHIGC-UHFFFAOYSA-N oxypurinol Chemical compound O=C1NC(=O)N=C2NNC=C21 HXNFUBHNUDHIGC-UHFFFAOYSA-N 0.000 description 1
- 229960000625 oxytetracycline Drugs 0.000 description 1
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 description 1
- 235000019366 oxytetracycline Nutrition 0.000 description 1
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 1
- 229960001723 oxytocin Drugs 0.000 description 1
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 1
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 1
- 229940098695 palmitic acid Drugs 0.000 description 1
- GVEAYVLWDAFXET-XGHATYIMSA-N pancuronium Chemical compound C[N+]1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 GVEAYVLWDAFXET-XGHATYIMSA-N 0.000 description 1
- 229960005457 pancuronium Drugs 0.000 description 1
- 229960003294 papaveretum Drugs 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 229960002858 paramethasone Drugs 0.000 description 1
- 229960000865 paramethasone acetate Drugs 0.000 description 1
- 229960001914 paromomycin Drugs 0.000 description 1
- 229960002296 paroxetine Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 210000000426 patellar ligament Anatomy 0.000 description 1
- 229940100460 peg-100 stearate Drugs 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 235000019369 penicillin G sodium Nutrition 0.000 description 1
- 229940056365 penicillin g benzathine Drugs 0.000 description 1
- 229940056367 penicillin v Drugs 0.000 description 1
- 229940090663 penicillin v potassium Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 1
- 229960005301 pentazocine Drugs 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- CYXKNKQEMFBLER-UHFFFAOYSA-N perhexiline Chemical compound C1CCCNC1CC(C1CCCCC1)C1CCCCC1 CYXKNKQEMFBLER-UHFFFAOYSA-N 0.000 description 1
- LUALIOATIOESLM-UHFFFAOYSA-N periciazine Chemical compound C1CC(O)CCN1CCCN1C2=CC(C#N)=CC=C2SC2=CC=CC=C21 LUALIOATIOESLM-UHFFFAOYSA-N 0.000 description 1
- 229960000769 periciazine Drugs 0.000 description 1
- 229960000762 perphenazine Drugs 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- NQFOGDIWKQWFMN-UHFFFAOYSA-N phenalene Chemical group C1=CC([CH]C=C2)=C3C2=CC=CC3=C1 NQFOGDIWKQWFMN-UHFFFAOYSA-N 0.000 description 1
- NONJJLVGHLVQQM-JHXYUMNGSA-N phenethicillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C(C)OC1=CC=CC=C1 NONJJLVGHLVQQM-JHXYUMNGSA-N 0.000 description 1
- 229960004894 pheneticillin Drugs 0.000 description 1
- 229960001190 pheniramine Drugs 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 229960005323 phenoxyethanol Drugs 0.000 description 1
- 229960004227 phensuximide Drugs 0.000 description 1
- 229960003562 phentermine Drugs 0.000 description 1
- 229960001999 phentolamine Drugs 0.000 description 1
- MRBDMNSDAVCSSF-UHFFFAOYSA-N phentolamine Chemical compound C1=CC(C)=CC=C1N(C=1C=C(O)C=CC=1)CC1=NCCN1 MRBDMNSDAVCSSF-UHFFFAOYSA-N 0.000 description 1
- 229940067107 phenylethyl alcohol Drugs 0.000 description 1
- 229940096826 phenylmercuric acetate Drugs 0.000 description 1
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- GPFAJKDEDBRFOS-FKQDBXSBSA-N pholcodine Chemical compound O([C@@H]1[C@]23CCN([C@H](C4)[C@@H]3C=C[C@@H]1O)C)C1=C2C4=CC=C1OCCN1CCOCC1 GPFAJKDEDBRFOS-FKQDBXSBSA-N 0.000 description 1
- 229960002808 pholcodine Drugs 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 229960001416 pilocarpine Drugs 0.000 description 1
- KASDHRXLYQOAKZ-ZPSXYTITSA-N pimecrolimus Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](Cl)[C@H](OC)C1 KASDHRXLYQOAKZ-ZPSXYTITSA-N 0.000 description 1
- 229960005330 pimecrolimus Drugs 0.000 description 1
- YVUQSNJEYSNKRX-UHFFFAOYSA-N pimozide Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCN1CCC(N2C(NC3=CC=CC=C32)=O)CC1 YVUQSNJEYSNKRX-UHFFFAOYSA-N 0.000 description 1
- 229960003634 pimozide Drugs 0.000 description 1
- 229960002508 pindolol Drugs 0.000 description 1
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 description 1
- 229960002292 piperacillin Drugs 0.000 description 1
- 229960005264 piperacillin sodium Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- FIADGNVRKBPQEU-UHFFFAOYSA-N pizotifen Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CCC2=C1C=CS2 FIADGNVRKBPQEU-UHFFFAOYSA-N 0.000 description 1
- 229960004572 pizotifen Drugs 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 150000003058 platinum compounds Chemical class 0.000 description 1
- DIJNSQQKNIVDPV-UHFFFAOYSA-N pleiadene Chemical group C1=C2[CH]C=CC=C2C=C2C=CC=C3[C]2C1=CC=C3 DIJNSQQKNIVDPV-UHFFFAOYSA-N 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- ONJQDTZCDSESIW-UHFFFAOYSA-N polidocanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO ONJQDTZCDSESIW-UHFFFAOYSA-N 0.000 description 1
- 229960002226 polidocanol Drugs 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229940044476 poloxamer 407 Drugs 0.000 description 1
- 229920000075 poly(4-vinylpyridine) Polymers 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920000218 poly(hydroxyvalerate) Polymers 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 229920002463 poly(p-dioxanone) polymer Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 239000000622 polydioxanone Substances 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 1
- 229940113115 polyethylene glycol 200 Drugs 0.000 description 1
- 229940068886 polyethylene glycol 300 Drugs 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229960003548 polymyxin b sulfate Drugs 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010988 polyoxyethylene sorbitan tristearate Nutrition 0.000 description 1
- 239000001816 polyoxyethylene sorbitan tristearate Substances 0.000 description 1
- 229940100528 polyoxyl 8 stearate Drugs 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229940099511 polysorbate 65 Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940113171 polysorbate 85 Drugs 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- IWZKICVEHNUQTL-UHFFFAOYSA-M potassium hydrogen phthalate Chemical compound [K+].OC(=O)C1=CC=CC=C1C([O-])=O IWZKICVEHNUQTL-UHFFFAOYSA-M 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
- 229960001289 prazosin Drugs 0.000 description 1
- 229950011122 prednisolamate Drugs 0.000 description 1
- ILZSJEITWDWIRX-FOMYWIRZSA-N prednisolamate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)CN(CC)CC)(O)[C@@]1(C)C[C@@H]2O ILZSJEITWDWIRX-FOMYWIRZSA-N 0.000 description 1
- 229950000696 prednival Drugs 0.000 description 1
- BOFKYYWJAOZDPB-FZNHGJLXSA-N prednival Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCCC)[C@@]1(C)C[C@@H]2O BOFKYYWJAOZDPB-FZNHGJLXSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- INDBQLZJXZLFIT-UHFFFAOYSA-N primaquine Chemical compound N1=CC=CC2=CC(OC)=CC(NC(C)CCCN)=C21 INDBQLZJXZLFIT-UHFFFAOYSA-N 0.000 description 1
- 229960005179 primaquine Drugs 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229960002393 primidone Drugs 0.000 description 1
- DQMZLTXERSFNPB-UHFFFAOYSA-N primidone Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NCNC1=O DQMZLTXERSFNPB-UHFFFAOYSA-N 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- REQCZEXYDRLIBE-UHFFFAOYSA-N procainamide Chemical compound CCN(CC)CCNC(=O)C1=CC=C(N)C=C1 REQCZEXYDRLIBE-UHFFFAOYSA-N 0.000 description 1
- 229960000244 procainamide Drugs 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 229960005253 procyclidine Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 229940095055 progestogen systemic hormonal contraceptives Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229960003598 promazine Drugs 0.000 description 1
- NEOZOXKVMDBOSG-UHFFFAOYSA-N propan-2-yl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCC(=O)OC(C)C NEOZOXKVMDBOSG-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 229960002662 propylthiouracil Drugs 0.000 description 1
- 150000003815 prostacyclins Chemical class 0.000 description 1
- PXGPLTODNUVGFL-YNNPMVKQSA-N prostaglandin F2alpha Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(O)=O PXGPLTODNUVGFL-YNNPMVKQSA-N 0.000 description 1
- 229940048914 protamine Drugs 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- 239000003881 protein kinase C inhibitor Substances 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 229960002601 protriptyline Drugs 0.000 description 1
- BWPIARFWQZKAIA-UHFFFAOYSA-N protriptyline Chemical compound C1=CC2=CC=CC=C2C(CCCNC)C2=CC=CC=C21 BWPIARFWQZKAIA-UHFFFAOYSA-N 0.000 description 1
- 229960001801 proxazole Drugs 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 229960005134 pyrantel Drugs 0.000 description 1
- YSAUAVHXTIETRK-AATRIKPKSA-N pyrantel Chemical compound CN1CCCN=C1\C=C\C1=CC=CS1 YSAUAVHXTIETRK-AATRIKPKSA-N 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- FGVVTMRZYROCTH-UHFFFAOYSA-N pyridine-2-thiol N-oxide Chemical compound [O-][N+]1=CC=CC=C1S FGVVTMRZYROCTH-UHFFFAOYSA-N 0.000 description 1
- WKSAUQYGYAYLPV-UHFFFAOYSA-N pyrimethamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1 WKSAUQYGYAYLPV-UHFFFAOYSA-N 0.000 description 1
- 229960000611 pyrimethamine Drugs 0.000 description 1
- 230000006824 pyrimidine synthesis Effects 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 229960002026 pyrithione Drugs 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 229960002778 pyrvinium Drugs 0.000 description 1
- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 description 1
- GPKJTRJOBQGKQK-UHFFFAOYSA-N quinacrine Chemical compound C1=C(OC)C=C2C(NC(C)CCCN(CC)CC)=C(C=CC(Cl)=C3)C3=NC2=C1 GPKJTRJOBQGKQK-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- AGMMTXLNIQSRCG-UHFFFAOYSA-N quinethazone Chemical compound NS(=O)(=O)C1=C(Cl)C=C2NC(CC)NC(=O)C2=C1 AGMMTXLNIQSRCG-UHFFFAOYSA-N 0.000 description 1
- 229960000577 quinethazone Drugs 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- DEJPVKFRZBVWEP-UHFFFAOYSA-N quinoline;1,2,8,10-tetrazaspiro[4.5]deca-1,3-diene-6,7,9-trione Chemical class N1=CC=CC2=CC=CC=C21.N1C(=O)NC(=O)C(=O)C21N=NC=C2 DEJPVKFRZBVWEP-UHFFFAOYSA-N 0.000 description 1
- 229960005442 quinupristin Drugs 0.000 description 1
- WTHRRGMBUAHGNI-LCYNINFDSA-N quinupristin Chemical compound N([C@@H]1C(=O)N[C@@H](C(N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(=CC=2)N(C)C)C(=O)N2C[C@@H](CS[C@H]3C4CCN(CC4)C3)C(=O)C[C@H]2C(=O)N[C@H](C(=O)O[C@@H]1C)C=1C=CC=CC=1)=O)CC)C(=O)C1=NC=CC=C1O WTHRRGMBUAHGNI-LCYNINFDSA-N 0.000 description 1
- 108700028429 quinupristin Proteins 0.000 description 1
- 229960003876 ranibizumab Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000003488 releasing hormone Substances 0.000 description 1
- 229940107685 reopro Drugs 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 102000000568 rho-Associated Kinases Human genes 0.000 description 1
- 108010041788 rho-Associated Kinases Proteins 0.000 description 1
- 229960001225 rifampicin Drugs 0.000 description 1
- 229960003292 rifamycin Drugs 0.000 description 1
- IYMMESGOJVNCKV-SKDRFNHKSA-N rimiterol Chemical compound C([C@@H]1[C@@H](O)C=2C=C(O)C(O)=CC=2)CCCN1 IYMMESGOJVNCKV-SKDRFNHKSA-N 0.000 description 1
- 229960001457 rimiterol Drugs 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- 239000011435 rock Substances 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 229960005224 roxithromycin Drugs 0.000 description 1
- WEMQMWWWCBYPOV-UHFFFAOYSA-N s-indacene Chemical group C=1C2=CC=CC2=CC2=CC=CC2=1 WEMQMWWWCBYPOV-UHFFFAOYSA-N 0.000 description 1
- 229960000581 salicylamide Drugs 0.000 description 1
- 229960000953 salsalate Drugs 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 235000017709 saponins Nutrition 0.000 description 1
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- MABNMNVCOAICNO-UHFFFAOYSA-N selenophene Chemical compound C=1C=C[se]C=1 MABNMNVCOAICNO-UHFFFAOYSA-N 0.000 description 1
- 231100000879 sensorineural hearing loss Toxicity 0.000 description 1
- 208000023573 sensorineural hearing loss disease Diseases 0.000 description 1
- 229950011343 serlopitant Drugs 0.000 description 1
- 230000000697 serotonin reuptake Effects 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229940057910 shea butter Drugs 0.000 description 1
- 210000002832 shoulder Anatomy 0.000 description 1
- 229910000161 silver phosphate Inorganic materials 0.000 description 1
- 229960003600 silver sulfadiazine Drugs 0.000 description 1
- UEJSSZHHYBHCEL-UHFFFAOYSA-N silver(1+) sulfadiazinate Chemical compound [Ag+].C1=CC(N)=CC=C1S(=O)(=O)[N-]C1=NC=CC=N1 UEJSSZHHYBHCEL-UHFFFAOYSA-N 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 230000008591 skin barrier function Effects 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- CODUSAVZTZYYDD-UHFFFAOYSA-M sodium 2-oxo-3-sulfanylpropanoate Chemical compound [Na+].[O-]C(=O)C(=O)CS CODUSAVZTZYYDD-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229960001315 sodium aurothiomalate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 239000003195 sodium channel blocking agent Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940057950 sodium laureth sulfate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
- 235000010334 sodium propionate Nutrition 0.000 description 1
- 239000004324 sodium propionate Substances 0.000 description 1
- 229960003212 sodium propionate Drugs 0.000 description 1
- YVOFSHPIJOYKSH-NLYBMVFSSA-M sodium rifomycin sv Chemical compound [Na+].OC1=C(C(O)=C2C)C3=C([O-])C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O YVOFSHPIJOYKSH-NLYBMVFSSA-M 0.000 description 1
- 229940080350 sodium stearate Drugs 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- FVEFRICMTUKAML-UHFFFAOYSA-M sodium tetradecyl sulfate Chemical compound [Na+].CCCCC(CC)CCC(CC(C)C)OS([O-])(=O)=O FVEFRICMTUKAML-UHFFFAOYSA-M 0.000 description 1
- HVBBVDWXAWJQSV-UHFFFAOYSA-N sodium;(3-benzoylphenyl)-(difluoromethylsulfonyl)azanide Chemical compound [Na+].FC(F)S(=O)(=O)[N-]C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 HVBBVDWXAWJQSV-UHFFFAOYSA-N 0.000 description 1
- QRIBXVGHDLFNNE-BMCBYEKFSA-M sodium;(6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-8-oxo-3-[(2s)-oxolan-2-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)/C(=N/OC)C=2N=C(N)SC=2)CC=1[C@@H]1CCCO1 QRIBXVGHDLFNNE-BMCBYEKFSA-M 0.000 description 1
- XNRNJIIJLOFJEK-UHFFFAOYSA-N sodium;1-oxidopyridine-2-thione Chemical compound [Na+].[O-]N1C=CC=CC1=S XNRNJIIJLOFJEK-UHFFFAOYSA-N 0.000 description 1
- SXHLENDCVBIJFO-UHFFFAOYSA-M sodium;2-[2-(2-dodecoxyethoxy)ethoxy]ethyl sulfate Chemical compound [Na+].CCCCCCCCCCCCOCCOCCOCCOS([O-])(=O)=O SXHLENDCVBIJFO-UHFFFAOYSA-M 0.000 description 1
- FWFUWXVFYKCSQA-UHFFFAOYSA-M sodium;2-methyl-2-(prop-2-enoylamino)propane-1-sulfonate Chemical compound [Na+].[O-]S(=O)(=O)CC(C)(C)NC(=O)C=C FWFUWXVFYKCSQA-UHFFFAOYSA-M 0.000 description 1
- OIYOMRFNKQEDEH-UHFFFAOYSA-M sodium;2-sulfanylidene-1,3-dihydrobenzimidazole-5-sulfonate;dihydrate Chemical compound O.O.[Na+].[O-]S(=O)(=O)C1=CC=C2NC(=S)NC2=C1 OIYOMRFNKQEDEH-UHFFFAOYSA-M 0.000 description 1
- FRTIVUOKBXDGPD-UHFFFAOYSA-M sodium;3-sulfanylpropane-1-sulfonate Chemical compound [Na+].[O-]S(=O)(=O)CCCS FRTIVUOKBXDGPD-UHFFFAOYSA-M 0.000 description 1
- IZUPJOYPPLEPGM-UHFFFAOYSA-M sodium;hydron;phthalate Chemical compound [Na+].OC(=O)C1=CC=CC=C1C([O-])=O IZUPJOYPPLEPGM-UHFFFAOYSA-M 0.000 description 1
- UPUIQOIQVMNQAP-UHFFFAOYSA-M sodium;tetradecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCOS([O-])(=O)=O UPUIQOIQVMNQAP-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical class C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229940075620 somatostatin analogue Drugs 0.000 description 1
- 229940075554 sorbate Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 235000011071 sorbitan monopalmitate Nutrition 0.000 description 1
- 239000001570 sorbitan monopalmitate Substances 0.000 description 1
- 229940031953 sorbitan monopalmitate Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002370 sotalol Drugs 0.000 description 1
- ZBMZVLHSJCTVON-UHFFFAOYSA-N sotalol Chemical compound CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 ZBMZVLHSJCTVON-UHFFFAOYSA-N 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 229960000268 spectinomycin Drugs 0.000 description 1
- 229960000887 spectinomycin hydrochloride Drugs 0.000 description 1
- 229940063675 spermine Drugs 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960000912 stanozolol Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229960001203 stavudine Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 238000012414 sterilization procedure Methods 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940120904 succinylcholine chloride Drugs 0.000 description 1
- YOEWQQVKRJEPAE-UHFFFAOYSA-L succinylcholine chloride (anhydrous) Chemical compound [Cl-].[Cl-].C[N+](C)(C)CCOC(=O)CCC(=O)OCC[N+](C)(C)C YOEWQQVKRJEPAE-UHFFFAOYSA-L 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 1
- 229960004739 sufentanil Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004306 sulfadiazine Drugs 0.000 description 1
- 229960004673 sulfadoxine Drugs 0.000 description 1
- 229960005158 sulfamethizole Drugs 0.000 description 1
- VACCAVUAMIDAGB-UHFFFAOYSA-N sulfamethizole Chemical compound S1C(C)=NN=C1NS(=O)(=O)C1=CC=C(N)C=C1 VACCAVUAMIDAGB-UHFFFAOYSA-N 0.000 description 1
- 229960003329 sulfinpyrazone Drugs 0.000 description 1
- MBGGBVCUIVRRBF-UHFFFAOYSA-N sulfinpyrazone Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(=O)C1CCS(=O)C1=CC=CC=C1 MBGGBVCUIVRRBF-UHFFFAOYSA-N 0.000 description 1
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 229960002573 sultiame Drugs 0.000 description 1
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
- 229960003708 sumatriptan Drugs 0.000 description 1
- 235000020238 sunflower seed Nutrition 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229940104261 taurate Drugs 0.000 description 1
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 1
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 description 1
- 229960003865 tazobactam Drugs 0.000 description 1
- 229960003947 tedizolid phosphate Drugs 0.000 description 1
- QCGUSIANLFXSGE-GFCCVEGCSA-N tedizolid phosphate Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](COP(O)(O)=O)C2)=O)F)=N1 QCGUSIANLFXSGE-GFCCVEGCSA-N 0.000 description 1
- 229960005240 telavancin Drugs 0.000 description 1
- ONUMZHGUFYIKPM-MXNFEBESSA-N telavancin Chemical compound O1[C@@H](C)[C@@H](O)[C@](NCCNCCCCCCCCCC)(C)C[C@@H]1O[C@H]1[C@H](OC=2C3=CC=4[C@H](C(N[C@H]5C(=O)N[C@H](C(N[C@@H](C6=CC(O)=C(CNCP(O)(O)=O)C(O)=C6C=6C(O)=CC=C5C=6)C(O)=O)=O)[C@H](O)C5=CC=C(C(=C5)Cl)O3)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](NC(=O)[C@@H](CC(C)C)NC)[C@H](O)C3=CC=C(C(=C3)Cl)OC=2C=4)O[C@H](CO)[C@@H](O)[C@@H]1O ONUMZHGUFYIKPM-MXNFEBESSA-N 0.000 description 1
- 108010089019 telavancin Proteins 0.000 description 1
- 229960003250 telithromycin Drugs 0.000 description 1
- LJVAJPDWBABPEJ-PNUFFHFMSA-N telithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)[C@@H](C)C(=O)O[C@@H]([C@]2(OC(=O)N(CCCCN3C=C(N=C3)C=3C=NC=CC=3)[C@@H]2[C@@H](C)C(=O)[C@H](C)C[C@@]1(C)OC)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O LJVAJPDWBABPEJ-PNUFFHFMSA-N 0.000 description 1
- 229960003188 temazepam Drugs 0.000 description 1
- 210000001738 temporomandibular joint Anatomy 0.000 description 1
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- 229960002722 terbinafine Drugs 0.000 description 1
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 description 1
- 229960000351 terfenadine Drugs 0.000 description 1
- FBWNMEQMRUMQSO-UHFFFAOYSA-N tergitol NP-9 Chemical compound CCCCCCCCCC1=CC=C(OCCOCCOCCOCCOCCOCCOCCOCCOCCO)C=C1 FBWNMEQMRUMQSO-UHFFFAOYSA-N 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 239000004250 tert-Butylhydroquinone Substances 0.000 description 1
- 235000019281 tert-butylhydroquinone Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229950007324 tesicam Drugs 0.000 description 1
- 229950000997 tesimide Drugs 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 229960004989 tetracycline hydrochloride Drugs 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- GEKDEMKPCKTKEC-UHFFFAOYSA-N tetradecane-1-thiol Chemical compound CCCCCCCCCCCCCCS GEKDEMKPCKTKEC-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 230000003685 thermal hair damage Effects 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
- NMFKEMBATXKZSP-UHFFFAOYSA-N thieno[3,2-b]thiophene Chemical compound S1C=CC2=C1C=CS2.S1C=CC2=C1C=CS2 NMFKEMBATXKZSP-UHFFFAOYSA-N 0.000 description 1
- XCTYLCDETUVOIP-UHFFFAOYSA-N thiethylperazine Chemical compound C12=CC(SCC)=CC=C2SC2=CC=CC=C2N1CCCN1CCN(C)CC1 XCTYLCDETUVOIP-UHFFFAOYSA-N 0.000 description 1
- 229960004869 thiethylperazine Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940035024 thioglycerol Drugs 0.000 description 1
- 229960004906 thiomersal Drugs 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- AIUHRQHVWSUTGJ-UHFFFAOYSA-N thiopropazate Chemical compound C1CN(CCOC(=O)C)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 AIUHRQHVWSUTGJ-UHFFFAOYSA-N 0.000 description 1
- 229960004728 thiopropazate Drugs 0.000 description 1
- 229960002784 thioridazine Drugs 0.000 description 1
- LJJKNPQAGWVLDQ-SNVBAGLBSA-N thiorphan Chemical compound OC(=O)CNC(=O)[C@@H](CS)CC1=CC=CC=C1 LJJKNPQAGWVLDQ-SNVBAGLBSA-N 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 239000003769 thromboxane A2 receptor blocking agent Substances 0.000 description 1
- 229960000874 thyrotropin Drugs 0.000 description 1
- 230000001748 thyrotropin Effects 0.000 description 1
- 229940034208 thyroxine Drugs 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- 229960004659 ticarcillin Drugs 0.000 description 1
- 229960004075 ticarcillin disodium Drugs 0.000 description 1
- 229960002010 ticlatone Drugs 0.000 description 1
- POPOYOKQQAEISW-UHFFFAOYSA-N ticlatone Chemical compound ClC1=CC=C2C(=O)NSC2=C1 POPOYOKQQAEISW-UHFFFAOYSA-N 0.000 description 1
- 229960005001 ticlopidine Drugs 0.000 description 1
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 1
- 229960004089 tigecycline Drugs 0.000 description 1
- 229960005221 timolol maleate Drugs 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- 229960004402 tiopronin Drugs 0.000 description 1
- 229960005013 tiotixene Drugs 0.000 description 1
- COKMIXFXJJXBQG-NRFANRHFSA-N tirofiban Chemical compound C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 COKMIXFXJJXBQG-NRFANRHFSA-N 0.000 description 1
- 229960003425 tirofiban Drugs 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- 229960002277 tolazamide Drugs 0.000 description 1
- OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
- FUSNMLFNXJSCDI-UHFFFAOYSA-N tolnaftate Chemical compound C=1C=C2C=CC=CC2=CC=1OC(=S)N(C)C1=CC=CC(C)=C1 FUSNMLFNXJSCDI-UHFFFAOYSA-N 0.000 description 1
- 229960004880 tolnaftate Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000008181 tonicity modifier Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
- PHTUQLWOUWZIMZ-GZTJUZNOSA-N trans-dothiepin Chemical compound C1SC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 PHTUQLWOUWZIMZ-GZTJUZNOSA-N 0.000 description 1
- 239000003558 transferase inhibitor Substances 0.000 description 1
- 229960003741 tranylcypromine Drugs 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 229960002368 travoprost Drugs 0.000 description 1
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 description 1
- 229960001332 trenbolone acetate Drugs 0.000 description 1
- 229950007229 tresperimus Drugs 0.000 description 1
- 229940126307 triamcinolone acetate Drugs 0.000 description 1
- 229960001288 triamterene Drugs 0.000 description 1
- 229960003386 triazolam Drugs 0.000 description 1
- JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 description 1
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 229950000451 triflumidate Drugs 0.000 description 1
- ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 description 1
- 229960002324 trifluoperazine Drugs 0.000 description 1
- 229960001032 trihexyphenidyl Drugs 0.000 description 1
- QDWJJTJNXAKQKD-UHFFFAOYSA-N trihexyphenidyl hydrochloride Chemical compound Cl.C1CCCCC1C(C=1C=CC=CC=1)(O)CCN1CCCCC1 QDWJJTJNXAKQKD-UHFFFAOYSA-N 0.000 description 1
- 229940035722 triiodothyronine Drugs 0.000 description 1
- CHQOEHPMXSHGCL-UHFFFAOYSA-N trimethaphan Chemical compound C12C[S+]3CCCC3C2N(CC=2C=CC=CC=2)C(=O)N1CC1=CC=CC=C1 CHQOEHPMXSHGCL-UHFFFAOYSA-N 0.000 description 1
- 229940035742 trimethaphan Drugs 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960004490 trimethoprim hydrochloride Drugs 0.000 description 1
- 229940113165 trimethylolpropane Drugs 0.000 description 1
- 229960002431 trimipramine Drugs 0.000 description 1
- ZSCDBOWYZJWBIY-UHFFFAOYSA-N trimipramine Chemical compound C1CC2=CC=CC=C2N(CC(CN(C)C)C)C2=CC=CC=C21 ZSCDBOWYZJWBIY-UHFFFAOYSA-N 0.000 description 1
- 125000005580 triphenylene group Chemical group 0.000 description 1
- JQZIKLPHXXBMCA-UHFFFAOYSA-N triphenylmethanethiol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(S)C1=CC=CC=C1 JQZIKLPHXXBMCA-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 229940048081 trisodium ethylenediamine disuccinate Drugs 0.000 description 1
- QEHXDDFROMGLSP-VDBFCSKJSA-K trisodium;(2s)-2-[2-[[(1s)-1-carboxy-2-carboxylatoethyl]amino]ethylamino]butanedioate Chemical compound [Na+].[Na+].[Na+].OC(=O)C[C@@H](C([O-])=O)NCCN[C@H](C([O-])=O)CC([O-])=O QEHXDDFROMGLSP-VDBFCSKJSA-K 0.000 description 1
- UXQDWARBDDDTKG-UHFFFAOYSA-N tromantadine Chemical compound C1C(C2)CC3CC2CC1(NC(=O)COCCN(C)C)C3 UXQDWARBDDDTKG-UHFFFAOYSA-N 0.000 description 1
- 229960000832 tromantadine Drugs 0.000 description 1
- 238000009810 tubal ligation Methods 0.000 description 1
- JFJZZMVDLULRGK-URLMMPGGSA-O tubocurarine Chemical compound C([C@H]1[N+](C)(C)CCC=2C=C(C(=C(OC3=CC=C(C=C3)C[C@H]3C=4C=C(C(=CC=4CCN3C)OC)O3)C=21)O)OC)C1=CC=C(O)C3=C1 JFJZZMVDLULRGK-URLMMPGGSA-O 0.000 description 1
- 229960001844 tubocurarine Drugs 0.000 description 1
- 229960002859 tulathromycin Drugs 0.000 description 1
- 239000002447 tumor necrosis factor alpha converting enzyme inhibitor Substances 0.000 description 1
- 229950007816 turosteride Drugs 0.000 description 1
- WMPQMBUXZHMEFZ-YJPJVVPASA-N turosteride Chemical compound CN([C@@H]1CC2)C(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)N(C(C)C)C(=O)NC(C)C)[C@@]2(C)CC1 WMPQMBUXZHMEFZ-YJPJVVPASA-N 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 150000003673 urethanes Chemical class 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 229960001572 vancomycin hydrochloride Drugs 0.000 description 1
- LCTORFDMHNKUSG-XTTLPDOESA-N vancomycin monohydrochloride Chemical compound Cl.O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 LCTORFDMHNKUSG-XTTLPDOESA-N 0.000 description 1
- 229950007952 vapiprost Drugs 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
- 229960003819 vecuronium Drugs 0.000 description 1
- BGSZAXLLHYERSY-XQIGCQGXSA-N vecuronium Chemical compound N1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 BGSZAXLLHYERSY-XQIGCQGXSA-N 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229940087652 vioxx Drugs 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- 229920003176 water-insoluble polymer Polymers 0.000 description 1
- 238000009941 weaving Methods 0.000 description 1
- 229940124024 weight reducing agent Drugs 0.000 description 1
- 239000013585 weight reducing agent Substances 0.000 description 1
- 210000003857 wrist joint Anatomy 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229940118318 xanthinol Drugs 0.000 description 1
- 229920001221 xylan Polymers 0.000 description 1
- 150000004823 xylans Chemical class 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
- 229960002300 zeranol Drugs 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 description 1
- 229950009819 zotarolimus Drugs 0.000 description 1
- 239000002888 zwitterionic surfactant Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/713—Double-stranded nucleic acids or oligonucleotides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/14—Liposomes; Vesicles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/41—Particular ingredients further characterized by their size
- A61K2800/413—Nanosized, i.e. having sizes below 100 nm
Definitions
- the present disclosure relates generally to functionalized polymers including crosslinked embodiments thereof, and methods for preparation and uses thereof.
- the polymers of the present disclosure provide useful properties that are not available from polymers currently available.
- Hyaluronic acid is a non-sulphated glycosaminoglycan (GAG) and is composed of repeating polymeric disaccharides of D-glucuronic acid and N-acetyl-D-glucosamine linked by a glucuronidic 0 ( 1— > 3) bond.
- Native HA is hydrophilic which makes it challenging to incorporate into a local hydrophobic environment.
- HA can be modified to incorporate hydrophobic groups onto the HA backbone. Ester bonds have been used to accomplish this modification with the HYAFF® (Anika) being one example of a hydrophobically modified HA. These materials are hydrolytically unstable and thus, prolonged exposure to an aqueous environment can be detrimental to the properties of these materials.
- the present disclosure provides polymers, method of making polymers, methods of using polymers and compositions that comprise polymers.
- the present disclosure provides compositions that comprise at least one type of lipid and a derivative of a hyaluronic acid polymer in which one or more hydroxyl groups of the hyaluronic acid is a modified hydroxyl group, wherein the derivative of hyaluronic acid has the structure HA- (OC ⁇ CHzSOzCHzCFh-X-Ri-Yjn where HA hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic with at least four consecutive -CH2- groups, a cholesterol moiety, a lipid moiety or aromatic moiety and n is the number of modified hydroxyl groups where n is an integer and n > 1, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a
- compositions that comprise at least one type of lipid anda derivative of hyaluronic acid, in which two or more hydroxyl groups of the hyaluronic acid are modified hydroxyl groups, wherein the derivative of hyaluronic acid has the structure (Y-R2-X-CH2CH2SO2CH2CH2O) m -HA-(OCH2CH2SO2CH 2 CH2-X-Ri-Y)n where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic, a cholesterol moiety, a lipid moiety or aromatic moiety, R2 is a substituted or unsubstituted C5-C20 aliphatic or aromatic moiety wherein Ri and R2 are different from each other, wherein n and m are each integers, and n > land m > 1, and Y is H; a carboxylic acid group, or
- the present disclosure provides derivatives of hyaluronic acid such as described above, wherein 0.25-50% of a sum of the hydroxyl groups and the modified hydroxyl groups are a modified hydroxyl group.
- compositions comprising derivatives of hyaluronic acid such as described above and at least one type of lipid and wherein at least one lipid is a phospholipid.
- the present disclosure provides compositions of derivatives of hyaluronic acid such as described above, and further comprising at least one type of lipid and and cholesterol.
- the present disclosure provides compositions of derivatives of hyaluronic acid such as described above and a lipid wherein the compositions are in the form of liposomes.
- compositions of derivatives of hyaluronic acid such as described above that are a component of a polymeric particle.
- compositions that comprises a derivative of a hyaluronic acid polymer in which one or more hydroxyl groups of the hyaluronic acid is a modified hydroxyl group, wherein the derivative of hyaluronic acid has the structure HA- (OCH2CH 2 SO2CH 2 CH2-X-Ri-Y)n where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic with at least four consecutive -CH 2 - groups, a cholesterol moiety, a lipid moiety or aromatic moiety and n is the number of modified hydroxyl groups where n is an integer and n > 1, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group; and an oil phase.
- compositions that comprise a derivative of hyaluronic acid, in which two or more hydroxyl groups of the hyaluronic acid are modified hydroxyl groups, wherein the derivative of hyaluronic acid has the structure (Y-R 2 -X- CH2CH2SO2CH2CH2O)m-HA-(OCH2CH2SO2CH 2 CH2-X-Ri-Y)n where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic, a cholesterol moiety, a lipid moiety or aromatic moiety, R 2 is a substituted or unsubstituted C5-C20 aliphatic, a cholesterol moiety, a lipid moiety or aromatic moiety wherein Ri and R 2 are different from each other, wherein n and m are each integers, and n > land m > 1, and Y is H; a carb
- compositions that comprises a derivative of a hyaluronic acid polymer in which one or more hydroxyl groups of the hyaluronic acid is a modified hydroxyl group, wherein the derivative of hyaluronic acid has the structure HA- (OCH 2 CH 2 SO 2 CH 2 CH 2 -X-Ri-Y) n where HA hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted Cs-C 2 o aliphatic with at least four consecutive -CH 2 - groups, a cholesterol moiety, a lipid moietyor aromatic moiety and n is the number of modified hydroxyl groups where n is an integer and n > 1, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group; a water phase and a
- compositions that comprise a derivative of hyaluronic acid, in which two or more hydroxyl groups of the hyaluronic acid are modified hydroxyl groups, wherein the derivative of hyaluronic acid has the structure (Y-R 2 -X- CH2CH2SO2CH2CH2O)m-HA-(OCH2CH2SO2CH 2 CH2-X-Ri-Y)n where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic, a cholesterol moiety, a lipid moiety or aromatic moiety, R 2 is a substituted or unsubstituted C5-C20 aliphatic or aromatic moiety wherein Ri and R 2 are different from each other, wherein n and m are each integers, and n > land m > 1, and Y is H; a carboxylic acid group, or a salt or ester;
- the present disclosure provides a derivative of a hyaluronic acid, prepared by any of the processes identified herein.
- the present disclosure provides a crosslinked polymer prepared by any of the processes disclosed herein.
- the present disclosure provides a composition comprising a derivative of a hyaluronic acid, wherein the composition may further comprise an excipient.
- the present disclosure provides a composition comprising a crosslinked hyaluronic acid derivative e.g. a crosslinked polymer of a derivative of hyaluronic acid, as described herein.
- a composition may further comprise an excipient.
- Each of the compositions disclosed herein may optionally include one or more of a pharmaceutically acceptable synthetic polymer, thermosreversible polymer, biodegradable polymer, buffer, complexing agent, tonicity modulator, ionic strength modifier, solvent, anti-oxidant, preservative, viscosity modifier, pH modifier, surfactant, emulsifier, phospholipid, stabilizer and porogen.
- a composition as disclosed herein may further comprise a biologically active agent.
- Derivatized polymers and compositions comprising one or more derivatized polymers disclosed herein exhibit shear thinning.
- Shear thinning is the non-Newtonioan behavior of fluids whose viscosity decreases under shear strain.
- the present disclosure provides method of using the polymers and compositions as disclosed herein.
- the present disclosure provides the following aspects:
- a wound healing device comprising a composition as described herein.
- a method for wound healing comprising administering to a subject in need thereof an effective amount of a composition as described herein.
- a bulking agent comprising a composition as described herein.
- a dermal filler comprising a composition as described herein.
- a method of filling a void in a subject in need thereof comprising administering to the subject a dermal filler as described herein.
- a viscosupplement comprising a composition as described herein.
- a method of relieving joint pain in a subject in need thereof comprising administering to the subject a viscosupplement as described herein.
- a method of preventing surgical adhesions in a subject in need thereof comprising administering the subject an effective amount of a composition as described herein.
- a tissue sealant comprising a composition as described herein.
- a method of sealing tissue in a subject in need thereof comprising administering to the subject an effective amount of a tissue sealant as described herein.
- a method of treating bacterial vaginosis in a subject in need thereof comprising administering to the subject an effective amount of a composition as described herein.
- a nasal treatment device comprising a composition as described herein.
- a method of treacling a nasal condition in a subject in need thereof comprising administering the subject an effective amount of a composition as described herein.
- An eye drop comprising a composition as described herein.
- a method of treating an ocular condition in a subject in need thereof comprising administering the subject an effective amount of a composition as described herein.
- a punctal plug comprising a composition as described herein.
- a method of treating mucocitis in a subject in need thereof comprising administering to the subject an effective amount of a composition as described herein.
- An anti-bacterial formulation comprising a composition as described herein.
- An ear treatment device comprising a composition as described herein.
- a method of treating an ear condition comprising administering to a subject in need thereof an effective amount of a composition as described herein.
- a method of drug delivery to a subject in need thereof comprising administering to the subject an effective amount of a composition as described herein that comprises the drug.
- a biopsy plug comprising a composition as described herein.
- a plug for female sterilization comprising a composition as described herein.
- a method of female sterilization to a subject in need thereof comprising administering to the subject an effective amount of a composition as described herein.
- a tissue scaffold comprising a composition as described herein.
- the method of supporting tissue growth in a subject in need thereof comprising implanting in the subject a tissue scaffold as described herein.
- a burr hole plug comprising a composition as described herein.
- a nerve guide comprising a composition as described herein.
- a vaginal lubricant comprising a composition as described herein.
- a coating for a device comprising a composition as described herein.
- a cosmetic comprising a composition described herein.
- a liposome comprising a composition described herein.
- a lipid nanoparticle comprising a composition described herein.
- An emulsion comprising a composition herein.
- a method for coating a device comprising applying a coating as described herein onto a surface of the device.
- a method of administering an injectable formulation comprising a composition as described herein to treat cancer comprising a composition as described herein to treat cancer.
- a method of administering an injectable formulation comprising a composition as described herein to elicit an immune response comprising a composition as described herein to elicit an immune response.
- a method of administering an injectable formulation comprising a composition as described herein to enable RNA to enter a cell comprising a composition as described herein to enable RNA to enter a cell.
- a method for additive manufacturing comprising a polymer as described herein, e.g., a derivative of hyaluronic acid as described herein, or prepared by a process as described herein, to provide a derivative of the polymer, e.g., hyaluronic acid, and depositing the derivative onto a substrate to provide an article formed by additive manufacturing.
- An electrospun material or article comprising a composition as described herein.
- a method for producing an electrospun material or article comprising producing, with an electrospinning device, a material or an article comprising a derivative of hyaluronic acid described herein.
- a textile material or article comprising a composition as described herein.
- a method for producing a textile material or article comprising producing, with an electrospinning device, a material or an article comprising a derivative of hyaluronic acid described herein.
- FIG. 1 shows exemplary reactions of the present disclosure.
- FIG. 2 shows exemplary reactions of the present disclosure.
- the present disclosure provides functionalized HA polymers and copolymers, and including compositions thereof.
- a functionalized polymer or copolymer refers to an organic polymer/copolymer comprising hydroxyl groups, and optionally also comprises on or more functional groups, including, but not limited to, a carboxylic acid, amine , or sulfonic acid group.
- the term "polymer” includes copolymer unless specifically noted, and those of skill in the
- the present disclosure provides a derivative of HA in which one or more hydroxyl groups of the HA is a modified hydroxyl group, wherein the derivative of hyaluronic acid has the structure HA-(OCH2CH2SO2CH2CH2-X-Ri-Y) n where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic with at least four consecutive -CH2- groups, a cholesterol moiety, a lipid moiety or an aromatic moiety and n is the number of modified hydroxyl groups where n is an integer and n > 1, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, a phosphonic acid group or a salt thereof, or an amine group.
- the present disclosure provides a derivative of HA in which two or more hydroxyl groups of the hyaluronic acid are modified hydroxyl groups, wherein the derivative of hyaluronic acid or other polyhydric polymer has the structure (Y-R2-X- CH2CH2SO2CH2CH2O)m-HA-(OCH2CH2SO2CH 2 CH2-X-Ri-Y)n where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic, a cholesterol moiety, a lipid moiety or aromatic moiety, R 2 is a substituted or unsubstituted C5-C20 aliphatic or aromatic moiety wherein Ri and R2 are different from each other, wherein n and m are each integers, and n > land m > 1, and Y is H; a carboxylic acid group, or a salt or ester; thereof; a
- the substituted or unsubstituted aliphatic is a Cs to C20 aliphatic In an aspect, the substituted or unsubstituted aliphatic, is a Cg to C20 aliphatic. In another aspect, the substituted or unsubstituted aliphatic, is a C10 to C20 aliphatic. In another aspect, the C5 to C20 aliphatic has at least four consecutive -CH 2 - groups. In another aspect, the C 8 to C 2 o aliphatic has at least six consecutive -CH2- groups. In another aspect, the C10 to C20 aliphatic has at least six consecutive -CH 2 - groups. In another aspect, the Cw to C 2 o aliphatic has at least eight consecutive -CH2- groups.
- the present disclosure provides derivatives of HA such as described above, which are further characterized by the derivative wherein 0.25-50% of a sum of the hydroxyl groups and the modified hydroxyl groups are a modified hydroxyl group.
- the present disclosure comprises crosslinked polymers comprising a reaction product of a derivative of hyaluronic acid, and optionally, may comprise a crosslinking agent, wherein as used herein, a crosslinking agent may comprise known crosslinking agents, such as crosslinking compounds, for example, OH crosslinking agents or vinyl crosslinking agents, FeCI 3 , or compounds and/or energy sources, including but not limited to, UV and related photoinitiator compounds.
- crosslinking agents such as crosslinking compounds, for example, OH crosslinking agents or vinyl crosslinking agents, FeCI 3 , or compounds and/or energy sources, including but not limited to, UV and related photoinitiator compounds.
- the present disclosure utilizes HA with one or more available hydroxyl groups and reacts one or more of those hydroxyl groups under specific conditions as disclosed herein with divinyl sulfone such that only one of the vinyl groups of the divinyl sulfone reacts with the hydroxyl group via an addition reaction to form an ether bond between the polysaccharide and the residue of the divinyl sulfone.
- the degree of reaction can range from about 0.5% to about 50% of the available hydroxyl groups. At higher substitution, i.e., around 50%, some degree of crosslinking will typically occur.
- the present disclosure provides vinyl sulfone substituted polysaccharide polymers with minimal to no crosslinking, or polysaccharide polymers that have a level of vinyl sulfone substitution crosslinking due to double reaction of the divinyl sulfone (i.e., reaction of both ethenyl groups of the DVS with hydroxyl groups).
- the residual vinyl group of the vinyl sulfone can be then reacted with a compound that has a reactive thiol group. This reaction occurs via a Michael addition between the residual vinyl group of the divinyl sulfone and the free thiol group such that a thioether bond is formed.
- a degree of substitution the degree of substitution, the thiol derivative used, the sequence of the reactions and the replication of reactions that provide a large variety of derivatives of polymeric polyhydric alcohols and compositions contemplated and disclosed herein.
- Derivatives of HA can be crosslinked in many different ways, and compositions comprising such crosslinked derivatives of HA are contemplated and disclosed herein.
- the derivatives of HA and compositions thereof have numerous medical and non-medical applications. Methods of use or treatment disclosed herein may comprise derivatives of HA and compositions thereof. Derivatives of HA may also be referred to herein as HA derivatives.
- HA and compositions thereof of the present disclosure are prepared as described herein.
- a HA polymer having hydroxyl groups is combined with divinyl sulfone (DVS) under suitable reaction conditions.
- Those reaction conditions include a suitable pH of the solution, where the reaction typically occurs under basic conditions, e.g., a pH of 11-14, or 12-13, e.g., about 12.3.
- the reaction conditions include a suitable solvent, where water or DMSO are suitable solvents, e.g., the reaction may be conducted in water.
- the description of reaction conditions may further include stirring the reacting mixture, e.g., stirring with a stirring rate of > 200 rpm (rotations per minute), such as 250-800 rpm.
- reaction conditions may include specification of the relative amounts of DVS and polymer (e.g., polysaccharide) that are combined, where these relative amounts may be expressed in terms of moles of DVS to moles of repeat unit in the polymer.
- the method for preparing the functionalized polymer may be described in terms of the ratio of DVS:polymer repeat unit, where this ratio may be at least 0.5:1, e.g., up to about 5:1, or up to about 7.5:1, or up to about 10:1, or up to about 15:1, or up to about 20:1.
- the present disclosure provides a process wherein HA that has an available hydroxyl group, i.e., a hydroxyl group that is capable of undergoing a reaction with divinyl sulfone, is reacted with DVS under basic conditions. If the conditions are selected appropriately, the reaction can be controlled such that one of the vinyl groups of the divinyl sulfone will react with a free hydroxyl group of the polysaccharide such that the polysaccharide does not crosslink to such an extent that it forms a hydrogel.
- the reaction may be performed under basic conditions with a pH of greater than 11.
- the pH is in the range of 12.0 to 13.5.
- the pH is in the range is in the 12.0 to 12.5 range.
- the pH range is in the 12.2 to 12.7 range.
- the molar ratio of the divinyl sulfone to that of the polysaccharide repeat units is greater than 1. In one aspect, the molar ratio of the divinyl sulfone to that of the polysaccharide repeat units is greater than 5. In one aspect, the molar ratio of the divinyl sulfone to that of the polysaccharide repeat units is greater than 7.
- the molar ratio of the divinyl sulfone to that of the polysaccharide repeat units is greater than 10. In one aspect, the molar ratio of the divinyl sulfone to that of the polysaccharide repeat units is greater than 15. In an aspect, the molar ratio of the divinyl sulfone to that of the polysaccharide repeat units is from about 1 to about 20, or from about 1 to about 15, or from about 1 to about 10, or from about 1 to about 5, or from about 5 to about 20, or from about 5 to about 15, or from about 5 to about 10, of from about 10 to about 20, or from about 10 to 15, or is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
- the reaction mixture may be stirred.
- Methods and devices for adequate mixing are known to those of skill in the art.
- the rotational speed of the mixing impellor may be controlled.
- the revolutions per minute (rpm) of the mixing impellor may be in the range of 200 to 400 rpm.
- the revolutions per minute (rpm) of the mixing impellor may be in the range of 400 to 600 rpm.
- the revolutions per minute (rpm) of the mixing impellor may be in the range of 600 to 800 rpm.
- the amount of substitution accomplished may be controlled, in part, by the duration of exposure of the polysaccharide to the divinyl sulfone at a pH of greater than 11 (reaction time).
- reaction time can range from 10 seconds through to 60 minutes.
- reaction time can be in the range of 2 minutes to 35 minutes.
- reaction time can be in the range of 4 minutes to 30 minutes, or from 20 minutes to 60 minutes, from 15 minutes to 20 minutes, from 5 minutes to 10 minutes, from 10 seconds to 30 seconds, from 30 second to 1.5 minutes, and ranges thereinbetween
- the solvent that can be used for the reaction can be water, water with an ionic modifier, forexample NaCI, a combination of water and a water-miscible solvent.
- Water miscible solvents can include but are not limited to methanol, ethanol, isopropanol, dimethyl formamide (DMF), acetone, 1,4-dioxane, pyridine, dimethyl sulfoxide (DMSO), tetra hydrofuran (THF) and acetonitrile.
- the temperature of the reaction mixture can also be used to influence the amount of substitution of the polysaccharide by the divinyl sulfone.
- the reaction mixture can be maintained at a temperature that is lower than 25°C so as to reduce the rate of the reaction. This can enable lower substitution levels for the same duration as compared to room temperature or it can allow for a longer reaction time that that at room temperature to yield a similar amount of substitution.
- the temperature can be in the 15°C to 20 °C range.
- the reaction mixture can be in the 10°C to 15°C range.
- the temperature can be in the 2 °C to 10°C range.
- the temperature can be increase above 25°C so as to provide shorter reaction times as compared to 25°C to get similar amounts of substitution or to get greater substitution as compared to 25°C for an equivalent amount of reaction time.
- the reaction mixture can be in the 28°C to 35°C range.
- the reaction mixture can be in the 36°C to 50°C range.
- the reaction mixture can be in the 51°C to 75°C range.
- the amount of substitution as measured by the molar ratio of the attached vinyl group from the divinyl sulfone to the polysaccharide repeat unit, can be greater than 5%. In one aspect, for polysaccharides with at least one hydroxyl group, the amount of substitution is in the range of 5% to 35%. In another aspect, for polysaccharides with at least one hydroxyl group, the amount of substitution is in the range of 36% to 70% range. In another aspect, for polysaccharides with at least one hydroxyl group, the amount of substitution is in the range of 71% to 100% range. In another aspect, for polysaccharides with at least two hydroxyl groups, the amount of substitution is in the range of 101% to 200% range.
- the molecular weight of the HA can be selected. Molecular weights from 1,000 to 5,000,000 may be used. In one aspect, the HA has a molecular weight of over 1,000. In another aspect, the HA has a molecular weight in the range of 1,000 to 10,000. In another aspect, the HA has a molecular weight in the range of 10,000 to 50,000. In another aspect, the HA has a molecular weight in the range of 50,000 to 200,000. In another aspect, the HA has a molecular weight in the range of 200,000 to 600,000. In an aspect, the HA has a molecular weight in the range of 600,000 to 1,000,000. In an aspect, the HA has a molecular weight in the range of 1,000,000 to 2,500,000. In yet another aspect, the HA has a molecular weight in the range of 2,500,000 to 5,000,000. The molecular weight can be measured by known methods, including, but not limited to, gel permeation chromatography or intrinsic viscosity.
- a nucleophile e.g., a thiol derivative
- R 1 is substituted or unsubstituted C5-C20 aliphatic, a cholesterol moiety, a lipid moiety or aromatic
- R 2 is substituted or unsubstituted C5-C20 aliphatic or aromatic
- X is a nucleophilic group
- Y is selected from carboxylic acid, sulfonic acid and hydroxyl.
- the nucleophile contains a thiol group as X in a thiol derivative.
- the thiol derivative can be a single compound or a mixture of thiol compounds. Examples are alkyl thiols, which may be, e.g., linear, branched, or cyclic, such as methanethiol, ethanethiol, etc.
- the thiol may be an aryl thiol, a thiol-containing cholesterol derivative, a thiol containing lipid, a charged thiol, a polymeric thiol, peptides with thiol groups, proteins with thiol groups, heterocycles with thiol groups, drugs, e.g., active pharmaceutical ingredients, that contain thiol groups, growth factors with thiol groups, and biologically active agents with thiol groups.
- thiol compounds that can be used in the present disclosure are compounds that contain at least one free thiol group that is capable of reaction with a vinyl sulfone group via a Michael addition reaction.
- the thiol compound may be identified by the formula RiSH or R2SH, where Ri and R2 may be an aliphatic or aromatic moiety, either of which may have one or more substituents, e.g., be a substituted aliphatic moiety or a substituted aromatic moiety.
- An aliphatic moiety refers to an alkyl or cycloalkyl moiety, either having 1-20 carbon atoms.
- Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to the specified number of carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.
- the alkyl group has 1 carbon.
- the alkyl group has 2 carbons.
- the alkyl group has 3 carbons. In one aspect the alkyl group has 4 carbons. In one aspect the alkyl group has 4 carbons. In one aspect the alkyl group has 5 carbons. In one aspect the alkyl group has 6 carbons. Two or more of these aspects may be combined to describe derivatives of the disclosure.
- Cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond.
- Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically herein, a cycloalkyl group may be optionally substituted by one or more substituents independently selected at each occurrence.
- An aromatic moiety refers to a carbocyclic aromatic moiety, a.k.a., an aryl moiety, or a heteroaromatic moiety, a.k.a., a heteroaryl moiety, either having 1-20 carbon atoms, the heteroaromatic moiety having at least one heteroatom selected from sulfur, oxygen and nitrogen.
- Aryl refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. In one aspect the aryl ring system has 6 to 12 carbon atoms. In one aspect the aryl ring system has 6 to 10 carbon atoms.
- the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
- Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
- an aryl group may be optionally substituted by one or more substituents independently selected at each occurrence.
- Heteroaryl refers to "aryl” as defined herein, wherein the aromatic ring includes one or more heteroatoms, preferably selected from N, O and S.
- a heteroaryl radical refers to an aromatic ring system radical wherein the ring atoms are selected from carbon, nitrogen, oxygen and sulfur, and include at least one of nitrogen, oxygen and sulfur.
- the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
- the heteroaryl radical is a 5-, 6- or 7-membered heteroaryl group.
- heteroaryl groups include 5-membered rings, such as pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, furan, thiophene, selenophene, oxazole, isoxazole, 1,2-thiazole, 1,3- thiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole.
- 5-membered rings such as pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, furan, thiophene, selenophene, oxazole, isoxazole, 1,2-thiazole, 1,3-
- the heteroaryl group may be a 6- membered ring, such as pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, 1,2,4,5-tetrazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, or fused rings including a 6- membered ring such as indole, isoindole, indolizine, indazole, benzimidazole, benzotriazole, purine, naphthimidazole, phenanthrimidazole, pyridimidazole, pyrazinimidazole, quinoxalinimidazole, benzoxazole, naphthoxazole, anthroxazole, phenanthroxazole, isoxazole, benzothiazole, benzofuran, isobenzofuran, dibenzofuran
- a substituted C 5 -C 20 aliphatic or aromatic moiety refers to a C 5 -C 20 aliphatic or aromatic moiety having one or more substituents, where a "substituent” refers to monovalent group that may be attached to a mentioned moiety.
- a "substituted phenyl” refers to a phenyl ring having 1, 2, 3 or 4 substituents attached to the phenyl ring.
- Substituents may be selected from halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 hydroxyalkyl, -OH, -O(Ci-C 6 alkyl), -O(Ci- Cehaloalkyl), -OfCi-Cehydroxyalkyl), -S(Ci-Cealkyl), -S(Ci-Ceha loa Ikyl), -S(Ci-Cehydroxyalkyl), cyano, amino (-NH 2 ), formyl (-CHO), carboxylic acid (-COOH), carboxylate ester (-COOR where R is a Ci-Cio alkyl group).
- thiol compounds include alkyl thiols which may be linear, branched or cyclic, aryl thiols, charged thiol compounds, polymers that contain a free thiol, peptides that contain a free thiol, heterocycles that contain a free thiol, drugs or biologically active compounds with a free thiol, growth factors with a free thiol, antibodies or antibody fragments with a free thiol and proteins with a free thiol.
- thiol compounds include, and are not limited to thiophenol, 2-phenylethanethiol, triphenylmethanethiol, 4-methylbenzenethiol, 4- aminothiophenol, 2-aminothiophenol, 4-methoxy-a-toluenethiol, 4-nitrothiophenol, 4-tert- butylbenzenethiol, 2-mercapto-2-phenylacetic acid, 4-mercaptobenzoic acid, 2- mercaptobenzoic acid (thiosalicylic acid), 3-mercapto-l-propanol, l-mercapto-2-propanol, 4- mercapto-l-butanol, 3-mercapto-l-hexanol, 6-mercapto-l-hexanol, 8-mercapto-l-octanol, 9- mercapto-l-nonanol, 11-mercapto-l-undecanol, 4-mercapto-4-methylp
- 2-mercapto-5-nitrobenzimidazole 2-mercapto-5-benzimidazolesulfonic acid sodium salt dihydrate, 3-mercapto-N-nonylpropionamide, 2-mercapto-4-methylpyrimidine hydrochloride, 2- mercapto-2-phenylacetic acid, 2-mercapto-3-(trifluoromethyl)pyridine, 2-mercapto-N-m- tolylacetamide, 4-mercapto-4-methylpentan-2-ol, thiocholesterol (CAS 1249-81-6), and Cholesterol-PEG-thiol, l,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-N-
- thiol compounds (mercaptopropyl), l,2-Dipalmitoyl-sn-Glycero-3-Phosphothioethanol, and 1,2-Distearoyl-sn- glycero-3-phosphoethanolamine-N-N-(mercapto-polyethyleneglycol) [DSPE-PEG-SH] are exemplary thiol compounds.
- Polymers with free thiols include but are not limited to Thiol-PEG3-phosphonic acid, poly(L-lactide), thiol terminated 5000, poly(L-lactide), thiol terminated 2500, PEG-SH 3000, PEG-SH 5000, thiol-functionalized hyaluronic acid, thiol-functionalized chitosan, thiol functionalized alginate, thiol functionalized dextran, thiol functionalized chondroitin sulfate and thiol functionalized carboxymethyl cellulose.
- thiol functionalized hyaluronic acid examples include but are not limited to a thiol group linked to hyaluronic acid through a hydrazide compound as described in US 7,981,871, through carbodiimide groups as described in US 6,884,788, as well as those described in US 8,124,757.
- thiol functionalized chitosan examples include but are not limited to chitosancysteine conjugates, chitosan-thioglycolic acid conjugates and chitosan-4-thio-butylamidine conjugates.
- Non-degradable thiol functionalized polymers include but are not limited to polycarbophil-cysteamine conjugates, polycarbophil-cysteine conjugates, and poly(acrylic acid) - homocysteine conjugates.
- Thiolated peptides or peptides that contain at least of free thiol include but are not limited to a cysteine terminated peptide containing residues 73-92 of the knuckle epitope of BMP-2 (N->C: KIPKASSVPTELSAISTLYLSGGC), thiolated gelatin (see, e.g., U.S. Pat. Nos.
- Thiol containing drugs include but are not limited to Captopril, Thiorphan, Tiopronin and Penicillamine.
- Suitable proteins that contain a cysteine group include but are not limited to an IL-3 variant (see, e.g., US 5,166,322), an IL-2 variant (see, e.g., US 5,206,344), protease nexin-1 varients (see, e.g., US 5,766,897), Cysteine variants of granulocyte-macrophage colonystimulating factor (see, e.g., US 7,148,333; and Bioconjugate Chem., 2005, 16 (5), pp 1291-1298; DOI: 10.1021/bc050172r), cysteine modified maize ribosome-inactivating protein (maize RIP) [see, e.g., Toxins 2016, 8, 298; doi:10.3390/toxins8100298], cysteine analog of erythropoietin [see, e.g., Int J Nanomedicine.
- an IL-3 variant see, e.g.
- Suitable growth factors that comprise a free thiol group include but are not limited to Cysteine Analogs of Human Basic Fibroblast Growth Factor (hbFGF) [see, e.g., Tropical Journal of Pharmaceutical Research October 2014; 13 (10): 1601-1607; http://dx.doi.Org/10.4314/tjpr.vl3il0.5; and Protein Expr. Purif. 2006 Jul;48(l):24- 7https://doi.org/10.1016/j.pep.2006.02.002]).
- hbFGF Cysteine Analogs of Human Basic Fibroblast Growth Factor
- the HA derivative has the structure HA-(OCH2CH2SO2CH2CH2-X-RI- Y) n where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic moiety which has at least 4 consecutive -CH2- groups , a cholesterol moiety, a lipid moiety or aromatic moiety and n is the number of modified hydroxyl groups where n is an integer and n > 1, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine.
- the HA derivative has the structure HA-(OCH2CH2SO2CH2CH2-X-Ri) n where X is S, Ri is a substituted or unsubstituted C5-C20 aliphatic moiety which has at least 4 consecutive -CH 2 - groups and n is the number of modified hydroxyl groups where n is an integer and n > 1.
- the hyaluronic acid detivative is the product of a reaction of a vinylsulfone derivatized HA with 1-octadecanethiol, 1-hexadecanethiol, 1-dodecanethiol, 1- undecanethiol, 1-decanethiol, 1-nonanethiol, 1-octanethiol, 1-heptanethiol, 1-hexanethiol, or 1- pentanethiol.
- the HA derivative has the structure HA-(OCH2CH2SO2CH2CH2-X-Ri) n where X is S, Ri is a cholesterol moiety and n is the number of modified hydroxyl groups where n is an integer and n > 1.
- the hyaluronic acid detivative is the product of a reaction of a vinylsulfone derivatized HA with thiocholesterol (CAS 1249-81-6) or cholesterol-PEG-thiol compound.
- the HA derivative has the structure HA-(OCH2CH2SO2CH2CH2-X-Ri) n where X is S, Ri is a lipid moiety and n is the number of modified hydroxyl groups where n is an integer and n > 1.
- the hyaluronic acid detivative is the product of a reaction of a vinylsulfone derivatized HA with l,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-N- (mercaptopropyl) [DSPE-SH], l,2-Dipalmitoyl-sn-Glycero-3-Phosphothioethanol or 1,2- Distearoyl-sn-glycero-3-phosphoethanolamine-N-N-(mercapto-polyethyleneglycol) [DSPE-PEG- SH] compound.
- the present disclosure provides a derivative hyaluronic acid, in which two or more hydroxyl groups of the hyaluronic acid are modified hydroxyl groups, wherein the derivative of hyaluronic acid has the structure (R2-X-CH2CH2SO2CH2CH 2 O)m-HA- (OCH 2 CH 2 SO 2 CH 2 CH 2 -X-Ri) n where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic with at least four consecutive -CH2- groups, or a lipid or a cholesterol comprising moiety, R 2 is a substituted or unsubstituted Cs-C 2 o aliphatic with at least four consecutive -CH2- groups or a lipid or a cholesterol comprising moiety wherein Ri and R 2 are different from each other, wherein n and m are each integers, and n > land m > 1.
- the present disclosure provides a process comprising: reacting hydroxyl groups attached to a polymer, such as hydroxyl groups on hyaluronic acid (HA), with divinyl sulfone (DVS) to provide a first derivative of the polymer; and reacting the first derivative of the polymer with a nucleophile of a formula selected from X-R 1 and X-R 2 -Y to provide a second derivative of the polymer.
- the first derivative will have a number of ethenyl (vinyl) groups attached to sulfone groups that are, in turn attached through an oxyethylene group to the polymer.
- Some or all of these vinyl groups are reacted with a nucleophilic compound, e.g., a thiol derivative as described above.
- the extent to which these vinyl groups undergo reaction may be specified according to the present disclosure.
- all or nearly all, e.g., 100%, or 99- 100%, or 98-100%, or 97-100%, or 96-100%, or 95-100% are substituted with the thiol derivative.
- partial substitution is achieved with the thiol derivative, e.g., 1-95% of the free available vinyl sulfone groups are derivatized.
- the number of vinyl sulfone residues, that are attached to the polysaccharide, and that can be reacted with a free thiol-containing compound can be altered.
- the percentage of the residual vinyl sulfone groups reacted with a free thiol-containing compound can vary from 1% to 100%.
- NMR such as X H-NMR, can be used to determine the percent substitution.
- 100% substitution of the vinyl sulfone groups occurs, essentially all of the available vinyl sulfone residues attached to the polysaccharide have reacted with the free thiol -containing compound to form a thioether linkage.
- the polysaccharide will comprise both vinyl sulfone groups as well as compounds attached via a thioether linkage.
- the fraction of the repeat units of the polysaccharide that are substituted through a thioether linkage can be determined by NMR, usually 1 H-NMR.
- the percent substitution, often calculated on a molar basis, can range from l% to 100%, preferably greater than 10% and more preferably greater than 25%.
- the Michael addition reaction of a free-thiol compound with the vinyl sulfone residue on the polysaccharide can occur using a single free-thiol containing compound.
- the addition reaction can occur using more than 1 free thiol- containing compound in which the free thiol-containing compounds are different from each other.
- Fig. 1 illustrates options for performing polymer derivatization reactions according to the present disclosure.
- "A" identifies a hydroxyl-substituted polymer such as hyaluronic acid or polyvinylalcohol.
- the polymer A may be characterized in terms of molecular weight.
- the intrinsic viscosity of polymer A is used as an indicator of the polymer's molecular weight.
- the intrinsic viscosity of polymer A is in the range of 0.3 to 3 m 3 /Kg.
- chromatography is used to characterize the molecular weight of polymer A.
- the weight average molecular weight of polymer A is approximately 75,000 Da to 3,000,000 Da.
- Polymer B identifies the product of reacting polymer Awith divinyl sulfone (DVS) under basic conditions (NaOH in an aqueous solvent).
- Polymer B is a compound of the present disclosure.
- Polymer B is shown as two polymer As joined together through X linkages, where X represents a diethyl sulfone group of the formula -CH2-CH2-SO2-CH2-CH2- which is linked at each of its ends to an oxygen atom that was formerly part of a hydroxyl group from polymer A.
- the X groups are created by reaction of two hydroxyl groups reacting with two vinyl groups of divinyl sulfone.
- the X groups are shown linking together two different A polymers, however an X group may also link together two hydroxyl groups of a single A polymer to provide a polymer B according to the present disclosure.
- Fig. 1 contains three X linkages between two A polymers in addition to three VS groups.
- a VS group is the result of a divinyl sulfone substitution reaction with a hydroxyl group of an A polymer.
- one and only one of the two vinyl groups of a divinyl sulfone molecule reacts with one and only one hydroxyl group of a polymer A.
- hydroxy-substituted polymers (“A") are reacted with divinyl sulfone (DVS) to create linkages between two or more hydroxyl groups in a mixture of hydroxyl substituted polymer chains, and additionally to create vinyl sulfone substituents on one or more hydroxyl-substituted polymer chains (shown as polymer B in Fig. 1).
- DVS divinyl sulfone
- the polymer B still contains unreacted hydroxyl groups.
- the addition of DVS will consume at least 5%, or least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80% of those initial hydroxyl groups in the formation of X and VS groups present in polymer B.
- the number of hydroxyl groups present after reaction of DVS may also, or alternatively be described in terms of the residual hydroxyl groups, so that at least 15%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80% of the initial hydroxyl groups are still present in polymer B.
- the number of hydroxyl groups present in polymer B may also be expressed as a range of the initial number of hydroxyl group present in polymer A, e.g., the conversion of polymer A to polymer B may consume 5-10% of the available hydroxyl groups, or in other aspects, 5-15%, or 5-20%, or 5-25%, or 5-30%, or 5-35%, or 10-15%, or 10-20%, or 10-25%, or 10-30%, or 10-35%, or 10-40% of the initially available hydroxyl groups.
- the polymer B contains both X and VS substituents.
- the polymer B contains both X and VS substituents in a molar ratio of where the number of VS groups exceeds the number of X groups.
- the number of X groups exceeds the number of VS groups.
- the X groups provide at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or at least 90% of the total number of X and VS groups.
- polymer B may serve as a reactant to create either polymer C or polymer D, each of which is a polymer according to the present disclosure.
- a mixture of nucleophilic compounds represented as RiSH and R2SH in Fig. 2 is reacted with polymer B.
- RiSH nucleophilic compound
- a single nucleophilic compound represented as RiSH in Fig. 2 is reacted with polymer B.
- the present disclosure provides polymer B, polymer C, polymer D as well as reactions to create polymer B from polymer A, reactions to create polymer C from polymer B, and reactions to create polymer D from polymer B.
- each of polymers A, B and C is a derivatized hyaluronic acid.
- Polymer D contains X moieties which link together two polymer A chains.
- polymer D contains Z-S-Ri moieties which are created by the reaction of the vinyl sulfone (VS) groups of polymer B with thiol compound RiSH to provide -O-CH2-CH2-SO2-CH2-CH2- S-Ri moieties, which are abbreviated as Z-S-Rl moieties in Fig. 2.
- the present disclosure provides polymer D having a mixture of X groups and Z-S-Ri groups.
- X groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the X and Z-S-Ri groups.
- Z-S-Ri groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the X and Z-S-Ri groups.
- the present disclosure provides polymer E having a structure as set forth in Fig. 1. In one aspect, the present disclosure provides polymer F having a structure as identified in Fig. 1. In another aspect, the present disclosure provides polymer G having a structure as identified in Fig. 1. In yet another aspect, the present disclosure provides polymer H having a structure as identified in Fig. 1.
- polymer A may be reacted with divinyl sulfone under basic conditions to provide polymer E.
- polymer E may be formed from polymer A by reaction of the hydroxyl groups of polymer A with divinyl sulfone (DVS) to convert them to vinyl sulfone (VS) groups.
- VDS divinyl sulfone
- VS vinyl sulfone
- the VS groups constitute at least 80%, or at least 85%, or at least 90%, or at least, 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.9% of the total of X and VS groups present in polymer E.
- Polymer E may be reacted with RiSH, optionally in combination with one or more additional nucleophilic compounds, e.g., R 2 SH, to provide polymers of structure F, G or H, as shown in Fig. 1.
- Polymer F has a mixture of residual VS groups and Z-S-Rl groups formed by reaction of VS groups with RiSH.
- the charge of RiSH is less than 100% of the total number of VS groups present on polymer E, calculated on a molar basis. Based on this stoichiometry, not all of the VS groups will react with RiSH molecules, and accordingly polymer F has a mixture of VS and Z-S-Ri groups.
- VS groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the VS and Z-S-Rl groups.
- Z-S-Ri groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the VS and Z-S-Rl groups.
- Polymer G has a majority of Z-S-Ri groups, and little or no X and VS groups.
- the Z-S-Ri groups constitute at least 80%, or at least 85%, or at least 90%, or at least, 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.9% of the total of X, VS and Z-S-Ri groups present in polymer G.
- Polymer G may be formed by reaction of polymer E and an equimolar or molar excess of RiSH molecules, based on the moles of available VS groups.
- Polymer H has a majority of Z-S-Ri and Z-S-R2 groups, and little or no X and VS groups.
- the total of the Z-S-Ri and Z-S-R 2 groups constitute at least 80%, or at least 85%, or at least 90%, or at least, 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.9% of the total of X, VS, Z-S-Ri and Z-S-R 2 groups present in polymer H.
- Polymer H may be formed by reaction of polymer E and a mixture of nucleophilic compounds, e.g., a mixture of RiSH and R2SH, such as shown in Fig. 1.
- the present disclosure provides polymer I having a structure as set forth in Fig. 1.
- the present disclosure provides polymer J which is a gel prepared as shown in Fig. 1.
- the present disclosure provides polymer K which is a gel prepared as shown in Fig. 1.
- Polymer I has a mixture of Z-S-Ri and VS substituents.
- the present disclosure provides polymer I having a mixture of VS groups and Z-S-Ri groups.
- VS groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the VS and Z-S-Ri groups.
- Z-S-Ri groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the VS and Z-S-Ri groups.
- Polymer I may be formed by reacting polymer G with divinylsulfone under basic conditions. This reaction converts hydroxyl groups present on polymer G (not shown in Fig. 1) to vinyl sulfone (VS) groups.
- Polymers J and K are gels which may be prepared as shown in Fig. 1.
- Polymer J may be formed by crosslinking polymer G.
- Polymer K may be formed by crosslinking polymer H.
- the present disclosure provides polymer L having a structure as set forth in Fig. 1.
- the present disclosure provides polymer M having a structure as identified in Fig. 1.
- the present disclosure provides polymer N having a structure as identified in Fig. 1.
- Polymer L as shown in Fig. 1 contains a mixture of Z-S-Ri and Z-S-R2 substituents. Polymer L may additionally contain hydroxyl substituents (not shown). In various aspects, the total of the Z-S-Ri and Z-S-R2 groups constitute at least 80%, or at least 85%, or at least 90%, or at least, 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.9% of the total of X, VS, Z-S-Ri and Z-S-R2 groups present in polymer L. Polymer L may be formed by reaction of polymer F, which contains Z-S-Ri and VS substituents, with R 2 SH, to thereby convert the VS substituents to Z-S-R2 substituents.
- Polymer M as shown in Fig. 1 contains a mixture of X, Z-S-Ri and Z-S-R 2 groups. Polymer M may additionally contain hydroxyl substituents (not shown). Polymer M may be
- T1 formed by adding a crosslinker, such as divinylsulfone, to Polymer L that contains residual hydroxyl groups.
- the crosslinker creates X groups between hydroxyl groups present on polymer L.
- Polymer N as shown in Fig. 2 contains a mixture of Z-S-Ri and -R- groups, where an R group forms a linkage between different polymer A chains.
- the R groups may be introduced by reacting a precursor polymer, such as polymer F or other polymer containing VS groups, with a polyfunctional nucleophile, such as R(SH)n where n is greater than or equal to 2.
- R(SH)n R represents an aliphatic or aromatic group that is optionally substituted.
- the present disclosure provides polymer O which is a gel that may be formed as shown in Fig. 1.
- polymer P which is a gel that may be formed as shown in Fig. 1.
- Polymer O may be formed from Polymer I by a two-step reaction.
- polymer I is reacted with a nucleophilic compound, such as RiSH, to convert VS groups present on polymer I, into the corresponding Z-S-Ri groups.
- a crosslinker X is added to this intermediate polymer to provide a polymeric gel O.
- Polymer P may be formed from Polymer I by a two-step reaction.
- polymer I is reacted with a nucleophilic compound, such as R 2 SH, to convert VS groups present on polymer I, into the corresponding Z-S-R 2 groups.
- a crosslinker X is added to this intermediate polymer to provide a polymeric gel P.
- Polymer I may also serve as a precursor to a crosslinked polymer having -R- groups as the linkage between polymer chains.
- the R groups may be introduced by reacting a polymer I, or another polymer containing VS groups, with a polyfunctional nucleophile, such as R(SH)n where n is greater than or equal to 2.
- R(SH)n R represents an aliphatic or aromatic group that is optionally substituted.
- Fig. 2 illustrates options for performing polymer derivatization reactions according to the present disclosure.
- "A" identifies a hydroxyl-substituted polymer such as hyaluronic acid or polyvinylalcohol, which is likewise shown as polymer A in Fig. 2.
- the reaction schemes of Fig. 2 begin by performing a crosslinking reaction on polymer A, and achieving little or no conversion of hydroxyl groups on polymer A into an alternative monofunctional reactive group.
- polymer A may be reacted with a crosslinking agent, to provide a crosslinked version of polymer A, which is denoted as polymer B in Fig. 2.
- a crosslinking agent to provide a crosslinked version of polymer A, which is denoted as polymer B in Fig. 2.
- Suitable crosslinking reactions for hydroxyl-containing polymers are described elsewhere herein.
- the present disclosure provides polymer C having a structure as set forth in Fig. 2. In another aspect, the present disclosure provides polymer D having a structure as identified in Fig. 2. In yet another aspect, the present disclosure provides polymer E having a structure as identified in Fig. 2.
- Polymer C may be formed by reacting polymer B with divinyl sulfone (DVS) under basic conditions. Under these reaction conditions, hydroxyl groups present on polymer B (not shown) react with DVS to convert hydroxyl groups to VS groups.
- VS groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the VS and X groups present in polymer C.
- X groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the VS and X groups present in polymer C.
- Polymer D in Fig. 2 is a crosslinked polymer having both Z-S-Ri and Z-S-R 2 substituents.
- Polymer D may be formed by reacting polymer C with a mixture of nucleophilic compounds, such as RiSH and R 2 SH as shown in Fig. 2.
- the total of the Z-S-Ri and Z-S-R 2 groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the Z-S-Ri, Z- S-R 2 and X groups present in polymer D.
- X groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the Z-S-Ri, Z-S-R 2 and X groups present in polymer D.
- Polymer E in Fig. 2 is a crosslinked polymer having Z-S-Ri substituents (but not having any and Z-S-R 2 substituents).
- Polymer E may be formed by reacting polymer C of Fig. 2 with a nucleophilic compound, such as RiSH as shown in Fig. 2.
- the Z-S-Ri groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the Z-S-Ri and X groups present in polymer E.
- X groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the Z-S-Ri and X groups present in polymer E.
- polymers of structure F and of structure G as well as crosslinked gels thereof.
- Polymer F of Fig. 2 contains Z-S-Rl substituents
- polymer G contains a mixture of Z-S-Rl and Z-S-R2 substituents.
- Neither of polymers F or G are crosslinked polymers.
- each of polymers F and G may be treated with a crosslinking agent, or exposing to crosslinking conditions, to provide the corresponding crosslinked polymer which will have the form of a gel (identified as polymer H in Fig. 2).
- the present disclosure provides vinyl sulfone functionalization (i.e., derivatization) of a HA ("a first derivative") followed by reaction of the vinyl sulfone substituent with one or more free thiol-containing compounds ("a second derivative") which is in turn followed by a second functionalization (i.e., derivatization) reaction with divinyl sulfone to produce a polysaccharide that is functionalized with compounds through a thioether linkage as well as with vinyl sulfone functional groups ("a third derivative").
- the above compounds can be further reacted with free thiol-containing compounds ("a fourth derivative").
- the molar ratio of the free thiol-compound used for the reaction can be altered such that 1% to 100% of the second added vinyl sulfone functional groups are reacted.
- the free thiol-containing compound that is used in the second Michael addition reaction can be the same or it can be different from that used in the first Michael addition reaction.
- a single free thiol-containing compound can be used or a mixture of 2 or more different free-thiol containing compounds can be used.
- at least one additional round of vinyl sulfone / free thiol-containing compound reactions cycles can be performed using the same free-thiol containing compound or one or more different free- thiol containing compounds.
- a process of the present disclosure further comprises crosslinking a second derivative of the polymer, e.g., crosslinking by reacting the second derivative of the polymer with a crosslinking agent. Upon crosslinking, the second derivative is converted to a third derivative of the polymer, where the third derivative is a crosslinked polymer.
- a HA derivatized with one or more free-thiol containing compounds and also comprises residual available vinyl sulfone functional groups can undergo crosslinking by subjecting a solution of the derivatized HA to basic conditions that are sufficient to allow the residual available vinyl sulfone group to react with a hydroxyl group of the derivatized HA.
- the reaction pH is greater than 12 for example, in the 12.5 to 13.0 pH range.
- the amount of residual vinyl sulfone functional groups often measured as percent substitution as measured by ⁇ -NMR, reaction time and reaction temperature can be selected to achieve the desired degree of crosslinking.
- a HA derivatized with one or more free-thiol containing compounds and also comprises residual available vinyl sulfone functional groups can be mixed with a polysaccharide derivatized with one or more free-thiol containing compounds and also comprises residual available vinyl sulfone functional groups wherein the free-thiol containing compounds can be the same or different or a combination thereof.
- the resultant mixture can undergo crosslinking by subjecting a solution of the derivatized HA to basic conditions that are sufficient to allow the residual available vinyl sulfone group to react with a hydroxyl group of the polysaccharide.
- the reaction pH is greater than 12, for example, in the 12.2 to 13 pH range.
- the amount of residual vinyl sulfone functional groups, often measured as percent substitution as measured by ⁇ -NMR, reaction time and reaction temperature can be selected to achieve the desired degree of crosslinking.
- a non-derivatized polysaccharide can be added to the crosslinking reaction mixtures described above and the resultant mixture can undergo crosslinking by subjecting the solution of derivatized HA and the non-derivatized polysaccharide to basic conditions that are sufficient to allow the residual available vinyl sulfone groups of the derivatized HA to react with a hydroxyl group of the polysaccharide.
- the reaction pH is greater than 12, for example, in the 12.2 to 13 pH range.
- the amount of residual vinyl sulfone functional groups often measured as percent substitution as measured by 1H-NMR, reaction time and reaction temperature can be selected to achieve the desired degree of crosslinking.
- Crosslinking may be achieved by using an external crosslinking agent.
- a crosslinking agent is added to the second derivative of the polymer.
- exemplary crosslinking agents that could be used include: carbodiimides, bisepoxides, divinyl sulfone derivatives, and combinations thereof.
- Another suitable crosslinking agent is a multiple thioether derivative.
- at least 2 (could be 2, 3, 4, etc.) different thioether derivatives are combined with a crosslinking agent and conditions are adjusted such that the derivatives of polyhydric polymers become either fully crosslinked or partially crosslinked.
- exemplary crosslinking agents include, without limitation, carbodiimides, bisepoxides, divinyl sulfone derivatives and combination thereof.
- a HA derivatized with one or more free-thiol containing compounds can be crosslinked by adding a crosslinking agent and adjusting the pH of the reaction mixture such that the derivatized HA forms a crosslinked derivatized HA composition.
- Crosslinking agents that can be used include but are not limited to biscarbodiimides, bisepoxides, divinyl sulfone derivatives, di-isocyanates, dihalide chlorides, disuccinimidyl derivatives and combinations thereof.
- Biscarbodiimide compounds can include but are not limited to para-phenylenebis- (ethyl)-carbodiimide, 1,6-hexamethylene bis(ethylcarbodiimide), 1,8-octamethylene bis(ethylcarbodiimide), 1,10 decamethylene bis(ethylcarbodiimide), 1,12 dodecamethylene bis(ethylcarbodiimide), PEG-bis(propyl(ethylcarbodiimide)), 2,2'-dithioethyl bis(ethylcarbodiimde), l,l'-dithio-p-phenylene bis(ethylcarbodiimide); para-phenylene- bis(ethylcarbodiimide), and l,l'-dithio-m-phenylene bis(ethylcarbodiimide).
- the biscarbodiimide When utilizing a biscarbodiimide crosslinker, the biscarbodiimide is mixed with a buffered aqueous solution of the derivatized carboxylic acid containing polysaccharide.
- the target pH of the buffered solution can be between pH 5 and pH 6.5.
- Bisepoxide compounds can include but are not limited to 1,4-butanediol diglycidyl ether (BDDE), 1,2,7,8-diepoxyoctane (DEO), polyethylene glycol) diepoxide.
- the bisepoxide When utilizing a bisepoxide crosslinker, the bisepoxide is mixed with an aqueous solution of the derivatized polysaccharide and the pH is raised to a pH > 9. The reaction can be carried out at 40°C for greater than 4 hours to produce a crosslinked derivatized HA polymer.
- Divinyl sulfone crosslinking agents can include but are not limited to divinyl sulfone and poly(ethylene glycol) bisvinyl sulfone.
- reaction pH in an aqueous solution can be raised to a pH greater than 12 to effect crosslinking.
- the degree of crosslinking can be altered by changing the amount of crosslinking agent added, reaction time, the reaction pH and reaction temperature.
- a mixture of at least 2 different thioether derivatized HA can be mixed together, a crosslinking agent can be added and the reactions conditions adjusted such that the derivatized HA polymers are crosslinked.
- the relative ratios of the different derivatized HA can be altered such that crosslinked derivatized HA polymers with different properties are obtained. These properties include but are not limited to equilibrium swelling, swelling rate, drug release characteristics, elastic modulus, storage modulus, loss modulus, degradation, tensile strength, tissue adhesiveness and lubricity.
- derivatized HA polymers may also include compositions comprising one or more derivatized HA polymers.
- At least 2 different crosslinking agents can be used to crosslink the derivatized HA.
- two different crosslinking agents from the same group could be used to crosslink the derivatized HA polymers.
- divinyl sulfone and polyethylene glycol) bisvinyl sulfone or 1,4-butanediol diglycidyl ether (BDDE) and poly(ethylene glycol) diepoxide could be used.
- two different crosslinking agents from different groups could be used.
- divinyl sulfone and 1,4-butanediol diglycidyl ether (BDDE) may be used to crosslink the derivatized HA.
- the crosslinker can be added sequentially such that initial crosslinking occurs in the presence of the first crosslinked and then the second crosslinker is added such that secondary crosslinking occurs.
- the reaction conditions may be changed after the first crosslinking reaction and prior to the second crosslinking reaction. Reaction conditions such as temperature, pH, buffer, ionic strength and solvent composition can be altered.
- crosslinked derivatized HA polymers can be prepared though ionic crosslinking. This can be accomplished by mixing a derivatized polyhydric polymer of this disclosure that has a negative charge with a compound that has two or more positive charges.
- a solution of the derivatized HA polymer of this disclosure that has a negative charge can be prepared and then mixed with a solution of a compound that has two or more positive charges.
- Inorganic compounds that can be used include but are not limited to ferric chloride, aluminum chloride, chromium sulfate, and aluminum sulfate.
- Positively charged polymers that can be used include polymers that comprise more than two lysines, arginine or histadine amino acids, chitosan and chitosan derivatives, deacetylated hyaluronic acid, polyethyleneimine (PEI), poly(A/,A/-dimethylaminoethyl methacrylate), poly(4-vinylpyridine), polyethyleneglycolpolylysine block copolymers (PEG-PLL), dextran grafted polylysine copolymers, or combinations thereof.
- PEI polyethyleneimine
- PEG-PLL polyethyleneglycolpolylysine block copolymers
- dextran grafted polylysine copolymers or combinations thereof.
- the positively charged or the negatively charged polymer can first be applied. This can then be followed by application of the oppositely charged polymer such that at the interface of the two layers, ionic interactions occur such that the polymers are crosslinked together. In another aspect, the process can be repeated at least one more time.
- a second derivative of the polymer may be crosslinked via internal and external crosslinking.
- a polysaccharide derivatized with one or more free-thiol containing compound and also comprising residual available vinyl sulfone functional groups can be crosslinked in the presence of an external crosslinking agent.
- the reaction conditions can be adjusted such that the residual available vinyl sulfone groups and the added external crosslinked react simultaneously.
- divinyl sulfone can be added as the external crosslinker and then the pH can be increased to a pH > 12 which will result is crosslinking.
- the crosslinking via the residual available vinyl sulfone functional groups can take place first which is then followed by the addition of the external crosslinker.
- the reaction conditions for example pH
- the reaction conditions can be changed to effect the crosslinking reaction of the external added crosslinker.
- the pH of the derivatized HA that contains the residual available vinyl sulfone functional groups can be raised to a pH > 12.
- the pH can be changed to between pH 5 and pH 6.5 with a buffer and then biscarbodiimide crosslinker, for example para-phenylenebis-(ethyl)- carbodiimide, can be added to the reaction mixture and allowed to react until the desired level of crosslinking is obtained.
- the biscarbodimide crosslinking can take place first by adjusting the pH of the derivatized polysaccharide to between 5 and 6.5, adding the biscarbodiimide, allowing the crosslinking to proceed to the desired level, then raising the pH to pH > 12 to allow the residual vinyl sulfone functional groups to crosslink.
- a HA derivatized with one or more free-thiol containing compound and also comprises residual available vinyl sulfone functional groups can be crosslinked in the presence of an external crosslinking agent that has at least two free thiol functional groups. These free thiol groups may be positioned upon a central molecule, "C".
- the central molecule may be a linear or cyclic alkane, a polyethylene glycol (PEG) oliogomer or polymer, or any other such suitable central molecule.
- PEG-based crosslinking agents the PEG may be linear, branched (having two polymer arms), or multi-armed (e.g., having 3, 4, 5, 6, 7, 8 or more polymer arms).
- the central molecule will typically a linear PEG, a branched PEG having 2 arms, or a multi-armed PEG having PEG arms emanating from a central core.
- Illustrative cores for such multi-armed polymers include erythritol, pentaerythritol, trimethylolpropane, glycerol, glycerol dimer (3,3'-oxydipropane-l,2-diol), glycerol oligomers, sorbitol, hexaglycerol, and the like.
- Illustrative thiol crosslinking agents include PEG-dithiol (HS-PEG-SH), 3-arm PEG- tri-thiol (glycerine core), 4-arm PEG-tetrathiol (pentaerythritol core), or 8-arm PEG-octa-thiol (hexaglycerine core).
- the foregoing multi-armed PEG reagents may also have fewer than all arms functionalized with thiol. Additional suitable thiol reagents having PEG as the central molecule are available from Laysan Bio (Arab, Ala.), as well as aromatic dithiols such as those available from NanoScience.
- thiol crosslinking agents include dimercaptosuccinic acid, 2,3- dimercapto-l-propanesulfonic acid, Trimethylolpropane tris(3-mercaptopropionate), dithiol functionalized pluronics F127, dithiol functionalized F68, dihydrolipoic acid, peptides containing at least 2 cysteine amino acids, thiol functionalized dextran, and thiol-functionalized hyaluronic acid.
- the polymers of the present disclosure may be processed into numerous forms.
- exemplary compositions of the derivatized HA polymers include, but are not limited to, a solution, a suspension, an emulsion, a film, a gel, a coating on a surface of an article, an electrospun matrix, a microparticle, a fiber, a lyophilized solid, a rod, a disc, a gel, a powder or in a particulate form.
- a particulate form can be prepared by milling (e.g., jet milling, roller milling, cryomilling, mechanical milling) fragmentation, spray drying, precipitation or grinding.
- milling e.g., jet milling, roller milling, cryomilling, mechanical milling
- compositions of the derivatized HA polymer can be as a suspension, a film, an electrospun matrix, a fiber, a lyophilized solid, a rod, a disc, a gel, a powder or in a particulate form.
- the particulate form can be prepared by milling (jet milling, roller milling, cryomilling, mechanical milling) fragmentation, spray drying, precipitation or grinding.
- a solution of the derivatized HA polymer can be prepared by dissolving the derivatized HA polymer in an appropriate solvent or a combination of solvents.
- an appropriate solvent or a combination of solvents for example, water or a combination of water and water-miscible solvent can be used.
- Water-miscible solvents can include but are not limited to methanol, ethanol, isopropanol, dimethyl formamide (DMF) acetone, 1,4-dioxane, pyridine, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF) and acetonitrile.
- the prepared solutions can be sterilized by filtering through a 0.2 pm sterile filter.
- a solution can be prepared using one derivatized HA.
- the concentration of the prepared solutions can range from, e.g., 0.01% (w/v) to about 50% (w/v). In one aspect, the concentration is in the 0.1% (w/v) to 10% (w/v) range.
- a film of non-crosslinked derivatized HA polymers of this disclosure can be prepared by preparing a solution of the derivatized HA polymer. This solution can be then placed in a mold or drawn out on a surface using a gardner knife. The surface used can be glass, metal foil, stainless steel, Teflon, nylon, polyethylene, polypropylene or a release liner. The solvent can then be removed to form the film. The rate of solvent removal can be altered by using at least one of the following parameters: temperature, air or inert gas flow and pressure. To increase the rate of solvent evaporation, the temperature could be increased, the air or inert gas flow rate could be increased or the pressure could be decreased. A combination of these process could also be used.
- a film can comprise one of the derivatized HA polymers of this disclosure.
- the films can also comprise two or more different derivatized HA polymers of this disclosure.
- a composite film can be prepared by preparing a first film and then casting a second film on top of the first film.
- a composite film can be prepared by casting additional layers sequentially on top of the previous layer.
- the layers of the composite film can comprise the same derivatized HA polymer if the disclosure, different derivatized HA polymers of this disclosure or a combination thereof.
- Lyophilized forms of the non-crosslinked derivatized HA polymers of this disclosure can be prepared by making a solution of the derivatized HA polymer, freezing the solution and then placing the frozen derivatized HA polymer solution under a vacuum such that the solvent is sublimed off to leave the derivatized HA polymer composition in the solid form.
- a lyophilized form of the derivatized HA polymer composition of this disclosure can comprise one of the derivatized HA polymers of this disclosure.
- the lyophilized form of the derivatized HA polymers and/or compositions of this disclosure can comprise two or more different derivatized HA polymers of this disclosure.
- a lyophilized composition of one or more derivatized HA polymers can comprise one or more derivatized HA polymers in addition to an additive such as chitosan or chitosan derivatives (e.g. chitosan HCL, chitosan acetate, or chitosan lactate).
- the form of the lyophilized derivatized HA polymer compositions may be dependent on the form of the container into which the solution was poured.
- the form of the lyophilized derivatized HA polymer may be dependent on the form of the contained into which the solution was poured and frozen.
- the form can be a rectangle, square, disk, triangle, trapezoid, rod or any other form in which a mold can be made.
- Derivatized HA polymer compositions of this disclosure can be in the form of a powder or particulate.
- the powder or particulate may be obtained directly via precipitation.
- a powder or particulate form can also be obtained through a milling, grinding, spray drying or fragmentation process.
- Compositions, including but not limited to, films, precipitated derivatized HA polymers, dried derivatized HA polymers and/or compositions, lyophilized derivatized HA polymers and/or compositions, or derivatized HA polymers and/or compositions, dried in a form can be further process via a milling process (jet milling, roller milling, cryomilling, mechanical milling), a grinding or a fragmentation process.
- a milling process jet milling, roller milling, cryomilling, mechanical milling
- Derivatized HA polymer composition with particle size in the range of 100 nm to 5 mm can be prepared.
- Specific size ranges of the powdered or particulate derivatized HA polymer compositionsof this disclosure can be prepared by separating the derivatized HA polymer composition particles according to size using sieves.
- the distribution of particle sizes can be broad with a standard deviation of the average size of greater than 40%.
- the distribution of particle sizes can be narrow with a standard deviation of the average size of less than 30%.
- the final powdered or particulate form of the derivatized HA polymer compositions of this disclosure can comprise a single distribution of average particle sizes or it can comprise two or more distributions of particles prepared by mixing particles of different average particle size.
- a derivatized HA polymer compositions of this disclosure can be formed into a solid form by preparing a solution of a derivatized HA polymer in a solvent that can be removed, pouring this solution into a mold of a specific shape and then removing the solvent such that a solid form of derivatized HA polymer composition is obtained.
- the molds used can be of various shapes and can include but are not limited to cubes, rectangles, rods, semi-circular rode and tubes. The solid derivatized HA polymer composition of this disclosure can then be removed from the mold.
- a derivatized HA polymer composition of the disclosure can be processed into an electrospun matrix.
- a solution of the derivatized HA polymer of the disclosure is prepared.
- the solvent used can be an organic solvent, water or a combination thereof.
- water/ethanol or water/dimethylformamide (DMF) solvent mixtures can be used.
- Solutions with a concentration of 0.5 to 5% (w/v) can be prepared.
- the solution that is to be electrospun can be placed in a syringe with a needle. The syringe is then placed in a syringe pump.
- the needle can have a blunt end and an inner diameter in the range of 0.25 to 1 mm.
- the needle and collection plate are attached to a high voltage supply.
- a voltage is then applied to the system.
- the applied voltage can be in the lOkV to 45 kV.
- the syringe pump can extrude the solution.
- the flow rate of the syringe pump can be in the range of lOuL/min to 1000 uL/min.
- the collector plate can be static, rotating or moving in a specific linear direction to give the fibers some directional orientation.
- the shape of the collector plate can be varied with the collector plate having but not limited to the following shapes: a flat surface, a textured surface, a curved surface, a square rod, a rectangular rod, a round mandrel, an oval mandrel, a semi-circular mandrel or a combination of these shapes.
- the temperature of the solution can be controlled as well as the collection plate and the surrounding environment.
- the distance of the needle tip to the collector plate can be altered.
- the distance of the needle tip to the collector plate can be in the 2-20 cm range.
- the collection plate can also be submerged in or sprayed with a solvent that assists in the precipitation of the newly spun fibers. For example, an ethanol bath may be used during the electrospinning of hyaluronic acid derivatized HA polymers and/or compositions of this disclosure.
- a derivatized HA polymer of the disclosure can be incorporated through a solution coating or submersion of an electrospun matrix produced in the following manner. In this process, single or multiple polymer solutions are prepared.
- the polymers used can be biodegradable polymers then include but are not limited to polyester, polyanhydride, polyorthoester, polycarbonate, poly-ester-co-carbonate), polyhydroxybutyrates or combinations thereof.
- Biodegradable polymers can include polylactice-co-glycolide copolymers, polydioxanone, polylactide-trimethylene carbonate copolymers as well as copolymers that comprise repeat units derived from at least one of the following monomers: l-lactide, dl-lactide, glycolide, trimethylene carbonate, epsilon-caprolactone, p-dioxanone and a morpholinedione [00194]
- the solvents used can be an organic solvent, water or a combination thereof. For example, HFIP, DMSO, NMP, Chloroform, acetic acid, ethanol, dimethylformamide (DMF) solvents or mixtures of solvents can be used.
- Solutions with a concentration of 0.5 to 25% (w/v) can be prepared.
- the solution that is to be electrospun can be placed in a syringe with a needle.
- the syringe is then placed in a syringe pump.
- the needle can have a blunt end and an inner diameter in the range of 0.25 to 2.5 mm.
- the needle and collection plate are attached to a high voltage supply.
- a voltage is then applied to the system.
- the applied voltage can be in the lOkV to 45 kV.
- the syringe pump can extrude the solution.
- the flow rate of the syringe pump can be in the range of 0.0001 uL/min to 423 mL/min.
- the collector plate can be static, rotating or moving in a specific linear direction to give the fibers some directional orientation.
- the shape of the collector plate can be varied with the collector plate having but not limited to the following shapes: a flat surface, a textured surface, a curved surface, a square rod, a rectangular rod, a round mandrel, an oval mandrel, a semi-circular mandrel or a combination of these shapes.
- the distance of the needle tip to the collector plate can be altered.
- the distance of the needle tip to the collector plate can be in the 2-50 cm range.
- the collection plate can also be submerged in or sprayed with a solvent that assists in the precipitation of the newly spun fibers. For example, an ethanol bath may be used during the electrospinning of hyaluronic acid based derivatized HA polymers of this disclosure.
- the derivatized HA polymers and/or compositionsof this disclosure can be processed into the form of a fiber.
- a solution of a derivatized HA polymer of the disclosure is prepared. This solution is then extruded through an orifice to produce a solvent containing fiber. This fiber can be extruded into one or more solvent baths that assists in the formation of the fiber.
- the fiber is then dried to produce a solid fiber.
- the fibers can be prepared as a monofilament or a multifilament fiber. In one aspect, this fiber can then be further processed through an annealing step.
- a fiber may be further processed by knitting or weaving, resulting in a knitted or woven composition.
- the knitted or woven composition can be in the form of a mesh.
- the mesh can comprise a single derivatized HA polymer and/or composition of this disclosure.
- the mesh can comprise 2 or more different derivatized HA polymers and/or compositions, of this disclosure.
- the fiber can be further processed into a braid.
- the braid can comprise a single derivatized HA polymer and/or composition of this disclosure.
- the braid can comprise 2 or more different derivatized HA polymers and/or compositions of this disclosure.
- the derivatized HA polymers and/or compositions used can result in the mesh or braid having properties that change as a function of time. This includes degradation rates, water absorption, elongation, elastic modulus, tensile strength, physical shape, lubricity, cell adhesion, or a combination of these properties.
- the knitted, woven or braided derivatized HA polymers and/or compositions can be manufactured in the presence of a degradable or non-degradable non-polysaccharide based material.
- a degradable or non-degradable non-polysaccharide based material include polyethylene, polypropylene, polyethylene terephthalate (PET), polytetrafluorethylene (PTFE), nylon, polyurethane, polyester, polyanhydride, polyorthoester, polycarbonate, poly-ester-co-carbonate), polyhydroxybutyrates or combinations thereof.
- Crosslinked polymers of the present disclosure may take various physical forms, including particle, film, lyophilized sponge, powder, particulate (e.g., milled, fragmented, precipitated and ground particulates), and may be formed in-situe, e.g., spray or liquid.
- particulate e.g., milled, fragmented, precipitated and ground particulates
- a film of crosslinked derivatized HA polymers and/or compositions of this disclosure can be prepared by preparing a solution of the derivatized HA polymer and/or compositions to be crosslinked.
- the derivatized HA polymer can be crosslinked by known methods and/or those described herein.
- the crosslinker Prior to the final crosslinking process, the crosslinker is added, if required, and the solution pH can be adjusted to initiate the crosslinking process. This solution can be then placed in a mold or drawn out on a surface, for example, using a Gardner knife.
- the surface used can be glass, metal foil, stainless steel, Teflon, nylon, polyethylene, polypropylene or a release liner. The solution is then allowed to crosslink to form a gel.
- a film of crosslinked derivatized HA polymers of this disclosure can be prepared by preparing a solution of the derivatized HA polymer to be crosslinked.
- the derivatized HA polymer can be crosslinked by one of the methods described above. This solution can be then placed in a mold or drawn out on a surface using a Gardner knife.
- the surface used can be glass, metal foil, stainless steel, Teflon, nylon, polyethylene, polypropylene, polystyrene, or a release liner.
- the crosslinking agent may be added prior to or following drying of the derivatized HA polymer to form a crosslinked film or gel.
- the rate of residual solvent removal can be altered by using at least one of the following parameters: temperature, air or inert gas flow and pressure.
- temperature could be increased, the air or inert gas flow rate could be increased or the pressure could be decreased.
- a combination of these process could also be used.
- temperature could be decreased, the air or inert gas flow rate could be reduced or the pressure could be increased.
- a combination of these process could also be used.
- a film can comprise one of the derivatized HA polymers of this disclosure.
- the films can also comprise two or more different derivatized HA polymers of this disclosure.
- a composite film can be prepared by preparing a first film and then casting a second film on top of the first film.
- a composite film can be prepared by casting additional layers sequentially on top of the previous layer.
- the layers of the composite film can comprise the same derivatized HA polymer if the disclosure, different derivatized HA polymers of this disclosure or a combination thereof.
- the films can comprise both crosslinked and non-crosslinked derivatized HA polymers of this disclosure.
- Lyophilized forms of the crosslinked derivatized HA polymers of this disclosure can be prepared by making a solution of the derivatized HA polymer, crosslinking the derivatized HA polymer, freezing the crosslinked derivatized HA polymer composition and then placing the frozen derivatized HA polymer composition under a vacuum such that the solvent is sublimed off to leave the resulting derivatized HA polymer composition in the solid form.
- a lyophilized form of the derivatized HA polymer of this disclosure can comprise one of the derivatized HA polymers of this disclosure.
- the lyophilized form of the derivatized HA polymer of this disclosure can comprise two or more different derivatized HA polymers of this disclosure.
- the form of the lyophilized derivatized HA polymer composition is dependent on the form of the container into which the solution was poured and frozen.
- the form can be a rectangle, square, disk, triangle, trapezoid, rod or any other form in which a mold can be made.
- the lyophilized derivatized HA polymer compositions of this disclosure can comprise both crosslinked and noncrosslinked derivatized HA polymers of this disclosure.
- the lyophilized derivatized HA polymer composition, crosslinked or non-crosslinked can be rehydrated in the presence of other materials disclosed herein.
- a second lyophilization step may be performed on a rehydrated derivatized HA polymer composition.
- the solution used to rehydrate the first lyophilized derivatized HA polymer can be crosslinked.
- the derivatized HA polymer composition produced from the second crosslinking step can be lyophilized to produce a dry porous derivatized HA polymer composition.
- the derivatized HA polymer solution may be directly combined with a biologically active agent prior to lyophilization.
- the lyophilized polyhydric polymer composition s may be combined with a biologically active agent through a rehydration process, which follows the first lyophilization, which may or may not be be followed by further drying.
- Crosslinked derivatized HA polymer compositions of this disclosure can be in the form of a powder or particulate.
- a powder or particulate form can also be obtained through a milling, grinding, spray drying or fragmentation process.
- Films, precipitated derivatized HA polymers and/or compositions, dried derivatized HA polymers and/or compositions, lyophilized derivatized HA polymer and/or compositions or derivatized HA polymers and/or compositions in dried in a form can be further process via a milling process (jet milling, roller milling, cryomilling, mechanical milling), a grinding or a fragmentation process. A combination of these processes can be used.
- Derivatized HA polymer compositions with particle size in the range of 100 nm to 5 mm can be prepared.
- Specific size ranges of the powdered or particulate derivatized HA polymer compositions of this disclosure can be prepared by separating the derivatized HA polymer compositions according to size using sieves.
- the distribution of particle sizes can be broad with a standard deviation of the average size of greater than 40%.
- the distribution of particle sizes can be narrow with a standard deviation of the average size of less than 30%.
- the final powdered or particulate form of the derivatized HA polymers and/or compositions of this disclosure can comprise a single distribution of average particle sizes or it can comprise two or more distributions of particles prepared by mixing particles of different average particle size.
- the crosslinked derivatized HA polymerscompositions of this disclosure can be formed into a solid form by preparing a solution of the derivatized HA polymer in a solvent that can be removed, pouring this solution into a mold of a specific shape, crosslinking the derivatized HA polymer in the mold, and then removing the solvent such that a solid form of the crosslinked derivatized HA polymer composition is obtained.
- the molds used can be of various shapes and can include but are not limited to cubes, rectangles, rods, semi-circular rode and tubes.
- the solid derivatized HA polymer composition of this disclosure can then be removed from the mold.
- the derivatized HA polymers of this disclosure can be used to prepare an in-situ gel forming composition.
- a derivatized HA polymer of this disclosure that contains available vinyl sulfone groups can be reacted with a compound that contains at least two available free thiol groups or a compound that contains at least 2 available amine groups, preferably primary or secondary amines.
- Illustrative thiol containing compounds include PEG- dithiol (HS-PEG-SH), 3-arm PEG-tri-thiol (glycerine core), 4-arm PEG-tetrathiol (pentaerythritol core), or 8-arm PEG-octa-thiol (hexaglycerine core).
- the foregoing multi-armed PEG reagents may also have fewer than all arms functionalized with thiol. Additional suitable thiol reagents having PEG as the central molecule are available from Laysan Bio (Arab, Ala.), as well as aromatic dithiols such as those available from NanoScience.
- thiol crosslinking agents include dimercaptosuccinic acid, 2,3-dimercapto-l-propanesulfonic acid, dihydrolipoic acid, peptides containing at least 2 cysteine amino acids, a thiol functionalized polysaccharide, thiol functionalized dextran, and thiol-functionalized hyaluronic acid.
- the derivatized HA polymers of this invention can be prepared as a solution. This solution can be mixed with either a solution of the thiol containing compound or the solid form of the thiol containing compound to produce the gel composition.
- the derivatized HA polymers of the present disclosure may be in combination with one or more other derivatized HA polymers or other components, such as pharmaceutically acceptable excipients, or other known or common components of compositions.
- the present disclosure provides compositions comprising derivatized HA polymers of the present disclosure.
- the derivatized HA polymers and compositions thereof of this disclosure can be used to treat living organisms. These living organisms include humans, animals, birds, fish, insects and plants.
- the derivatized HA polymers and compositions thereof used in the indications described below can comprise, non-crosslinked derivatized HA polymers, crosslinked derivatized HA polymers or a combination thereof.
- the derivatized HA polymer compositions used can comprise only one of the derivatized HA polymers of this disclosure.
- the derivatized HA polymer compositions used can comprise two or more of the derivatized HA polymers of this disclosure.
- the derivatized HA polymers and compositions thereof can further comprise one or more excipients.
- the derivatized HA polymers and compositions thereof can further comprise one or more biologically active agents.
- the derivatized HA polymers and compositions thereof that are used in the indications described below can be in a sterile form. Sterilization can be attained through sterile filtration, aseptic manufacture, gamma radiation, e-beam radiation, ethylene oxide, dry heat, autoclaving, or a combination thereof.
- the derivatized HA polymer compositions of this disclosure can also comprise an excipient.
- the excipient may be a pharmaceutically acceptable excipient.
- Excipients that can be used include but are not limited to natural polymers, synthetic polymers, thermosreversible polymers, biodegradable polymers, buffers, complexing agents, tonicity modulators, ionic strength modifiers, solvents, anti-oxidants, preservatives, viscosity modifiers, pH modifiers, surfactants, emulsifiers, phospholipids, lipids, stabilizers and porogens.
- Excipient polymers that can be used include but are not limited to sodium alginate, calcium alginate, dextran, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, hyaluronic acid, hyaluronic acid derivatives, dextran, heparin, chitosan, chitosan acetate, chitosan lactate, chitin, xantham gum, Xylan, guar gum, pullulan, locust bean gum, starch, gelatin, collagen, derivatized collagen, and acacia (gum Arabic).
- Excipient degradable polymers that can be used include but are not limited to polyesters, polyether esters, polyorthoesters, poly ester carbonates, polycarbonates, polyanhydrides, polyhydroyalkonate (e.g. Polyhydroxybutyrate, polyhydroxyvalerates), polyurethanes, poly ester urethanes.
- the polymers can be in the form of linear, branched, or star shaped.
- the polymers can be initiated from compounds that us a single point of initiation, two points of initiation, 3 points of initiation, four points of initiation, 6 points of initiation or 8 points of initiation.
- Polymers can include but are not limited to polymers that are comprise repeat units derived from at least one of the following monomers: l-lactide, dl-lactide, glycolide, trimethylene carbonate, epsilon-caprolactone, p-dioxanone and a morpholinedione
- Excipient synthetic polymers that can be used include but are not limited to polyacrylic acid and salts thereof, polyvinylpyrollidone, Pluronics 127, pluronics F68, polyethylene glycol, polyethylene oxide, polyvinyl alcohol.
- Complexing agents can include but are not limited to _a-cyclodextrin, _
- Lipids and phospholipids that can be used include but are not limited to hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, L-a- di myristoylphosphatidylcholine, L-a-dimyristoylphosphatidylglycerol, 1,2-distearoyl-sn-glycero- 3-phospho-(l'-rac-glycerol) (sodium salt) (DSPG), l,2-distearoyl-sn-glycero-3- phosphoethanolamine (DSPE), l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl- sn-glycero-3-ethylphosphocholine (chloride salt) (18:1 EPC), L-a-phosphatidylcholine (Soy-PC), l,2-distearoyl-sn-g
- Lipids include branched lipids, ionizable lipids, pegylated lipids and cationic lipids.
- Cationic and ionizable lipids include but are not limited to DDAB (CAS 3700-67-2), DOTAP (CAS 113669-21-9), cholesterol-(2-dimethlaminoethyl)carbamate (DC-chol), dioctadecylamine, DOTMA (CAS 137056-72.5), CLONfectin, DMRIE (CAS 153312-64-2), DOGS (transfectam, CAS 124050-77-7), l,2-di(oleoyloxy)-3-(dimethylamino)propane (DODAP), DLinDMA (CAS 871258-12- 7), DLin-MC3-DMA (CAS 1224606-06-7), DOSPA (CAS 168479-03-6), EDOPC (CAS 183283-20-7), DLin-K-XTC2-DMA
- Surfactants that can be used include ionic and non-ionic surfactants.
- Ionic surfactants can include cationic, anionic and zwitterionic surfactants.
- Non-ionic surfactants can include but are not limited to (Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-_- tocopherol polyethylene glycol 1000 succinate, Brij, Myrj, polysorbate 20, polysorbate 80, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 85, Solutol HS 15, sorbitan monooleate (Span 80), Sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan trioleate (Span 8) poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44/14, nonoxynol-9, Softigen 767, octyl beta-D-glycopyrano
- Anionic surfactants can include but are not limited to sodium lauryl sulfate, fatty acid salts, sodium laureth sulfate, dioctyl sodium sulfosuccinate.
- Cationic surfactants can include but are not limited to Phosphatidylcholine (Lecithin), cetrimide, cetrimonium bromide, benethonium chloride, dimethyldioctadecyl ammonium chloride, tetradecyl trimethyl ammonium bromide, cetylpyridinium chloride, esterquat, and benzalkonium chloride.
- Zwiterionic surfactants can include but are not limited to Cocamidopropyl betaine, (3-[(3- Cholamidopropyl)dimethylammonio]-l-propanesulfonate) and cocamidopropyl hydroxysultaine, phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, and sphingomyelins.
- Solvents that can be used include water-soluble organic solvents.
- Water-soluble organic solvents include but are not limited to polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide.
- Tonicity modifiers that can be used include but are not limited to dextrose, sucrose, mannitol, glycerin, sodium chloride, and potassium chloride.
- pH modifiers that can be used include but are not limited to citric acid and its salts, salts of phosphoric acid, tartatic acid, lactic acid, glycolic acid, sodium hydroxide, phosphoric acid, sulfuric acid, oxalic acid and hydrochloric acid.
- Anti-oxidants that can be used include but are not limited to ascorbic acid, butylated hydroxyanisole, Butyl hydroxytoluene, Vitamin A, vitamin E, a-tocopherol, thioglycerol, cysteine, acetylcysteine, cystine, dithioerythreitol, dithiothreitol, glutathione, Sodium bisulfite, Sodium metabisulfite, thiourea, uric acid, melatonin, propyl gallate, tertiary butylhydroquinone and combinations thereof.
- Emulsifiers that can be used include but are not limited to Glyceryl Monostearate, Isopropyl Palmitate, Polyethylene Glycol 400 Monostearate, sodium stearate, sodium stearyl glutamate, as well as the compounds listed as surfactants and combinations thereof.
- Preservatives that can be used include but are not limited to benzoic acid, sorbic acid, boric acid, methylparaben, ethylparaben, propylparaben, butylparaben, sodium benzoate, sodium propionate, phenyl ethyl alcohol, chlorobutanol, benzyl alcohol, potassium sorbate, phenol, chlorocresol, o-phenyl phenol, thiomersal, nitromersol, phenylmercuric nitrate, phenylmercuric acetate, phenoxyethanol, benzalkonium and combinations thereof.
- the excipients can include at least one solvent.
- the solvents used can include but are not limited to water, ethanol, dimethylsulfoxide, ethyl lactate, ethyl acetate, benzyl alcohol, benzyl benzoate, triacetin, N-methylpyrrolidone, 2-pyrrolidone, propylene carbonate, polyethylene glycol (PEG200), polyethylene glycol (PEG400), glycofurol and combinations thereof.
- Buffers that can be used include aqueous solutions prepared using one or more of the following: potassium hydrogen phthalate, sodium hydrogen phthalate, potassium or sodium dihydrogen phosphate, dipotassium or disodium hydrogen phosphate, phosphoric acid, boric acid, sodium acetate, acetic acid, ammonium chloride, ammonium acetate, (4-(2-hydroxyethyl)- 1-piperazineethanesulfonic acid), citric acid and sodium citrate.
- the derivatized HA polymer compositions of this disclosure can further comprise an inorganic compound.
- the inorganic compounds that can be used include but are not limited to barium sulfate, calcium hydroxylapatite or hydroxyapatite, tricalcium phosphate (TCP) [ including the various forms, for example a-TCP, -TCP, and Biphasic Tricalcium Phosphate (BCP)], calcium phosphate and calcium sulphate.
- the Hyaluronic acid derivative can further comprise compounds that comprise an emulsion.
- the emulsion comprises an oil phase and an aquesous phase.
- Compounds that can comprise an emulsion include but are not limited to sodium stearate, sodium stearyl glutamate, coconut oil, shea butter oil, olive oil, mineral oil, beeswax, sunflower seed oil, grape seed oil, Isohexadecane, Isopropyl Isostearate, Dimethicone, Caprylic/Capric Triglyceride, Ethylhexylglycerin, Hydroxyacetophenone, Dimethiconol, Cetearyl Glucoside, Cetearyl Alcohol, Stearic Acid, Palmitic Acid, Stearyl Alcohol, Cetyl Alcohol, Sodium Acrylates Copolymer, PEG-100 Stearate, cetearyl olivate, polyacrylamide, sorbitan olivate, cetearyl o
- the derivatized HA polymers of this disclosure can be prepared as a composition that comprises one or more excipients.
- the derivatized HA polymers of this disclosure can be suspended in a composition that comprises one or more excipients.
- the derivatized HA polymers of this disclosure can be rehydrated in a composition that comprises one or more excipients.
- the derivatized HA polymers of this disclosure can be prepared as separate compositions that can comprise one or more excipients with the separate solutions being mixed prior to use.
- the derivatized HA polymers of this disclosure can be prepared in the presence of one or more excipients and then converted to a solid form by one or more of the methods described in this disclosure.
- compositions of the present disclosure may comprise a biologically active agent in addition to a derivatized HA polymer as described herein and optionally other components.
- biologically active agents include, without limitation, small molecule drugs, peptides, proteins, growth factors, hormones, antibodies, agonists, antagonists, anti-bacterial and/or antifungal agents.
- Biologically active agents that can be incorporated into formulations with the compositions described include: antiandrogens, antibacterial, antioestrogens, androgens and anabolic agents, antibiotics, antimigraine drugs, antihistamines, antianxiety drugs, antidiuretics, antihistamines, antirheumatoid agents, antigens, analgesics, antidepressants, antiinflammatories, anesthetics, aminoglycosides antibodies, antiviral, adrenergic stimulants, anticonvulsants, antiangina agents, antiarrhyrthmics, antimalarials, anti-mitotic, anthelmintics, anoretic agents, antitussives, antipruritics, antipyretics, anti-alzheimer's agents, anti-Parkinson's agents, antiemetics and antinauseants, antihypertensives, anticoagulants, antifungals, , antimicrobials, allergen
- alpha. -IFN and .gamma. -IFN immunosuppressants, muscle relaxants, microorganisms, non-steroidal anti-inflammatory agents, nucleic acids, nutritional agents, neuromuscular blocking agents, neuroleptics, Neurotoxins , nutraceuticals, nucleotide, oligonucleotides, oestrogens, obstetric drugs, ovulation inducers, opioids, progestogens, pituitary hormones, Pituitary inhibitors proteins, peptides, polysaccharides, protease inhibitors, prostaglandins, quinolones, reductase inhibitors, sulfa drugs, sclerosant, sedatives, sodium channel blockers, steroids, steroidal anti-inflammatory agents, smoking cessation agents, toxins, thrombolytic agents, thyroid hormones, tumor necrosis factor; vesicles, vitamins, viruses, vasodilators, vaccines
- Additional representative examples of biologically active agents include, but are not limited to: Antidiarrheals such as diphenoxylate, loperamide and hyoscyamine; Antihypertensives such as hydralazine, minoxidil, captopril, enalapril, clonidine, prazosin, debrisoquine, diazoxide, guanethidine, methyldopa, reserpine, trimethaphan; Calcium channel blockers such as diltiazem, felodipine, amlodipine, nitrendipine, nifedipine and verapamil; Antiarrhyrthmics such as amiodarone, flecainide, disopyramide, procainamide, mexiletene and quinidine, Antiangina agents such as glyceryl trinitrate, erythrityl te
- oclacitinib maleate can include oclacitinib maleate, Serlopitant, and Lokivetmab, Anti- alzheimer's agents such as tacrine; Anti-Parkinson's agents such as amantadine, benserazide, carbidopa, levodopa, benztropine, biperiden, benzhexol, procyclidine and dopamine-2 agonists such as S (-)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0923), Anticonvulsants such as phenytoin, valproic acid, primidone, phenobarbitone, methylphenobarbitone and carbamazepine, ethosuximide, methsuximide, phensuximide, sulthiame and clonazepam, Antiemetics and antinauseants such as the phenothiazines
- alpha. -methyl-19-noriestosterone and fluoxymesterone 5-alpha reductase inhibitors such as finasteride, turosteride, LY-191704 and MK-306; Corticosteroids such as betamethasone, betamethasone valerate, cortisone, dexamethasone, dexamethasone 21-phosphate, fludrocortisone, flumethasone, fluocinonide, fluocinonide desonide, fluocinolone, fluocinolone acetonide, fluocortolone, halcinonide, halopredone, hydrocortisone, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrocortisone 21-acetate, methylprednisolone, prednisolone, prednisolone 21-phosphate, prednisone, triamcinolone, triamcinolone acetonide; Glycosylated proteins
- Antiviral agents may be included in the compositions of the present disclosure, where exemplary antiviral agents include acyclovir and acyclovir prodrugs, famcyclovir, zidovudine, didanosine, stavudine, lamivudine, zalcitabine, saquinavir, indinavir, ritonavir, n- docosanol, tromantadine and idoxuridine.
- exemplary antiviral agents include acyclovir and acyclovir prodrugs, famcyclovir, zidovudine, didanosine, stavudine, lamivudine, zalcitabine, saquinavir, indinavir, ritonavir, n- docosanol, tromantadine and idoxuridine.
- Anthelmintics such as mebendazole, thiabendazole, niclosamide, praziquantel, pyrantel embonate and diethylcarbamazine
- Cytotoxic agents such as plicamycin, cyclophosphamide, dacarbazine, fluorouracil and its prodrugs (described, for example, in International Journal of Pharmaceutics, 111, 223-233 (1994)), methotrexate, procarbazine, 6-mercaptopurine and mucophenolic acid
- Anorectic and weight reducing agents including dexfenflurarnine, fenfluramine, diethylpropion, mazindol and phentermine
- Agents used in hypercalcaemia such as calcitriol, dihydrotachysterol and their active derivatives or analogs
- Antitussives such as ethylmorphine, dextromethorphan and pholcodine
- compositions of the present disclosure may include: an expectorant such as carbolcysteine, bromihexine, emetine, quanifesin, ipecacuanha and saponins; Decongestants such as phenylephrine, phenylpropanolamine and pseudoephedrine; Bronchospasm relaxants such as ephedrine, fenoterol, orciprenaline, rimiterol, salbutamol, sodium cromoglycate, cromoglycic acid and its prodrugs (described, for example, in International Journal of Pharmaceutics 7, 63-75 (1980)), terbutaline, ipratropium bromide, salmeterol and theophylline and theophylline derivatives; Antihistamines such as meclozine, cyclizine, chlorcyclizine, hydroxyzine, brompheniramine, chlorpheniramine, clemastine, c
- Neuromuscular blocking agents such as suxamethonium, alcuronium, pancuronium, atracurium, gallamine, tubocurarine and vecuronium;
- sclerocing agents or sclerosants may be a surfactant or it may be selected from the group consisting of ethanol, dimethyl sulfoxide, sucrose, sodium chloride, dextrose, glycerin, minocycline, tetracycline, doxycycline, polidocanol, sodium tetradecyl sulfate, sodium morrhuate, and sotradecol.
- an angiogenesis inhibitor an angiogenesis inhibitor; a 5-lipoxygenase inhibitor or antagonist; a chemokine receptor antagonist; a cell cycle inhibitor; a taxane; an anti-microtubule agent; paclitaxel; an analogue or derivative of paclitaxel; a vinca alkaloid; camptothecin or an analogue or derivative thereof; a podophyllotoxin, wherein the podophyl lotoxin may be an etoposide or an analogue or derivative thereof; an anthracycline, wherein the anthracycline may be doxorubicin or an analogue or derivative thereof or the anthracycline may be mitoxantrone or an analogue or derivative thereof; a platinum compound; a nitrosourea; a nitroimidazole; a folic acid antagonist; a cytidine analogue; a pyrimidine analogue; a fluoropyrimidine analogue;
- alpha. -25 dihydroxy vitamin D.sub.3 or an analogue or derivative thereof a leukotriene inhibitor; an MCP-1 antagonist; an MMP inhibitor; an NF kappa B inhibitor, which may be Bay 11-7082; an NO antagonist; a p38 MAP kinase inhibitor, which may be SB 202190; a phosphodiesterase inhibitor; a TGF-.beta.
- thromboxane A2 antagonist a TNF-alpha- antagonist
- TACE TNF-alpha- antagonist
- TACE TNF-alpha- antagonist
- tyrosine kinase inhibitor vitronectin inhibitor
- a fibroblast growth factor inhibitor a protein kinase inhibitor; a PDGF receptor kinase inhibitor; an endothelial growth factor receptor kinase inhibitor; a retinoic acid receptor antagonist; a platelet derived growth factor receptor kinase inhibitor; a fibrinogen antagonist
- an antimycotic agent sulconizole
- a bisphosphonate a phospholipase Al inhibitor
- histamine H1/H2/H3 receptor antagonist a macrolide antibiotic
- GPIIb/llla receptor antagonist an endothelin receptor antagonist
- a peroxisome proliferator-activated receptor agonist an estrogen receptor agent
- a somastostatin analogue a neurokinin 1 antagonist
- sub.2-. alpha, inhibitor a PPAR agonist; an immunosuppressant; an Erb inhibitor; an apoptosis agonist; a lipocortin agonist; a VCAM-1 antagonist; a collagen antagonist; an .alpha. -2 integrin antagonist; a TNF-.alpha.
- anti-fibrin and fibrinolytic agents including plasmin, streptokinase, single chain urokinase, urokinase, t-PA (tissue type plasminogen activator), aminocaproic acid; anti-platelet agents including, aspirin, prostacyclins (and analogues); glycoprotein llb/llla agents including monoclonal antibodies, peptides (e.g.
- ReoPro Cilastagel, eptifibatide, tirofiban, ticlopidine, Vapiprost, dipyridamole, forskolin, angiopeptin, argatroban), thromboxane inhibitors; anti-thrombin and anti-coagulant agents, including dextan, heparin, LMW heparin (Enoxaparin, Dalteparin), hirudin, recombinant hirudin, anti-thrombin, synthetic antithrombins, thrombin inhibitors, Warfarin (and other coumarins); anti-mitotic, antiproliferative and cytostatic agents, including vincristine, vinblastine, paclitaxel, methotrexate, cisplatin, fluorouracil, rapamycin, azathioprine, cyclophosphamide, mycophenolic acid, corticosteroids, colchicine, nitroprusside; antiangiogenic and angiostatic agents,
- Cilazapril Lisinopril, Captopril
- growth factor e.g. VEGF, FGF
- antioxidants and vitamins e.g. Probucol, Tocopherol
- calcium channel blockers e.g. nifedipine
- fish oil omega 3-fatty acid
- phosphodiesterase inhibitors e.g. dipyridamole
- nitric acid donor e.g. Molsidomine
- somatostatin analogues e.g. angiopeptin
- immunosuppresives and anti-inflammatory agents e.g. prednisolone, glucocorticoid and dexamethasone
- antimicrobials e.g.
- rifamycin and radionuclides, including alpha, beta and gamma emitting isotopes (e.g. Re-188, Re-186, 1-125, Y-90); COX-2 inhibitors such as Celecoxib and Vioxx; kinase inhibitors, such as epidermal growth factor kinase inhibitor, tyrosine kinase inhibitors, MAP kinase inhibitors protein transferase inhibitors, Resten-NG, smoking cessation agents such as nicotine, bupropion and ibogaine; Insecticides and other pesticides which are suitable for local application; Dermatological agents, such as vitamins A, C, Bl, B2, B6, B 12, B 12.
- Dermatological agents such as vitamins A, C, Bl, B2, B6, B 12, B 12.
- alpha.., and E vitamin E acetate and vitamin E sorbate
- Allergens for desensitisation such as house, dust or mite allergens
- Nutritional agents and neutraceuticals such as vitamins, essential amino acids and fats
- Macromolecular pharmacologically active agents such as proteins, enzymes, peptides, polysaccharides (such as cellulose, amylose, dextran, chitin), nucleic acids, cells, tissues, and the like
- Bone mending biochemicals such as calcium carbonate, calcium phosphate, tricalcium phosphate, hydroxya petite or bone morphogenic protein (BMP);
- Angiogenic growth factors such as Vascular Endothelial Growth Factor (VEGF) and epidermal growth factor (EFG), cytokines interleukins, fibroblasts and cytotaxic chemicals
- Keratolytics such as the alpha-hydroxy acids, glycolic acid and salicylic acid; and DNA, RNA or other oligonu
- Vaccines that contain Hendra virus (HeV) G glycoprotein and/or Nipah virus G glycoprotein, Lutenising Hormone Releasing Hormone (LHRH) peptide, LHRH-diphtheria toxoid conjugate, porcine circovirus type 2 (PCV2) antigen, a porcine reproductive and respiratory syndrome virus antigen, Mycoplasma hyopneumoniae protein antigen.
- Hendra virus Hendra virus
- LHRH Lutenising Hormone Releasing Hormone
- PCV2 porcine circovirus type 2
- Mycoplasma hyopneumoniae protein antigen Mycoplasma hyopneumoniae protein antigen.
- Proteins or protein fragments for example ORFI Torque teno virus protein, or other TTV proteins or fragments, antigens against Aeromonas salmonicida, antigens against Vibrio anguillarum, and antigens against V. salmonicida.
- Growth factors include but are not limited to Vascular Endothelial Growth Factor (VEGF) and epidermal growth factor (EFG), Growth Differentiation Factors (GDFs), Fibroblast Growth Factors ( FGF-1 through FGF-23), Osteoprotegerin, Cartilage Derived Morphogenic Proteins (CDMPs, which can be a foundation for soft or hard tissue), Lim Mineralization Proteins (LMPs)lnterleukins (IL-1 through IL-13), Insulin-like Growth Factor-1, Connective Tissue Growth Factor (CTGF), platelet derived growth factor (PDGF), nerve growth factors, neutrophins Brain-derived neurotrophic factor (BDNF), Nerve growth factor (NGF), Neurotrophin-3 (NT-3), Neurotrophin-4 (NT-4)], Transforming growth factors (TGF-a, TGF-fS), Tumor necrosis factor (TNF), Growth factor Agonists or antagonists as well as antibodies against these growth factors.
- compositions of the present disclosure are formulated into lipid nanoparticles, degradable polymeric particles or liposomes.
- the composition of the present disclosure comprises a derivatized hyaluronic acid of the present disclosure, and one or more lipids.
- the composition of the present disclosure comprise a derivatized hyaluronic acid of the present disclosure, one or more lipids and cholesterol.
- the derivatized hyaluronic acid in the lipid nanoparticles, degradable polymeric particles or liposomes comprises a lipid moiety, or a cholesterol moiety, or a substituted or unsubstituted C 5 - C20 aliphatic moiety which has at least 4 consecutive -CH2- groups.
- the lipid nanoparticles, degradable polymeric particles or liposomes that comprise a derivatized hyaluronic acid of the present disclosure can further comprise a biologically active agent.
- compositions of the present disclosure are formulated into cosmetic product.
- Cosmetic products can include but are not limited to serums, creams, lotions, emuisions, micelle formulations, lip balms and lipsticks.
- the composition of the present disclosure comprise a derivatized hyaluronic acid of the present disclosure, and one or compounds that comprise an emulsion.
- the derivatized hyaluronic acid in the cosmetic product comprises a lipid moiety, or a cholesterol moiety, or a substituted or unsubstituted C5-C20 aliphatic moiety which has at least 4 consecutive -CH2- groups or an aromatic moiety.
- compositions of the present disclosure are formulated for, and are useful for, wound healing.
- Compositions may be formulated for suitable administration, e.g., nasal or topical administration.
- Compositions may include one or more suitable biologically active agents for wound healing.
- the wounds treated can include but are not limited to diabetic ulcers, burns, pressure wounds, abrasions, incisions, corneal abrasion, incisions following ocular surgery, blisters, damaged tissue following sinus surgery, abdominal surgery, tendon repair or joint repair.
- derivatized HA polymer compositionsof the disclosure can be in the form of dry particles.
- the derivatized HA polymer compositions of the disclosure can be in the form of a lyophilized derivatized HA polymer compositions.
- the derivatized HA polymer compositions of the disclosure can be on the form of a non-woven derivatized HA polymer compositions.
- the non-woven derivatized HA polymer compositions can be produced by an electrospinning process.
- the derivatized HA polymer of the disclosure can be in the form of a film. Compositions can be packaged directly or indirectly in a foil pouch to minimize moisture absorption during storage.
- Derivatized HA polymer compositions of the disclosure can be applied directly to a wound site.
- the derivatized HA polymer compositions can absorb exudate from the wound. Once sufficient exudate is absorbed, the dry derivatized HA polymer compositionswill turn into a gel.
- the derivatized HA polymer compositions of the disclosure further comprise water or saline such that a gel is obtained. In one aspect, the gel can be applied directly to the wound.
- the derivatized HA polymer compositions of the disclosure once applied to the wound, can be covered by a have a moisture retaining semi-permeable film.
- the film can further comprise an adhesive that will retain the film at the site of application.
- the moisture retaining semi-permeable adhesive film can be made from a polyurethane or a silicone material with an adhesive coating on at least the border or edges of the film.
- the adhesive can be an acrylic based adhesive.
- the semi-permeable film is permeable to oxygen and carbon dioxide, as well as water vapor but will prevent bacterial transmission.
- the derivatized HA polymers and compositions thereof of the disclosure can be applied to a semi-permeable film such that the product is premade and ready to use in that the derivatized HA polymer compositionsof the disclosure and the semipermeable film are a single unit.
- Compositions can be packaged directly or indirectly in a foil pouch.
- the derivatized HA polymer of the disclosure comprises a hyaluronic acid that has been derivatized with sulfonate groups, where such a derivatized HA polymer may be used, for example, in a composition intended for wound healing.
- the derivatized HA polymers and compositions of the disclosure can be used as bulking agents. These bulking agents can be used to treat stress urinary incontinence, fecal incontinence, Gastroesophageal Reflux Disease (GERD), prostate-rectum spacer for reduction in rectal damage as a result of radiation treatment for prostate cancer.
- the injected derivatized HA polymer compositions can be in the form of derivatized HA polymer that may or may not comprise crosslinks.
- the derivatized HA polymers and compositions of the disclosure can be used as a dermal filler to fill voids, defects and to treat moderate to severe wrinkles and folds.
- Derivatized HA polymer compositions can be injected as a solution or suspension.
- at least one derivatized HA polymer in a derivatized HA polymer composition is crosslinked.
- the crosslinked derivatized HA polymer of this disclosure used in the dermal filler composition has a hyaluronidase (or corresponding polysaccharide degrading enzyme for other polysaccharides) degradation rate that is the same as or less than that of polyhydric polymer (e.g., hyaluronic acid) that is not derivatized.
- the derivatized HA polymers and compositions can be used treat areas where dermal depressions, wrinkles or scars are found including, but not limited to nasolabial folds, forehead, furrow lines and vertical lip lines.
- the derivatized HA polymers and compositions can be used for lip augmentation and breast augmentation.
- the derivatized HA polymers and compositions used as dermal fillers may comprise a drug (e.g., biologically active agent) to reduce pain associated with the procedure.
- a biologically active agent includes compounds or molecules that may be referred to as a drug. Such compounds include benzocaine, bupivacaine, amethocaine, lignocaine, lidocaine, cocaine, cinchocaine, dibucaine, mepivacaine, prilocaine, etidocaine, veratridine (specific c-fiber blocker) and procaine.
- the derivatized HA polymers and compositions used as dermal fillers may comprise a degradable water-insoluble polymer (e.g. polyester such as PLGA, PLLA etc), a water insoluble non-degradable polymer (e.g. polymethylmethacrylate [PMMA]) or inorganic material (e.g. calcium hydroxyapatite).
- a degradable water-insoluble polymer e.g. polyester such as PLGA, PLLA etc
- PMMA polymethylmethacrylate
- the derivatized HA polymers and compositions used as dermal fillers are in the form of particles of a crosslinked hydrogel.
- median size (Dv50) of the particles are in the range of 100 pm to 800 pm.
- the median size (Dv50) of the particles are in the range of 200 pm to 600 pm.
- the crosslinked hydrogel particles are suspended in a saline solution. In another aspect, the hydrogel particles are suspended in a solution of hyaluronic acid oa hyaluronic acid derivative of this disclosure. In one aspect, the crosslinked hydrogel suspension is in a prefilled syringe in which the contents of the syringe are sterile. In another aspect, the hydrogel particle suspension is injectable through at least a 27G needle.
- the derivatized HA polymers and compositions as disclosed herein are formulated for, and are useful for, viscosupplementation.
- the derivatized HA polymers may or may not crosslinked, and the compositions may optionally contain a biologically active agent.
- Viscosupplementation is the process of injecting a derivatized HA polymer composition into the joint to relieve pain.
- the polyhydric polymer is hyaluronic acid or a derivative thereof.
- Derivatized HA polymer compositions can be injected into one or more joint spaces of the body.
- Suitable joints include, but are not limited to, knee, shoulder, ankle, elbow, hip, trapeziometacarpal joint, finger joint, wrist joints, temporomandibular joint, back and neck.
- the derivatized HA polymers used can comprise crosslinked derivatized HA polymers.
- the derivatized HA polymer compositions can comprise one or more excipients or diluents.
- the derivatized HA polymer compositions of the disclosure that can be used for osteoarthritis treatment can be injected through a needle of between 18 gauge and 21 gauge.
- Derivatized HA polymer composition of the disclosure can comprise a biologically active agent.
- the biologically active agent can be, but is not limited to, a corticosteroid, a local anesthetic, an antibody, a peptide or an anti-inflammatory compound or molecule.
- the volume of the solution that comprises the derivatized HA polymer composition of the disclosure can range from 0.5 ml to 10 mL with the preferred aspect being in the 2 mL to 6 mL for injection into the knee.
- crosslinked derivatized HA polymer hydrogel particles are suspended in a saline solution.
- the derivatized HA polymer particles are suspended in a solution of hyaluronic acid or a hyaluronic acid derivative on this disclosure.
- the crosslinked derivatized HA polymer suspension is in a prefilled syringe in which the contents of the syringe are sterile.
- the derivatized HA polymers and compositions as disclosed herein are formulated for, and are useful for, adhesion prevention.
- the derivatized HA polymers may or may not crosslinked, and the compositions may optionally comprise a biologically active agent.
- Areas of the body where methods of treatment for adhesion prevention is wanted include spinal and abdominal areas, particularly after surgical procedures, as a coating on dura substitute, in nasal procedures or devices, in conjunction with ear, elbow, and tendon medical procedures.
- Exemplary biologically active agents include, but are not limited to, anti-inflammatory and pain medicines.
- the derivatized HA polymers of this disclosure may be used to reduce the incidence and severity of adhesions and scar tissue that may occur following injury or a surgical procedure.
- adhesions can include abdominal adhesions, pelvic adhesions, heart adhesions, joint adhesions, tendon adhesions (e.g. flexor tendon, Achilles tendon, patella tendon), spinal adhesions, lumbar adhesions, nerve adhesions, dural adhesions, sinus adhesions.
- the derivatized HA polymer compositions can further comprise one or more excipient.
- the derivatized HA polymer compositions of the disclosure can further comprise a biologically active agent.
- the biologically active agent can be, but is not limited to, a corticosteroid, a local anesthetic, an antibody, a peptide or an anti-inflammatory.
- the derivatized HA polymer of this disclosure is derived from hyaluronic acid or a hyaluronic acid derivative.
- the derivatized HA polymer can be in the form of a crosslinked hydrogel.
- the derivatized HA polymer of the disclosure can be in a crosslinked form that has been lyophilized to form a porous foam or it could be as a solid or perforated film.
- the derivatized HA polymers and compositions as disclosed herein are formulated for, and are useful for, tissue sealing.
- the derivatized HA polymers may or may not crosslinked, and the compositions may optionally comprise a biologically active agent.
- the derivatized HA polymer of the disclosure that contains residual vinyl sulfone groups can be reacted with a compound that has 2 or more free thiol functional groups such that a crosslinked derivatized HA polymer is produced.
- the derivatized HA polymer of the disclosure that contains free vinyl sulfone groups can be prepared as a solution.
- the solution can be prepared using saline.
- the derivatized HA polymer of the disclosure that contains residual vinyl sulfone groups can be prepared as a first solution and the derivatized HA polymer that has 2 or more free thiol functional groups can be prepared as a second solution.
- the pH of either the first or the second solution can be adjusted such that the pH of the solution is greater than pH 8. This can be accomplished by using a solution that has a pH of greater than 8 to dissolve either the derivatized HA polymer of the disclosure that contains residual vinyl sulfone groups or the compound that has 2 or more free thiol functional groups, adding buffer components to either the derivatized HA polymer of the disclosure that contains residual vinyl sulfone groups or to the compound that has 2 or more free thiol functional groups.
- the first and second solution can be combined and applied to the tissue surface resulting in a mixture.
- the mixture can be applied through a needle or canula.
- the mixture can be applied using a spray applicator.
- spray applicators include but are not limited to the Fibrijet SA-3674 and SA-3675 (Nordson Medical, 261 Cedar Hill Street, Marlborough, MA 01752, United States).
- the mixture can be applied using a gas assisted spray applicator.
- gas assisted spray applicators include but are not limited to the Fibrijet SA-3651 and SA-3652, (Nordson Medical, 261 Cedar Hill Street, Marlborough, MA 01752, United States).
- the derivatized HA polymer composition can be applied to the tissue in a liquid form and after 3 minutes the derivatized HA polymer composition is in a gel form.
- the time required to convert from the liquid form to the gel form depends on the specific application. In one aspect the liquid to gel conversion can take less than 2 minutes. In another aspect the liquid to gel conversion can take less than 30 seconds. In another aspect, the liquid to gel conversion can take less than 15 seconds.
- the derivatized HA polymer composition for tissue sealing may further comprise an excipient.
- the derivatized HA polymer composition can further comprise a biologically active agent.
- the derivatized HA polymer compositions of this disclosure are combined with a biologically active agent to treat bacterial vaginosis.
- the derivatized HA polymer compositions of this disclosure can be formulated such that the derivatized HA polymer compositions is tissue adhesive and adheres to the vaginal tissue for a period of greater than 2 hours.
- the derivatized HA polymer compositions can further comprise one or more excipient.
- the derivatized HA polymer compositions of the disclosure can further comprise a biologically active agent.
- the biologically active agent can be an antibacterial agent.
- the antibacterial can be, but is not limited to, clindamycin, tinidazole, metronidazole, secnidazole and ornidazole.
- Formulations comprising the derivatized HA polymers of this disclosure, can be applied intravaginally.
- the derivatized HA polymers and compositions of the disclosure are selected to provide ocular application.
- derivatized HA polymer compositions of this disclosure can be used as eye drops.
- the eye drops can be used to treat dry eyes, a disease of the eye, infected ocular tissue, inflamed ocular tissue, as a lubricant for the surface of the eye, as a lubricant for use with contact lenses and to assist in healing of the eye following trauma or a surgical procedure to the eye or surrounding tissue.
- Surgical procedures to the eye can include but are not limited to cataract surgery, intra-ocular lens replacement, fixing detatched retinas, tumor removal, glaucoma surgery, refractive surgery, corneal surgery, vitreo-retinal surgery, eye muscle surgery, oculoplastic surgery, surgery involving the lacrimal punctum, canaliculus, and sac.
- An ocular formulation comprising derivatized HA polymers of this disclosure can further comprise an excipient.
- the derivatized HA polymers of this disclosure can be formulated into a solution or suspension which is then administered to the eye.
- An ocular formulation comprising derivatized HA polymers of this disclosure can further comprise a biologically active agent.
- the biologically active agent can be present as part of the solution or it can be in the form of a suspension or emulsion.
- the derivatized HA polymers of this disclosure can be formulated into a solution or suspension which is then administered to the eye.
- derivatized HA polymer compositions of this disclosure can be prepared to be used to lubricate and wet contact lenses.
- the contact lens can be immersed prior to use or could be stored in a solution that contains derivatized HA polymers of this disclosure.
- the solution can comprise one or more excipients.
- the solution can further comprise boric acid or sodium borate.
- the solution can be formulated to be preservative free.
- derivatized HA polymers of this disclosure can be formed into a formulation that is inserted into the lacrimal punctum, the lacrimal canaliculus or the lacrimal sac.
- Derivatized HA polymers of the disclosure can be in the form of a solution, swollen hydrogel or a dehydrated hydrogel.
- the derivatized HA polymer compositions can further comprise an excipient.
- the derivatized HA polymer is crosslinked.
- derivatized HA polymer compositions further comprise a biologically active agent.
- the biologically active agent can be but is not limited to a corticosteroid (for example, dexamethasone, mometasone fuorate, triamcinolone acetonide, triamcinolone hexacetonide, triamcinolone acetate, betamethasone, fluoromethalone, hydrocortisone, medrysone or prednisolone), prostaglandins (for example, latanoprost, travoprost or bimatoprost) , beta blockers (for example timolol or betaxolol) , alpha-adrenergic agonists (for example apraclonidine or brimonidine), carbonic anhydrase inhibitors (for example dorzolamide or brinzolamide), mitotic or chlorinergic agents (for example pilocarpine)
- a corticosteroid for example, dexamethasone, mometasone fuorate, triamcinolone
- a derivatized HA polymer and/or compositions is crosslinked in the presence of a biologically active agent and then dried.
- a derivatized HA polymer is crosslinked, dried, reswollen in the presence of a biologically active agent and then dried.
- the biological agent is incorporated into the uncrosslinked derivatized HA polymer in solution.
- the derivatized HA polymer is dried, reswollen in the presence of a biologically active agent and then dried. Any of the dried formulations can be of suitable dimensions such that it can be placed in the lacrimal punctum.
- the dried formulation Upon contact with lachrymal fluid and tears, the final dried formulation hydrates, and swells in such a manner as to be physically retained in the punctum.
- the dried formulation can be inserted into the canaliculus. Upon contact with lachrymal fluid and tears, the dried formulation hydrates, and swell in such a manner as to be physically retained in the canaliculus.
- the formulation could then release the contained biologically active agent over a period of 24 hours to 3 weeks.
- the biologically active agent is released in a sustained manner for a period of 7 days.
- the biologically active agent is released in a sustained manner for a period of 4 weeks.
- the dried formulation can be inserted intravitreally so that the biologically active agent is delivered into the vitreous of the eye.
- the dried formulation is inserted into the anterior chamber of the eye.
- the derivatized HA polymers and compositions of the disclosure are selected to provide a punctal plug.
- the punctal plug may comprise a biologically active agent, e.g., steroid or a pain relief drug.
- the derivatized HA polymer compositions of this disclosure can be used to treat mucositis.
- mucositis include oral and vaginal mucositis.
- the rapidly divided epithelial cells lining the gastro-intestinal tract (which goes from the mouth to the anus) break down leaving the mucosal tissue open to ulceration and infection. This leads to mucocitis.
- Oral mucositis can often occur following chemotherapy and radiation treatments. It can lead pain and increased risk of infection. This can lead to nutritional problems due to these symptoms reducing the ability and desire to eat. Providing a coating that covers these lesions, can reduce the pain and potential for infection.
- the derivatized HA polymers of this disclosure can be formulated such that the derivatized HA polymer compositions is tissue adhesive and adheres to the mucosal tissue of the mouth tissue or the vagina for a period of greater than 2 hours.
- the derivatized HA polymer compositions can further comprise one or more excipients.
- the derivatized HA polymer compositions of the disclosure can further comprise a biologically active agent.
- the biologically active agent can be, but is not limited to, a local anesthetic, an anti-infective, an anti-inflammatory or a combination thereof.
- Local anesthetics can include but are not limited to benzocaine, bupivacaine, amethocaine, lignocaine, lidocaine, cocaine, cinchocaine, dibucaine, mepivacaine, prilocaine, etidocaine, veratridine (specific c-fiber blocker) and procaine.
- the derivatized HA polymer compositions of the disclosure can be formulated such that it can be applied as an oral rinse or applied as a gel.
- the derivatized HA polymer compositions of the disclosure can be formulated such that it can be applied intravaginally to the vaginal tissue surface.
- derivatized HA polymer compositions of this disclosure can be used to treat a surgical site during and following canalplasty, tympanoplasty, myringoplasty, stapedectomy mastoid procedures, or any other procedure related to the ear.
- Derivatized HA polymer compositions can be used to modulate wound healing as well as to control bleeding.
- the derivatized HA polymer compositions of this disclosure can be in the form of a lyophilized sponge, an electrospun matrix, a film, a gel or a combination of these forms.
- the derivatized HA polymer compositionsof the disclosure can comprise an excipient.
- the derivatized HA polymer compositionsof the disclosure can comprise a biologically active agent.
- the derivatized HA polymer compositions and compositions thereof disclosed herein can be used to treat cancer.
- Such compositions will comprise a chemotherapeutic agent, a protein, a peptide, an antibody, a nucleotide sequence or a combination thereof.
- the derivatized HA polymer compositions and compositions thereof disclosed herein can be administered systemically or locally.
- derivatized HA polymer compositions and compositions thereof disclosed herein can be delivered by direct injection into a tumor or tissue from which the tumor has been surgically removed.
- the derivatized HA polymer compositions and compositions thereof disclosed herein can be used to elicit an immune response.
- the derivatized HA polymer compositions and compositions thereof disclosed herein can be used to transfer RNA into a cell.
- the derivatized HA polymer compositions of the disclosure can be used to treat otitis media, acute otitis externa, balance disorders (for example Meniere' disease, tinnitus and sensorineural hearing loss.
- Derivatized HA polymer compositionsof this disclosure can be in the form of a solution, a suspension, a lyophilized sponge, an electrospun matrix, a film, a gel, a solid rod-like form, or a combination of these forms.
- Derivatized HA polymer compositionsof the disclosure can comprise an excipient.
- a derivatized HA polymer compositions of the disclosure can comprise a biologically active agent.
- the derivatized HA polymer can comprise an antibiotic, an antibacterial, an antiviral, an antifungal or a combination thereof.
- derivatized HA polymer compositionscomprising at least one biologically active agent include, but are not limited to, amoxicillin, clavulanate, cefuroxime axetil, ceftriaxone, Levofloxacin, a cephalosporin, a trimethoprim-sulfamethoxazole, a macrolide, ofloxacin, gentamicin sulfate, tobramycin sulfate and ciproflaxin,
- derivatized HA polymer compositions can comprise a corticosteroid.
- Corticosteroids can include but are not limited to betamethasone, betamethasone valerate, cortisone, dexamethasone, dexamethasone 21-phosphate, fludrocortisone, flumethasone, fluocinonide, fluocinonide desonide, fluocinolone, fluocinolone acetonide, fluocortolone, halcinonide, halopredone, hydrocortisone, hydrocortisone 17- valerate, hydrocortisone 17-butyrate, hydrocortisone 21-acetate, methylprednisolone, prednisolone, prednisolone 21-phosphate, prednisone, triamcinolone, triamcinolone acetonide, mometasone fuorate.
- a combination of an antibiotic and a corticosteroid can be added to the derivatized HA polymer compositionsof the disclosure.
- the derivatized HA polymer compositions of the disclosure can be applied to the area to be treated by being applied with a dropper, a syringe, through a needle or catheter or by physically placing a derivatized HA polymer compositions.
- the derivatized HA polymer compositions of the disclosure can comprise a biologically active agent.
- the derivatized HA polymers of this disclosure can be used as a matrix from which the biologically active agent can be delivered.
- the release profile of the biologically active agent into a phosphate buffered saline solution if slower than that of the normal dissolution profile of the biologically active agent.
- the derivatized HA polymer compositions of the disclosure can be in the form of a crosslinked gel.
- the treatment using the drug delivery formulation can be a single injection or could be two or more injections that are separated by a period of time.
- the composition can be injected systemically, intra-ocularly, intratumorally, intravenously subcutaneously, intra-dermally or intra-muscularly.
- the derivatized HA polymer compositions can be injected through a needle, trocar, catheter, tube, or canula.
- the contents of the prefilled syringe or vial are sterile.
- the contents of the prefilled syringe or vial are stable at 2-8°C or 20-25°C for at least 6 months, preferably 12 months and most preferably 24 months.
- the drug delivery formulation can be applied topically or by instillation.
- the derivatized HA polymers of this disclosure in a crosslinked form can be used as device to plug a defect following the removal of a piece of tissue or the needle track following a biopsy procedure.
- a crosslinked form of the derivatized HA polymer compositionscan be prepared and then dried.
- the dried derivatized HA polymer compositionscan be delivered into the needle track or the site that a piece of tissue was removed.
- the dried derivatized HA polymer compositionscan absorb moisture from the surrounding tissue to rehydrate and swell such that the swollen size is larger than the initial size of the derivatized HA polymer compositions.
- the crosslinked dried derivatized HA polymer composition can be used to seal a hole in the tissue where the crosslinked derivatized HA polymer compositionis placed in the hole and it swells to seal off the hole.
- An example of this could be to seal lung tissue following puncturing of the lung following a biopsy or surgical procedure.
- the crosslinked dried derivatized HA polymer composition can comprise an element, such as a metal piece that is visible under x-ray or fluoroscopy examination.
- the metal piece can take on various forms such as but not limited to a flat piece, a rod, a coil, a loop, a hoop, hook, a number and a letter of the alphabet.
- the crosslinked dried derivatized HA polymer composition can comprise a biologically active agent.
- the biologically active agent can have hemostatic properties.
- the crosslinked dried derivatized HA polymer composition can comprise collagen, chitosan or thrombin.
- the derivatized HA polymers and compositions of the present disclosure are formulated for, and are useful for, a plug for female sterilization.
- Female sterilization can be accomplished by inserting a plug into the fallopian tube. This plug can provide a physical barrier to the passage of the ovum into the uterus as well as to the sperm reaching the ovum.
- the fallopian tubes can be closed using clips or rings to clamp then closed.
- Cauterization has also been used to seal the fallopian tubes.
- the Essure system consisted of a device insert that is loaded into a single-use delivery system.
- the device consisted of an inner coil of stainless steel and polyethylene terephthalate (PET) fibers and an outer coil of nickel-titanium (nitinol).
- PET polyethylene terephthalate
- nitinol nickel-titanium
- the metal components hold the device in place while the PET fibers allow tissue ingrowth into the device which will lead to occlusion of the fallopian tube. This ingrowth process does take time and so the patient must use other forms of contraception for 3 months.
- a hysterosa I pingogram is performed to confirm placement and tubal occlusion.
- the device is permanent and remains in the patient for the rest of the patient's life. This product received a black box warning over potential safety concerns, and was subsequently removed from the market in the US. The device had previously been removed from the market overseas.
- the Adiana® sterilization method used radiofrequency energy to cause controlled thermal damage of the lining of the fallopian tube lumen. Following the thermal injury to the fallopian tube, a porous non-degradable silicone plug is placed in the thermally injured fallopian tube. Over a few weeks, tissue ingrowth into the porous plug results in occlusion of the fallopian tube. A hysterosa I pingogram is performed at 3 months to confirm tubal occlusion. The silicone plug is a permanent implant. The Adiana® system has been withdrawn from the market.
- the method and devices described herein provide a means to occlude the fallopian tube that will result in a reduction in the ability of a female to become pregnant. The method involves mechanically injuring the lining of the fallopian tube followed by the insertion of a degradable plug.
- a method for mechanically injuring the fallopian tube is to insert a device that comprises a rough surface into the fallopian tube and then physically move the device in a rotational motion, a linear motion that follows the fallopian tube or a combination thereof. This motion can be repeated more than once. This physical movement is continued until the endothelial layer of the fallopian tube where the physical motion occurs is either partially removed or completely removed.
- the device used to denude the endothelial layer of the fallopian tube can comprise a series of fiber radiating from a central core.
- this device is similar in structure to a bottle brush, e.g., a rod with bristles (fibers) extending perpendicularly from the rod.
- the fibers can be spaced evenly apart in a continuous manner.
- the fibers can be in rows with spaces between the rows.
- the fibers could be oriented in a spiral shape along the axis of the device.
- the fibers can be oriented in one or more linear rows that are aligned about parallel with the axis from which they emanate.
- the fibers are in one or more rows such that the rows are about perpendicular to the axis from which they emanate.
- the fibers can be made from a non degradable polymer.
- the polymers that can be used to prepare the fibers include but are not limited to polyethylene, polypropylene, polyethylene terephthalate (PET), nylon, polyurethane, polyetheretherketone (PEEK), polyaryletherketone (PAEK), fluorocarbon polymers such as polytetrafluoroethylene, silk and combinations thereof.
- the fibers can be made from a metal.
- the metals that can be used to prepare the fibers include but are not limited to stainless steel, titanium, nitinol, magnesium, alloys of Co-Cr-Mo, Cr-Ni-Cr-Mo, CP-Ti, Ti-AI-V, Ti-AI-Nb, Ti-13Nb-13Zr, Ti-Mo-Zr-Fe or combinations thereof.
- the central core (rod) of the denuding device can comprise a core prepared from the twisting of 2 or more metal strands together such that the fibers are trapped between the twisted metal strands.
- the metals that can be used to prepare the central core include but are not limited to stainless steel, titanium, nitinol, magnesium, alloys of Co-Cr-Mo, Cr-Ni-Cr-Mo, CP-Ti, Ti-AI-V, Ti-AI-Nb, Ti-13Nb-13Zr, Ti-Mo-Zr-Fe or combinations thereof.
- the terminal end of the central core (rod) that is first introduced into the fallopian tube can comprise an atraumatic tip that does not damage the tissue as the device is being guided into the desired location in the fallopian tube.
- This atraumatic tip can be a rounded end cap, a domed shaped end, a cone shaped end with a rounded tip.
- the surface of the atraumatic tip can have a smooth surface.
- the atraumatic tip can be made of a non- degradable polymer or a metal.
- the non-degradable polymers that can be used to manufacture the atraumatic tip include but are not limited to polyethylene, polypropylene, polyethylene terephthalate (PET), nylon, polyurethane, polyetheretherketone (PEEK), polyaryletherketone (PAEK), fluorocarbon polymers such as polytetrafluoroethylene, silk and combinations thereof.
- the metals that can be used to prepare the atraumatic tip include but are not limited to stainless steel, titanium, nitinol, magnesium, alloys of Co-Cr-Mo, Cr-Ni-Cr-Mo, CP-Ti, Ti-AI-V, Ti-AI-Nb, Ti- 13Nb-13Zr, Ti-Mo-Zr-Fe or combinations thereof.
- the atraumatic tip can be attached to the central core by a crimping process, a molding process, a process that uses an adhesive to bond the tip to the central core, or a thermal process.
- the plug can comprise a hydrogel.
- the hydrogel is prepared using one or more crosslinked derivatized HA polymer and/or compositions of this disclosure.
- a hydrogel comprising a polyhydric polymer composition in the form a rod that is larger than the size of the fallopian tube is prepared.
- the hydrogel rod is then dried.
- the hydrogel can be dried at normal atmospheric pressures or under reduced atmospheric pressure.
- the hydrogel can be lyophilized. Once delivered to the desired site, the hydrogel plug would absorb moisture from the fallopian tube and swell. The swelling of the hydrogel plug will enable the hydrogel plug to be retained at the site where it was placed.
- the hydrogel further comprises a porogen to facilitate the formation of pores within the hydrogel.
- the porogen can comprise particulates.
- the particulates can comprise a degradable polymer.
- Degradable polymers that can be used as porogens include but are not limited to degradable polyesters, polyanhydrides, polyurethanes, polyether-esters, polycarbonates, polyether-carbonates, polyether-ester carbonates, polkyhydroxyalkanoates, polyamides and polymers that are synthesized from one or more monomers from the group of I- lactide, dl-lactide, glycolide, s-caprolactone, trimethylene carbonate, morpholine-dione, p- dioxanone and l,5-dioxapan-2-one.
- the porogen can be leeched out of the hydrogel during the device manufacturing process. This can be accomplished by incubating the porogen containing hydrogen in a solvent in which the porogen will dissolve.
- the solvent is preferably a water miscible solvent.
- the porogen can remain in the device throughout the manufacturing process and will degrade and leech out once the hydrogel plug is inserted into the patient.
- the plug comprises a degradable polymer.
- Degradable polymers that can be used in the plug include but are not limited to degradable polyesters, polyanhydrides, polyurethanes, polyether-esters, polycarbonates, polyether-carbonates, polyether-ester carbonates, polkyhydroxyalkanoates, polyamides and polymers that are synthesized from one or more monomers from the group of l-lactide, dl-lactide, glycolide, s-caprolactone, trimethylene carbonate, morpholine-dione, p-dioxanone and l,5-dioxapan-2-one.
- the plug can comprise a monofilament structure, a multifilament structure, or a braided structure.
- the plug can be prepared by taking particles or chopped fibers of the degradable polymer and compression mold them into a shape. Heat can be used to thermally fuse the particulates together such that a porous structure is obtained.
- the shape can be in the form of a rod. The porous rod can then be cut to a predetermined length.
- the plug can be made from an electrospun degradable polymer.
- the plug is made from a thin film of electrospun derivatized HA polymer and/or compositions. The plug can be cut directly from a sheet of the electrospun composition.
- the plug can be prepared by rolling an electrospun film into a roll.
- the electrospun plug or the rolled rod shaped structure can be coated with a second degradable polymer such that the rolled configuration is retained.
- the polymer used to prepare the rolled structure has a degradation time that is longer than the polymer used to coat the rolled structure. This can allow the plug to be more rigid which makes handling easier during manufacturing but upon delivery to the desired site, the faster degrading material will start degrading and facilitate tissue ingrowth while the first longer lasting polymer provides a scaffold for the ingrowing tissue.
- the electrospun plug can be coated or dipped into a solution of a water-soluble polymer.
- the plug is then dried at ambient pressure or at reduced pressure.
- the plug may also be dried by lyophilization.
- the presence of the water soluble polymer can make the electrospun composition more rigid and thus easier to handle during manufacturing and delivery to the intended site.
- the polymer Once positioned at the intended site, the polymer will start to dissolve and leech out of the electrospun composition.
- the tissue from the mechanically damaged fallopian tube can then grow into the electrospun composition.
- the electrospun composition will degrade over time leaving an occluded fallopian tube.
- the water soluble polymer can be selected from the group of polyethylene oxide, polyethylene glycol, block copolymers of polyethylene glycol and polypropylene glycol (e.g. Pluronics F126 and Pluronics F68, Sigma-Aldrich Corp., St. Louis, MO, USA), dextran, hyaluronic acid, or a hyaluronic acid derivative of this disclosure.
- the degradable polymer used to form the plug can further comprise a porogen.
- the porogen can comprises an inorganic salt, an organic small molecule or a polymer.
- the porogen is selected such that it is soluble in a solvent in which the biodegradable polymer used to prepare the plug has limited solubility.
- Inorganic salts that can be used as porogens include but not limited to sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts, copper salts, barium salts, iron salts.
- these salts include but are not limited to sodium chloride, sodium bromide, sodium iodide, sodium sulfate, sodium phosphate, sodium hydrogen phosphate, or combinations thereof.
- a porous plug can be prepared by 3D-printing the plug.
- a degradable polymer can be used to 3D print the plug.
- the degradable polymer that can be used in the plug include but are not limited to degradable polyesters, polyanhydrides, polyurethanes, polyetheresters, polycarbonates, polyether-carbonates, polyether-ester carbonates, polkyhydroxyalkanoates, polyamides and polymers that are synthesized from one or more monomers from the group of l-lactide, dl-lactide, glycolide, 8-caprolactone, trimethylene carbonate, morpholine-dione, p-dioxanone and l,5-dioxapan-2-one.
- the plug can comprise position retaining features. These features can include non- symmetrical shapes, barbs, ridges, pores, slits, slots, or a combination thereof.
- the barbs can be unidirectional in that they all point in the same direction or the barbs could point in two or more different directions. The barbs could be uniformly spaced on the plug or they could be present in only specific portions of the plug.
- plug can be dipped into a solution of the derivatized HA polymers of the disclosure.
- the solution can then be activated to allow the solution to crosslink such that the pores of the plug comprise the crosslinked derivatized HA polymer.
- the crosslinking process can be activated by adjusting pH of the solution, addition of a crosslinking agent, elevation of temperature, addition of an initiator or a combination of one or more of these.
- the derivatized HA polymer compositions of the disclosure can be used as a scaffold to allow the ingrowth of tissue or bone.
- derivatized HA polymers of this disclosure can be prepared as a crosslinked matrix that is then lyophilized.
- the lyophilized derivatized HA polymer composition can then be rehydrated in the presence of cells such that the hydrated matrix acts as a scaffold that allows the growth of the cells on and into the scaffold.
- the derivatized HA polymers of this disclosure that have residual vinyl sulfone groups can be electrospun to form a porous matrix.
- the electospun fibers can then be crosslinked using heat, ultraviolet, e-beam or gamma radiation.
- the derivatized HA polymer of the disclosure that contains residual vinyl sulfone groups can further comprise a photocrosslinker.
- a solution of this composition can be electrospun and then the electrospun matrix can be subjected to ultraviolet radiation such that the photocrosslinker results in crosslinking of the derivatized HA polymer.
- the resultant matrix can be rehydrated in the presence of cells such that it acts as a scaffold for tissue growth.
- carboxylic acid containing derivatized HA polymers of this disclosure can be electospun into a matrix by mixing a solution of the derivatized HA polymer of this disclosure with a solution of a multivalent cation just prior to electrospinning.
- a solution of a carboxylic acid containing composition of this disclosure could be placed in one syringe and a solution of a multivalent cation or a cationic polymer can be placed in another syringe.
- the syringes can be connected via a y-connector and a needle can be connected to final arm of the y-connector. They two solutions can then be pumped through the needle and this mixture can be electrospun onto a surface such that the derivatized HA polymer of the disclosure is ionically crosslinked.
- Multivalent cations can include calcium magnesium, ferric ions, ferrous ions, aluminum and chromium.
- Cationic polymers that can be used include but are not limited to chitosan and derivatives thereof, polyvinyl pyrollidone, peptides containing more than one lysine group and polyethyleneimine.
- a solution of a derivatized HA polymer compositionsof this disclosure can be used to coat a degradable or non-degradable scaffold matrix.
- a derivatized HA polymer of this disclosure that has been modified with alkyl or aryl groups can be used to coat a scaffold for tissue growth. The alkyl or aryl groups will interact with the scaffold through hydrophobic bond while the hydrophilic portion of the derivatized HA polymer will allow for cell growth on the coated scaffold surface.
- the derivatized HA polymers of this disclosure that have residual vinyl sulfone groups can be coated onto the scaffold. The coated scaffold can be subjected to heat which will result in the derivatized HA polymer transforming into a crosslinked derivatized HA polymer.
- the derivatized HA polymers and/or compositions of the disclosure can comprise a sulfonate group.
- the derivatized HA polymers and/or compositions of the disclosure can comprise both hydrophobic groups and sulfonate groups.
- the hydrophobic groups can be alkyl or aromatic based.
- tissue scaffold support structure can be 3D printed or electrospun using a degradable polymer.
- the degradable polymer that can be used can include but not limited to degradable polyesters, polyanhydrides, polyurethanes, polyether-esters, polycarbonates, polyether-carbonates, polyether-ester carbonates, polkyhydroxyalkanoates, polyamides and polymers that are synthesized from one or more monomers from the group of I- lactide, dl-lactide, glycolide, s-caprolactone, trimethylene carbonate, morpholine-dione, p- dioxanone and l,5-dioxapan-2-one.
- a single or multiple polymer solutions can be prepared.
- the polymers used can be biodegradable polymers then include but are not limited to polyester, polyanhydride, polyorthoester, polycarbonate, poly-ester-co-carbonate), polyhydroxybutyrates or combinations thereof.
- Biodegradable polymers can include polylactice-co-glycolide copolymers, polydioxanone, polylactidetrimethylene carbonate copolymers as well as copolymers that comprise repeat units derived from at least one of the following monomers: l-lactide, dl-lactide, glycolide, trimethylene carbonate, epsilon-caprolactone, p-dioxanone and a morpholinedione
- the solvents used can be an organic solvent, water or a combination thereof.
- HFIP, DMSO, NMP, Chloroform, acetic acid, ethanol, dimethylformamide (DMF) solvents or mixtures of solvents can be used.
- Solutions with a concentration of 0.5 to 25% (w/v) can be prepared.
- the solution that is to be electrospun can be placed in a syringe with a needle.
- the syringe is then placed in a syringe pump.
- the needle can have a blunt end and an inner diameter in the range of 0.25 to 2.5 mm.
- the needle and collection plate are attached to a high voltage supply. In some applications, more than one needle can be used to prepare a single sheet.
- the needles can be arranged such that the same polymer solution flows through all the needles, different solutions flow through different needles or a combination thereof.
- the needles can be arranged such that adjacent needles allow different polymer solutions to flow through them. This alternation pattern can be repeated.
- a voltage is then applied to the system.
- the applied voltage can be in the lOkV to 45 kV.
- the syringe pump can extrude the solution.
- the flow rate of the syringe pump can be in the range of 0.0001 uL/min to 423 mL/min.
- the collector plate can be static, rotating or moving in a specific linear direction to give the fibers some directional orientation.
- the shape of the collector plate can be varied with the collector plate having but not limited to the following shapes: a flat surface, a textured surface, a curved surface, a square rod, a rectangular rod, a round mandrel, an oval mandrel, a semi-circular mandrel or a combination of these shapes.
- the distance of the needle tip to the collector plate can be altered.
- the distance of the needle tip to the collector plate can be in the 2-50 cm range.
- the collection plate can also be submerged in or sprayed with a solvent that assists in the precipitation of the newly spun fibers. For example, an ethanol bath may be used during the electrospinning of hyaluronic acid based derivatized HA polymers of this disclosure.
- the derivatized HA polymer of the disclosure can be incorporated through a solution coating or submersion of an electrospun matrix.
- the polymer composition used to 3D print or electrospin the scaffold can further comprise an inorganic filler or a combination of inorganic fillers.
- the inorganic filler can be selected from the group calcium carbonate, calcium phosphate, tricalcium phosphate, hydroxyapatite, bioglass, or a combination thereof.
- 3D-printed or electrospun scaffold can be coated with a solution of the derivatized HA polymers of the disclosure.
- This derivatized HA polymer can be coated onto the scaffold through a dip coating or spray coating process.
- the derivatized HA polymer can be dispersed into the scaffold through compressive application.
- the derivatized HA polymer can be dispersed into the scaffold through submersion in solution which may or may not include sonication to aid in dispersion.
- the coated scaffold can be dried. The drying process can include drying at elevated temperature, drying at reduced pressure or lyophilization.
- the solution of the derivatized HA polymer compositions of the disclosure can further comprise a biologically active agent.
- scaffold in another aspect, can be dipped into a solution of the derivatized HA polymers of the disclosure.
- the solution can then be activated to allow the solution to crosslink such that the pores of the scaffold comprise the crosslinked derivatized HA polymer.
- the crosslinking process can be activated by adjusting pH of the solution, addition of a crosslinked, elevation of temperature, addition of an initiator or a combination of one or more of these.
- scaffold in another aspect, can be dipped into a solution of the derivatized HA polymers of the disclosure and allowed to dry or be lyophilized.
- the derivatized HA polymers within the substrate can then be dipped into a crosslinking solution to allow the solution to crosslink such that the pores of the scaffold comprise the crosslinked derivatized HA polymer.
- the crosslinking process can be activated by adjusting pH of the solution, addition of a crosslinked, elevation of temperature, addition of an initiator or a combination of one or more of these.
- scaffold in another aspect, can be dipped into a solution of the derivatized HA polymers of the disclosure and a crosslinking agent.
- the rate of the crosslinking reaction can be controlled such that the scaffold can be coated with the derivatized HA polymer and/or composition prior to complete crosslinking of the derivatized HA polymer.
- a biologically active agent can be incorporated into the derivatized HA polymer and/or compositions before or immediately following the initiation of the crosslinking reaction.
- the scaffold can then be coated with this composition and once applied to the scaffold, the crosslinking reaction is completed such that the device comprises the crosslinked derivatized HA polymer with the biologically active agent essentially encapsulated by the crosslinked derivatized HA polymer composition.
- the derivatized HA polymers and/or compositions of this disclosure are used to prepare a scaffold or to coat the scaffold can comprise a biologically active agent.
- the biologically active agent can enhance cell growth.
- the biologically active agent can be one or more growth factors or peptides that enhance cell growth and cell adhesion.
- the derivatized HA polymers and/or compositions of this disclosure used to prepare a scaffold or to coat the scaffold can further comprise an excipient.
- the derivatized HA polymer compositions of the disclosure can comprise one or more extracellular matrix components.
- the extracellular matrix component can include but are not limited to heparan sulfate, chondroitin sulfate, keratin sulfate, hyaluronic acid, collagen, elastin, fibronectin, and laminin.
- the cells that can be added to the scaffolds that contain the derivatized HA polymer compositions of this disclosure include embryonic stem cells, mesenchymal stem cells, adipose-derived stem cell, endothelial stem cells, dental pulp stem cells, tumor cells, chondrocytes, osteoblasts, dermal fibroblasts, protomyofibroblasts, myofibroblasts, hepatocytes, smooth muscle cells, endothelial cells, epithelial cells, adipose tissue, adipose cells and cardiac cells
- the derivatized HA polymers and compositions of the present disclosure comprise free vinyl sulfone functional groups and can be used to 3D print structures.
- the derivatized HA polymers can be prepared as solutions with viscosities that allow them to be 3d printed.
- a solution of the derivatized HA polymer with residual vinyl sulfone groups can be prepared.
- a second solution containing a derivatized HA polymer with at least two free thiol groups can be prepared.
- the first and second solution can be mixed together.
- the pH of the mixture can be adjusted to a pH of greater than 8, preferably greater than 9, such that the mixture can be printed and then cure following printing.
- the pH can be adjusted by mixing the mixture with a buffer solution that has a pH of greater than 8. The mixing takes place just prior to the print head ensuring that the mixture does not gel up in the print head and thus clot the printer.
- the solution of the derivatized HA polymer that comprises the residual vinyl sulfone functional groups can has its pH adjusted to a pH of greater than 8 by mixing it with a buffer solution. This solution can then be mixed with solution 2 just prior to the print head such that the mixture is printed and then allowed to complete gelation once printed.
- the viscosity of the mixture can be used to control the retention of the printed structure until gelation is completed.
- a thermogelling material can be added to either the first, second or buffer solution.
- the mixture can be printed and then the temperature of the printed environment can be different from the solution prior to printing such that following the printing process the printed solution undergoes thermal gelation to preserve the initial printed structure while the crosslinking process is moving towards completion.
- Thermogelling materials can include but are not limited to polyethylene-block- polypropylene co polymers such as Pluronics F127 or F68 (Sigma-Aldrich Corp., St. Louis, MO, USA) or polyester-polyethylene glycol block co polymers.
- the polyester-polyethylene glycol copolymers can include deblock and triblock copolymers.
- the polyester component are polymers that are synthesized from at least one of the monomers from the group of l-lactide, dl-lactide, glycolide, s-caprolactone, morpholine-dione, p-dioxanone and l,5-dioxapan-2-one.
- a thermogelling polymer that comprises trimethylene carbonate can be used.
- the printed construct can be rinsed to neutralize the pH of the printed gel.
- the printed structure can be dried such that the residual water content is less than 10%.
- the printed structure can be lyophilized.
- the printed structure can be used as a tissue scaffold, for wound healing applications, for occlusion of a lumen, a biopsy site or a needle tract.
- holes are often drilled into the skull. These are often referred to as burr holes. In many instances, these burr holes are left untreated following the surgical procedure and the scalp is replaced directly over these holes. This can lead to scalp depressions at the burr hole. These scalp depressions can lack mechanical strength. In order to prevent this, a burr hole plug can be inserted into the burr hole such that it can facilitate and support bone regrowth.
- Autologous bone can be used to fill the burr holes but this requires harvesting of the bone.
- Synthetic materials can be used as burr hole plugs.
- a degradable burr hole plug that degrades while facilitating bone ingrowth will allow the healing of the burr hole without leaving residual material.
- a polycaprolactone (PCL) burr hole plug has been commercialized. The challenge with PCL is that it is slow degrading and the interface between the polymer and the in-growing tissue is usually not the best due to the hydrophobicity of the polymer.
- the derivatized HA polymers and compositions thereof of the disclosure can be made into a burr hole plug.
- a solution of a derivatized HA polymer can be placed in the mold and then the derivatized HA polymer compositioncan be lyophilized to produce a porous structure that can be inserted into the burr hole.
- the derivatized HA polymer compositions of the disclosure can be electrospun and then cut to form a plug that can be inserted into the burr hole.
- a solution of the derivatized HA polymer of the disclosure can be placed in a mold and the solution can be crosslinked. The crosslinked plug can be used directly.
- the crosslinked derivatized HA polymer compositions can be lyophilized to yield a porous crosslinked structure that can be used as a burr hole plug.
- a burr hole plug can be 3D printed or electrospun using a degradable polymer.
- the degradable polymer that can be used can include but not limited to degradable polyesters, polyanhydrides, polyurethanes, polyether-esters, polycarbonates, polyether-carbonates, polyether-ester carbonates, polkyhydroxyalkanoates, polyamides and polymers that are synthesized from one or more monomers from the group of l-lactide, dl- lactide, glycolide, s-caprolactone, trimethylene carbonate, morpholine-dione, p-dioxanone and l,5-dioxapan-2-one.
- the polymer used to 3D print or electrospin the burr hole plug can further comprise an inorganic filler or a combination of inorganic fillers.
- the inorganic filler can be selected from the group calcium carbonate, calcium phosphate, tricalcium phosphate and hydroxyapatite.
- the 3d-printed or electrospun burr plug can further comprise an extracellular matrix material.
- the extracellular matrix material can be selected from the group collagen, hyaluronic acid, chondroitin sulfate, heparan sulfate, keratin sulfate, elastin, fibronectin and laminin.
- 3D-printed or electrospun plug can be coated with a solution of the derivatized HA polymers of the disclosure.
- This derivatized HA polymer composition can be coated onto the plug through a dip coating or spray coating process.
- the coated plug can be dried. The drying process can include drying at elevated temperature, drying at reduced pressure or lyophilization.
- polymeric degradable plug can be dipped into a solution of the derivatized HA polymers of the disclosure.
- the solution can then be activated to allow the solution to crosslink such that the pores of the plug comprise the crosslinked derivatized HA polymer composition.
- the crosslinking process can be activated by adjusting pH of the solution, addition of a crosslinker, elevation of temperature, addition of an initiator or a combination of one or more of these.
- polymeric degradable plug can be dipped into a solution of the derivatized HA polymers of the disclosure that contain residual vinyl sulfone groups.
- the coateddevice can be dried at elevated temperatures to remove the solvent and to allow crosslinking of the coating such that the pores of the plug comprise the crosslinked derivatized HA polymer composition.
- the crosslinked forms of the derivatized HA polymers and/or compositions of this disclosure can be used to form nerve guides.
- the nerve guides can be prepared by lyophilization.
- collagen, gelatin, chitosan heparan sulfate or a combination of these can be further added to the derivatized HA polymers and/or compositions of the disclosure to form the nerve guides.
- Schwann cells can be incorporated into the derivatized HA polymer compositions during the formation of the nerve guide.
- the derivatized HA polymers if this disclosure can be prepared as a solution that has a viscosity of greater than 50 cP. In one aspect, this solution can be applied to tissue to reduce the coefficient of friction with the tissue surface. In one aspect, the derivatized HA polymer composition can be used as a vaginal lubricant. In another aspect, the solution can be applied to a device that is to be inserted into an opening, orifice or cavity such that the solution act to lubricate the passage of the device through the opening, orifice or cavity. In one aspect the device could be an endoscope.
- the derivatized HA polymer and compositions thereof of this disclosure can be used to coat a medical device.
- Medical devices that can be coated include but are not limited to a catheter, a needle, a biopsy needle, a tissue marker, a guide wire, and endoluminal sheath, a suture, a braid, a trocar, a hernia mesh, a surgical mesh, a contact lens, an intra-ocular lens, a stent (for example vascular stent, esophageal stent, biliary stent coronary stent, renal stent, peripheral vascular stent) , a nasal splint, a vascular graft, a stent-graft, aneurysm coils, introducer sheaths, balloon catheters, vascular closure devices, inferior vena cava filter, and Hydrocephalic shunts.
- a catheter for example vascular stent, esophageal stent, bil
- the derivatized HA polymer of the disclosure can be prepared as a solution which can then be applied by spray coating or dip coating. The solvent can then be removed to leave a coating of the derivatized HA polymer composition of the disclosure on the device surface.
- the solution can be an aqueous solution.
- the solution can comprise an organic solvent.
- the solution can comprise water and a water-miscible organic solvent.
- the derivatized HA polymer of the disclosure can be functionalized with aliphatic or aromatic groups such that there is a hydrophobic interaction with these groups and the device surface.
- the derivatized HA polymer of this disclosure that has residual vinyl sulfone groups can be coated onto a medical device by dip coating or spray coating.
- the coating is dried.
- the coating can be exposed to heat, gamma, e- beam or ultraviolet radiation to crosslink the derivatized HA polymer.
- the coating can further comprise a biologically active agent.
- the coating when hydrated increase the lubricity of the coated device.
- the increased lubricity of the coated device can be measure by a decrease of the water contact angle by at least 20°.
- the increased lubricity can be measured as a decrease in the friction coefficient by at least 20%.
- the device can be partially coated with some part of the device remaining uncoated.
- the device can be precoated with binding polymer coating that enhances the binding of the coating derivatized HA polymer composition of this disclosure.
- the coating can further comprise heparin, to give the coating anti-thrombotic properties.
- a process for making a derivative polymer of a polyhydric polymer comprising: a) reacting hydroxyl groups of a polyhydric polymer, with divinyl sulfone (DVS) to provide a first polyhydric derivative; and b) reacting the first polyhydric polymer derivative with a nucleophile of a formula X'-l -Y, or X'-R 2 -Y 7 or both to provide a second polyhydric polymer derivative; wherein R 1 and R 2 are different, and each is a substituted or unsubstituted C5-C20 aliphatic or aromatic moiety, , X' is a nucleophilic group of SH or NH2, and Y is the same or different, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group.
- VDS divinyl sulfone
- This process wherein the polyhydric polymer is hyaluronic acid (HA).
- This process may further further comprise step c) derivatizing the second polyhydric polymer derivative by repeating, one or more times, step a) or step a) and step b).
- a freshly prepared solution of 15.5 g divinyl sulfone in 92.4 g of DI water was then rapidly added to the stirring solution. After 4.5 minutes, 63 g of a 1 M HCI solution was added to the reaction mixture. 1 M NaOH was then added dropwise until the solution pH was between 5 and 7. 8.4 g NaCI was then added to the solution. Once the NaCI had dissolved, 1.5 L acetone was slowly added over a period of 30 minutes. The suspension was stirred for about 3 hours. 300 mL denatured ethanol was added and the solution was stirred for about 30 minutes. The precipitate was filtered under vacuum using a sintered glass funnel through a 0.22 pm PTFE filter membrane.
- Example 2 The reaction as described in Example 2 was performed using a reaction time of 6 minutes. The percent substitution, as determined according to the procedure described in Example 1, was found to be about 31%.
- 0.5 g vinyl sulfone derivatized HA (approx. 9%, as per Example 1) was added to 50 g DI water in a 250 mL round bottom flask. The solution was stirred overnight until the material had dissolved. The flask was then purged with nitrogen. 0.022 g 3-mercaptopropionic acid (MPA) was added to the solution. After the MPA had dissolved, the pH was adjusted to about 9 using 0.25 M NaOH. The solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCI. 1.25 g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. 150 mL cold acetone was slowly added to the solution.
- MPA 3-mercaptopropionic acid
- the reaction mixture was stirred for 1.5 hours. 25 mL ethanol was added and the resultant mixture was stirred for 15 minutes. The precipitate was isolated using vacuum filtration. The precipitate was washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate was dried under vacuum at room temperature. A sample of the material was dissolved in D2O and the 1 H-NMR spectrum was measured. The presence of MPA substitution was evidenced by peaks at 2.3-2.4 ppm (triplet) and 2.6-2.8 ppm (triplet). The MPA substitution, as calculated from the integrals at 2.3-2.4 ppm (MPA - CH2) and 1.7-2 ppm (HA - acetamide), was 7.6%.
- 0.5 g vinyl sulfone derivatized HA (approx. 9%, as per Example 1) was added to 50 g DI water in a 250 mL round bottom flask. The solution was stirred for about 4 hours at room temperature. About 15.8 g denatured ethanol was added and the mixture was stirred for about 18 hrs at which point the material had dissolved. The flask was then purged with nitrogen. 0.023 g 1-octanethiol in 7.9 g ethanol was then added to the solution of derivatized HA. The pH of the reaction mixture was adjusted to about 9 using 0.25 M NaOH.
- the solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCL 0.5g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. 150 mL cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. The precipitate was isolated using vacuum filtration. The precipitate was washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate was dried under vacuum at room temperature. A sample of the material was dissolved in D2O and the 1 H-NMR spectrum was measured.
- HA-DVS2-oct-DMF 1-octanethiol
- HA-DVS2-oct-DMF 1-octanethiol
- the solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCI.
- About 0.25 g NaCI was added to the reaction solution.
- the solution was stirred until the NaCI had dissolved.
- 150 mL cold acetone was slowly added to the solution.
- the reaction mixture was stirred for 1.5 hours.
- 25 mL ethanol was added and the resultant mixture was stirred for 15 minutes.
- the precipitate was isolated using vacuum filtration.
- the precipitate was washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry.
- the precipitate was dried under vacuum at room temperature.
- a sample of the material was dissolved in D2O and the 1 H-NMR spectrum was measured.
- the octanethiol molar substitution as calculated from the integrals at 2.4-2.5 ppm (Oct - CH 2 -S-) and 1.7-2 ppm (HA - acetamide), was 5.5%.
- 0.5 g vinyl sulfone derivatized HA (approx. 9%, as per Example 1) was added to 50 g DI water in a 250 mL round bottom flask. The solution was stirred for about 4 hours at room temperature. About 15.8 g denatured ethanol was added and the mixture was stirred for about 18 hrs at which point the material had dissolved. The flask was then purged with nitrogen. 0.04 g 1-dodecanethiol in 7.9g ethanol was then added to the solution of derivatized HA. The pH of the reaction mixture was adjusted to about 9 using 0.25 M NaOH. The solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCI.
- the precipitate was isolated using vacuum filtration. The precipitate was washed 4 times with 50 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate was dried under vacuum at room temperature. A sample of the material was dissolved in D2O and the 1H-NMR spectrum was measured. The presence of MPA substitution was evidenced by peaks at 2.4-2.6 ppm (-CH2-COOH), 2.7-2.8 ppm (-CH2-S-) and 2.9-3.1 ppm (-S-CH2-). The MPA substitution, as calculated from the integrals at 2.4-2.6 ppm (MPA - CH2) and 1.7-2 ppm (HA - acetamide), was 79.4%.
- the vinyl sulfone derivatized HA reaction (produced in the same manner as Example 25) was added to 660 g DI water in a 5L reaction kettle. The solution was stirred for about 1 hr at 300 rpm at 30°C. 426.06g Ethanol was then added and the solution was stirred for about 18 hrs at 300 rpm at 30°C. The stirring speed was then increased to 500 rpm. 8.305 g MBA was then added to the derivatized HA solution and allowed to stir for ten (10) minutes. The pH of the reaction mixture was monitored and adjusted to about 9 using 1 M NaOH. The solution was stirred for 2 hours after which the pH was adjusted to about 7 using IM HCI.
- the ph was adjusted to 12.32 using IM HCI solution.
- a freshly prepared solution of 50 g divinyl sulfone in 282.5 g of DI water was then rapidly added to the stirring solution.
- the pH was monitored and adjusted with IM NaOH to maintain pH range of 12.2-12.3 over the course of the reaction time of twenty (20) minutes.
- 35g of a IM HCI solution was added to the reaction mixture and pH was adjusted to a value between 5 and 7.
- About 19.5 g NaCI was then added to the solution.
- 2 Lacetone was slowly added over a period of ⁇ 30 minutes.
- the suspension was stirred for about 3 hours. 400 mL ethanol was added and the solution was stirred for about 30 minutes.
- the precipitate was filtered under vacuum using a sintered glass funnel. Once all the solution had been filtered, the vacuum was disconnected and 200 mL ethanol was used to rinse the precipitate. The ethanol was then removed by vacuum filtration. This process was repeated an additional 3 times with each aliquot standing in static ethanol for five (5) minutes prior to applying vacuum. The product was immediately dissolved for the reaction described in Example 58. The percent substitution was found to be 51.6% by the following NMR method. Approx. 10- 20 mg of the dried sample was added to a vial. D 2 O was added to the sample to make the final concentration of the solution about 6 mg/mL. The sample was shaken on an orbital shaker until dissolved.
- the sample was transferred into a NMR tube and the 2 H-NMR spectrum of the sample was recorded on a NMR spectrometer.
- the percent modification is calculated on molar ratio of the vinyl CH protons (6.8-7.0 ppm) to the acetamide (1.7-2.0 ppm) protons.
- the vinyl sulfone derivatized HA reaction product (produced in the same manner as Example 28) was added to 660 g DI water in a 5L reaction kettle. The solution was stirred for about 1 hr at 300 rpm at 30°C. 426.06g Ethanol was then added and the solution was stirred for about 18 hrs at 300 rpm at 30°C. The stirring speed was then increased to 500 rpm. 10.881g Thiophenol was then added to the derivatized HA solution and allowed to stir for ten (10) minutes. The pH of the reaction mixture was monitored and adjusted to about 9 using 1 M NaOH.
- the solution was stirred for 2 hours after which the pH was adjusted to about 7 using IM HCL About 9 g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. IL cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. The precipitate was isolated using vacuum filtration. Once all the solution had been filtered, the vacuum was disconnected and 200 mL ethanol was used to rinse the precipitate. The ethanol was then removed by vacuum filtration. This process was repeated an additional 3 times with each aliquot standing in static ethanol for five (5) minutes prior to applying vacuum. The product was dried under vacuum at room temp conditions. A sample of the material was dissolved in D2O and the 1 H-NMR spectrum was measured.
- the vinyl sulfone derivatized HA reaction product (produced in the same manner as Example 29) was added to 660 g DI water in a 5L reaction kettle. The solution was stirred for about 1 hr at 300 rpm at 30°C. 426.06g ethanol was then added and the solution was stirred for about 18 hrs at 300 rpm at 30°C. The stirring speed was then increased to 500 rpm. 15.227 g MBA was then added to the derivatized HA solution and allowed to stir for ten (10) minutes. The pH of the reaction mixture was monitored and adjusted to about 9 using 1 M NaOH. The solution was stirred for 2 hours after which the pH was adjusted to about 7 using IM HCI.
- the lid, overhead stirrer and anchor impellor were attached to the reaction kettle. 1133 g deionized water was added to the kettle.
- the temperature controller for the Bioreactor heater (Chemglass CLS-1380-19V) was set to 25° C.
- the solution was stirred at about 300 rpm for approximately 18 hrs.
- the stirring speed was increased to 750 rpm.
- 30 g of a IM NaOH solution was then added to the dissolved sodium hyaluronate.
- the pH of the solution was measured after 2min and was found to be 12.26.
- the ph was adjusted to 12.30 using IM HCI solution.
- a freshly prepared solution of 50 g divinyl sulfone in 282.5 g of DI water was then rapidly added to the stirring solution.
- the pH was monitored and adjusted with IM NaOH to maintain pH range of 12.2-12.3 over the course of the reaction time of ten (10) minutes. After 10 minutes, 27g of a IM HCI solution was added to the reaction mixture and pH was adjusted to a value between 5 and 7. About 19.5 g NaCI was then added to the solution. Once the NaCI had dissolved, 2 L acetone was slowly added over a period of ⁇ 30 minutes. The suspension was stirred for about 3 hours. 500 mL ethanol was added and the solution was stirred for about 30 minutes. An additional 500 ml of cold acetone was added to ensure everything had precipitated. The precipitate was filtered under vacuum using a sintered glass funnel through a 0.22 pm PTFE filter membrane.
- Example 63 The percent substitution, as determined by the following NMR method, was found to be 25.1%. Approx. 10-20 mg of the dried sample was added to a vial. D2O was added to the sample to make the final concentration of the solution about 6 mg/mL. The sample was shaken on an orbital shaker until dissolved.
- the sample was transferred into a NMR tube and the X H-NMR spectrum of the sample was recorded on a NMR spectrometer.
- the percent modification is calculated on molar ratio of the vinyl CH protons (6.8-7 ppm) to the acetamide (1.7-2.0 ppm) protons.
- the vinyl sulfone derivatized HA reaction product described in example 31 was added to 660 g DI water in a 5L reaction kettle. The solution was stirred for about 1 hr at 300 rpm at 30°C. 426.06g ethanol was then added and the solution was stirred for about 18 hrs at 300 rpm at 30°C. The stirring speed was then increased to 500 rpm. 5.935g Thiophenol was then added to the derivatized HA solution and allowed to stir for ten (10) minutes. The pH of the reaction mixture was monitored and adjusted to about 9 using 1 M NaOH. The solution was stirred for 2 hours after which the pH was adjusted to about 7 using IM HCI.
- the solution is stirred for 24 hours after which the pH is adjusted to about 7 using 0.25 M HCL About 0.25 g NaCI is added to the reaction solution. The solution is stirred until the NaCI had dissolved. 150 mL cold acetone is slowly added to the solution. The reaction mixture is stirred for 1.5 hours. The precipitate is isolated using vacuum filtration. The precipitate is washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate is dried under vacuum at room temperature.
- the solution is stirred for 24 hours after which the pH is adjusted to about 7 using 0.25 M HCI.
- About 0.25 g NaCI is added to the reaction solution.
- the solution is stirred until the NaCI had dissolved.
- 150 mL cold acetone is slowly added to the solution.
- the reaction mixture is stirred for 1.5 hours.
- the precipitate is isolated using vacuum filtration.
- the precipitate is washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry.
- the precipitate is dried under vacuum at room temperature.
- the solution is stirred for 24 hours after which the pH is adjusted to about 7 using 0.25 M HCL About 0.25 g NaCI is added to the reaction solution. The solution is stirred until the NaCI had dissolved. 150 mL cold acetone is slowly added to the solution. The reaction mixture is stirred for 1.5 hours. The precipitate is isolated using vacuum filtration. The precipitate is washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate is dried under vacuum at room temperature.
- 0.5 g vinyl sulfone derivatized HA (approx. 8%, as per Example 14) is added to 27.5 g DI water in a 250 mL round bottom flask. The solution is stirred for about 4 hours at room temperature. 16 g denatured ethanol is added and the mixture is stirred for about 18 hrs at which point the material had dissolved. The flask is then purged with nitrogen and then placed in a water bath (temp - 30 ⁇ 2 °C). 1.0 g DSPE-PEG-thiol (BroadPharm) in 6 g ethanol is then added to the solution of derivatized HA. The pH of the reaction mixture is adjusted to about 9.5 using 0.25 M NaOH.
- the solution is stirred for 24 hours after which the pH is adjusted to about 7 using 0.25 M HCL About 0.25 g NaCI is added to the reaction solution. The solution is stirred until the NaCI had dissolved. 150 mL cold acetone is slowly added to the solution. The reaction mixture is stirred for 1.5 hours. The precipitate is isolated using vacuum filtration. The precipitate is washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate is dried under vacuum at room temperature.
- DSPE 1,2-distearoyl-sn-glycero-3-phosphoethanolamine
- DSPG 1,2-distearoyl-sn- glycero-3-phospho-(l'-rac-glycerol)
- DSPC Cholesterol and l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) is dissolved in chloroform.
- a lipid mixture composed of 31 mol% DSPC, 31 mol% cholesterol, 31 mol% DSPG and 6 mol% DSPE is prepared by adding the appropriate amounts of each solution in 50 mL round bottom flask and methanol is added dropwise until the solution becomes clear. The solvent is removed using a BUCHI rotovap system under heat ( ⁇ 60 -C) until dry ( ⁇ 16 mBarr) to make a thin lipid film. A Branson sonicator bath is filled with mi I liQ. water and heated until >65-C. A 0.01% (w/w) solution of the cholesterol HA derivative (above) is prepared using deionized water.
- the round bottom flask containing the lipid film is partially submerged in the water bath and cholesterol HA derivative solution is added to re-suspend the lipid film to a concentration of 2 mg lipid/mL solution.
- the solution is sonicated for 1 minute and then removed for 2 minute. This step is repeated three times and is then transferred to an Avestin LiposoFast LF-50 liposome extruder.
- the extruder is connected to a heated recirculator bath to maintain a temperature > 655C throughout the extruder.
- the liposome solution is extruded through sequentially smaller nucleopore membranes until a 50-100 nm liposome is obtained. This usually requires two passes through a stack of one 400 and one 200 nm membrane followed by two passes through one 100 nm membrane and two passes through a 50 nm membrane.
- the liposome manufacturing process is repeated using the DSPE derivatized HA (above), the Cholesterol-PEG derivatized HA (abovr) and the DSPE-PEG derivatized HA (above).
- the liposome manufacturing process is repeated using each of the above HA derivatives with paclitaxel being added to the initial lipid chloroform solution such that the final paclitaxel concentration is 0.02 mg/mL.
- the liposome manufacturing process is repeated using each of the above HA derivatives with RNA being added to the HA derivative solution.
- a neutral lipid DOPE (l,2-dioleoyl-sn-glycero-3-phosphoethanolamine, Sigma, USA) and a cationic lipid DOTAP (N-[l-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride, Sigma, USA) are dissolved in chloroform.
- the lipid solutions are mixed in required ratios to provide DOTAP:DOPE at a 1:1 weight ratio in a 50 mL round bottom flask.
- the solvent is removed using a rotavap and the lipid film is placed under vacuum overnight.
- a 0.1% (w/w) solution of the cholesterol HA derivative (above) is prepared using deionized water.
- HA derivative solution is added to dried lipid films to produce final lipid concentrations of 12 mg/mL.
- the solution is vortexed for 1 min and then sonicated at 40 °C for 20 min in a sonication bath.
- the liposome manufacturing process is repeated using the DSPE derivatized HA (above), the Cholesterol-PEG derivatized HA (above) and the DSPE-PEG derivatized HA (above).
- the liposome manufacturing process is repeated separately using each of the above HA derivatives with RNA being added to each of the HA derivative solution.
- Lipid nanoparticles are prepared using ionizable lipid SM-102 (Heptadecan-9-yl 8- ⁇ (2-hydroxyethyl)[6-oxo-6-(undecyloxy)hexyl]amino ⁇ octa noate, BroadPharm), distearoylphosphatidylcholine (DSPC), and cholesterol at a molar ratio of 55:10:35. (SM- 102:DSPC:cholesterol). RNA is used at a lipid nitrogen to RNA phosphate ratio of 3 (approx, weight ratio of 10:1 of total lipid:RNA. A RNA solution at ⁇ 1 mg/ml is prepared in 10 mmol/l citrate buffer, pH 4.
- the lipids are dissolved in ethanol in the appropriate ratios.
- the syringes containing RNA solution and lipid solution are placed in a syringe pump and are connected to a union connector (0.05 in thru hole, #P-728; IDEX Health & Science, Oak Harbor, WA) with PEEK high-performance liquid chromatography tubing (0.02 in ID for siRNA solution and 0.01 in ID for lipid solution).
- the outlet of the union connector is connected to a length of PEEK high- performance liquid chromatography tubing (0.04 in ID).
- the end of the tubing is placed in a collection tube.
- the RNA solution and lipid solution are set at 15 and 5 ml/min, respectively and the two solutions are mixed and collected in the collection tube.
- a solution of the Cholesterol derivatized HA (Example 33) is added to the solution such that the HA cholesterol derivative to total lipid ratio is 40:1 on a weight basis.
- the resultant solution is vortexed for 10 minutes and left for 2hrs.
- the resultant solution is dialyzed (Spectra/Por MWCO 6000 to 8000) against phosphate-buffered saline (155 mmol/l NaCI, 3 mmol/l Na2HPO4, 1 mmol/l KH2PO4, pH 7.2).
- the lipid particle manufacturing process is repeated using the DSPE derivatized HA (above), the Cholesterol-PEG derivatized HA (Example 35) and the DSPE-PEG derivatized HA (above).
- any concentration range, percentage range, ratio range, or integer range provided herein is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.
- any number range recited herein relating to any physical feature, such as polymer subunits, size or thickness are to be understood to include any integer within the recited range, unless otherwise indicated.
- the term "about” means ⁇ 20% of the indicated range, value, or structure, unless otherwise indicated.
Abstract
Hyaluronic acid polymers may be converted to derivatives thereof by reaction with divinyl sulfone to provide vinyl sulfone substituted polymers, where the polymers may additionally be further derivatized, including crosslinked, and the crosslinked and non-crosslinked derivatives may be used in biomedical and other applications.
Description
FUNCTIONALIZED AND CROSSLINKED POLYMER METHODS AND COMPOSITIONS
[0001] RELATED APPLICATIONS
[0002] CROSS-REFERENCE TO RELATED APPLICATIONS
[0003] This application claims the benefit of priority to United States Provisional Application No. 63/394,148, filed August 1, 2022, the disclosure of which is incorporated herein by reference in its entirety.
[0004] Field of the Disclosure
[0005] The present disclosure relates generally to functionalized polymers including crosslinked embodiments thereof, and methods for preparation and uses thereof. The polymers of the present disclosure provide useful properties that are not available from polymers currently available.
[0006] BACKGROUND
[0007] Hyaluronic acid (HA) is a non-sulphated glycosaminoglycan (GAG) and is composed of repeating polymeric disaccharides of D-glucuronic acid and N-acetyl-D-glucosamine linked by a glucuronidic 0 ( 1— > 3) bond. Native HA is hydrophilic which makes it challenging to incorporate into a local hydrophobic environment. HA can be modified to incorporate hydrophobic groups onto the HA backbone. Ester bonds have been used to accomplish this modification with the HYAFF® (Anika) being one example of a hydrophobically modified HA. These materials are hydrolytically unstable and thus, prolonged exposure to an aqueous environment can be detrimental to the properties of these materials.
[0008] What is needed are derivatives of hyaluronic acid, compositions of such polymers and use of such polymers for multiple applications, such as cosmetic treatments, medical treatments and production of medical devices and medical device components.
SUMMARY
[0009] In brief, the present disclosure provides polymers, method of making polymers, methods of using polymers and compositions that comprise polymers. For example, in one aspect, the present disclosure provides compositions that comprise at least one type of lipid and
a derivative of a hyaluronic acid polymer in which one or more hydroxyl groups of the hyaluronic acid is a modified hydroxyl group, wherein the derivative of hyaluronic acid has the structure HA- (OC^CHzSOzCHzCFh-X-Ri-Yjn where HA hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic with at least four consecutive -CH2- groups, a cholesterol moiety, a lipid moiety or aromatic moiety and n is the number of modified hydroxyl groups where n is an integer and n > 1, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group.
[0010] In another aspect, the present disclosure provides compositions that comprise at least one type of lipid anda derivative of hyaluronic acid, in which two or more hydroxyl groups of the hyaluronic acid are modified hydroxyl groups, wherein the derivative of hyaluronic acid has the structure (Y-R2-X-CH2CH2SO2CH2CH2O)m-HA-(OCH2CH2SO2CH2CH2-X-Ri-Y)n where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic, a cholesterol moiety, a lipid moiety or aromatic moiety, R2 is a substituted or unsubstituted C5-C20 aliphatic or aromatic moiety wherein Ri and R2 are different from each other, wherein n and m are each integers, and n > land m > 1, and Y is H; a carboxylic acid group, or a salt or ester; thereof; a hydroxyl group; a sulfonic acid group, or a salt thereof, or an amine group.
[0011] In another aspect, the present disclosure provides compositions that comprise at least one type of lipid and a derivative of hyaluronic acid in which two or more hydroxyl groups of the hyaluronic acid are modified hydroxyl groups, wherein the derivative of hyaluronic acid has the structure (CH2=CH-SO2CH2CH2O)m-HA-(OCH2CH2SO2CH2CH2-X-Ri-Y)n where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic, a cholesterol moiety, a lipid moiety or an aromatic moiety, each of n and m is an integer, and n > 1 and m > 1, and Y is H; a carboxylic acid group, or a salt or ester; thereof; a hydroxyl group; a sulfonic acid group, or a salt thereof; or an amine group
[0012] In further aspects, the present disclosure provides derivatives of hyaluronic acid such as described above, wherein 0.25-50% of a sum of the hydroxyl groups and the modified hydroxyl groups are a modified hydroxyl group.
[0013] In another aspect, the present disclosure provides compositions comprising derivatives of hyaluronic acid such as described above and at least one type of lipid and wherein
at least one lipid is a phospholipid.
[0014] In another aspect, the present disclosure provides compositions of derivatives of hyaluronic acid such as described above and at least one type of lipid and wherein at least one lipid is an ionizable lipid.
[0015] In another aspect, the present disclosure provides compositions of derivatives of hyaluronic acid such as described above, and further comprising at least one type of lipid and and cholesterol. In another aspect, the present disclosure provides compositions of derivatives of hyaluronic acid such as described above and a lipid wherein the compositions are in the form of liposomes.
[0016] In another aspect, the present disclosure provides composition of derivatives of hyaluronic acid such as described above and a lipid wherein the compositions are in the form of lipid nanoparticles.
[0017] In another aspect, the present disclosure provides compositions of derivatives of hyaluronic acid such as described above that are a component of a polymeric particle.
[0018] In another aspect, the present disclosure provides compositions of derivatives of hyaluronic acid such as described above and a lipid wherein the composition further comprises a biologically active agent.
[0019] In another aspect, the present disclosure provides compositions of derivatives of hyaluronic acid such as described above and a lipid wherein the composition further comprises a biologically active agent wherein the biologically active agent is RNA
[0020] In another aspect, the present disclosure provides compositions of derivatives of hyaluronic acid such as described above and a lipid wherein the composition further comprises a biologically active agent that is a chemotherapeutic agent.
[0021] In an aspect, the present disclosure provides compositions that comprises a derivative of a hyaluronic acid polymer in which one or more hydroxyl groups of the hyaluronic acid is a modified hydroxyl group, wherein the derivative of hyaluronic acid has the structure HA- (OCH2CH2SO2CH2CH2-X-Ri-Y)n where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic with at least four consecutive -CH2- groups, a cholesterol moiety,
a lipid moiety or aromatic moiety and n is the number of modified hydroxyl groups where n is an integer and n > 1, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group; and an oil phase.
[0022] In another aspect, the present disclosure provides compositions that comprise a derivative of hyaluronic acid, in which two or more hydroxyl groups of the hyaluronic acid are modified hydroxyl groups, wherein the derivative of hyaluronic acid has the structure (Y-R2-X- CH2CH2SO2CH2CH2O)m-HA-(OCH2CH2SO2CH2CH2-X-Ri-Y)n where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic, a cholesterol moiety, a lipid moiety or aromatic moiety, R2 is a substituted or unsubstituted C5-C20 aliphatic, a cholesterol moiety, a lipid moiety or aromatic moiety wherein Ri and R2 are different from each other, wherein n and m are each integers, and n > land m > 1, and Y is H; a carboxylic acid group, or a salt or ester; thereof; a hydroxyl group; a sulfonic acid group, or a salt thereof, or an amine group; and an oil phase.
[0023] In another aspect, the present disclosure provides compositions that comprise a derivative of hyaluronic acid in which two or more hydroxyl groups of the hyaluronic acid are modified hydroxyl groups, wherein the derivative of hyaluronic acid has the structure (CH2=CH- SO2CH2CH2O)m-HA-(OCH2CH2SO2CH2CH2-X-Ri-Y)n where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic, a cholesterol moiety, a lipid moiety or aromatic moiety, each of n and m is an integer, and n > 1 and m > 1, and Y is H; a carboxylic acid group, or a salt or ester; thereof; a hydroxyl group; a sulfonic acid group, or a salt thereof; or an amine group; and an oil phase.
[0024] In an aspect, the present disclosure provides compositions that comprises a derivative of a hyaluronic acid polymer in which one or more hydroxyl groups of the hyaluronic acid is a modified hydroxyl group, wherein the derivative of hyaluronic acid has the structure HA- (OCH2CH2SO2CH2CH2-X-Ri-Y)n where HA hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted Cs-C2o aliphatic with at least four consecutive -CH2- groups, a cholesterol moiety, a lipid moietyor aromatic moiety and n is the number of modified hydroxyl groups where n is an integer and n > 1, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group; a water phase and a preservative.
[0025] In another aspect, the present disclosure provides compositions that comprise a derivative of hyaluronic acid, in which two or more hydroxyl groups of the hyaluronic acid are modified hydroxyl groups, wherein the derivative of hyaluronic acid has the structure (Y-R2-X- CH2CH2SO2CH2CH2O)m-HA-(OCH2CH2SO2CH2CH2-X-Ri-Y)n where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic, a cholesterol moiety, a lipid moiety or aromatic moiety, R2 is a substituted or unsubstituted C5-C20 aliphatic or aromatic moiety wherein Ri and R2 are different from each other, wherein n and m are each integers, and n > land m > 1, and Y is H; a carboxylic acid group, or a salt or ester; thereof; a hydroxyl group; a sulfonic acid group, or a salt thereof, or an amine group; a water phase and a preservative.
[0026] In another aspect, the present disclosure provides compositions that comprise a derivative of hyaluronic acid in which two or more hydroxyl groups of the hyaluronic acid are modified hydroxyl groups, wherein the derivative of hyaluronic acid has the structure (CH2=CH- SO2CH2CH2O)m-HA-(OCH2CH2SO2CH2CH2-X-Ri-Y)n where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted Cs-C2o aliphatic, a cholesterol moiety, a lipid moiety or aromatic moiety, each of n and m is an integer, and n > 1 and m > 1, and Y is H; a carboxylic acid group, or a salt or ester; thereof; a hydroxyl group; a sulfonic acid group, or a salt thereof; or an amine group; a water phase and a preservative.
[0027] In another aspect, the present disclosure provides a derivative of a hyaluronic acid, prepared by any of the processes identified herein. In another aspect, the present disclosure provides a crosslinked polymer prepared by any of the processes disclosed herein.
[0028] In another aspect, the present disclosure provides a composition comprising a derivative of a hyaluronic acid, wherein the composition may further comprise an excipient.
[0029] In another aspect, the present disclosure provides a composition comprising a crosslinked hyaluronic acid derivative e.g. a crosslinked polymer of a derivative of hyaluronic acid, as described herein. A composition may further comprise an excipient. Each of the compositions disclosed herein may optionally include one or more of a pharmaceutically acceptable synthetic polymer, thermosreversible polymer, biodegradable polymer, buffer, complexing agent, tonicity modulator, ionic strength modifier, solvent, anti-oxidant, preservative, viscosity modifier, pH modifier, surfactant, emulsifier, phospholipid, stabilizer and porogen. Also optionally, a
composition as disclosed herein may further comprise a biologically active agent.
[0030] Derivatized polymers and compositions comprising one or more derivatized polymers disclosed herein exhibit shear thinning. Shear thinning is the non-Newtonioan behavior of fluids whose viscosity decreases under shear strain.
[0031] In additional aspects, the present disclosure provides method of using the polymers and compositions as disclosed herein. For example, the present disclosure provides the following aspects:
[0032] A wound healing device comprising a composition as described herein.
[0033] A method for wound healing comprising administering to a subject in need thereof an effective amount of a composition as described herein.
[0034] A bulking agent comprising a composition as described herein.
[0035] A dermal filler comprising a composition as described herein.
[0036] A method of filling a void in a subject in need thereof comprising administering to the subject a dermal filler as described herein.
[0037] A viscosupplement comprising a composition as described herein.
[0038] A method of relieving joint pain in a subject in need thereof, comprising administering to the subject a viscosupplement as described herein.
[0039] A method of preventing surgical adhesions in a subject in need thereof comprising administering the subject an effective amount of a composition as described herein.
[0040] A tissue sealant comprising a composition as described herein.
[0041] A method of sealing tissue in a subject in need thereof comprising administering to the subject an effective amount of a tissue sealant as described herein.
[0042] A method of treating bacterial vaginosis in a subject in need thereof comprising administering to the subject an effective amount of a composition as described herein.
[0043] A nasal treatment device comprising a composition as described herein.
[0044] A method of treacling a nasal condition in a subject in need thereof comprising administering the subject an effective amount of a composition as described herein.
[0045] An eye drop comprising a composition as described herein.
[0046] A method of treating an ocular condition in a subject in need thereof comprising administering the subject an effective amount of a composition as described herein.
[0047] A punctal plug comprising a composition as described herein.
[0048] A method of treating mucocitis in a subject in need thereof comprising administering to the subject an effective amount of a composition as described herein.
[0049] An anti-bacterial formulation comprising a composition as described herein.
[0050] An ear treatment device comprising a composition as described herein.
[0051] A method of treating an ear condition comprising administering to a subject in need thereof an effective amount of a composition as described herein.
[0052] A method of drug delivery to a subject in need thereof comprising administering to the subject an effective amount of a composition as described herein that comprises the drug. [0053] A biopsy plug comprising a composition as described herein.
[0054] A plug for female sterilization comprising a composition as described herein.
[0055] A method of female sterilization to a subject in need thereof comprising administering to the subject an effective amount of a composition as described herein.
[0056] A tissue scaffold comprising a composition as described herein.
[0057] The method of supporting tissue growth in a subject in need thereof comprising implanting in the subject a tissue scaffold as described herein.
[0058] A burr hole plug comprising a composition as described herein.
[0059] A nerve guide comprising a composition as described herein.
[0060] A vaginal lubricant comprising a composition as described herein.
[0061] A coating for a device comprising a composition as described herein.
[0062] A cosmetic comprising a composition described herein.
[0063] A liposome comprising a composition described herein.
[0064] A lipid nanoparticle comprising a composition described herein.
[0065] An emulsion comprising a composition herein.
[0066] A method for coating a device comprising applying a coating as described herein onto a surface of the device.
[0067] A method of administering an injectable formulation comprising a composition as described herein.
[0068] A method of administering an injectable formulation comprising a composition as described herein to treat cancer.
[0069] A method of administering an injectable formulation comprising a composition as described herein to elicit an immune response.
[0070] A method of administering an injectable formulation comprising a composition as described herein to enable RNA to enter a cell.
[0071] A method for additive manufacturing comprising a polymer as described herein, e.g., a derivative of hyaluronic acid as described herein, or prepared by a process as described herein, to provide a derivative of the polymer, e.g., hyaluronic acid, and depositing the derivative onto a substrate to provide an article formed by additive manufacturing.
[0072] A method for additive manufacturing by deposition of a with a polymer as described herein, e.g., a derivative of hyaluronic acid as described herein on the surface or within a polymeric substrate.
[0073] A method of coating or penetrating an article formed by additive manufacturing with a polymer as described herein, e.g., a derivative of hyaluronic acid as described herein.
[0074] An electrospun material or article comprising a composition as described herein. [0075] A method for producing an electrospun material or article, comprising producing, with an electrospinning device, a material or an article comprising a derivative of hyaluronic acid described herein.
[0076] A method of coating or penetrating an article formed by electrospinning with a polymer as described herein, e.g., a derivative of hyaluronic acid as described herein.
[0077] A textile material or article comprising a composition as described herein.
[0078] A method for producing a textile material or article, comprising producing, with an electrospinning device, a material or an article comprising a derivative of hyaluronic acid described herein.
[0079] A method of coating or penetrating an article formed by electrospinning on a textile substrate with a polymer as described herein, e.g., a derivative of hyaluronic acid as described herein.
[0080] The above-mentioned and additional features of the present disclosure and the manner of obtaining them will become apparent, and the disclosure will be best understood by reference to the following more detailed description. All references disclosed herein are hereby incorporated by reference in their entirety as if each was incorporated individually.
[0081] This Brief Summary has been provided to introduce certain concepts in a simplified form that are further described in detail below in the Detailed Description. Except where otherwise expressly stated, this Brief Summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to limit the scope of the claimed subject matter.
[0082] The details of one or more aspects are set forth in the description below. The features illustrated or described in connection with one exemplary aspect may be combined with the features of other aspects. Thus, any of the various aspects described herein can be combined to provide further aspects. Aspects of the aspects can be modified, if necessary to employ concepts of the various patents, applications and publications as identified herein to provide yet further aspects. Other features, objects and advantages will be apparent from the description, the drawings, and the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0083] Exemplary features of the present disclosure, its nature and various advantages will be apparent from the accompanying drawings and the following detailed description of various aspects. Non-limiting and non-exhaustive aspects are described with reference to the accompanying drawings, wherein like labels or reference numbers refer to like parts throughout the various views unless otherwise specified. The sizes and relative positions of elements in the drawings are not necessarily drawn to scale. For example, the shapes of various elements are selected, enlarged, and positioned to improve drawing legibility. The particular shapes of the
elements as drawn have been selected for ease of recognition in the drawings. One or more aspects are described hereinafter with reference to the accompanying drawings in which:
[0084] FIG. 1 shows exemplary reactions of the present disclosure.
[0085] FIG. 2 shows exemplary reactions of the present disclosure.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0086] The present disclosure may be understood more readily by reference to the following detailed description of preferred aspects of the disclosure and the Examples included herein.
[0087] In one aspect, the present disclosure provides functionalized HA polymers and copolymers, and including compositions thereof. As used herein, a functionalized polymer or copolymer refers to an organic polymer/copolymer comprising hydroxyl groups, and optionally also comprises on or more functional groups, including, but not limited to, a carboxylic acid, amine , or sulfonic acid group. As used herein, the term "polymer" includes copolymer unless specifically noted, and those of skill in the
[0088] The present disclosure provides a derivative of HA in which one or more hydroxyl groups of the HA is a modified hydroxyl group, wherein the derivative of hyaluronic acid has the structure HA-(OCH2CH2SO2CH2CH2-X-Ri-Y)n where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic with at least four consecutive -CH2- groups, a cholesterol moiety, a lipid moiety or an aromatic moiety and n is the number of modified hydroxyl groups where n is an integer and n > 1, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, a phosphonic acid group or a salt thereof, or an amine group.
[0089] In another aspect, the present disclosure provides a derivative of HA in which two or more hydroxyl groups of the hyaluronic acid are modified hydroxyl groups, wherein the derivative of hyaluronic acid or other polyhydric polymer has the structure (Y-R2-X- CH2CH2SO2CH2CH2O)m-HA-(OCH2CH2SO2CH2CH2-X-Ri-Y)n where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic, a cholesterol moiety, a lipid moiety or aromatic moiety, R2 is a substituted or unsubstituted C5-C20 aliphatic or aromatic moiety wherein
Ri and R2 are different from each other, wherein n and m are each integers, and n > land m > 1, and Y is H; a carboxylic acid group, or a salt or ester; thereof; a hydroxyl group; a sulfonic acid group or a salt thereof; a phosphonic acid group or a salt therof; or an amine group.
[0090] In another aspect, the present disclosure provides a derivative of HA in which two or more hydroxyl groups of the hyaluronic acid are modified hydroxyl groups, wherein the derivative of hyaluronic acid has the structure (CH2=CH-SO2CH2CH2O)m-HA-(OCH2CH2SO2CH2CH2- X-Ri-Y)n where HA is hyaluronic acid or other polyhydric polymer, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic, a cholesterol moiety, a lipid moiety or aromatic moiety, each of n and m is an integer, and n > 1 and m > 1, and Y is H; a carboxylic acid group, or a salt or ester; thereof; a hydroxyl group; a sulfonic acid group, or a salt thereof; a phosphonic acid group or a salt therof; or an amine group.
[0091] In another aspect, the substituted or unsubstituted aliphatic, is a Cs to C20 aliphatic In an aspect, the substituted or unsubstituted aliphatic, is a Cg to C20 aliphatic. In another aspect, the substituted or unsubstituted aliphatic, is a C10 to C20 aliphatic. In another aspect, the C5 to C20 aliphatic has at least four consecutive -CH2- groups. In another aspect, the C8 to C2o aliphatic has at least six consecutive -CH2- groups. In another aspect, the C10 to C20 aliphatic has at least six consecutive -CH2- groups. In another aspect, the Cw to C2o aliphatic has at least eight consecutive -CH2- groups.
[0092] In further aspects, the present disclosure provides derivatives of HA such as described above, which are further characterized by the derivative wherein 0.25-50% of a sum of the hydroxyl groups and the modified hydroxyl groups are a modified hydroxyl group.
[0093] In another aspect, the present disclosure comprises crosslinked polymers comprising a reaction product of a derivative of hyaluronic acid, and optionally, may comprise a crosslinking agent, wherein as used herein, a crosslinking agent may comprise known crosslinking agents, such as crosslinking compounds, for example, OH crosslinking agents or vinyl crosslinking agents, FeCI3, or compounds and/or energy sources, including but not limited to, UV and related photoinitiator compounds.
[0094] In one aspect the present disclosure utilizes HA with one or more available hydroxyl groups and reacts one or more of those hydroxyl groups under specific conditions as
disclosed herein with divinyl sulfone such that only one of the vinyl groups of the divinyl sulfone reacts with the hydroxyl group via an addition reaction to form an ether bond between the polysaccharide and the residue of the divinyl sulfone. The degree of reaction can range from about 0.5% to about 50% of the available hydroxyl groups. At higher substitution, i.e., around 50%, some degree of crosslinking will typically occur. Thus, the present disclosure provides vinyl sulfone substituted polysaccharide polymers with minimal to no crosslinking, or polysaccharide polymers that have a level of vinyl sulfone substitution crosslinking due to double reaction of the divinyl sulfone (i.e., reaction of both ethenyl groups of the DVS with hydroxyl groups).
[0095] The residual vinyl group of the vinyl sulfone can be then reacted with a compound that has a reactive thiol group. This reaction occurs via a Michael addition between the residual vinyl group of the divinyl sulfone and the free thiol group such that a thioether bond is formed. There are numerous variations of the degree of substitution, the thiol derivative used, the sequence of the reactions and the replication of reactions that provide a large variety of derivatives of polymeric polyhydric alcohols and compositions contemplated and disclosed herein. Derivatives of HA can be crosslinked in many different ways, and compositions comprising such crosslinked derivatives of HA are contemplated and disclosed herein. The derivatives of HA and compositions thereof have numerous medical and non-medical applications. Methods of use or treatment disclosed herein may comprise derivatives of HA and compositions thereof. Derivatives of HA may also be referred to herein as HA derivatives.
[0096] The derivatives of HA and compositions thereof of the present disclosure are prepared as described herein. Typically, a HA polymer having hydroxyl groups is combined with divinyl sulfone (DVS) under suitable reaction conditions. Those reaction conditions include a suitable pH of the solution, where the reaction typically occurs under basic conditions, e.g., a pH of 11-14, or 12-13, e.g., about 12.3. The reaction conditions include a suitable solvent, where water or DMSO are suitable solvents, e.g., the reaction may be conducted in water. The description of reaction conditions may further include stirring the reacting mixture, e.g., stirring with a stirring rate of > 200 rpm (rotations per minute), such as 250-800 rpm. Furthermore, the description of reaction conditions may include specification of the relative amounts of DVS and polymer (e.g., polysaccharide) that are combined, where these relative amounts may be
expressed in terms of moles of DVS to moles of repeat unit in the polymer. For instance, the method for preparing the functionalized polymer may be described in terms of the ratio of DVS:polymer repeat unit, where this ratio may be at least 0.5:1, e.g., up to about 5:1, or up to about 7.5:1, or up to about 10:1, or up to about 15:1, or up to about 20:1.
[0097] In one aspect, the present disclosure provides a process wherein HA that has an available hydroxyl group, i.e., a hydroxyl group that is capable of undergoing a reaction with divinyl sulfone, is reacted with DVS under basic conditions. If the conditions are selected appropriately, the reaction can be controlled such that one of the vinyl groups of the divinyl sulfone will react with a free hydroxyl group of the polysaccharide such that the polysaccharide does not crosslink to such an extent that it forms a hydrogel. This results in the polysaccharide being functionalized with the divinyl sulfone such that one of the vinyl groups undergoes reaction with a hydroxyl group of the polysaccharide and the other vinyl group remains functional. The vinyl group of the divinyl sulfone reacts with the hydroxyl group by an addition reaction that results in an ether linkage.
[0098] The reaction may be performed under basic conditions with a pH of greater than 11. Optionally, the pH is in the range of 12.0 to 13.5. Optionally, the pH is in the range is in the 12.0 to 12.5 range. Optionally, the pH range is in the 12.2 to 12.7 range.
[0099] To ensure that the predominant reaction is a single reaction of one of the vinyl groups of the divinyl sulfone, and not a crosslinking reaction in which predominantly both the vinyl groups react with hydroxyl groups of the polysaccharide to form a crosslinked gel, the molar ratio of the divinyl sulfone to that of the polysaccharide repeat units is greater than 1. In one aspect, the molar ratio of the divinyl sulfone to that of the polysaccharide repeat units is greater than 5. In one aspect, the molar ratio of the divinyl sulfone to that of the polysaccharide repeat units is greater than 7. In one aspect, the molar ratio of the divinyl sulfone to that of the polysaccharide repeat units is greater than 10. In one aspect, the molar ratio of the divinyl sulfone to that of the polysaccharide repeat units is greater than 15. In an aspect, the molar ratio of the divinyl sulfone to that of the polysaccharide repeat units is from about 1 to about 20, or from about 1 to about 15, or from about 1 to about 10, or from about 1 to about 5, or from about 5 to about 20, or from about 5 to about 15, or from about 5 to about 10, of from about 10 to
about 20, or from about 10 to 15, or is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
[00100] To provide intimate contact between the reactants, the reaction mixture may be stirred. Methods and devices for adequate mixing are known to those of skill in the art. For example, in order to ensure that there is adequate stirring of the reaction solution during the reaction, the rotational speed of the mixing impellor may be controlled. In one aspect, the revolutions per minute (rpm) of the mixing impellor may be in the range of 200 to 400 rpm. In another aspect, the revolutions per minute (rpm) of the mixing impellor may be in the range of 400 to 600 rpm. In another aspect, the revolutions per minute (rpm) of the mixing impellor may be in the range of 600 to 800 rpm.
[00101] The amount of substitution accomplished may be controlled, in part, by the duration of exposure of the polysaccharide to the divinyl sulfone at a pH of greater than 11 (reaction time). In one aspect, the reaction time can range from 10 seconds through to 60 minutes. In one aspect, the reaction time can be in the range of 2 minutes to 35 minutes. In another aspect, the reaction time can be in the range of 4 minutes to 30 minutes, or from 20 minutes to 60 minutes, from 15 minutes to 20 minutes, from 5 minutes to 10 minutes, from 10 seconds to 30 seconds, from 30 second to 1.5 minutes, and ranges thereinbetween
[00102] The solvent that can be used for the reaction can be water, water with an ionic modifier, forexample NaCI, a combination of water and a water-miscible solvent. Water miscible solvents can include but are not limited to methanol, ethanol, isopropanol, dimethyl formamide (DMF), acetone, 1,4-dioxane, pyridine, dimethyl sulfoxide (DMSO), tetra hydrofuran (THF) and acetonitrile.
[00103] The temperature of the reaction mixture can also be used to influence the amount of substitution of the polysaccharide by the divinyl sulfone. In one aspect, the reaction mixture can be maintained at a temperature that is lower than 25°C so as to reduce the rate of the reaction. This can enable lower substitution levels for the same duration as compared to room temperature or it can allow for a longer reaction time that that at room temperature to yield a similar amount of substitution. In one aspect, the temperature can be in the 15°C to 20 °C range. In another aspect, the reaction mixture can be in the 10°C to 15°C range. In yet another aspect,
the temperature can be in the 2 °C to 10°C range. In another aspect, the temperature can be increase above 25°C so as to provide shorter reaction times as compared to 25°C to get similar amounts of substitution or to get greater substitution as compared to 25°C for an equivalent amount of reaction time. In one aspect, the reaction mixture can be in the 28°C to 35°C range. In another aspect, the reaction mixture can be in the 36°C to 50°C range. In another aspect, the reaction mixture can be in the 51°C to 75°C range.
[00104] The amount of substitution, as measured by the molar ratio of the attached vinyl group from the divinyl sulfone to the polysaccharide repeat unit, can be greater than 5%. In one aspect, for polysaccharides with at least one hydroxyl group, the amount of substitution is in the range of 5% to 35%. In another aspect, for polysaccharides with at least one hydroxyl group, the amount of substitution is in the range of 36% to 70% range. In another aspect, for polysaccharides with at least one hydroxyl group, the amount of substitution is in the range of 71% to 100% range. In another aspect, for polysaccharides with at least two hydroxyl groups, the amount of substitution is in the range of 101% to 200% range.
[00105] The molecular weight of the HA can be selected. Molecular weights from 1,000 to 5,000,000 may be used. In one aspect, the HA has a molecular weight of over 1,000. In another aspect, the HA has a molecular weight in the range of 1,000 to 10,000. In another aspect, the HA has a molecular weight in the range of 10,000 to 50,000. In another aspect, the HA has a molecular weight in the range of 50,000 to 200,000. In another aspect, the HA has a molecular weight in the range of 200,000 to 600,000. In an aspect, the HA has a molecular weight in the range of 600,000 to 1,000,000. In an aspect, the HA has a molecular weight in the range of 1,000,000 to 2,500,000. In yet another aspect, the HA has a molecular weight in the range of 2,500,000 to 5,000,000. The molecular weight can be measured by known methods, including, but not limited to, gel permeation chromatography or intrinsic viscosity.
[00106] After the functionalized polymer has been reacted with DVS to create a first derivative of the polymer, this first derivative is then reacted with a nucleophile, e.g., a thiol derivative, of a formula selected from X-R1 and X-R2-Y to provide a second derivative of the polymer. In these formulae, R1 is substituted or unsubstituted C5-C20 aliphatic, a cholesterol moiety, a lipid moiety or aromatic, R2 is substituted or unsubstituted C5-C20 aliphatic or aromatic,
X is a nucleophilic group, and Y is selected from carboxylic acid, sulfonic acid and hydroxyl. The nucleophile contains a thiol group as X in a thiol derivative. In general, the thiol derivative can be a single compound or a mixture of thiol compounds. Examples are alkyl thiols, which may be, e.g., linear, branched, or cyclic, such as methanethiol, ethanethiol, etc. Alternatively, the thiol may be an aryl thiol, a thiol-containing cholesterol derivative, a thiol containing lipid, a charged thiol, a polymeric thiol, peptides with thiol groups, proteins with thiol groups, heterocycles with thiol groups, drugs, e.g., active pharmaceutical ingredients, that contain thiol groups, growth factors with thiol groups, and biologically active agents with thiol groups.
[00107] For example, thiol compounds that can be used in the present disclosure are compounds that contain at least one free thiol group that is capable of reaction with a vinyl sulfone group via a Michael addition reaction.
[00108] The thiol compound may be identified by the formula RiSH or R2SH, where Ri and R2 may be an aliphatic or aromatic moiety, either of which may have one or more substituents, e.g., be a substituted aliphatic moiety or a substituted aromatic moiety. An aliphatic moiety refers to an alkyl or cycloalkyl moiety, either having 1-20 carbon atoms.
[00109] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to the specified number of carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. In one aspect the alkyl group has 1 carbon. In one aspect the alkyl group has 2 carbons. In one aspect the alkyl group has 3 carbons. In one aspect the alkyl group has 4 carbons. In one aspect the alkyl group has 4 carbons. In one aspect the alkyl group has 5 carbons. In one aspect the alkyl group has 6 carbons. Two or more of these aspects may be combined to describe derivatives of the disclosure.
[00110] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically herein, a cycloalkyl group may be optionally substituted by one or more substituents independently selected at each occurrence.
[00111] An aromatic moiety refers to a carbocyclic aromatic moiety, a.k.a., an aryl moiety, or a heteroaromatic moiety, a.k.a., a heteroaryl moiety, either having 1-20 carbon atoms, the heteroaromatic moiety having at least one heteroatom selected from sulfur, oxygen and nitrogen.
[00112] "Aryl" refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. In one aspect the aryl ring system has 6 to 12 carbon atoms. In one aspect the aryl ring system has 6 to 10 carbon atoms. For purposes of this disclosure, the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl group may be optionally substituted by one or more substituents independently selected at each occurrence.
[00113] "Heteroaryl" refers to "aryl" as defined herein, wherein the aromatic ring includes one or more heteroatoms, preferably selected from N, O and S. Thus, a heteroaryl radical refers to an aromatic ring system radical wherein the ring atoms are selected from carbon, nitrogen, oxygen and sulfur, and include at least one of nitrogen, oxygen and sulfur. For purposes of this disclosure, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Optionally, the heteroaryl radical is a 5-, 6- or 7-membered heteroaryl group. When there are multiple O and S atoms in the heteroaryl ring system, the O atoms and/or S atoms are preferably not linked directly to one another. Exemplary heteroaryl groups include 5-membered rings, such as pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, furan, thiophene, selenophene, oxazole, isoxazole, 1,2-thiazole, 1,3- thiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole,
1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole. The heteroaryl group may be a 6- membered ring, such as pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, 1,2,4,5-tetrazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, or fused rings including a 6- membered ring such as indole, isoindole, indolizine, indazole, benzimidazole, benzotriazole, purine, naphthimidazole, phenanthrimidazole, pyridimidazole, pyrazinimidazole, quinoxalinimidazole, benzoxazole, naphthoxazole, anthroxazole, phenanthroxazole, isoxazole, benzothiazole, benzofuran, isobenzofuran, dibenzofuran, quinoline, isoquinoline, pteridine, benzo-5,6-quinoline, benzo-6,7-quinoline, benzo-7,8-quinoline, benzoisoquin-oline, acridine, phenothiazine, phenoxazine, benzopyridazine, benzopyrimi-dine, quinoxaline, phenazine, naphthyridine, azacarbazole, benzocarboline, phenanthridine, phenanthroline, thieno[2,3b]thiophene, thieno[3,2b]thiophene, dithienothiophene, isobenzothiophene, dibenzothiophene, and benzothiadiazo-thiophene. Unless stated otherwise specifically in the specification, the ring atoms of a heteroaryl group may be optionally substituted by one or more substituents independently selected at each ring atom.
[00114] A substituted C5-C20 aliphatic or aromatic moiety refers to a C5-C20 aliphatic or aromatic moiety having one or more substituents, where a "substituent" refers to monovalent group that may be attached to a mentioned moiety. For example, a "substituted phenyl" refers to a phenyl ring having 1, 2, 3 or 4 substituents attached to the phenyl ring. Substituents may be selected from halogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, -OH, -O(Ci-C6alkyl), -O(Ci- Cehaloalkyl), -OfCi-Cehydroxyalkyl), -S(Ci-Cealkyl), -S(Ci-Ceha loa Ikyl), -S(Ci-Cehydroxyalkyl), cyano, amino (-NH2), formyl (-CHO), carboxylic acid (-COOH), carboxylate ester (-COOR where R is a Ci-Cio alkyl group).
[00115] These thiol compounds include alkyl thiols which may be linear, branched or cyclic, aryl thiols, charged thiol compounds, polymers that contain a free thiol, peptides that contain a free thiol, heterocycles that contain a free thiol, drugs or biologically active compounds with a free thiol, growth factors with a free thiol, antibodies or antibody fragments with a free thiol and proteins with a free thiol. Examples of such thiol compounds include, and are not limited to thiophenol, 2-phenylethanethiol, triphenylmethanethiol, 4-methylbenzenethiol, 4- aminothiophenol, 2-aminothiophenol, 4-methoxy-a-toluenethiol, 4-nitrothiophenol, 4-tert-
butylbenzenethiol, 2-mercapto-2-phenylacetic acid, 4-mercaptobenzoic acid, 2- mercaptobenzoic acid (thiosalicylic acid), 3-mercapto-l-propanol, l-mercapto-2-propanol, 4- mercapto-l-butanol, 3-mercapto-l-hexanol, 6-mercapto-l-hexanol, 8-mercapto-l-octanol, 9- mercapto-l-nonanol, 11-mercapto-l-undecanol, 4-mercapto-4-methylpentan-2-ol, ethanethiol, 1- propanethiol, 2-propanethiol, 1-butanetiol, 1-Pentanethiol, 1-hexanethiol, 2- ethylhexanethiol, 1-heptanethiol, 1-octanethiol, 1-nonanethiol, 1-decanethiol, 1-undecanethiol,
1-dodecanethiol, 1-tetradecanethiol, 1-hexadecanethiol, cis-9-octadecene-l-thiol, 1- octadecanethiol, 2-methyl-l-butanethiol, 3-methyl-l-butanethiol, cycloalkyl, cyclohexanethiol, cyclopentanethiol, sodium 3-mercapto-l-propanesulfonate, sodium mercaptopyruvate, 6- mercaptohexanoic acid, 8-mercaptooctanoic acid , 11-mercaptoundecanoic acid, 16- mercaptohexadecanoic acid, sodium 2-mercaptoethanesulfonate, 3-mercaptopropionic acid, 2- amino-4-mercaptobutyric acid (DL-homocysteine), L-cysteine, 11-mercaptoundecylphosphoric acid, 2-mercapto-l-methylimidazole, l-benzyl-2-mercaptoimidazole, 2-mercapto-6- methylpyridine, 3-mercapto-2-butanone, 3-mercapto-3-methyl-l-butyl-l-formate, 3-mercapto- 3-methylbutan-l-ol, 7-mercapto-4-methylcoumarin, 2-mercapto-4-methyl-5-thiazoleacetic acid,
2-mercapto-5-nitrobenzimidazole, 2-mercapto-5-benzimidazolesulfonic acid sodium salt dihydrate, 3-mercapto-N-nonylpropionamide, 2-mercapto-4-methylpyrimidine hydrochloride, 2- mercapto-2-phenylacetic acid, 2-mercapto-3-(trifluoromethyl)pyridine, 2-mercapto-N-m- tolylacetamide, 4-mercapto-4-methylpentan-2-ol, thiocholesterol (CAS 1249-81-6), and Cholesterol-PEG-thiol, l,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-N-
(mercaptopropyl), l,2-Dipalmitoyl-sn-Glycero-3-Phosphothioethanol, and 1,2-Distearoyl-sn- glycero-3-phosphoethanolamine-N-N-(mercapto-polyethyleneglycol) [DSPE-PEG-SH] are exemplary thiol compounds.
[00116] Polymers with free thiols include but are not limited to Thiol-PEG3-phosphonic acid, poly(L-lactide), thiol terminated 5000, poly(L-lactide), thiol terminated 2500, PEG-SH 3000, PEG-SH 5000, thiol-functionalized hyaluronic acid, thiol-functionalized chitosan, thiol functionalized alginate, thiol functionalized dextran, thiol functionalized chondroitin sulfate and thiol functionalized carboxymethyl cellulose.
[00117] Examples of thiol functionalized hyaluronic acid include but are not limited to a
thiol group linked to hyaluronic acid through a hydrazide compound as described in US 7,981,871, through carbodiimide groups as described in US 6,884,788, as well as those described in US 8,124,757.
[00118] Examples of thiol functionalized chitosan include but are not limited to chitosancysteine conjugates, chitosan-thioglycolic acid conjugates and chitosan-4-thio-butylamidine conjugates.
[00119] Non-degradable thiol functionalized polymers include but are not limited to polycarbophil-cysteamine conjugates, polycarbophil-cysteine conjugates, and poly(acrylic acid) - homocysteine conjugates.
[00120] Thiolated peptides or peptides that contain at least of free thiol, include but are not limited to a cysteine terminated peptide containing residues 73-92 of the knuckle epitope of BMP-2 (N->C: KIPKASSVPTELSAISTLYLSGGC), thiolated gelatin (see, e.g., U.S. Pat. Nos. 7,928,069 and 7,981,871), cysteine terminated cell adhesion epitopes such as Arg-Gly-Asp (RGD), Arg-Gly- Asp-Ser (RGDS) and lle-Lys-Val-Ala-Val (IKVAV), cysteine terminated TAT peptide (GRKKRRQRRRPQ), laminin peptide sequence Cys-Ser-Arg-Ala-Arg-Lys-GIn-Ala-Ala-Ser-lle-Lys- Val-Ala-Val-Ser-Ala-Asp-Arg (CSRARKQAASIKVAVSADR; lam-lKVAV), and cysteine terminated Elastin-like polypeptides such as those of the sequence (V P G X G )n where X= any amino acid except proline.
[00121] Thiol containing drugs include but are not limited to Captopril, Thiorphan, Tiopronin and Penicillamine.
[00122] Suitable proteins that contain a cysteine group include but are not limited to an IL-3 variant (see, e.g., US 5,166,322), an IL-2 variant (see, e.g., US 5,206,344), protease nexin-1 varients (see, e.g., US 5,766,897), Cysteine variants of granulocyte-macrophage colonystimulating factor (see, e.g., US 7,148,333; and Bioconjugate Chem., 2005, 16 (5), pp 1291-1298; DOI: 10.1021/bc050172r), cysteine modified maize ribosome-inactivating protein (maize RIP) [see, e.g., Toxins 2016, 8, 298; doi:10.3390/toxins8100298], cysteine analog of erythropoietin [see, e.g., Int J Nanomedicine. 2011; 6: 1217-1227; doi: 10.2147/IJN.S19081], reduced antibody fragments [see, e.g., Protein Eng Des Sei (2007) 20 (5): 227-234. DOI: https://doi.org/10.1093/protein/gzm015], and cysteine analogues of Bone Morphogenetic
Protein-2 (see, e.g.. Bioconjugate Chem., 2010, 21 (10), pp 1762-1772; DOI: 10.1021/bc9005706. [00123] Suitable growth factors that comprise a free thiol group include but are not limited to Cysteine Analogs of Human Basic Fibroblast Growth Factor (hbFGF) [see, e.g., Tropical Journal of Pharmaceutical Research October 2014; 13 (10): 1601-1607; http://dx.doi.Org/10.4314/tjpr.vl3il0.5; and Protein Expr. Purif. 2006 Jul;48(l):24- 7https://doi.org/10.1016/j.pep.2006.02.002]).
[00124] In one aspect, the HA derivative has the structure HA-(OCH2CH2SO2CH2CH2-X-RI- Y)n where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic moiety which has at least 4 consecutive -CH2- groups , a cholesterol moiety, a lipid moiety or aromatic moiety and n is the number of modified hydroxyl groups where n is an integer and n > 1, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine.
[00125] In one aspect, the HA derivative has the structure HA-(OCH2CH2SO2CH2CH2-X-Ri)n where X is S, Ri is a substituted or unsubstituted C5-C20 aliphatic moiety which has at least 4 consecutive -CH2- groups and n is the number of modified hydroxyl groups where n is an integer and n > 1. In one aspect, the hyaluronic acid detivative is the product of a reaction of a vinylsulfone derivatized HA with 1-octadecanethiol, 1-hexadecanethiol, 1-dodecanethiol, 1- undecanethiol, 1-decanethiol, 1-nonanethiol, 1-octanethiol, 1-heptanethiol, 1-hexanethiol, or 1- pentanethiol.
[00126] In one aspect, the HA derivative has the structure HA-(OCH2CH2SO2CH2CH2-X-Ri)n where X is S, Ri is a cholesterol moiety and n is the number of modified hydroxyl groups where n is an integer and n > 1. In one aspect, the hyaluronic acid detivative is the product of a reaction of a vinylsulfone derivatized HA with thiocholesterol (CAS 1249-81-6) or cholesterol-PEG-thiol compound.
[00127] In one aspect, the HA derivative has the structure HA-(OCH2CH2SO2CH2CH2-X-Ri)n where X is S, Ri is a lipid moiety and n is the number of modified hydroxyl groups where n is an integer and n > 1. In one aspect, the hyaluronic acid detivative is the product of a reaction of a vinylsulfone derivatized HA with l,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-N- (mercaptopropyl) [DSPE-SH], l,2-Dipalmitoyl-sn-Glycero-3-Phosphothioethanol or 1,2-
Distearoyl-sn-glycero-3-phosphoethanolamine-N-N-(mercapto-polyethyleneglycol) [DSPE-PEG- SH] compound.
[00128] In another aspect, the present disclosure provides a derivative hyaluronic acid, in which two or more hydroxyl groups of the hyaluronic acid are modified hydroxyl groups, wherein the derivative of hyaluronic acid has the structure (R2-X-CH2CH2SO2CH2CH2O)m-HA- (OCH2CH2SO2CH2CH2-X-Ri)n where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic with at least four consecutive -CH2- groups, or a lipid or a cholesterol comprising moiety, R2 is a substituted or unsubstituted Cs-C2o aliphatic with at least four consecutive -CH2- groups or a lipid or a cholesterol comprising moiety wherein Ri and R2 are different from each other, wherein n and m are each integers, and n > land m > 1.
[00129] In another aspect, the present disclosure provides a derivative of hyaluronic acid, in which two or more hydroxyl groups of the hyaluronic acid are modified hydroxyl groups, wherein the derivative of hyaluronic acid has the structure (CH2=CH-SO2CH2CH2O)m-HA- (OCH2CH2SO2CH2CH2-X-Ri)n where HA is hyaluronic acid, X is S or NH, Ri is a substituted or unsubstituted C5-C20 aliphatic with at least four consecutive -CH2- groups, a lipid or a cholesterol comprising moiety, each of n and m is an integer, and n > 1 and m > 1, and Y is H; a carboxylic acid group, or a salt or ester; thereof; a hydroxyl group; a sulfonic acid group, or a salt thereof; or an amine group.
[00130] In one aspect, the present disclosure provides a process comprising: reacting hydroxyl groups attached to a polymer, such as hydroxyl groups on hyaluronic acid (HA), with divinyl sulfone (DVS) to provide a first derivative of the polymer; and reacting the first derivative of the polymer with a nucleophile of a formula selected from X-R1 and X-R2-Y to provide a second derivative of the polymer. The first derivative will have a number of ethenyl (vinyl) groups attached to sulfone groups that are, in turn attached through an oxyethylene group to the polymer. Some or all of these vinyl groups are reacted with a nucleophilic compound, e.g., a thiol derivative as described above. The extent to which these vinyl groups undergo reaction may be specified according to the present disclosure. In one aspect, all or nearly all, e.g., 100%, or 99- 100%, or 98-100%, or 97-100%, or 96-100%, or 95-100% are substituted with the thiol derivative. In another aspect, partial substitution is achieved with the thiol derivative, e.g., 1-95% of the free
available vinyl sulfone groups are derivatized.
[00131] For example, in one aspect the number of vinyl sulfone residues, that are attached to the polysaccharide, and that can be reacted with a free thiol-containing compound can be altered. The percentage of the residual vinyl sulfone groups reacted with a free thiol-containing compound can vary from 1% to 100%. NMR, such as XH-NMR, can be used to determine the percent substitution. When 100% substitution of the vinyl sulfone groups occurs, essentially all of the available vinyl sulfone residues attached to the polysaccharide have reacted with the free thiol -containing compound to form a thioether linkage. If less than 100% of the available vinyl sulfone groups react with the free thiol-containing compound, the polysaccharide will comprise both vinyl sulfone groups as well as compounds attached via a thioether linkage. The fraction of the repeat units of the polysaccharide that are substituted through a thioether linkage can be determined by NMR, usually 1H-NMR. The percent substitution, often calculated on a molar basis, can range from l% to 100%, preferably greater than 10% and more preferably greater than 25%.
[00132] In one aspect, the Michael addition reaction of a free-thiol compound with the vinyl sulfone residue on the polysaccharide can occur using a single free-thiol containing compound. In another aspect, the addition reaction can occur using more than 1 free thiol- containing compound in which the free thiol-containing compounds are different from each other.
[00133] Fig. 1 illustrates options for performing polymer derivatization reactions according to the present disclosure. In Fig. 1, "A" identifies a hydroxyl-substituted polymer such as hyaluronic acid or polyvinylalcohol. The polymer A may be characterized in terms of molecular weight. In one aspect, the intrinsic viscosity of polymer A is used as an indicator of the polymer's molecular weight. Optionally, the intrinsic viscosity of polymer A is in the range of 0.3 to 3 m3/Kg. In another aspect, chromatography is used to characterize the molecular weight of polymer A. Optionally, the weight average molecular weight of polymer A is approximately 75,000 Da to 3,000,000 Da.
[00134] In Fig. 1, "B" identifies the product of reacting polymer Awith divinyl sulfone (DVS) under basic conditions (NaOH in an aqueous solvent). Polymer B is a compound of the present
disclosure. Polymer B is shown as two polymer As joined together through X linkages, where X represents a diethyl sulfone group of the formula -CH2-CH2-SO2-CH2-CH2- which is linked at each of its ends to an oxygen atom that was formerly part of a hydroxyl group from polymer A. The X groups are created by reaction of two hydroxyl groups reacting with two vinyl groups of divinyl sulfone. The X groups are shown linking together two different A polymers, however an X group may also link together two hydroxyl groups of a single A polymer to provide a polymer B according to the present disclosure.
[00135] In Fig. 1, "B" contains three X linkages between two A polymers in addition to three VS groups. A VS group is the result of a divinyl sulfone substitution reaction with a hydroxyl group of an A polymer. In order to create a VS group, one and only one of the two vinyl groups of a divinyl sulfone molecule reacts with one and only one hydroxyl group of a polymer A. In one aspect of the present disclosure, hydroxy-substituted polymers ("A") are reacted with divinyl sulfone (DVS) to create linkages between two or more hydroxyl groups in a mixture of hydroxyl substituted polymer chains, and additionally to create vinyl sulfone substituents on one or more hydroxyl-substituted polymer chains (shown as polymer B in Fig. 1).
[00136] In one aspect, the polymer B still contains unreacted hydroxyl groups. For example, when a flask is charged with a desired amount of polymer A comprising a specified number of hydroxyl groups, the addition of DVS will consume at least 5%, or least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80% of those initial hydroxyl groups in the formation of X and VS groups present in polymer B. The number of hydroxyl groups present after reaction of DVS may also, or alternatively be described in terms of the residual hydroxyl groups, so that at least 15%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80% of the initial hydroxyl groups are still present in polymer B. The number of hydroxyl groups present in polymer B may also be expressed as a range of the initial number of hydroxyl group present in polymer A, e.g., the conversion of polymer A to polymer B may consume 5-10% of the available hydroxyl groups, or in other aspects, 5-15%, or 5-20%, or 5-25%, or 5-30%, or 5-35%, or 10-15%, or 10-20%, or 10-25%, or 10-30%, or 10-35%, or 10-40% of the initially available hydroxyl groups.
[00137] In one aspect, the polymer B contains both X and VS substituents. In one aspect, the polymer B contains both X and VS substituents in a molar ratio of where the number of VS groups exceeds the number of X groups. However, in another aspect, the number of X groups exceeds the number of VS groups. In other aspects, the X groups provide at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or at least 90% of the total number of X and VS groups.
[00138] As shown in Fig. 1, polymer B may serve as a reactant to create either polymer C or polymer D, each of which is a polymer according to the present disclosure. To create polymer C, a mixture of nucleophilic compounds, represented as RiSH and R2SH in Fig. 2, is reacted with polymer B. To create polymer D, a single nucleophilic compound, represented as RiSH in Fig. 2, is reacted with polymer B. The present disclosure provides polymer B, polymer C, polymer D as well as reactions to create polymer B from polymer A, reactions to create polymer C from polymer B, and reactions to create polymer D from polymer B. In one aspect, each of polymers A, B and C is a derivatized hyaluronic acid.
[00139] Polymer D contains X moieties which link together two polymer A chains. In addition, polymer D contains Z-S-Ri moieties which are created by the reaction of the vinyl sulfone (VS) groups of polymer B with thiol compound RiSH to provide -O-CH2-CH2-SO2-CH2-CH2- S-Ri moieties, which are abbreviated as Z-S-Rl moieties in Fig. 2. In one aspect, the present disclosure provides polymer D having a mixture of X groups and Z-S-Ri groups. In one aspect, X groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the X and Z-S-Ri groups. In one aspect, Z-S-Ri groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the X and Z-S-Ri groups.
[00140] In one aspect, the present disclosure provides polymer E having a structure as set forth in Fig. 1. In one aspect, the present disclosure provides polymer F having a structure as identified in Fig. 1. In another aspect, the present disclosure provides polymer G having a structure as identified in Fig. 1. In yet another aspect, the present disclosure provides polymer H having a structure as identified in Fig. 1.
[00141] As shown in Fig. 1, polymer A may be reacted with divinyl sulfone under basic
conditions to provide polymer E. As shown in Fig. 1, polymer E may be formed from polymer A by reaction of the hydroxyl groups of polymer A with divinyl sulfone (DVS) to convert them to vinyl sulfone (VS) groups. In polymer E, there are few, if any, X groups which link together two hydroxyl groups of polymer A. In various aspects, the VS groups constitute at least 80%, or at least 85%, or at least 90%, or at least, 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.9% of the total of X and VS groups present in polymer E.
[00142] Polymer E may be reacted with RiSH, optionally in combination with one or more additional nucleophilic compounds, e.g., R2SH, to provide polymers of structure F, G or H, as shown in Fig. 1. Polymer F has a mixture of residual VS groups and Z-S-Rl groups formed by reaction of VS groups with RiSH. The charge of RiSH is less than 100% of the total number of VS groups present on polymer E, calculated on a molar basis. Based on this stoichiometry, not all of the VS groups will react with RiSH molecules, and accordingly polymer F has a mixture of VS and Z-S-Ri groups. In one aspect, VS groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the VS and Z-S-Rl groups. In one aspect, Z-S-Ri groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the VS and Z-S-Rl groups.
[00143] Polymer G has a majority of Z-S-Ri groups, and little or no X and VS groups. In various aspects, the Z-S-Ri groups constitute at least 80%, or at least 85%, or at least 90%, or at least, 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.9% of the total of X, VS and Z-S-Ri groups present in polymer G. Polymer G may be formed by reaction of polymer E and an equimolar or molar excess of RiSH molecules, based on the moles of available VS groups.
[00144] Polymer H has a majority of Z-S-Ri and Z-S-R2 groups, and little or no X and VS groups. In various aspects, the total of the Z-S-Ri and Z-S-R2 groups constitute at least 80%, or at least 85%, or at least 90%, or at least, 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.9% of the total of X, VS, Z-S-Ri and Z-S-R2 groups present in polymer H. Polymer H may be formed by reaction of polymer E and a mixture of
nucleophilic compounds, e.g., a mixture of RiSH and R2SH, such as shown in Fig. 1.
[00145] In one aspect, the present disclosure provides polymer I having a structure as set forth in Fig. 1. In one aspect, the present disclosure provides polymer J which is a gel prepared as shown in Fig. 1. In another aspect, the present disclosure provides polymer K which is a gel prepared as shown in Fig. 1.
[00146] Polymer I has a mixture of Z-S-Ri and VS substituents. In one aspect, the present disclosure provides polymer I having a mixture of VS groups and Z-S-Ri groups. In one aspect, VS groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the VS and Z-S-Ri groups. In one aspect, Z-S-Ri groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the VS and Z-S-Ri groups. Polymer I may be formed by reacting polymer G with divinylsulfone under basic conditions. This reaction converts hydroxyl groups present on polymer G (not shown in Fig. 1) to vinyl sulfone (VS) groups.
[00147] Polymers J and K are gels which may be prepared as shown in Fig. 1. Polymer J may be formed by crosslinking polymer G. Polymer K may be formed by crosslinking polymer H. [00148] In one aspect, the present disclosure provides polymer L having a structure as set forth in Fig. 1. In another aspect, the present disclosure provides polymer M having a structure as identified in Fig. 1. In yet another aspect, the present disclosure provides polymer N having a structure as identified in Fig. 1.
[00149] Polymer L as shown in Fig. 1 contains a mixture of Z-S-Ri and Z-S-R2 substituents. Polymer L may additionally contain hydroxyl substituents (not shown). In various aspects, the total of the Z-S-Ri and Z-S-R2 groups constitute at least 80%, or at least 85%, or at least 90%, or at least, 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.9% of the total of X, VS, Z-S-Ri and Z-S-R2 groups present in polymer L. Polymer L may be formed by reaction of polymer F, which contains Z-S-Ri and VS substituents, with R2SH, to thereby convert the VS substituents to Z-S-R2 substituents.
[00150] Polymer M as shown in Fig. 1 contains a mixture of X, Z-S-Ri and Z-S-R2 groups. Polymer M may additionally contain hydroxyl substituents (not shown). Polymer M may be
T1
formed by adding a crosslinker, such as divinylsulfone, to Polymer L that contains residual hydroxyl groups. The crosslinker creates X groups between hydroxyl groups present on polymer L.
[00151] Polymer N as shown in Fig. 2 contains a mixture of Z-S-Ri and -R- groups, where an R group forms a linkage between different polymer A chains. The R groups may be introduced by reacting a precursor polymer, such as polymer F or other polymer containing VS groups, with a polyfunctional nucleophile, such as R(SH)n where n is greater than or equal to 2. In R(SH)n, R represents an aliphatic or aromatic group that is optionally substituted.
[00152] In one aspect, the present disclosure provides polymer O which is a gel that may be formed as shown in Fig. 1. In another aspect, the present disclosure provides polymer P which is a gel that may be formed as shown in Fig. 1.
[00153] Polymer O may be formed from Polymer I by a two-step reaction. In a first step, polymer I is reacted with a nucleophilic compound, such as RiSH, to convert VS groups present on polymer I, into the corresponding Z-S-Ri groups. In a second step, a crosslinker X is added to this intermediate polymer to provide a polymeric gel O.
[00154] Polymer P may be formed from Polymer I by a two-step reaction. In a first step, polymer I is reacted with a nucleophilic compound, such as R2SH, to convert VS groups present on polymer I, into the corresponding Z-S-R2 groups. In a second step, a crosslinker X is added to this intermediate polymer to provide a polymeric gel P.
[00155] Polymer I may also serve as a precursor to a crosslinked polymer having -R- groups as the linkage between polymer chains. The R groups may be introduced by reacting a polymer I, or another polymer containing VS groups, with a polyfunctional nucleophile, such as R(SH)n where n is greater than or equal to 2. In R(SH)n, R represents an aliphatic or aromatic group that is optionally substituted.
[00156] Fig. 2 illustrates options for performing polymer derivatization reactions according to the present disclosure. In Fig. 2, "A" identifies a hydroxyl-substituted polymer such as hyaluronic acid or polyvinylalcohol, which is likewise shown as polymer A in Fig. 2. However, in contrast to Fig. 1, the reaction schemes of Fig. 2 begin by performing a crosslinking reaction on polymer A, and achieving little or no conversion of hydroxyl groups on polymer A into an
alternative monofunctional reactive group.
[00157] As shown in Fig. 2, polymer A may be reacted with a crosslinking agent, to provide a crosslinked version of polymer A, which is denoted as polymer B in Fig. 2. Suitable crosslinking reactions for hydroxyl-containing polymers are described elsewhere herein.
[00158] In one aspect, the present disclosure provides polymer C having a structure as set forth in Fig. 2. In another aspect, the present disclosure provides polymer D having a structure as identified in Fig. 2. In yet another aspect, the present disclosure provides polymer E having a structure as identified in Fig. 2.
[00159] Polymer C may be formed by reacting polymer B with divinyl sulfone (DVS) under basic conditions. Under these reaction conditions, hydroxyl groups present on polymer B (not shown) react with DVS to convert hydroxyl groups to VS groups. In one aspect, VS groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the VS and X groups present in polymer C. In one aspect, X groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the VS and X groups present in polymer C.
[00160] Polymer D in Fig. 2 is a crosslinked polymer having both Z-S-Ri and Z-S-R2 substituents. Polymer D may be formed by reacting polymer C with a mixture of nucleophilic compounds, such as RiSH and R2SH as shown in Fig. 2. In one aspect, the total of the Z-S-Ri and Z-S-R2 groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the Z-S-Ri, Z- S-R2 and X groups present in polymer D. In one aspect, X groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the Z-S-Ri, Z-S-R2 and X groups present in polymer D.
[00161] Polymer E in Fig. 2 is a crosslinked polymer having Z-S-Ri substituents (but not having any and Z-S-R2 substituents). Polymer E may be formed by reacting polymer C of Fig. 2 with a nucleophilic compound, such as RiSH as shown in Fig. 2. In one aspect, the Z-S-Ri groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the Z-S-Ri and X groups
present in polymer E. In one aspect, X groups provide at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the total of the Z-S-Ri and X groups present in polymer E.
[00162] As also shown in Fig. 2, the present disclosure provides polymers of structure F and of structure G, as well as crosslinked gels thereof. Polymer F of Fig. 2 contains Z-S-Rl substituents, while polymer G contains a mixture of Z-S-Rl and Z-S-R2 substituents. Neither of polymers F or G are crosslinked polymers. However, each of polymers F and G may be treated with a crosslinking agent, or exposing to crosslinking conditions, to provide the corresponding crosslinked polymer which will have the form of a gel (identified as polymer H in Fig. 2).
[00163] Though not wishing to be bound by any particular theory, it is believed that there may be none to a low level of crosslinking occurring when vinyl groups are present in in a solution of derivatized HA polymer molecules. This "accidental" crosslinking may be present but is not measurable and the solution does not exhibit characteristics of cross-linking, and would be referred to herein as a solution or composition comprising non-cross-linked derivatives of polymeric polyhydric alcohols.
[00164] Thus, in one aspect, the present disclosure provides vinyl sulfone functionalization (i.e., derivatization) of a HA ("a first derivative") followed by reaction of the vinyl sulfone substituent with one or more free thiol-containing compounds ("a second derivative") which is in turn followed by a second functionalization (i.e., derivatization) reaction with divinyl sulfone to produce a polysaccharide that is functionalized with compounds through a thioether linkage as well as with vinyl sulfone functional groups ("a third derivative"). In another aspect, the above compounds can be further reacted with free thiol-containing compounds ("a fourth derivative"). The molar ratio of the free thiol-compound used for the reaction can be altered such that 1% to 100% of the second added vinyl sulfone functional groups are reacted. The free thiol-containing compound that is used in the second Michael addition reaction (derivatization reaction) can be the same or it can be different from that used in the first Michael addition reaction. For the second Michael addition reaction, a single free thiol-containing compound can be used or a mixture of 2 or more different free-thiol containing compounds can be used. In another aspect, at least one additional round of vinyl sulfone / free thiol-containing compound reactions cycles
can be performed using the same free-thiol containing compound or one or more different free- thiol containing compounds.
[00165] In one aspect, a process of the present disclosure further comprises crosslinking a second derivative of the polymer, e.g., crosslinking by reacting the second derivative of the polymer with a crosslinking agent. Upon crosslinking, the second derivative is converted to a third derivative of the polymer, where the third derivative is a crosslinked polymer.
[00166] For example, in one aspect, a HA derivatized with one or more free-thiol containing compounds and also comprises residual available vinyl sulfone functional groups can undergo crosslinking by subjecting a solution of the derivatized HA to basic conditions that are sufficient to allow the residual available vinyl sulfone group to react with a hydroxyl group of the derivatized HA. In one aspect, the reaction pH is greater than 12 for example, in the 12.5 to 13.0 pH range. The amount of residual vinyl sulfone functional groups, often measured as percent substitution as measured by ^-NMR, reaction time and reaction temperature can be selected to achieve the desired degree of crosslinking.
[00167] In another aspect, a HA derivatized with one or more free-thiol containing compounds and also comprises residual available vinyl sulfone functional groups can be mixed with a polysaccharide derivatized with one or more free-thiol containing compounds and also comprises residual available vinyl sulfone functional groups wherein the free-thiol containing compounds can be the same or different or a combination thereof. The resultant mixture can undergo crosslinking by subjecting a solution of the derivatized HA to basic conditions that are sufficient to allow the residual available vinyl sulfone group to react with a hydroxyl group of the polysaccharide. In one aspect, the reaction pH is greater than 12, for example, in the 12.2 to 13 pH range. The amount of residual vinyl sulfone functional groups, often measured as percent substitution as measured by ^-NMR, reaction time and reaction temperature can be selected to achieve the desired degree of crosslinking.
[00168] In another aspect, a non-derivatized polysaccharide can be added to the crosslinking reaction mixtures described above and the resultant mixture can undergo crosslinking by subjecting the solution of derivatized HA and the non-derivatized polysaccharide to basic conditions that are sufficient to allow the residual available vinyl sulfone groups of the
derivatized HA to react with a hydroxyl group of the polysaccharide. In one aspect, the reaction pH is greater than 12, for example, in the 12.2 to 13 pH range. The amount of residual vinyl sulfone functional groups, often measured as percent substitution as measured by 1H-NMR, reaction time and reaction temperature can be selected to achieve the desired degree of crosslinking.
[00169] Crosslinking may be achieved by using an external crosslinking agent. In one aspect, a crosslinking agent is added to the second derivative of the polymer. Exemplary crosslinking agents that could be used include: carbodiimides, bisepoxides, divinyl sulfone derivatives, and combinations thereof. Another suitable crosslinking agent is a multiple thioether derivative. In one aspect, at least 2 (could be 2, 3, 4, etc.) different thioether derivatives are combined with a crosslinking agent and conditions are adjusted such that the derivatives of polyhydric polymers become either fully crosslinked or partially crosslinked. In this case, exemplary crosslinking agents include, without limitation, carbodiimides, bisepoxides, divinyl sulfone derivatives and combination thereof.
[00170] For example, in one aspect, a HA derivatized with one or more free-thiol containing compounds can be crosslinked by adding a crosslinking agent and adjusting the pH of the reaction mixture such that the derivatized HA forms a crosslinked derivatized HA composition. Crosslinking agents that can be used include but are not limited to biscarbodiimides, bisepoxides, divinyl sulfone derivatives, di-isocyanates, dihalide chlorides, disuccinimidyl derivatives and combinations thereof.
[00171] Biscarbodiimide compounds can include but are not limited to para-phenylenebis- (ethyl)-carbodiimide, 1,6-hexamethylene bis(ethylcarbodiimide), 1,8-octamethylene bis(ethylcarbodiimide), 1,10 decamethylene bis(ethylcarbodiimide), 1,12 dodecamethylene bis(ethylcarbodiimide), PEG-bis(propyl(ethylcarbodiimide)), 2,2'-dithioethyl bis(ethylcarbodiimde), l,l'-dithio-p-phenylene bis(ethylcarbodiimide); para-phenylene- bis(ethylcarbodiimide), and l,l'-dithio-m-phenylene bis(ethylcarbodiimide).
[00172] When utilizing a biscarbodiimide crosslinker, the biscarbodiimide is mixed with a buffered aqueous solution of the derivatized carboxylic acid containing polysaccharide. The target pH of the buffered solution can be between pH 5 and pH 6.5.
[00173] Bisepoxide compounds can include but are not limited to 1,4-butanediol diglycidyl ether (BDDE), 1,2,7,8-diepoxyoctane (DEO), polyethylene glycol) diepoxide. When utilizing a bisepoxide crosslinker, the bisepoxide is mixed with an aqueous solution of the derivatized polysaccharide and the pH is raised to a pH > 9. The reaction can be carried out at 40°C for greater than 4 hours to produce a crosslinked derivatized HA polymer.
[00174] Divinyl sulfone crosslinking agents can include but are not limited to divinyl sulfone and poly(ethylene glycol) bisvinyl sulfone.
[00175] When utilizing a divinyl sulfone crosslinker, the reaction pH in an aqueous solution can be raised to a pH greater than 12 to effect crosslinking. The degree of crosslinking can be altered by changing the amount of crosslinking agent added, reaction time, the reaction pH and reaction temperature.
[00176] In another aspect, a mixture of at least 2 different thioether derivatized HA can be mixed together, a crosslinking agent can be added and the reactions conditions adjusted such that the derivatized HA polymers are crosslinked. The relative ratios of the different derivatized HA can be altered such that crosslinked derivatized HA polymers with different properties are obtained. These properties include but are not limited to equilibrium swelling, swelling rate, drug release characteristics, elastic modulus, storage modulus, loss modulus, degradation, tensile strength, tissue adhesiveness and lubricity. As used herein "derivatized HA polymers" may also include compositions comprising one or more derivatized HA polymers.
[00177] In another aspect, at least 2 different crosslinking agents can be used to crosslink the derivatized HA. In one aspect, two different crosslinking agents from the same group could be used to crosslink the derivatized HA polymers. For example, divinyl sulfone and polyethylene glycol) bisvinyl sulfone or 1,4-butanediol diglycidyl ether (BDDE) and poly(ethylene glycol) diepoxide could be used.
[00178] In another aspect, two different crosslinking agents from different groups could be used. For example, divinyl sulfone and 1,4-butanediol diglycidyl ether (BDDE) may be used to crosslink the derivatized HA. In another aspect, the crosslinker can be added sequentially such that initial crosslinking occurs in the presence of the first crosslinked and then the second crosslinker is added such that secondary crosslinking occurs. The reaction conditions may be
changed after the first crosslinking reaction and prior to the second crosslinking reaction. Reaction conditions such as temperature, pH, buffer, ionic strength and solvent composition can be altered.
[00179] In one aspect, crosslinked derivatized HA polymers can be prepared though ionic crosslinking. This can be accomplished by mixing a derivatized polyhydric polymer of this disclosure that has a negative charge with a compound that has two or more positive charges. In one aspect, a solution of the derivatized HA polymer of this disclosure that has a negative charge can be prepared and then mixed with a solution of a compound that has two or more positive charges. Inorganic compounds that can be used include but are not limited to ferric chloride, aluminum chloride, chromium sulfate, and aluminum sulfate. Positively charged polymers that can be used include polymers that comprise more than two lysines, arginine or histadine amino acids, chitosan and chitosan derivatives, deacetylated hyaluronic acid, polyethyleneimine (PEI), poly(A/,A/-dimethylaminoethyl methacrylate), poly(4-vinylpyridine), polyethyleneglycolpolylysine block copolymers (PEG-PLL), dextran grafted polylysine copolymers, or combinations thereof.
[00180] In one aspect, the positively charged or the negatively charged polymer can first be applied. This can then be followed by application of the oppositely charged polymer such that at the interface of the two layers, ionic interactions occur such that the polymers are crosslinked together. In another aspect, the process can be repeated at least one more time.
[00181] A second derivative of the polymer (e.g., HA-(OCH2CH2SO2CH2CH2-X-Ri-Y)n) may be crosslinked via internal and external crosslinking. For example, in one aspect, a polysaccharide derivatized with one or more free-thiol containing compound and also comprising residual available vinyl sulfone functional groups can be crosslinked in the presence of an external crosslinking agent. In one aspect, the reaction conditions can be adjusted such that the residual available vinyl sulfone groups and the added external crosslinked react simultaneously. For example, divinyl sulfone can be added as the external crosslinker and then the pH can be increased to a pH > 12 which will result is crosslinking.
[00182] As another example, the crosslinking via the residual available vinyl sulfone functional groups can take place first which is then followed by the addition of the external
crosslinker. The reaction conditions, for example pH, can be changed to effect the crosslinking reaction of the external added crosslinker. For example, the pH of the derivatized HA that contains the residual available vinyl sulfone functional groups can be raised to a pH > 12. Once the reaction has been reached the desired level, the pH can be changed to between pH 5 and pH 6.5 with a buffer and then biscarbodiimide crosslinker, for example para-phenylenebis-(ethyl)- carbodiimide, can be added to the reaction mixture and allowed to react until the desired level of crosslinking is obtained. In another aspect, the biscarbodimide crosslinking can take place first by adjusting the pH of the derivatized polysaccharide to between 5 and 6.5, adding the biscarbodiimide, allowing the crosslinking to proceed to the desired level, then raising the pH to pH > 12 to allow the residual vinyl sulfone functional groups to crosslink.
[00183] In one aspect, a HA derivatized with one or more free-thiol containing compound and also comprises residual available vinyl sulfone functional groups can be crosslinked in the presence of an external crosslinking agent that has at least two free thiol functional groups. These free thiol groups may be positioned upon a central molecule, "C". The central molecule may be a linear or cyclic alkane, a polyethylene glycol (PEG) oliogomer or polymer, or any other such suitable central molecule. In the case of PEG-based crosslinking agents, the PEG may be linear, branched (having two polymer arms), or multi-armed (e.g., having 3, 4, 5, 6, 7, 8 or more polymer arms). Thus, in such instances, the central molecule will typically a linear PEG, a branched PEG having 2 arms, or a multi-armed PEG having PEG arms emanating from a central core.
[00184] Illustrative cores for such multi-armed polymers include erythritol, pentaerythritol, trimethylolpropane, glycerol, glycerol dimer (3,3'-oxydipropane-l,2-diol), glycerol oligomers, sorbitol, hexaglycerol, and the like.
[00185] Illustrative thiol crosslinking agents include PEG-dithiol (HS-PEG-SH), 3-arm PEG- tri-thiol (glycerine core), 4-arm PEG-tetrathiol (pentaerythritol core), or 8-arm PEG-octa-thiol (hexaglycerine core). The foregoing multi-armed PEG reagents may also have fewer than all arms functionalized with thiol. Additional suitable thiol reagents having PEG as the central molecule are available from Laysan Bio (Arab, Ala.), as well as aromatic dithiols such as those available from NanoScience. Other suitable thiol crosslinking agents include dimercaptosuccinic acid, 2,3-
dimercapto-l-propanesulfonic acid, Trimethylolpropane tris(3-mercaptopropionate), dithiol functionalized pluronics F127, dithiol functionalized F68, dihydrolipoic acid, peptides containing at least 2 cysteine amino acids, thiol functionalized dextran, and thiol-functionalized hyaluronic acid.
[00186] The polymers of the present disclosure, e.g., the first, second and third derivatives of HA, may be processed into numerous forms. For the non-crosslinked derivatized HA polymers, exemplary compositions of the derivatized HA polymers include, but are not limited to, a solution, a suspension, an emulsion, a film, a gel, a coating on a surface of an article, an electrospun matrix, a microparticle, a fiber, a lyophilized solid, a rod, a disc, a gel, a powder or in a particulate form. A particulate form can be prepared by milling (e.g., jet milling, roller milling, cryomilling, mechanical milling) fragmentation, spray drying, precipitation or grinding. For the crosslinked derivatized HA polymers, compositions of the derivatized HA polymer can be as a suspension, a film, an electrospun matrix, a fiber, a lyophilized solid, a rod, a disc, a gel, a powder or in a particulate form. The particulate form can be prepared by milling (jet milling, roller milling, cryomilling, mechanical milling) fragmentation, spray drying, precipitation or grinding.
[00187] A solution of the derivatized HA polymer can be prepared by dissolving the derivatized HA polymer in an appropriate solvent or a combination of solvents. For example, water or a combination of water and water-miscible solvent can be used. Water-miscible solvents can include but are not limited to methanol, ethanol, isopropanol, dimethyl formamide (DMF) acetone, 1,4-dioxane, pyridine, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF) and acetonitrile. The prepared solutions can be sterilized by filtering through a 0.2 pm sterile filter. In one aspect, a solution can be prepared using one derivatized HA. The concentration of the prepared solutions can range from, e.g., 0.01% (w/v) to about 50% (w/v). In one aspect, the concentration is in the 0.1% (w/v) to 10% (w/v) range.
[00188] A film of non-crosslinked derivatized HA polymers of this disclosure can be prepared by preparing a solution of the derivatized HA polymer. This solution can be then placed in a mold or drawn out on a surface using a gardner knife. The surface used can be glass, metal foil, stainless steel, Teflon, nylon, polyethylene, polypropylene or a release liner. The solvent can then be removed to form the film. The rate of solvent removal can be altered by using at least
one of the following parameters: temperature, air or inert gas flow and pressure. To increase the rate of solvent evaporation, the temperature could be increased, the air or inert gas flow rate could be increased or the pressure could be decreased. A combination of these process could also be used. To slow the rate of solvent evaporation, the temperature could be decreased, the air or inert gas flow rate could be reduced or the pressure could be increased. A combination of these process could also be used. A film can comprise one of the derivatized HA polymers of this disclosure. The films can also comprise two or more different derivatized HA polymers of this disclosure. A composite film can be prepared by preparing a first film and then casting a second film on top of the first film. A composite film can be prepared by casting additional layers sequentially on top of the previous layer. The layers of the composite film can comprise the same derivatized HA polymer if the disclosure, different derivatized HA polymers of this disclosure or a combination thereof.
[00189] Lyophilized forms of the non-crosslinked derivatized HA polymers of this disclosure can be prepared by making a solution of the derivatized HA polymer, freezing the solution and then placing the frozen derivatized HA polymer solution under a vacuum such that the solvent is sublimed off to leave the derivatized HA polymer composition in the solid form. A lyophilized form of the derivatized HA polymer composition of this disclosure can comprise one of the derivatized HA polymers of this disclosure. In another aspect, the lyophilized form of the derivatized HA polymers and/or compositions of this disclosure can comprise two or more different derivatized HA polymers of this disclosure. In another aspect, a lyophilized composition of one or more derivatized HA polymers can comprise one or more derivatized HA polymers in addition to an additive such as chitosan or chitosan derivatives (e.g. chitosan HCL, chitosan acetate, or chitosan lactate). The form of the lyophilized derivatized HA polymer compositions may be dependent on the form of the container into which the solution was poured. In another aspect, the form of the lyophilized derivatized HA polymer may be dependent on the form of the contained into which the solution was poured and frozen. The form can be a rectangle, square, disk, triangle, trapezoid, rod or any other form in which a mold can be made.
[00190] Derivatized HA polymer compositions of this disclosure can be in the form of a powder or particulate. The powder or particulate may be obtained directly via precipitation. A
powder or particulate form can also be obtained through a milling, grinding, spray drying or fragmentation process. Compositions, including but not limited to, films, precipitated derivatized HA polymers, dried derivatized HA polymers and/or compositions, lyophilized derivatized HA polymers and/or compositions, or derivatized HA polymers and/or compositions, dried in a form can be further process via a milling process (jet milling, roller milling, cryomilling, mechanical milling), a grinding or a fragmentation process. A combination of these processes can be used. Derivatized HA polymer composition with particle size in the range of 100 nm to 5 mm can be prepared. Specific size ranges of the powdered or particulate derivatized HA polymer compositionsof this disclosure can be prepared by separating the derivatized HA polymer composition particles according to size using sieves. The distribution of particle sizes can be broad with a standard deviation of the average size of greater than 40%. The distribution of particle sizes can be narrow with a standard deviation of the average size of less than 30%. The final powdered or particulate form of the derivatized HA polymer compositions of this disclosure can comprise a single distribution of average particle sizes or it can comprise two or more distributions of particles prepared by mixing particles of different average particle size.
[00191] A derivatized HA polymer compositions of this disclosure can be formed into a solid form by preparing a solution of a derivatized HA polymer in a solvent that can be removed, pouring this solution into a mold of a specific shape and then removing the solvent such that a solid form of derivatized HA polymer composition is obtained. The molds used can be of various shapes and can include but are not limited to cubes, rectangles, rods, semi-circular rode and tubes. The solid derivatized HA polymer composition of this disclosure can then be removed from the mold.
[00192] A derivatized HA polymer composition of the disclosure can be processed into an electrospun matrix. In this process, a solution of the derivatized HA polymer of the disclosure is prepared. The solvent used can be an organic solvent, water or a combination thereof. For example, for hyaluronic acid based derivatized HA polymers, water/ethanol or water/dimethylformamide (DMF) solvent mixtures can be used. Solutions with a concentration of 0.5 to 5% (w/v) can be prepared. The solution that is to be electrospun can be placed in a syringe with a needle. The syringe is then placed in a syringe pump. The needle can have a blunt
end and an inner diameter in the range of 0.25 to 1 mm. The needle and collection plate are attached to a high voltage supply. A voltage is then applied to the system. The applied voltage can be in the lOkV to 45 kV. The syringe pump can extrude the solution. The flow rate of the syringe pump can be in the range of lOuL/min to 1000 uL/min. The collector plate can be static, rotating or moving in a specific linear direction to give the fibers some directional orientation. The shape of the collector plate can be varied with the collector plate having but not limited to the following shapes: a flat surface, a textured surface, a curved surface, a square rod, a rectangular rod, a round mandrel, an oval mandrel, a semi-circular mandrel or a combination of these shapes. The temperature of the solution can be controlled as well as the collection plate and the surrounding environment. The distance of the needle tip to the collector plate can be altered. The distance of the needle tip to the collector plate can be in the 2-20 cm range. The collection plate can also be submerged in or sprayed with a solvent that assists in the precipitation of the newly spun fibers. For example, an ethanol bath may be used during the electrospinning of hyaluronic acid derivatized HA polymers and/or compositions of this disclosure.
[00193] A derivatized HA polymer of the disclosure can be incorporated through a solution coating or submersion of an electrospun matrix produced in the following manner. In this process, single or multiple polymer solutions are prepared. The polymers used can be biodegradable polymers then include but are not limited to polyester, polyanhydride, polyorthoester, polycarbonate, poly-ester-co-carbonate), polyhydroxybutyrates or combinations thereof. Biodegradable polymers can include polylactice-co-glycolide copolymers, polydioxanone, polylactide-trimethylene carbonate copolymers as well as copolymers that comprise repeat units derived from at least one of the following monomers: l-lactide, dl-lactide, glycolide, trimethylene carbonate, epsilon-caprolactone, p-dioxanone and a morpholinedione [00194] The solvents used can be an organic solvent, water or a combination thereof. For example, HFIP, DMSO, NMP, Chloroform, acetic acid, ethanol, dimethylformamide (DMF) solvents or mixtures of solvents can be used. Solutions with a concentration of 0.5 to 25% (w/v) can be prepared. The solution that is to be electrospun can be placed in a syringe with a needle. The syringe is then placed in a syringe pump. The needle can have a blunt end and an inner
diameter in the range of 0.25 to 2.5 mm. The needle and collection plate are attached to a high voltage supply. A voltage is then applied to the system. The applied voltage can be in the lOkV to 45 kV. The syringe pump can extrude the solution. The flow rate of the syringe pump can be in the range of 0.0001 uL/min to 423 mL/min. The collector plate can be static, rotating or moving in a specific linear direction to give the fibers some directional orientation. The shape of the collector plate can be varied with the collector plate having but not limited to the following shapes: a flat surface, a textured surface, a curved surface, a square rod, a rectangular rod, a round mandrel, an oval mandrel, a semi-circular mandrel or a combination of these shapes. The distance of the needle tip to the collector plate can be altered. The distance of the needle tip to the collector plate can be in the 2-50 cm range. The collection plate can also be submerged in or sprayed with a solvent that assists in the precipitation of the newly spun fibers. For example, an ethanol bath may be used during the electrospinning of hyaluronic acid based derivatized HA polymers of this disclosure.
[00195] The derivatized HA polymers and/or compositionsof this disclosure can be processed into the form of a fiber. A solution of a derivatized HA polymer of the disclosure is prepared. This solution is then extruded through an orifice to produce a solvent containing fiber. This fiber can be extruded into one or more solvent baths that assists in the formation of the fiber. The fiber is then dried to produce a solid fiber. The fibers can be prepared as a monofilament or a multifilament fiber. In one aspect, this fiber can then be further processed through an annealing step. US9228027, US5520916, US5824335, US8389498, US20130309494, US20150119783 describe exemplary methods to produce fibers from a polysaccharide. These are incorporated by reference as means to produce fibers from derivatized HA polymers and/or compositions of this disclosure.
[00196] A fiber may be further processed by knitting or weaving, resulting in a knitted or woven composition. The knitted or woven composition can be in the form of a mesh. The mesh can comprise a single derivatized HA polymer and/or composition of this disclosure. In another aspect, the mesh can comprise 2 or more different derivatized HA polymers and/or compositions, of this disclosure. In another aspect, the fiber can be further processed into a braid. The braid can comprise a single derivatized HA polymer and/or composition of this disclosure. In another
aspect, the braid can comprise 2 or more different derivatized HA polymers and/or compositions of this disclosure. For meshes or braids that use different derivatized HA polymers and/or compositions of this disclosure, the derivatized HA polymers and/or compositions used can result in the mesh or braid having properties that change as a function of time. This includes degradation rates, water absorption, elongation, elastic modulus, tensile strength, physical shape, lubricity, cell adhesion, or a combination of these properties.
[00197] The knitted, woven or braided derivatized HA polymers and/or compositions can be manufactured in the presence of a degradable or non-degradable non-polysaccharide based material. These materials include polyethylene, polypropylene, polyethylene terephthalate (PET), polytetrafluorethylene (PTFE), nylon, polyurethane, polyester, polyanhydride, polyorthoester, polycarbonate, poly-ester-co-carbonate), polyhydroxybutyrates or combinations thereof.
[00198] Crosslinked polymers of the present disclosure may take various physical forms, including particle, film, lyophilized sponge, powder, particulate (e.g., milled, fragmented, precipitated and ground particulates), and may be formed in-situe, e.g., spray or liquid.
[00199] A film of crosslinked derivatized HA polymers and/or compositions of this disclosure can be prepared by preparing a solution of the derivatized HA polymer and/or compositions to be crosslinked. The derivatized HA polymer can be crosslinked by known methods and/or those described herein. Prior to the final crosslinking process, the crosslinker is added, if required, and the solution pH can be adjusted to initiate the crosslinking process. This solution can be then placed in a mold or drawn out on a surface, for example, using a Gardner knife. The surface used can be glass, metal foil, stainless steel, Teflon, nylon, polyethylene, polypropylene or a release liner. The solution is then allowed to crosslink to form a gel. Heat can be applied to increase the rate of crosslinking. The solvent can then be removed to form the film. [00200] A film of crosslinked derivatized HA polymers of this disclosure can be prepared by preparing a solution of the derivatized HA polymer to be crosslinked. The derivatized HA polymer can be crosslinked by one of the methods described above. This solution can be then placed in a mold or drawn out on a surface using a Gardner knife. The surface used can be glass, metal foil, stainless steel, Teflon, nylon, polyethylene, polypropylene, polystyrene, or a release
liner. The crosslinking agent may be added prior to or following drying of the derivatized HA polymer to form a crosslinked film or gel. The rate of residual solvent removal can be altered by using at least one of the following parameters: temperature, air or inert gas flow and pressure. To increase the rate of solvent evaporation, the temperature could be increased, the air or inert gas flow rate could be increased or the pressure could be decreased. A combination of these process could also be used. To slow the rate of solvent evaporation, the temperature could be decreased, the air or inert gas flow rate could be reduced or the pressure could be increased. A combination of these process could also be used. A film can comprise one of the derivatized HA polymers of this disclosure.
[00201] The films can also comprise two or more different derivatized HA polymers of this disclosure. A composite film can be prepared by preparing a first film and then casting a second film on top of the first film. A composite film can be prepared by casting additional layers sequentially on top of the previous layer. The layers of the composite film can comprise the same derivatized HA polymer if the disclosure, different derivatized HA polymers of this disclosure or a combination thereof. The films can comprise both crosslinked and non-crosslinked derivatized HA polymers of this disclosure.
[00202] Lyophilized forms of the crosslinked derivatized HA polymers of this disclosure can be prepared by making a solution of the derivatized HA polymer, crosslinking the derivatized HA polymer, freezing the crosslinked derivatized HA polymer composition and then placing the frozen derivatized HA polymer composition under a vacuum such that the solvent is sublimed off to leave the resulting derivatized HA polymer composition in the solid form. A lyophilized form of the derivatized HA polymer of this disclosure can comprise one of the derivatized HA polymers of this disclosure. In another aspect, the lyophilized form of the derivatized HA polymer of this disclosure can comprise two or more different derivatized HA polymers of this disclosure. The form of the lyophilized derivatized HA polymer composition is dependent on the form of the container into which the solution was poured and frozen. The form can be a rectangle, square, disk, triangle, trapezoid, rod or any other form in which a mold can be made. The lyophilized derivatized HA polymer compositions of this disclosure can comprise both crosslinked and noncrosslinked derivatized HA polymers of this disclosure. In another aspect, the lyophilized
derivatized HA polymer composition, crosslinked or non-crosslinked, can be rehydrated in the presence of other materials disclosed herein. In another aspect, a second lyophilization step may be performed on a rehydrated derivatized HA polymer composition.
[00203] In another aspect, the solution used to rehydrate the first lyophilized derivatized HA polymer, can be crosslinked. In another aspect, the derivatized HA polymer composition produced from the second crosslinking step can be lyophilized to produce a dry porous derivatized HA polymer composition.
[00204] In another aspect, the derivatized HA polymer solution may be directly combined with a biologically active agent prior to lyophilization. In another aspect, the lyophilized polyhydric polymer composition s may be combined with a biologically active agent through a rehydration process, which follows the first lyophilization, which may or may not be be followed by further drying.
[00205] Crosslinked derivatized HA polymer compositions of this disclosure can be in the form of a powder or particulate. A powder or particulate form can also be obtained through a milling, grinding, spray drying or fragmentation process. Films, precipitated derivatized HA polymers and/or compositions, dried derivatized HA polymers and/or compositions, lyophilized derivatized HA polymer and/or compositions or derivatized HA polymers and/or compositions in dried in a form can be further process via a milling process (jet milling, roller milling, cryomilling, mechanical milling), a grinding or a fragmentation process. A combination of these processes can be used. Derivatized HA polymer compositions with particle size in the range of 100 nm to 5 mm can be prepared. Specific size ranges of the powdered or particulate derivatized HA polymer compositions of this disclosure can be prepared by separating the derivatized HA polymer compositions according to size using sieves. The distribution of particle sizes can be broad with a standard deviation of the average size of greater than 40%. The distribution of particle sizes can be narrow with a standard deviation of the average size of less than 30%. The final powdered or particulate form of the derivatized HA polymers and/or compositions of this disclosure can comprise a single distribution of average particle sizes or it can comprise two or more distributions of particles prepared by mixing particles of different average particle size.
[00206] The crosslinked derivatized HA polymerscompositions of this disclosure can be
formed into a solid form by preparing a solution of the derivatized HA polymer in a solvent that can be removed, pouring this solution into a mold of a specific shape, crosslinking the derivatized HA polymer in the mold, and then removing the solvent such that a solid form of the crosslinked derivatized HA polymer composition is obtained. The molds used can be of various shapes and can include but are not limited to cubes, rectangles, rods, semi-circular rode and tubes. The solid derivatized HA polymer composition of this disclosure can then be removed from the mold.
[00207] In one aspect, the derivatized HA polymers of this disclosure can be used to prepare an in-situ gel forming composition. A derivatized HA polymer of this disclosure that contains available vinyl sulfone groups can be reacted with a compound that contains at least two available free thiol groups or a compound that contains at least 2 available amine groups, preferably primary or secondary amines. Illustrative thiol containing compounds include PEG- dithiol (HS-PEG-SH), 3-arm PEG-tri-thiol (glycerine core), 4-arm PEG-tetrathiol (pentaerythritol core), or 8-arm PEG-octa-thiol (hexaglycerine core). The foregoing multi-armed PEG reagents may also have fewer than all arms functionalized with thiol. Additional suitable thiol reagents having PEG as the central molecule are available from Laysan Bio (Arab, Ala.), as well as aromatic dithiols such as those available from NanoScience. Other suitable thiol crosslinking agents include dimercaptosuccinic acid, 2,3-dimercapto-l-propanesulfonic acid, dihydrolipoic acid, peptides containing at least 2 cysteine amino acids, a thiol functionalized polysaccharide, thiol functionalized dextran, and thiol-functionalized hyaluronic acid. In one aspect, the derivatized HA polymers of this invention can be prepared as a solution. This solution can be mixed with either a solution of the thiol containing compound or the solid form of the thiol containing compound to produce the gel composition.
[00208] The derivatized HA polymers of the present disclosure, e.g., the first, second and third derivatives of a starting polymer, may be in combination with one or more other derivatized HA polymers or other components, such as pharmaceutically acceptable excipients, or other known or common components of compositions. Thus, the present disclosure provides compositions comprising derivatized HA polymers of the present disclosure.
[00209] The derivatized HA polymers and compositions thereof of this disclosure can be used to treat living organisms. These living organisms include humans, animals, birds, fish,
insects and plants. The derivatized HA polymers and compositions thereof used in the indications described below can comprise, non-crosslinked derivatized HA polymers, crosslinked derivatized HA polymers or a combination thereof. In another aspect, the derivatized HA polymer compositions used can comprise only one of the derivatized HA polymers of this disclosure. In another aspect, the derivatized HA polymer compositions used can comprise two or more of the derivatized HA polymers of this disclosure. The derivatized HA polymers and compositions thereof can further comprise one or more excipients. The derivatized HA polymers and compositions thereof can further comprise one or more biologically active agents. The derivatized HA polymers and compositions thereof that are used in the indications described below can be in a sterile form. Sterilization can be attained through sterile filtration, aseptic manufacture, gamma radiation, e-beam radiation, ethylene oxide, dry heat, autoclaving, or a combination thereof.
[00210] For instance, the derivatized HA polymer compositions of this disclosure can also comprise an excipient. The excipient may be a pharmaceutically acceptable excipient. Excipients that can be used include but are not limited to natural polymers, synthetic polymers, thermosreversible polymers, biodegradable polymers, buffers, complexing agents, tonicity modulators, ionic strength modifiers, solvents, anti-oxidants, preservatives, viscosity modifiers, pH modifiers, surfactants, emulsifiers, phospholipids, lipids, stabilizers and porogens.
[00211] Excipient polymers that can be used include but are not limited to sodium alginate, calcium alginate, dextran, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, hyaluronic acid, hyaluronic acid derivatives, dextran, heparin, chitosan, chitosan acetate, chitosan lactate, chitin, xantham gum, Xylan, guar gum, pullulan, locust bean gum, starch, gelatin, collagen, derivatized collagen, and acacia (gum Arabic).
[00212] Excipient degradable polymers that can be used include but are not limited to polyesters, polyether esters, polyorthoesters, poly ester carbonates, polycarbonates, polyanhydrides, polyhydroyalkonate (e.g. Polyhydroxybutyrate, polyhydroxyvalerates), polyurethanes, poly ester urethanes. The polymers can be in the form of linear, branched, or star shaped. The polymers can be initiated from compounds that us a single point of initiation, two points of initiation, 3 points of initiation, four points of initiation, 6 points of initiation or 8
points of initiation. Polymers can include but are not limited to polymers that are comprise repeat units derived from at least one of the following monomers: l-lactide, dl-lactide, glycolide, trimethylene carbonate, epsilon-caprolactone, p-dioxanone and a morpholinedione
[00213] Excipient synthetic polymers that can be used include but are not limited to polyacrylic acid and salts thereof, polyvinylpyrollidone, Pluronics 127, pluronics F68, polyethylene glycol, polyethylene oxide, polyvinyl alcohol.
[00214] Complexing agents can include but are not limited to _a-cyclodextrin, _|3- cyclodextrin (2-Hydroxypropyl)-Beta-Cyclodextrin, Sulfobutylether Beta Cyclodextrin Sodium, Ethylenediaminetetraacetic acid (EDTA).
[00215] Lipids and phospholipids that can be used include but are not limited to hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, L-a- di myristoylphosphatidylcholine, L-a-dimyristoylphosphatidylglycerol, 1,2-distearoyl-sn-glycero- 3-phospho-(l'-rac-glycerol) (sodium salt) (DSPG), l,2-distearoyl-sn-glycero-3- phosphoethanolamine (DSPE), l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl- sn-glycero-3-ethylphosphocholine (chloride salt) (18:1 EPC), L-a-phosphatidylcholine (Soy-PC), l,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)-2000] (sodium salt) (MPEG-2k-DSPE, for Ab liposomes), l,2-distearoyl-sn-glycero-3- phosphoethanolamine-N-[methoxy (polyethylene glycol)- 2000] (ammonium salt) (PEG_PE), (4- hydroxybutyl)azanediyl)bis(hexane-6,l-diyl)bis(2-hexyldeca noate) [ALC-0315], (2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide) [ALC-0159], 9-Heptadecanyl 8-{(2-hydroxyethyl)[6- oxo-6-(undecyloxy)hexyl]amino}octa noate [SM102], l,2-dimyristoyl-rac-glycero-3- methoxypolyethylene glycol-2000 [PEG2000-DMG], l,2-dimyristoyl-rac-glycero-3- methoxypolyethylene glycol [PEG-DMG], dilauryl phosphatidyl choline (DLPC), dimyristol phosphatidyl choline (DMPC), dipalmitoyl phosphatidyl choline (DPPC), dioleolyl phosphatidyl choline(DOPC), dilauryl phosphatidyl ethanolamine (DLPE), distearoyl phosphatidyl choline (DSPC), dimyristoyl phosphatidyl ethanolamine (DMPE), distearoyl phosphatidyl ethanolamine (DSPE), dilauryl phosphatidyl glycerol (DLPG), dicetyl phosphate (DCP), and , dioleoyl phosphatidylserine (DOPS) .
[00216] Lipids include branched lipids, ionizable lipids, pegylated lipids and cationic lipids. Cationic and ionizable lipids include but are not limited to DDAB (CAS 3700-67-2), DOTAP (CAS 113669-21-9), cholesterol-(2-dimethlaminoethyl)carbamate (DC-chol), dioctadecylamine, DOTMA (CAS 137056-72.5), CLONfectin, DMRIE (CAS 153312-64-2), DOGS (transfectam, CAS 124050-77-7), l,2-di(oleoyloxy)-3-(dimethylamino)propane (DODAP), DLinDMA (CAS 871258-12- 7), DLin-MC3-DMA (CAS 1224606-06-7), DOSPA (CAS 168479-03-6), EDOPC (CAS 183283-20-7), DLin-K-XTC2-DMA (CAS 1190197-97-7), N-[2.3-Di(oleyloxy)propyl]-N,N-dimethylamine (DODMA), dipalmityamine (CAS 16724-63-3), dimyristylamine (CAS 17361-44-3), Dlin-K-DM4 (CAS 1169768-05-1), DLenDMA (CAS 874291-25-5), EDMPC (CAS 183283-19-4), C12-200 (CAS 1220890-25-4), DOSPER (CAS 178532-92-8), N4-spermine chlolesterol carbamate (CAS 179075- 30-0), bisguanidinium tren-cholesterol (CAS 182056-06-0), CLinDMA (CAS 908860-82-2), DLinDAP (CAS 230949-32-3), EDLPC (CAS 230949-32-3), DORIE (CAS 153312-60-8), L 319 (CAS 1351586-50- 9), ALN 100 (CAS 1226778-72-8), Octyl CLinDMA (CAS 1208381-69-4), SM-102 (CAS 2089251-47- 6), YSK 05 (CAS 1318793-78-0), DMOBA (CAS 908860-85-5), CDAN (CAS 200337-52-6), HGT 4003 (CAS 1415795-37-7), MVL 5 (CAS 760939-62-6), DLin-C-DAP (CAS 1169768-13-1), cholest-5-en- 3p-oxethane tosylate (CAS 30656-75-8), HisChol (CAS 44979-79-1), KL22 (CAS 1413010-97-5), KL10 (CAS 1413010-89-5), dimyristyloxypropylamine (CAS 396727-98-3), CpLinDMA (CAS 908860-83-3), CTAP (CAS 200337-57-1), DLin-S-DMA (CAS 1169768-15-3), DLin-2-DMAP (CAS 1169768-10-8), dioleylamine-A-succinyl paromomycin (DOSP, CAS 959664-11-0), C2-DLinDMA (CAS 1192257-55-8), GAP-DLRIE (CAS 208040-06-6), DLin-K-C4-DMA (CAS 1217306-47-2), and DLin-K-C3-DMA (CAS 1217306-46-1). Ionizable lipids include but are not limited to lipids that comprise a tertiary amine.
[00217] Surfactants that can be used include ionic and non-ionic surfactants. Ionic surfactants can include cationic, anionic and zwitterionic surfactants. Non-ionic surfactants can include but are not limited to (Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-_- tocopherol polyethylene glycol 1000 succinate, Brij, Myrj, polysorbate 20, polysorbate 80, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 85, Solutol HS 15, sorbitan monooleate (Span 80), Sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan trioleate (Span 8) poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol,
Gellucire 44/14, nonoxynol-9, Softigen 767, octyl beta-D-glycopyranoside (OGP), hexyl beta-D- glucopyranoside (HGP), Octyl beta-D-l-thioglucopyranoside (TGP), Decyl-beta-D- glucopyranoside (DGP), Dodecyl-beta-D-glucopyranoside (DdGP), N-octyl beta-D-Maltoside (ODM), decyl beta-D-maltopyranoside (DMP), cyclohexyl-ethanoyl-maltoside, n-decyl- and n- dodecyl-sucrose, and mono- and di-fatty acid esters of PEG 300, 400, or 1750. Anionic surfactants can include but are not limited to sodium lauryl sulfate, fatty acid salts, sodium laureth sulfate, dioctyl sodium sulfosuccinate. Cationic surfactants can include but are not limited to Phosphatidylcholine (Lecithin), cetrimide, cetrimonium bromide, benethonium chloride, dimethyldioctadecyl ammonium chloride, tetradecyl trimethyl ammonium bromide, cetylpyridinium chloride, esterquat, and benzalkonium chloride. Zwiterionic surfactants can include but are not limited to Cocamidopropyl betaine, (3-[(3- Cholamidopropyl)dimethylammonio]-l-propanesulfonate) and cocamidopropyl hydroxysultaine, phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, and sphingomyelins.
[00218] Solvents that can be used include water-soluble organic solvents. Water-soluble organic solvents include but are not limited to polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide.
[00219] Tonicity modifiers that can be used include but are not limited to dextrose, sucrose, mannitol, glycerin, sodium chloride, and potassium chloride.
[00220] pH modifiers that can be used include but are not limited to citric acid and its salts, salts of phosphoric acid, tartatic acid, lactic acid, glycolic acid, sodium hydroxide, phosphoric acid, sulfuric acid, oxalic acid and hydrochloric acid.
[00221] Anti-oxidants that can be used include but are not limited to ascorbic acid, butylated hydroxyanisole, Butyl hydroxytoluene, Vitamin A, vitamin E, a-tocopherol, thioglycerol, cysteine, acetylcysteine, cystine, dithioerythreitol, dithiothreitol, glutathione, Sodium bisulfite, Sodium metabisulfite, thiourea, uric acid, melatonin, propyl gallate, tertiary butylhydroquinone and combinations thereof.
[00222] Emulsifiers that can be used include but are not limited to Glyceryl Monostearate,
Isopropyl Palmitate, Polyethylene Glycol 400 Monostearate, sodium stearate, sodium stearyl glutamate, as well as the compounds listed as surfactants and combinations thereof.
[00223] Preservatives that can be used include but are not limited to benzoic acid, sorbic acid, boric acid, methylparaben, ethylparaben, propylparaben, butylparaben, sodium benzoate, sodium propionate, phenyl ethyl alcohol, chlorobutanol, benzyl alcohol, potassium sorbate, phenol, chlorocresol, o-phenyl phenol, thiomersal, nitromersol, phenylmercuric nitrate, phenylmercuric acetate, phenoxyethanol, benzalkonium and combinations thereof.
[00224] The excipients can include at least one solvent. The solvents used can include but are not limited to water, ethanol, dimethylsulfoxide, ethyl lactate, ethyl acetate, benzyl alcohol, benzyl benzoate, triacetin, N-methylpyrrolidone, 2-pyrrolidone, propylene carbonate, polyethylene glycol (PEG200), polyethylene glycol (PEG400), glycofurol and combinations thereof.
[00225] Buffers that can be used include aqueous solutions prepared using one or more of the following: potassium hydrogen phthalate, sodium hydrogen phthalate, potassium or sodium dihydrogen phosphate, dipotassium or disodium hydrogen phosphate, phosphoric acid, boric acid, sodium acetate, acetic acid, ammonium chloride, ammonium acetate, (4-(2-hydroxyethyl)- 1-piperazineethanesulfonic acid), citric acid and sodium citrate.
[00226] In another aspect, the derivatized HA polymer compositions of this disclosure can further comprise an inorganic compound. The inorganic compounds that can be used include but are not limited to barium sulfate, calcium hydroxylapatite or hydroxyapatite, tricalcium phosphate (TCP) [ including the various forms, for example a-TCP, -TCP, and Biphasic Tricalcium Phosphate (BCP)], calcium phosphate and calcium sulphate.
[00227] In anotheraspect, the Hyaluronic acid derivative can further comprise compounds that comprise an emulsion. The emulsion comprises an oil phase and an aquesous phase. Compounds that can comprise an emulsion include but are not limited to sodium stearate, sodium stearyl glutamate, coconut oil, shea butter oil, olive oil, mineral oil, beeswax, sunflower seed oil, grape seed oil, Isohexadecane, Isopropyl Isostearate, Dimethicone, Caprylic/Capric Triglyceride, Ethylhexylglycerin, Hydroxyacetophenone, Dimethiconol, Cetearyl Glucoside, Cetearyl Alcohol, Stearic Acid, Palmitic Acid, Stearyl Alcohol, Cetyl Alcohol, Sodium Acrylates
Copolymer, PEG-100 Stearate, cetearyl olivate, polyacrylamide, sorbitan olivate, cetearyl olivate, polyacrylamide, sorbitan olivate, laureth-7, carbomer, Butylene Glycol, Ammonium
Acryloyldimethyltaurate/Steareth-25 Methacrylate Crosspolymer, Cetearyl Alcohol, Trisodium Ethylenediamine Disuccinate, dicaprylyl carbonate, palmitic acid, ammonium polyacryloyldimethyl taurate, capryloyl salicylic acid, caprylyl glycol, xanthan gum, [00228] In one aspect, the derivatized HA polymers of this disclosure can be prepared as a composition that comprises one or more excipients. In another aspect, the derivatized HA polymers of this disclosure can be suspended in a composition that comprises one or more excipients. In another aspect, the derivatized HA polymers of this disclosure can be rehydrated in a composition that comprises one or more excipients. In another aspect, the derivatized HA polymers of this disclosure can be prepared as separate compositions that can comprise one or more excipients with the separate solutions being mixed prior to use. In another aspect, the derivatized HA polymers of this disclosure can be prepared in the presence of one or more excipients and then converted to a solid form by one or more of the methods described in this disclosure.
[00229] Compositions of the present disclosure may comprise a biologically active agent in addition to a derivatized HA polymer as described herein and optionally other components. Exemplary biologically active agents include, without limitation, small molecule drugs, peptides, proteins, growth factors, hormones, antibodies, agonists, antagonists, anti-bacterial and/or antifungal agents.
[00230] Biologically active agents that can be incorporated into formulations with the compositions described include: antiandrogens, antibacterial, antioestrogens, androgens and anabolic agents, antibiotics, antimigraine drugs, antihistamines, antianxiety drugs, antidiuretics, antihistamines, antirheumatoid agents, antigens, analgesics, antidepressants, antiinflammatories, anesthetics, aminoglycosides antibodies, antiviral, adrenergic stimulants, anticonvulsants, antiangina agents, antiarrhyrthmics, antimalarials, anti-mitotic, anthelmintics, anoretic agents, antitussives, antipruritics, antipyretics, anti-alzheimer's agents, anti-Parkinson's agents, antiemetics and antinauseants, antihypertensives, anticoagulants, antifungals, , antimicrobials, allergens, antidiarrheals, antihyperuricaemia agents, adrenergic stimulants,
antiparasitic agents, antiproliferative agents, antipsychotic drugs, antithyroid agents , beta- adrenergic blocking agents, bronchodilators; bronchospasm relaxants, blood clotting factors , blood coagulation factors, cytotoxic agents, cytostatic agents , chemotherapeutic agents, clot inhibitors, clot dissolving agents, cells, CNS stimulants, Corticosteroids , calcium channel blockers, cofactors, ceramides, cardiotonic glycosides, cytokines (e.g., lymphokines, monokines, chemokines); colony stimulating factors (e.g., GCSF, GM-CSF, MCSF); dermatological agents, decongestants, diuretics, expectorants, endectocide agents, growth factors, hemostatic agents, hypoglycemic agents, hormones and hormone analogs, hypercalcemia, Hypnotics, interleukins (IL-2, IL-3, IL-4, IL-6); interferons (.beta.-IFN, . alpha. -IFN and .gamma. -IFN); immunosuppressants, muscle relaxants, microorganisms, non-steroidal anti-inflammatory agents, nucleic acids, nutritional agents, neuromuscular blocking agents, neuroleptics, Neurotoxins , nutraceuticals, nucleotide, oligonucleotides, oestrogens, obstetric drugs, ovulation inducers, opioids, progestogens, pituitary hormones, Pituitary inhibitors proteins, peptides, polysaccharides, protease inhibitors, prostaglandins, quinolones, reductase inhibitors, sulfa drugs, sclerosant, sedatives, sodium channel blockers, steroids, steroidal anti-inflammatory agents, smoking cessation agents, toxins, thrombolytic agents, thyroid hormones, tumor necrosis factor; vesicles, vitamins, viruses, vasodilators, vaccines
[00231] Additional representative examples of biologically active agents that may be suitable for use in the compositions of the present disclosure include, but are not limited to: Antidiarrheals such as diphenoxylate, loperamide and hyoscyamine; Antihypertensives such as hydralazine, minoxidil, captopril, enalapril, clonidine, prazosin, debrisoquine, diazoxide, guanethidine, methyldopa, reserpine, trimethaphan; Calcium channel blockers such as diltiazem, felodipine, amlodipine, nitrendipine, nifedipine and verapamil; Antiarrhyrthmics such as amiodarone, flecainide, disopyramide, procainamide, mexiletene and quinidine, Antiangina agents such as glyceryl trinitrate, erythrityl tetranitrate, pentaerythritol tetranitrate, mannitol hexanitrate, perhexilene, isosorbide dinitrate and nicorandil; Beta-adrenergic blocking agents such as alprenolol, atenolol, bupranolol, carteolol, labetalol, metoprolol, nadolol, nadoxolol, oxprenolol, pindolol, propranolol, sotalol, timolol and timolol maleate; Cardiotonic glycosides such as digoxin and other cardiac glycosides and theophylline derivatives; Adrenergic stimulants
such as adrenaline, ephedrine, fenoterol, isoprenaline, orciprenaline, rimeterol, salbutamol, salmeterol, terbutaline, dobutamine, phenylephrine, phenylpropanolamine, pseudoephedrine and dopamine; Vasodilators such as cyclandelate, isoxsuprine, papaverine, dipyrimadole, isosorbide dinitrate, phentolamine, nicotinyl alcohol, co-dergocrine, nicotinic acid, glycerl trinitrate, pentaerythritol tetranitrate and xanthinol; Antiproliferative agents such as paclitaxel, estradiol, actinomycin D, sirolimus, tacrolimus, everolimus, 5-fluorouracil and dexamethasone; Antimigraine preparations such as ergotanmine, dihydroergotamine, methysergide, pizotifen and sumatriptan; Anticoagulants and thrombolytic agents such as warfarin, dicoumarol, low molecular weight heparins such as enoxaparin, streptokinase and its active derivatives; Hemostatic agents such as aprotinin, tranexamic acid and protamine; Analgesics and antipyretics including the opioid analgesics such as buprenorphine, dextromoramide, dextropropoxyphene, fentanyl, alfentanil, sufentanil, hydromorphone, methadone, morphine, oxycodone, papaveretum, pentazocine, pethidine, phenopefidine, codeine, dihydrocodeine; acetylsalicylic acid (aspirin), paracetamol, synthetic alpha2 -adrenoreceptor agonist, dexmedetomidine hydrochloride, flunixin meglumine, meperidine, phenylbutazone and phenazone; Immunosuppressants, antiproliferatives and cytostatic agents such as rapamycin (sirolimus) and its analogs (everolimus and tacrolimus); Neurotoxins such as capsaicin, botulinum toxin (botox); Hypnotics and sedatives such as the barbiturates amylobarbitone, butobarbitone and pentobarbitone and other hypnotics and sedatives such as chloral hydrate, chlormethiazole, hydroxyzine and meprobamate; Antianxiety agents such as the benzodiazepines alprazolam, bromazepam, chlordiazepoxide, clobazam, chlorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, nitrazepam, oxazepam, temazepam and triazolam; Neuroleptic and antipsychotic drugs such as the phenothiazines, chlorpromazine, fluphenazine, pericyazine, perphenazine, promazine, thiopropazate, thioridazine, trifluoperazine; and butyrophenone, droperidol and haloperidol; and other antipsychotic drugs such as pimozide, thiothixene and lithium; Antidepressants such as the tricyclic antidepressants amitryptyline, clomipramine, desipramine, dothiepin, doxepin, imipramine, nortriptyline, opipramol, protriptyline and trimipramine and the tetracyclic antidepressants such as mianserin and the monoamine oxidase inhibitors such as isocarboxazid, phenelizine, tranylcypromine and moclobemide and selective serotonin re-uptake
inhibitors such as fluoxetine, paroxetine, citalopram, fluvoxamine and sertraline; CNS stimulants such as caffeine and 3-(2-aminobutyl) indole; Antipruritics can include compounds such as synthetic Janus Kinase (JAK) inhibitors, NK-1 receptor antagonists, antibodies that neutralize interleukin-31 (IL-31). These can include oclacitinib maleate, Serlopitant, and Lokivetmab, Anti- alzheimer's agents such as tacrine; Anti-Parkinson's agents such as amantadine, benserazide, carbidopa, levodopa, benztropine, biperiden, benzhexol, procyclidine and dopamine-2 agonists such as S (-)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0923), Anticonvulsants such as phenytoin, valproic acid, primidone, phenobarbitone, methylphenobarbitone and carbamazepine, ethosuximide, methsuximide, phensuximide, sulthiame and clonazepam, Antiemetics and antinauseants such as the phenothiazines prochloperazine, thiethylperazine, a neurokinin (NK1) receptor antagonist, maropitant citrateand 5HT-3 receptor antagonists such as ondansetron and granisetron, as well as dimenhydrinate, diphenhydramine, metoclopramide, domperidone, hyoscine, hyoscine hydrobromide, hyoscine hydrochloride, clebopride and brompride; Non-steroidal anti-inflammatory agents including their racemic mixtures or individual enantiomers where applicable, preferably which can be formulated in combination with dermal and/or mucosal penetration enhancers, such as ibuprofen, flurbiprofen, ketoprofen, aclofenac, diclofenac, aloxiprin, aproxen, aspirin, diflunisal, fenoprofen, indomethacin, mefenamic acid, naproxen, phenylbutazone, piroxicam, salicylamide, salicylic acid, sulindac, desoxysulindac, tenoxicam, tramadol, ketoralac, flufenisal, salsalate, triethanolamine salicylate, aminopyrine, antipyrine, oxyphenbutazone, apazone, cintazone, flufenamic acid, clonixerl, clonixin, meclofenamic acid, 6-chloro-a-methyl-9H-carbazole-2-acetic acid (carprofen), flunixin, coichicine, demecolcine, allopurinol, oxypurinol, benzydamine hydrochloride, dimefadane, indoxole, intrazole, mimbane hydrochloride, paranylene hydrochloride, tetrydamine, benzindopyrine hydrochloride, fluprofen, ibufenac, naproxol, fenbufen, cinchophen, diflumidone sodium, fenamole, flutiazin, metazamide, letimide hydrochloride, nexeridine hydrochloride, octazamide, molinazole, neocinchophen, nimazole, proxazole citrate, tesicam, tesimide, tolmetin, and triflumidate; Antirheumatoid agents such as penicillamine, aurothioglucose, sodium aurothiomalate, methotrexate and auranofin; Muscle relaxants such as baclofen, diazepam, cyclobenzaprine hydrochloride, dantrolene, methocarbamol, orphenadrine and
quinine; Agents used in gout and hyperuricaemia such as allopurinol, colchicine, probenecid and sulphinpyrazone; Oestrogens such as estradiol, oestriol, estrone, ethinylestradiol, mestranol, stilbestrol, dienestrol, epiestriol, estropipate and zeranol; Progesterone and other progestagens such as allylestrenol, dydrgesterone, lynestrenol, norgestrel, norethyndrel, norethisterone, norethisterone acetate, gestodene, levonorgestrel, medroxyprogesterone and megestrol; Antiandrogens such as cyproterone acetate and danazol; Antioestrogens such as tamoxifen and epitiostanol and the aromatase inhibitors, exemestane and 4-hydroxy-androstenedione and its derivatives; Androgens and anabolic agents such as testosterone, methyltestosterone, clostebol acetate, drostanolone, furazabol, nandrolone oxandrolone, stanozolol, trenbolone acetate, dihydro-testosterone, 17-(. alpha. -methyl-19-noriestosterone and fluoxymesterone; 5-alpha reductase inhibitors such as finasteride, turosteride, LY-191704 and MK-306; Corticosteroids such as betamethasone, betamethasone valerate, cortisone, dexamethasone, dexamethasone 21-phosphate, fludrocortisone, flumethasone, fluocinonide, fluocinonide desonide, fluocinolone, fluocinolone acetonide, fluocortolone, halcinonide, halopredone, hydrocortisone, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrocortisone 21-acetate, methylprednisolone, prednisolone, prednisolone 21-phosphate, prednisone, triamcinolone, triamcinolone acetonide; Glycosylated proteins, proteoglycans, glycosaminoglycans such as chondroitin sulfate; chitin, acetyl-glucosamine, hyaluronic acid; Complex carbohydrates such as glucans; Further examples of steroidal anti-inflammatory agents such as cortodoxone, fludroracetonide, fludrocortisone, difluorsone diacetate, flurandrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and its other esters, chloroprednisone, clorcortelone, descinolone, desonide, dichlorisone, difluprednate, flucloronide, flumethasone, flunisolide, flucortolone, fluoromethalone, fluperolone, fluprednisolone, meprednisone, methylmeprednisolone, paramethasone, cortisone acetate, hydrocortisone cyclopentylpropionate, cortodoxone, flucetonide, fludrocortisone acetate, flurandrenolone, aincinafal, amcinafide, betamethasone, betamethasone benzoate, chloroprednisone acetate, clocortolone acetate, descinolone acetonide, desoximetasone, dichlorisone acetate, difluprednate, flucloronide, flumethasone pivalate, flunisolide acetate, fluperolone acetate, fluprednisolone valerate, paramethasone acetate, prednisolamate, prednival, triamcinolone
hexacetonide, cortivazol, formocortal and nivazol; Pituitary hormones and their active derivatives or analogs such as corticotrophin, thyrotropin, follicle stimulating hormone (FSH), a Gonadotropin-releasing hormone (GnRH) analog, u deslorelin acetate, cetrorelix acetate, Gonadorelin acetate , clomiphene, Human chorionic gonadotropin (HCG), luteinizing hormone (LH) and gonadotrophin releasing hormone (GnRH); Hypoglycemic agents such as insulin, chlorpropamide, glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide and metformin; Thyroid hormones such as calcitonin, thyroxine and liothyronine and antithyroid agents such as carbimazole and propylthiouracil; Other miscellaneous hormone agents such as octreotide; Pituitary inhibitors such as bromocriptine; Ovulation inducers such as clomiphene; Diuretics such as the thiazides, related diuretics and loop diuretics, bendrofluazide, chlorothiazide, chlorthalidone, dopamine, cyclopenthiazide, hydrochlorothiazide, indapamide, mefruside, methycholthiazide, metolazone, quinethazone, bumetanide, ethacrynic acid and frusemide and potasium sparing diuretics, spironolactone, amiloride and triamterene; Antidiuretics such as desmopressin, lypressin and vasopressin including their active derivatives or analogs; Obstetric drugs including agents acting on the uterus such as ergometrine, oxytocin and gemeprost; Prostaglandins such as alprostadil (PGE1), prostacyclin (PGI2), dinoprost (prostaglandin F2-a I pha ) and misoprostol; Antimicrobials including the cephalosporins such as cephalexin, cefoxytin and cephalothin; Penicillins such as amoxycillin, amoxycillin with clavulanic acid, ampicillin, bacampicillin, benzathine penicillin, benzylpenicillin, carbenicillin, cloxacillin, methicillin, phenethicillin, phenoxymethylpenicillin, flucioxacillin, meziocillin, piperacillin, ticarcillin and azlocillin; Tetracyclines such as minocycline, chlortetracycline, tetracycline, demeclocycline, doxycycline, methacycline and oxytetracycline and other tetracycline-type antibiotics; Amnioglycoides such as amikacin, amikin sulfate, gentamicin, kanamycin, neomycin, netilmicin and tobramycin; Antifungals such as amorolfine, isoconazole, clotrimazole, econazole, miconazole, nystatin, terbinafine, bifonazole, amphotericin, griseofulvin, ketoconazole, fluconazole and flucytosine, salicylic acid, fezatione, ticlatone, tolnaftate, triacetin, zinc, pyrithione and sodium pyrithione; Quinolones such as nalidixic acid, cinoxacin, ciprofloxacin, enoxacin and norfloxacin; Sulphonamides such as phthalysulphthiazole, sulfadoxine, sulphadiazine, sulphamethizole and sulphamethoxazole; Sulphones such as dapsone; Other
miscellaneous antibiotics such as chloramphenicol, clindamycin, erythromycin, erythromycin ethyl carbonate, erythromycin estolate, erythromycin glucepate, erythromycin ethylsuccinate, erythromycin lactobionate, roxithromycin, lincomycin, natamycin, nitrofurantoin, spectinomycin, vancomycin, aztreonarn, colistin IV, metronidazole, tinidazole, secnidazole, ornidazole, fusidic acid, trimethoprim, and 2-thiopyridine N-oxide; halogen compounds, particularly iodine and iodine compounds such as iodine-PVP complex and diiodohydroxyquin, hexachlorophene; chlorhexidine; chloroamine compounds, silver sulfadiazine, silver, nanoparticulate silver, silver nitrate, silver zeolites, silver cations, AgPO3 Ag3PO4, Ag4P2O7, exsalt®SD7 (Exciton Technologies) exsalt®T7 (Exciton Technologies); Lincomycin Hydrochloride, tricyclic tetrahydroquinoline antibacterial agents, 8-pyrazinyl-S-spiropyrimidinetrione- oxazinoquinoline derivatives, 3-spiropyrimidinetrione-quinoline derivatives, thiadiazol- spiropyrimidinetrione-quinoline derivatives, (2R,4S,4aS)-10-fluoro-2,4-dimethyl-8-(4- methyloxazol-2-yl)-2,4,4a,6-tetra- hydro-lH,l'H-spiro[[l,4]oxazino[4,3-a]quinoline-5,5'- pyrimidine]-2',4',6'(- 3'H)-trione, (2R,4S,4aS)-9,10-difluoro-2,4-dimethyl-8-(3-methylisoxazol-5- yl)-2,4,4a,6- -tetrahydro-lH, l'H-spiro[[l, 4]oxazino[4, 3-a]qui noline-5, 5'-pyrimidine]-2', -
4',6'(3'H)-trione, (2R,4S,4aS)-10-fluoro-2,4-dimethyl-8-(oxazol-2-yl)-2,4,4a,6-tetrahydro-lH- , l'H-spiro[ [1, 4]oxazino[4, 3-a]qui noline-5, S'-pyri midine]-2', 4', 6'(3'H)-tri- one, (2R,4S,4aS)-9,10- difluoro-2,4-dimethyl-8-(2-methyloxazol-5-yl)-2,4,4a,6-t- etrahydro-lH,l'H- spiro[[l,4]oxazino[4,3-a]quinoline-5,5'-pyrimidine]-2',4'- ,6'(3'H)-trione, (2R,4S,4aS)-9,10- difluoro-2,4-dimethyl-8-(oxazol-4-yl)-2,4,4a,6-tetrahydr- o-lH,l'H-spiro[[l,4]oxazino[4,3- a]quinoline-5,5'-pyrimidine]-2',4',6'(3'H)- -trione, (2R,4S,4aS)-9-fluoro-2,4-dimethyl-8-(4- methyloxazol-2-yl)-2,4,4a,6-tetrah- ydro-lH,l'H-spiro[[l,4]oxazino[4,3-a]quinoline-5, S'- pyri midine]-2', 4', 6'(3- 'H)-trione, (2R,4S,4aS)-9,10-difluoro-8-(4-(4-fluorophenyl)oxazol-5-yl)-2,4- dimethyl-- 2,4,4a,6-tetrahydro-lH,l'H-spiro[[l,4]oxazino[4,3-a]quinoline-5,5'-pyrimid- ine]- 2,,4',6'(3,H)-trione, (2S,4R,4aR)-2,4-dimethyl-8-(oxazol-5-yl)-2,4,4a,6-tetrahydro-lH,l'H-spiro- [[l,4]oxazino[4,3-a]quinoline-5,5'-pyrimidine]-2',4',6'(3'H)-trione, (2S,4R,4aR)-8-(4-ethyloxazol- 2-yl)-9,10-difluoro-2,4-dimethyl-2,4,4a,6-te- trahydro-lH,l'H-spiro[[l,4]oxazino[4,3- a]quinoline-5,5'-pyrimidine]-2',4',- 6'(3'H)-trione, (2R,4S,4aS)-9,10-difluoro-2,4-dimethyl-8-
(oxazol-2-yl)-2,4,4a,6-tetrahydr- o-lH,l'H-spiro[[l,4]oxazino[4,3-a]quinoline-5,5'-pyrimidine]-
2',4',6'(3'H)- -trione, benzoyl peroxide; Antituberculosis drugs such as ethambutol, isoniazid, pyrazinamide, rifampicin and clofazimine; Antimalarials such as primaquine, pyrimethamine, chloroquine, hydroxychloroquine, quinine, mefloquine and halofantrine; compounds such as Azithromycin, Aztreonam, Cefaclor, Cefadroxil , Cefazolin, Cefdinir, Cefepime Hydrochloride, (cefoperazone sodium, Ceftaroline fosamil, avibactam, Ceftazidime sodium, Ceftibuten, ceftiofur, Tazobactam, cefovecin sodium [(6R,7R)-7-[[(2Z)-(2-amino-4- thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-3-[(2S)-tetrahydro-2-furanyl]-5-thia-l- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, monosodium salt] Cefuroxime Axetil, Cefuroxime, Cephalexin, Chloramphenicol Sodium, Ciprofloxacin HCI, Clarithromycin, Clindamycin hydrochloride, Clindamycin Palmitate hydrochloride, Clindamycin phosphate, Dalbavancin Hydrochloride, Daptomycin, Demeclocycline hydrochloride, Dicloxacillin, Doripenem, Doxycycline, Doxycycline calcium, Doxycycline hyclate, Doxycycline monohydrate, Ertapenem sodium, Erythromycin, Erythromycin Ethylsuccinate, Erythromycin lactobionate, Erythromycin stearate, Erythromycin, Fosfomycin tromethamine, Gemifloxacin mesylate, Gentamicin Sulfate, Imipenem, Kanamycin, Levofloxacin, Lincomycin hydrochloride, Linezolid, Meropenem, Methenamine Hippurate, Metronidazole , Metronidazole , Micafungin sodium, Minocycline Hydrochloride, Minocycline, Moxifloxacin hydrochloride, Nafcillin, Nalidixic acid, Neomycin Sulfate, Nitrofurantoin, Norfloxacin, Ofloxacin, Oritavancin diphosphate, Oxacillin, Penicillin G, Penicillin G benzathine, Penicillin G Sodium, Penicillin V Potassium, Piperacillin Sodium, Polymyxin B Sulfate, Quinupristin, dalfopristin, Spectinomycin hydrochloride, Streptomycin, Sulfamethoxazole, Tedizolid Phosphate, Telavancin, Telithromycin, Tetracycline Hydrochloride, Ticarcillin disodium, Tigecycline, Tobramycin Sulfate, Tobramycin, Trimethoprim hydrochloride, tulathromycin, Vancomycin hydrochloride.
[00232] Antiviral agents may be included in the compositions of the present disclosure, where exemplary antiviral agents include acyclovir and acyclovir prodrugs, famcyclovir, zidovudine, didanosine, stavudine, lamivudine, zalcitabine, saquinavir, indinavir, ritonavir, n- docosanol, tromantadine and idoxuridine. Other suitable biologically active agents include Anthelmintics such as mebendazole, thiabendazole, niclosamide, praziquantel, pyrantel embonate and diethylcarbamazine; Cytotoxic agents such as plicamycin, cyclophosphamide,
dacarbazine, fluorouracil and its prodrugs (described, for example, in International Journal of Pharmaceutics, 111, 223-233 (1994)), methotrexate, procarbazine, 6-mercaptopurine and mucophenolic acid; Anorectic and weight reducing agents including dexfenflurarnine, fenfluramine, diethylpropion, mazindol and phentermine; Agents used in hypercalcaemia such as calcitriol, dihydrotachysterol and their active derivatives or analogs; Antitussives such as ethylmorphine, dextromethorphan and pholcodine; Antiparasitic and Endectocide agents such as moxidectin, Ivermectin, Niclosamide, Praziquantel, Pyrantel, Pyrvinium, Albendazole, Flubendazole, Mebendazole, Thiabendazole
[00233] Compositions of the present disclosure may include: an expectorant such as carbolcysteine, bromihexine, emetine, quanifesin, ipecacuanha and saponins; Decongestants such as phenylephrine, phenylpropanolamine and pseudoephedrine; Bronchospasm relaxants such as ephedrine, fenoterol, orciprenaline, rimiterol, salbutamol, sodium cromoglycate, cromoglycic acid and its prodrugs (described, for example, in International Journal of Pharmaceutics 7, 63-75 (1980)), terbutaline, ipratropium bromide, salmeterol and theophylline and theophylline derivatives; Antihistamines such as meclozine, cyclizine, chlorcyclizine, hydroxyzine, brompheniramine, chlorpheniramine, clemastine, cyproheptadine, dexchlorpheniramine, diphenhydramine, diphenylamine, doxylamine, mebhydrolin, pheniramine, tripolidine, azatadine, diphenylpyraline, methdilazine, terfenadine, astemizole, loratidine and cetirizine; Local anaesthetics such as benzocaine, bupivacaine, amethocaine, lignocaine, lidocaine, cocaine, cinchocaine, dibucaine, mepivacaine, prilocaine, etidocaine, veratridine (specific c-fiber blocker) and procaine; Stratum corneum lipids, such as ceramides, cholesterol and free fatty acids, for improved skin barrier repair [Man, et al. J. Invest. Dermatol., 106(5), 1096, (1996)]; Neuromuscular blocking agents such as suxamethonium, alcuronium, pancuronium, atracurium, gallamine, tubocurarine and vecuronium; sclerocing agents or sclerosants may be a surfactant or it may be selected from the group consisting of ethanol, dimethyl sulfoxide, sucrose, sodium chloride, dextrose, glycerin, minocycline, tetracycline, doxycycline, polidocanol, sodium tetradecyl sulfate, sodium morrhuate, and sotradecol. an angiogenesis inhibitor; a 5-lipoxygenase inhibitor or antagonist; a chemokine receptor antagonist; a cell cycle inhibitor; a taxane; an anti-microtubule agent; paclitaxel; an analogue or
derivative of paclitaxel; a vinca alkaloid; camptothecin or an analogue or derivative thereof; a podophyllotoxin, wherein the podophyl lotoxin may be an etoposide or an analogue or derivative thereof; an anthracycline, wherein the anthracycline may be doxorubicin or an analogue or derivative thereof or the anthracycline may be mitoxantrone or an analogue or derivative thereof; a platinum compound; a nitrosourea; a nitroimidazole; a folic acid antagonist; a cytidine analogue; a pyrimidine analogue; a fluoropyrimidine analogue; a purine analogue; a nitrogen mustard or an analogue or derivative thereof; a hydroxyurea; a mytomicin or an analogue or derivative thereof; an alkyl sulfonate; a benzamide or an analogue or derivative thereof; a nicotinamide or an analogue or derivative thereof; a halogenated sugar or an analogue or derivative thereof; a DNA alkylating agent; an anti-microtubule agent; a topoisomerase inhibitor; a DNA cleaving agent; an antimetabolite; a nucleotide interconversion inhibitor; a hydroorotate dehydrogenase inhibitor; a DNA intercalation agent; an RNA synthesis inhibitor; a pyrimidine synthesis inhibitor; a cyclin dependent protein kinase inhibitor; an epidermal growth factor kinase inhibitor; an elastase inhibitor; a factor Xa inhibitor; a farnesyltransferase inhibitor; a fibrinogen antagonist; a guanylate cyclase stimulant; a heat shock protein 90 antagonist; which may be a geldanamycin or an analogue or derivative thereof; a guanylate cyclase stimulant; a HMGCoA reductase inhibitor, which may be simvastatin or an analogue or derivative thereof; an IKK2 inhibitor; an IL-1 antagonist; an ICE antagonist; an IRAK antagonist; an IL-4 agonist; an immunomodulatory agent; sirolimus or an analogue or derivative thereof; everolimus or an analogue or derivative thereof; tacrolimus or an analogue or derivative thereof; bioImus or an analogue or derivative thereof; tresperimus or an analogue or derivative thereof; auranofin or an analogue or derivative thereof; 27-0-demethylrapamycin or an analogue or derivative thereof; gusperimus or an analogue or derivative thereof; pimecrolimus or an analogue or derivative thereof; ABT-578 or an analogue or derivative thereof; an inosine monophosphate dehydrogenase (IMPDH) inhibitor, which may be mycophenolic acid or an analogue or derivative thereof or 1-. alpha. -25 dihydroxy vitamin D.sub.3 or an analogue or derivative thereof; a leukotriene inhibitor; an MCP-1 antagonist; an MMP inhibitor; an NF kappa B inhibitor, which may be Bay 11-7082; an NO antagonist; a p38 MAP kinase inhibitor, which may be SB 202190; a phosphodiesterase inhibitor; a TGF-.beta. inhibitor; a thromboxane A2 antagonist; a TNF-alpha-
antagonist; a TACE inhibitor; a tyrosine kinase inhibitor; vitronectin inhibitor; a fibroblast growth factor inhibitor; a protein kinase inhibitor; a PDGF receptor kinase inhibitor; an endothelial growth factor receptor kinase inhibitor; a retinoic acid receptor antagonist; a platelet derived growth factor receptor kinase inhibitor; a fibrinogen antagonist; an antimycotic agent; sulconizole; a bisphosphonate; a phospholipase Al inhibitor; a histamine H1/H2/H3 receptor antagonist; a macrolide antibiotic; a GPIIb/llla receptor antagonist; an endothelin receptor antagonist; a peroxisome proliferator-activated receptor agonist; an estrogen receptor agent; a somastostatin analogue; a neurokinin 1 antagonist; a neurokinin 3 antagonist; a VLA-4 antagonist; an osteoclast inhibitor; a DNA topoisomerase ATP hydrolyzing inhibitor; an angiotensin I converting enzyme inhibitor; an angiotensin II antagonist; an enkephalinase inhibitor; a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer; a protein kinase C inhibitor; a ROCK (rho-associated kinase) inhibitor; a CXCR3 inhibitor; Itk inhibitor; a cytosolic phospholipase A. sub.2-. alpha, inhibitor; a PPAR agonist; an immunosuppressant; an Erb inhibitor; an apoptosis agonist; a lipocortin agonist; a VCAM-1 antagonist; a collagen antagonist; an .alpha. -2 integrin antagonist; a TNF-.alpha. inhibitor; a nitric oxide inhibitor; and a cathepsin inhibitor, anti-fibrin and fibrinolytic agents, including plasmin, streptokinase, single chain urokinase, urokinase, t-PA (tissue type plasminogen activator), aminocaproic acid; anti-platelet agents including, aspirin, prostacyclins (and analogues); glycoprotein llb/llla agents including monoclonal antibodies, peptides (e.g. ReoPro, Cilastagel, eptifibatide, tirofiban, ticlopidine, Vapiprost, dipyridamole, forskolin, angiopeptin, argatroban), thromboxane inhibitors; anti-thrombin and anti-coagulant agents, including dextan, heparin, LMW heparin (Enoxaparin, Dalteparin), hirudin, recombinant hirudin, anti-thrombin, synthetic antithrombins, thrombin inhibitors, Warfarin (and other coumarins); anti-mitotic, antiproliferative and cytostatic agents, including vincristine, vinblastine, paclitaxel, methotrexate, cisplatin, fluorouracil, rapamycin, azathioprine, cyclophosphamide, mycophenolic acid, corticosteroids, colchicine, nitroprusside; antiangiogenic and angiostatic agents, including paclitaxel, angiostatin and endostatin; genetic materials, DNA, DNA sequences, polynucleotides, and oligonucleotides; ACE inhibitors (e.g. Cilazapril, Lisinopril, Captopril); growth factor (e.g. VEGF, FGF) antagonists; antioxidants and vitamins (e.g. Probucol, Tocopherol); calcium channel
blockers (e.g. nifedipine); fish oil (omega 3-fatty acid); phosphodiesterase inhibitors (e.g. dipyridamole); nitric acid donor (e.g. Molsidomine); somatostatin analogues (e.g. angiopeptin); immunosuppresives and anti-inflammatory agents (e.g. prednisolone, glucocorticoid and dexamethasone); antimicrobials (e.g. rifamycin) and radionuclides, including alpha, beta and gamma emitting isotopes (e.g. Re-188, Re-186, 1-125, Y-90); COX-2 inhibitors such as Celecoxib and Vioxx; kinase inhibitors, such as epidermal growth factor kinase inhibitor, tyrosine kinase inhibitors, MAP kinase inhibitors protein transferase inhibitors, Resten-NG, smoking cessation agents such as nicotine, bupropion and ibogaine; Insecticides and other pesticides which are suitable for local application; Dermatological agents, such as vitamins A, C, Bl, B2, B6, B 12, B 12. alpha.., and E, vitamin E acetate and vitamin E sorbate; Allergens for desensitisation such as house, dust or mite allergens; Nutritional agents and neutraceuticals, such as vitamins, essential amino acids and fats; Macromolecular pharmacologically active agents such as proteins, enzymes, peptides, polysaccharides (such as cellulose, amylose, dextran, chitin), nucleic acids, cells, tissues, and the like; Bone mending biochemicals such as calcium carbonate, calcium phosphate, tricalcium phosphate, hydroxya petite or bone morphogenic protein (BMP); Angiogenic growth factors such as Vascular Endothelial Growth Factor (VEGF) and epidermal growth factor (EFG), cytokines interleukins, fibroblasts and cytotaxic chemicals; and Keratolytics such as the alpha-hydroxy acids, glycolic acid and salicylic acid; and DNA, RNA or other oligonucleotides. Vaccines that contain Hendra virus (HeV) G glycoprotein and/or Nipah virus G glycoprotein, Lutenising Hormone Releasing Hormone (LHRH) peptide, LHRH-diphtheria toxoid conjugate, porcine circovirus type 2 (PCV2) antigen, a porcine reproductive and respiratory syndrome virus antigen, Mycoplasma hyopneumoniae protein antigen. Proteins or protein fragments, for example ORFI Torque teno virus protein, or other TTV proteins or fragments, antigens against Aeromonas salmonicida, antigens against Vibrio anguillarum, and antigens against V. salmonicida. Growth factors include but are not limited to Vascular Endothelial Growth Factor (VEGF) and epidermal growth factor (EFG), Growth Differentiation Factors (GDFs), Fibroblast Growth Factors ( FGF-1 through FGF-23), Osteoprotegerin, Cartilage Derived Morphogenic Proteins (CDMPs, which can be a foundation for soft or hard tissue), Lim Mineralization Proteins (LMPs)lnterleukins (IL-1 through IL-13), Insulin-like Growth Factor-1,
Connective Tissue Growth Factor (CTGF), platelet derived growth factor (PDGF), nerve growth factors, neutrophins Brain-derived neurotrophic factor (BDNF), Nerve growth factor (NGF), Neurotrophin-3 (NT-3), Neurotrophin-4 (NT-4)], Transforming growth factors (TGF-a, TGF-fS), Tumor necrosis factor (TNF), Growth factor Agonists or antagonists as well as antibodies against these growth factors. Biologically active agents that can be used to treat macular degeneration include but are not limited to bevacizumab and ranibizumab
[00234] In one aspect, compositions of the present disclosure are formulated into lipid nanoparticles, degradable polymeric particles or liposomes. In an aspect, the composition of the present disclosure comprises a derivatized hyaluronic acid of the present disclosure, and one or more lipids. In an aspect, the composition of the present disclosure comprise a derivatized hyaluronic acid of the present disclosure, one or more lipids and cholesterol. In an aspect, the lipid nanoparticles, degradable polymeric particles or liposomes that comprise a derivatized hyaluronic acid of the present disclosure, target cells that express CD-44 receptor. In one aspect, the derivatized hyaluronic acid in the lipid nanoparticles, degradable polymeric particles or liposomes comprises a lipid moiety, or a cholesterol moiety, or a substituted or unsubstituted C5- C20 aliphatic moiety which has at least 4 consecutive -CH2- groups. In one aspect, the lipid nanoparticles, degradable polymeric particles or liposomes that comprise a derivatized hyaluronic acid of the present disclosure, can further comprise a biologically active agent.
[00235] In one aspect, compositions of the present disclosure are formulated into cosmetic product. Cosmetic products can include but are not limited to serums, creams, lotions, emuisions, micelle formulations, lip balms and lipsticks. In an aspect, the composition of the present disclosure comprise a derivatized hyaluronic acid of the present disclosure, and one or compounds that comprise an emulsion. In one aspect, the derivatized hyaluronic acid in the cosmetic product comprises a lipid moiety, or a cholesterol moiety, or a substituted or unsubstituted C5-C20 aliphatic moiety which has at least 4 consecutive -CH2- groups or an aromatic moiety.
[00236] In one aspect, compositions of the present disclosure are formulated for, and are useful for, wound healing. Compositions may be formulated for suitable administration, e.g., nasal or topical administration. Compositions may include one or more suitable biologically
active agents for wound healing. The wounds treated can include but are not limited to diabetic ulcers, burns, pressure wounds, abrasions, incisions, corneal abrasion, incisions following ocular surgery, blisters, damaged tissue following sinus surgery, abdominal surgery, tendon repair or joint repair.
[00237] For example, in one aspect, derivatized HA polymer compositionsof the disclosure can be in the form of dry particles. In another aspect, the derivatized HA polymer compositions of the disclosure can be in the form of a lyophilized derivatized HA polymer compositions. In another aspect, the derivatized HA polymer compositions of the disclosure can be on the form of a non-woven derivatized HA polymer compositions. In one aspect, the non-woven derivatized HA polymer compositions can be produced by an electrospinning process. In another aspect, the derivatized HA polymer of the disclosure can be in the form of a film. Compositions can be packaged directly or indirectly in a foil pouch to minimize moisture absorption during storage.
[00238] Derivatized HA polymer compositions of the disclosure can be applied directly to a wound site. The derivatized HA polymer compositions can absorb exudate from the wound. Once sufficient exudate is absorbed, the dry derivatized HA polymer compositionswill turn into a gel. In another aspect, the derivatized HA polymer compositions of the disclosure further comprise water or saline such that a gel is obtained. In one aspect, the gel can be applied directly to the wound.
[00239] In one aspect, the derivatized HA polymer compositions of the disclosure, once applied to the wound, can be covered by a have a moisture retaining semi-permeable film. The film can further comprise an adhesive that will retain the film at the site of application. The moisture retaining semi-permeable adhesive film can be made from a polyurethane or a silicone material with an adhesive coating on at least the border or edges of the film. In one aspect, the adhesive can be an acrylic based adhesive. The semi-permeable film is permeable to oxygen and carbon dioxide, as well as water vapor but will prevent bacterial transmission.
[00240] In another aspect, the derivatized HA polymers and compositions thereof of the disclosure can be applied to a semi-permeable film such that the product is premade and ready to use in that the derivatized HA polymer compositionsof the disclosure and the semipermeable film are a single unit. Compositions can be packaged directly or indirectly in a foil pouch. In one
aspect, the derivatized HA polymer of the disclosure comprises a hyaluronic acid that has been derivatized with sulfonate groups, where such a derivatized HA polymer may be used, for example, in a composition intended for wound healing.
[00241] In another aspect, the derivatized HA polymers and compositions of the disclosure can be used as bulking agents. These bulking agents can be used to treat stress urinary incontinence, fecal incontinence, Gastroesophageal Reflux Disease (GERD), prostate-rectum spacer for reduction in rectal damage as a result of radiation treatment for prostate cancer. In one aspect, the injected derivatized HA polymer compositions can be in the form of derivatized HA polymer that may or may not comprise crosslinks.
[00242] In one aspect, the derivatized HA polymers and compositions of the disclosure can be used as a dermal filler to fill voids, defects and to treat moderate to severe wrinkles and folds. Derivatized HA polymer compositions can be injected as a solution or suspension. In one aspect, at least one derivatized HA polymer in a derivatized HA polymer composition is crosslinked. In one aspect, the crosslinked derivatized HA polymer of this disclosure used in the dermal filler composition has a hyaluronidase (or corresponding polysaccharide degrading enzyme for other polysaccharides) degradation rate that is the same as or less than that of polyhydric polymer (e.g., hyaluronic acid) that is not derivatized. The derivatized HA polymers and compositions can be used treat areas where dermal depressions, wrinkles or scars are found including, but not limited to nasolabial folds, forehead, furrow lines and vertical lip lines. In another aspect, the derivatized HA polymers and compositions can be used for lip augmentation and breast augmentation.
[00243] In another aspect, the derivatized HA polymers and compositions used as dermal fillers may comprise a drug (e.g., biologically active agent) to reduce pain associated with the procedure. As used herein, a biologically active agent includes compounds or molecules that may be referred to as a drug. Such compounds include benzocaine, bupivacaine, amethocaine, lignocaine, lidocaine, cocaine, cinchocaine, dibucaine, mepivacaine, prilocaine, etidocaine, veratridine (specific c-fiber blocker) and procaine. In another aspect, the derivatized HA polymers and compositions used as dermal fillers may comprise a degradable water-insoluble polymer ( e.g. polyester such as PLGA, PLLA etc), a water insoluble non-degradable polymer (e.g.
polymethylmethacrylate [PMMA]) or inorganic material (e.g. calcium hydroxyapatite). In another aspect, the derivatized HA polymers and compositions used as dermal fillers are in the form of particles of a crosslinked hydrogel. In one aspect, median size (Dv50) of the particles are in the range of 100 pm to 800 pm. In another aspect, the median size (Dv50) of the particles are in the range of 200 pm to 600 pm. In one aspect, the crosslinked hydrogel particles are suspended in a saline solution. In another aspect, the hydrogel particles are suspended in a solution of hyaluronic acid oa hyaluronic acid derivative of this disclosure. In one aspect, the crosslinked hydrogel suspension is in a prefilled syringe in which the contents of the syringe are sterile. In another aspect, the hydrogel particle suspension is injectable through at least a 27G needle.
[00244] In one aspect, the derivatized HA polymers and compositions as disclosed herein are formulated for, and are useful for, viscosupplementation. The derivatized HA polymers may or may not crosslinked, and the compositions may optionally contain a biologically active agent. [00245] Viscosupplementation is the process of injecting a derivatized HA polymer composition into the joint to relieve pain. In the preferred aspect, the polyhydric polymer is hyaluronic acid or a derivative thereof. Derivatized HA polymer compositions can be injected into one or more joint spaces of the body. Suitable joints include, but are not limited to, knee, shoulder, ankle, elbow, hip, trapeziometacarpal joint, finger joint, wrist joints, temporomandibular joint, back and neck. In another aspect, the derivatized HA polymers used can comprise crosslinked derivatized HA polymers. The derivatized HA polymer compositions can comprise one or more excipients or diluents. The derivatized HA polymer compositions of the disclosure that can be used for osteoarthritis treatment can be injected through a needle of between 18 gauge and 21 gauge. Derivatized HA polymer composition of the disclosure can comprise a biologically active agent. In one aspect, the biologically active agent can be, but is not limited to, a corticosteroid, a local anesthetic, an antibody, a peptide or an anti-inflammatory compound or molecule. The volume of the solution that comprises the derivatized HA polymer composition of the disclosure can range from 0.5 ml to 10 mL with the preferred aspect being in the 2 mL to 6 mL for injection into the knee. In one aspect, crosslinked derivatized HA polymer hydrogel particles are suspended in a saline solution. In another aspect, the derivatized HA polymer particles are suspended in a solution of hyaluronic acid or a hyaluronic acid derivative
on this disclosure. In one aspect, the crosslinked derivatized HA polymer suspension is in a prefilled syringe in which the contents of the syringe are sterile.
[00246] In one aspect, the derivatized HA polymers and compositions as disclosed herein are formulated for, and are useful for, adhesion prevention. The derivatized HA polymers may or may not crosslinked, and the compositions may optionally comprise a biologically active agent. Areas of the body where methods of treatment for adhesion prevention is wanted include spinal and abdominal areas, particularly after surgical procedures, as a coating on dura substitute, in nasal procedures or devices, in conjunction with ear, elbow, and tendon medical procedures. Exemplary biologically active agents include, but are not limited to, anti-inflammatory and pain medicines.
[00247] In one aspect, the derivatized HA polymers of this disclosure may be used to reduce the incidence and severity of adhesions and scar tissue that may occur following injury or a surgical procedure. These adhesions can include abdominal adhesions, pelvic adhesions, heart adhesions, joint adhesions, tendon adhesions (e.g. flexor tendon, Achilles tendon, patella tendon), spinal adhesions, lumbar adhesions, nerve adhesions, dural adhesions, sinus adhesions. The derivatized HA polymer compositions can further comprise one or more excipient. The derivatized HA polymer compositions of the disclosure can further comprise a biologically active agent. In one aspect, the biologically active agent can be, but is not limited to, a corticosteroid, a local anesthetic, an antibody, a peptide or an anti-inflammatory. In one aspect, the derivatized HA polymer of this disclosure is derived from hyaluronic acid or a hyaluronic acid derivative. In one aspect, the derivatized HA polymer can be in the form of a crosslinked hydrogel. In another aspect, the derivatized HA polymer of the disclosure can be in a crosslinked form that has been lyophilized to form a porous foam or it could be as a solid or perforated film.
[00248] In one aspect, the derivatized HA polymers and compositions as disclosed herein are formulated for, and are useful for, tissue sealing. The derivatized HA polymers may or may not crosslinked, and the compositions may optionally comprise a biologically active agent.
[00249] In one aspect, the derivatized HA polymer of the disclosure that contains residual vinyl sulfone groups can be reacted with a compound that has 2 or more free thiol functional groups such that a crosslinked derivatized HA polymer is produced. In one aspect, the derivatized
HA polymer of the disclosure that contains free vinyl sulfone groups can be prepared as a solution. In one aspect, the solution can be prepared using saline. In one aspect, the derivatized HA polymer of the disclosure that contains residual vinyl sulfone groups can be prepared as a first solution and the derivatized HA polymer that has 2 or more free thiol functional groups can be prepared as a second solution. The pH of either the first or the second solution can be adjusted such that the pH of the solution is greater than pH 8. This can be accomplished by using a solution that has a pH of greater than 8 to dissolve either the derivatized HA polymer of the disclosure that contains residual vinyl sulfone groups or the compound that has 2 or more free thiol functional groups, adding buffer components to either the derivatized HA polymer of the disclosure that contains residual vinyl sulfone groups or to the compound that has 2 or more free thiol functional groups.
[00250] In one aspect, the first and second solution can be combined and applied to the tissue surface resulting in a mixture. In one aspect, the mixture can be applied through a needle or canula. In another aspect, the mixture can be applied using a spray applicator. Examples of spray applicators include but are not limited to the Fibrijet SA-3674 and SA-3675 (Nordson Medical, 261 Cedar Hill Street, Marlborough, MA 01752, United States). In another aspect, the mixture can be applied using a gas assisted spray applicator. Examples of gas assisted spray applicators include but are not limited to the Fibrijet SA-3651 and SA-3652, (Nordson Medical, 261 Cedar Hill Street, Marlborough, MA 01752, United States).
[00251] In one aspect, the derivatized HA polymer composition can be applied to the tissue in a liquid form and after 3 minutes the derivatized HA polymer composition is in a gel form. The time required to convert from the liquid form to the gel form depends on the specific application. In one aspect the liquid to gel conversion can take less than 2 minutes. In another aspect the liquid to gel conversion can take less than 30 seconds. In another aspect, the liquid to gel conversion can take less than 15 seconds.
[00252] The derivatized HA polymer composition for tissue sealing may further comprise an excipient. The derivatized HA polymer composition can further comprise a biologically active agent.
[00253] In one aspect, the derivatized HA polymer compositions of this disclosure are
combined with a biologically active agent to treat bacterial vaginosis. The derivatized HA polymer compositions of this disclosure can be formulated such that the derivatized HA polymer compositions is tissue adhesive and adheres to the vaginal tissue for a period of greater than 2 hours. The derivatized HA polymer compositions can further comprise one or more excipient. The derivatized HA polymer compositions of the disclosure can further comprise a biologically active agent. In an aspect, the biologically active agent can be an antibacterial agent. In an aspect, the antibacterial can be, but is not limited to, clindamycin, tinidazole, metronidazole, secnidazole and ornidazole. Formulations comprising the derivatized HA polymers of this disclosure, can be applied intravaginally.
[00254] In one aspect, the derivatized HA polymers and compositions of the disclosure are selected to provide ocular application. For example, eye drops for dry eyes / lubricating eye drops for contact lenses.
[00255] In one aspect, derivatized HA polymer compositions of this disclosure can be used as eye drops. The eye drops can be used to treat dry eyes, a disease of the eye, infected ocular tissue, inflamed ocular tissue, as a lubricant for the surface of the eye, as a lubricant for use with contact lenses and to assist in healing of the eye following trauma or a surgical procedure to the eye or surrounding tissue. Surgical procedures to the eye can include but are not limited to cataract surgery, intra-ocular lens replacement, fixing detatched retinas, tumor removal, glaucoma surgery, refractive surgery, corneal surgery, vitreo-retinal surgery, eye muscle surgery, oculoplastic surgery, surgery involving the lacrimal punctum, canaliculus, and sac. An ocular formulation comprising derivatized HA polymers of this disclosure can further comprise an excipient. The derivatized HA polymers of this disclosure can be formulated into a solution or suspension which is then administered to the eye. An ocular formulation comprising derivatized HA polymers of this disclosure can further comprise a biologically active agent. The biologically active agent can be present as part of the solution or it can be in the form of a suspension or emulsion. The derivatized HA polymers of this disclosure can be formulated into a solution or suspension which is then administered to the eye.
[00256] In another aspect, derivatized HA polymer compositions of this disclosure can be prepared to be used to lubricate and wet contact lenses. The contact lens can be immersed prior
to use or could be stored in a solution that contains derivatized HA polymers of this disclosure. The solution can comprise one or more excipients. The solution can further comprise boric acid or sodium borate. The solution can be formulated to be preservative free.
[00257] In one aspect, derivatized HA polymers of this disclosure can be formed into a formulation that is inserted into the lacrimal punctum, the lacrimal canaliculus or the lacrimal sac. Derivatized HA polymers of the disclosure can be in the form of a solution, swollen hydrogel or a dehydrated hydrogel. In one aspect, the derivatized HA polymer compositionscan further comprise an excipient. In another aspect, the derivatized HA polymer is crosslinked. In another aspect, derivatized HA polymer compositions further comprise a biologically active agent. In one aspect, the biologically active agent can be but is not limited to a corticosteroid (for example, dexamethasone, mometasone fuorate, triamcinolone acetonide, triamcinolone hexacetonide, triamcinolone acetate, betamethasone, fluoromethalone, hydrocortisone, medrysone or prednisolone), prostaglandins (for example, latanoprost, travoprost or bimatoprost) , beta blockers (for example timolol or betaxolol) , alpha-adrenergic agonists (for example apraclonidine or brimonidine), carbonic anhydrase inhibitors (for example dorzolamide or brinzolamide), mitotic or chlorinergic agents (for example pilocarpine)
[00258] In another aspect, a derivatized HA polymer and/or compositions is crosslinked in the presence of a biologically active agent and then dried. In another aspect, a derivatized HA polymer is crosslinked, dried, reswollen in the presence of a biologically active agent and then dried. In another aspect, the biological agent is incorporated into the uncrosslinked derivatized HA polymer in solution. In another aspect, the derivatized HA polymer is dried, reswollen in the presence of a biologically active agent and then dried. Any of the dried formulations can be of suitable dimensions such that it can be placed in the lacrimal punctum. Upon contact with lachrymal fluid and tears, the final dried formulation hydrates, and swells in such a manner as to be physically retained in the punctum. In another aspect, the dried formulation can be inserted into the canaliculus. Upon contact with lachrymal fluid and tears, the dried formulation hydrates, and swell in such a manner as to be physically retained in the canaliculus. The formulation could then release the contained biologically active agent over a period of 24 hours to 3 weeks. In one aspect, the biologically active agent is released in a sustained manner for a period of 7 days. In
one aspect, the biologically active agent is released in a sustained manner for a period of 4 weeks. In an aspect, the dried formulation can be inserted intravitreally so that the biologically active agent is delivered into the vitreous of the eye. In an aspect, the dried formulation is inserted into the anterior chamber of the eye.
[00259] In an aspect, the derivatized HA polymers and compositions of the disclosure are selected to provide a punctal plug. The punctal plug may comprise a biologically active agent, e.g., steroid or a pain relief drug.
[00260] In one aspect, the derivatized HA polymer compositions of this disclosure can be used to treat mucositis. Examples of mucositis include oral and vaginal mucositis. During cancer treatments, the rapidly divided epithelial cells lining the gastro-intestinal tract (which goes from the mouth to the anus) break down leaving the mucosal tissue open to ulceration and infection. This leads to mucocitis. Oral mucositis can often occur following chemotherapy and radiation treatments. It can lead pain and increased risk of infection. This can lead to nutritional problems due to these symptoms reducing the ability and desire to eat. Providing a coating that covers these lesions, can reduce the pain and potential for infection. The derivatized HA polymers of this disclosure can be formulated such that the derivatized HA polymer compositions is tissue adhesive and adheres to the mucosal tissue of the mouth tissue or the vagina for a period of greater than 2 hours. The derivatized HA polymer compositions can further comprise one or more excipients. The derivatized HA polymer compositions of the disclosure can further comprise a biologically active agent. In one aspect, the biologically active agent can be, but is not limited to, a local anesthetic, an anti-infective, an anti-inflammatory or a combination thereof. Local anesthetics can include but are not limited to benzocaine, bupivacaine, amethocaine, lignocaine, lidocaine, cocaine, cinchocaine, dibucaine, mepivacaine, prilocaine, etidocaine, veratridine (specific c-fiber blocker) and procaine. For oral mucositis, the derivatized HA polymer compositions of the disclosure can be formulated such that it can be applied as an oral rinse or applied as a gel. For vaginal mucositis, the derivatized HA polymer compositions of the disclosure can be formulated such that it can be applied intravaginally to the vaginal tissue surface.
[00261] In one aspect, derivatized HA polymer compositions of this disclosure can be used to treat a surgical site during and following canalplasty, tympanoplasty, myringoplasty,
stapedectomy mastoid procedures, or any other procedure related to the ear. Derivatized HA polymer compositions can be used to modulate wound healing as well as to control bleeding. The derivatized HA polymer compositions of this disclosure can be in the form of a lyophilized sponge, an electrospun matrix, a film, a gel or a combination of these forms. The derivatized HA polymer compositionsof the disclosure can comprise an excipient. In another aspect, the derivatized HA polymer compositionsof the disclosure can comprise a biologically active agent.
[00262] In another aspect, the derivatized HA polymer compositions and compositions thereof disclosed herein, can be used to treat cancer. Such compositions will comprise a chemotherapeutic agent, a protein, a peptide, an antibody, a nucleotide sequence or a combination thereof. In one aspect, the the derivatized HA polymer compositions and compositions thereof disclosed herein can be administered systemically or locally. In another aspect, derivatized HA polymer compositions and compositions thereof disclosed herein can be delivered by direct injection into a tumor or tissue from which the tumor has been surgically removed.
[00263] In another aspect, the derivatized HA polymer compositions and compositions thereof disclosed herein, can be used to elicit an immune response.
[00264] In another aspect, the derivatized HA polymer compositions and compositions thereof disclosed herein, can be used to transfer RNA into a cell.
[00265] In another aspect, the derivatized HA polymer compositions of the disclosure can be used to treat otitis media, acute otitis externa, balance disorders (for example Meniere' disease, tinnitus and sensorineural hearing loss. Derivatized HA polymer compositionsof this disclosure can be in the form of a solution, a suspension, a lyophilized sponge, an electrospun matrix, a film, a gel, a solid rod-like form, or a combination of these forms. Derivatized HA polymer compositionsof the disclosure can comprise an excipient. In another aspect, a derivatized HA polymer compositions of the disclosure can comprise a biologically active agent. To treat infections of the ear, the derivatized HA polymer can comprise an antibiotic, an antibacterial, an antiviral, an antifungal or a combination thereof. In one aspect, derivatized HA polymer compositionscomprising at least one biologically active agent include, but are not limited to, amoxicillin, clavulanate, cefuroxime axetil, ceftriaxone, Levofloxacin, a cephalosporin,
a trimethoprim-sulfamethoxazole, a macrolide, ofloxacin, gentamicin sulfate, tobramycin sulfate and ciproflaxin, In another aspect, derivatized HA polymer compositionscan comprise a corticosteroid. Corticosteroids can include but are not limited to betamethasone, betamethasone valerate, cortisone, dexamethasone, dexamethasone 21-phosphate, fludrocortisone, flumethasone, fluocinonide, fluocinonide desonide, fluocinolone, fluocinolone acetonide, fluocortolone, halcinonide, halopredone, hydrocortisone, hydrocortisone 17- valerate, hydrocortisone 17-butyrate, hydrocortisone 21-acetate, methylprednisolone, prednisolone, prednisolone 21-phosphate, prednisone, triamcinolone, triamcinolone acetonide, mometasone fuorate. In another aspect, a combination of an antibiotic and a corticosteroid can be added to the derivatized HA polymer compositionsof the disclosure. In one aspect, the derivatized HA polymer compositions of the disclosure can be applied to the area to be treated by being applied with a dropper, a syringe, through a needle or catheter or by physically placing a derivatized HA polymer compositions.
[00266] In one aspect, the derivatized HA polymer compositions of the disclosure can comprise a biologically active agent. The derivatized HA polymers of this disclosure can be used as a matrix from which the biologically active agent can be delivered. In one aspect the release profile of the biologically active agent into a phosphate buffered saline solution if slower than that of the normal dissolution profile of the biologically active agent. In one aspect, the derivatized HA polymer compositions of the disclosure can be in the form of a crosslinked gel.
[00267] In one aspect, the treatment using the drug delivery formulation can be a single injection or could be two or more injections that are separated by a period of time. The composition can be injected systemically, intra-ocularly, intratumorally, intravenously subcutaneously, intra-dermally or intra-muscularly. The derivatized HA polymer compositions can be injected through a needle, trocar, catheter, tube, or canula.
[00268] In another aspect, the contents of the prefilled syringe or vial are sterile. In another aspect, the contents of the prefilled syringe or vial are stable at 2-8°C or 20-25°C for at least 6 months, preferably 12 months and most preferably 24 months. In another aspect, the drug delivery formulation can be applied topically or by instillation.
[00269] In one aspect, the derivatized HA polymers of this disclosure in a crosslinked form
can be used as device to plug a defect following the removal of a piece of tissue or the needle track following a biopsy procedure. In another aspect, a crosslinked form of the derivatized HA polymer compositionscan be prepared and then dried. The dried derivatized HA polymer compositionscan be delivered into the needle track or the site that a piece of tissue was removed. The dried derivatized HA polymer compositionscan absorb moisture from the surrounding tissue to rehydrate and swell such that the swollen size is larger than the initial size of the derivatized HA polymer compositions. The swollen derivatized HA polymer compositionis then retained at the site into which it is placed. In another aspect, the crosslinked dried derivatized HA polymer composition can be used to seal a hole in the tissue where the crosslinked derivatized HA polymer compositionis placed in the hole and it swells to seal off the hole. An example of this could be to seal lung tissue following puncturing of the lung following a biopsy or surgical procedure. In another aspect, the crosslinked dried derivatized HA polymer compositioncan comprise an element, such as a metal piece that is visible under x-ray or fluoroscopy examination. The metal piece can take on various forms such as but not limited to a flat piece, a rod, a coil, a loop, a hoop, hook, a number and a letter of the alphabet. In one aspect, the crosslinked dried derivatized HA polymer composition can comprise a biologically active agent. In another aspect, the biologically active agent can have hemostatic properties. In one aspect, the crosslinked dried derivatized HA polymer composition can comprise collagen, chitosan or thrombin.
[00270] In one aspect, the derivatized HA polymers and compositions of the present disclosure are formulated for, and are useful for, a plug for female sterilization. Female sterilization can be accomplished by inserting a plug into the fallopian tube. This plug can provide a physical barrier to the passage of the ovum into the uterus as well as to the sperm reaching the ovum. The predominant procedure to effect female sterilization in a laparoscopic procedure in which the fallopian tubes are severed and then ligated. In other versions of the procedure, the fallopian tubes can be closed using clips or rings to clamp then closed. Cauterization has also been used to seal the fallopian tubes. These procedures are generally classed as major surgery, usually requires general anesthesia and the patient requires a recuperation period. Transvaginal sterilization procedures were an alternative to the laproscopic procedures as they were less invasive. Initial transvaginal procedures used chemical agents, such as sodium morrhuate, or
quinacrine, methyl cyanoacrylate and silver nitrate,but the success rates and side effects have limited their use. Hysteroscopic tubal sterilization has emerged as a minimally invasive alternative to conventional tubal ligation. Hysteroscopic tubal sterilization can be performed in approximately 10 minutes in an office setting without the use of general or even local anesthesia. [00271] Two hysteroscopic tubal sterilization products were commercialized, but both have been removed from the US market by the end of 2018. The Essure system consisted of a device insert that is loaded into a single-use delivery system. The device consisted of an inner coil of stainless steel and polyethylene terephthalate (PET) fibers and an outer coil of nickel-titanium (nitinol). The metal components hold the device in place while the PET fibers allow tissue ingrowth into the device which will lead to occlusion of the fallopian tube. This ingrowth process does take time and so the patient must use other forms of contraception for 3 months. At this stage a hysterosa I pingogram is performed to confirm placement and tubal occlusion. The device is permanent and remains in the patient for the rest of the patient's life. This product received a black box warning over potential safety concerns, and was subsequently removed from the market in the US. The device had previously been removed from the market overseas.
[00272] Another sterilization method was developed by Hologic. The Adiana® sterilization method used radiofrequency energy to cause controlled thermal damage of the lining of the fallopian tube lumen. Following the thermal injury to the fallopian tube, a porous non-degradable silicone plug is placed in the thermally injured fallopian tube. Over a few weeks, tissue ingrowth into the porous plug results in occlusion of the fallopian tube. A hysterosa I pingogram is performed at 3 months to confirm tubal occlusion. The silicone plug is a permanent implant. The Adiana® system has been withdrawn from the market.
[00273] The Essure system and the Adiana ® system both leave a permanent device in the patient. This can potentially lead to longer term safety issues for the patient. Having a system that comprises a degradable plug component would be beneficial in that little to no derivatized HA polymer and/or composition will remain permanently within the patient. The method and devices described herein provide a means to occlude the fallopian tube that will result in a reduction in the ability of a female to become pregnant. The method involves mechanically injuring the lining of the fallopian tube followed by the insertion of a degradable plug.
[00274] A method for mechanically injuring the fallopian tube is to insert a device that comprises a rough surface into the fallopian tube and then physically move the device in a rotational motion, a linear motion that follows the fallopian tube or a combination thereof. This motion can be repeated more than once. This physical movement is continued until the endothelial layer of the fallopian tube where the physical motion occurs is either partially removed or completely removed.
[00275] The device used to denude the endothelial layer of the fallopian tube can comprise a series of fiber radiating from a central core. In one aspect this device is similar in structure to a bottle brush, e.g., a rod with bristles (fibers) extending perpendicularly from the rod.
[00276] In one aspect, the fibers can be spaced evenly apart in a continuous manner. In one aspect, the fibers can be in rows with spaces between the rows. In one aspect, the fibers could be oriented in a spiral shape along the axis of the device. In one aspect, the fibers can be oriented in one or more linear rows that are aligned about parallel with the axis from which they emanate. In another aspect, the fibers are in one or more rows such that the rows are about perpendicular to the axis from which they emanate.
[00277] In one aspect, the fibers can be made from a non degradable polymer. The polymers that can be used to prepare the fibers include but are not limited to polyethylene, polypropylene, polyethylene terephthalate (PET), nylon, polyurethane, polyetheretherketone (PEEK), polyaryletherketone (PAEK), fluorocarbon polymers such as polytetrafluoroethylene, silk and combinations thereof.
[00278] In one aspect, the fibers can be made from a metal. The metals that can be used to prepare the fibers include but are not limited to stainless steel, titanium, nitinol, magnesium, alloys of Co-Cr-Mo, Cr-Ni-Cr-Mo, CP-Ti, Ti-AI-V, Ti-AI-Nb, Ti-13Nb-13Zr, Ti-Mo-Zr-Fe or combinations thereof.
[00279] In one aspect, the central core (rod) of the denuding device can comprise a core prepared from the twisting of 2 or more metal strands together such that the fibers are trapped between the twisted metal strands. The metals that can be used to prepare the central core include but are not limited to stainless steel, titanium, nitinol, magnesium, alloys of Co-Cr-Mo, Cr-Ni-Cr-Mo, CP-Ti, Ti-AI-V, Ti-AI-Nb, Ti-13Nb-13Zr, Ti-Mo-Zr-Fe or combinations thereof.
[00280] In one aspect, the terminal end of the central core (rod) that is first introduced into the fallopian tube can comprise an atraumatic tip that does not damage the tissue as the device is being guided into the desired location in the fallopian tube. This atraumatic tip can be a rounded end cap, a domed shaped end, a cone shaped end with a rounded tip. The surface of the atraumatic tip can have a smooth surface. The atraumatic tip can be made of a non- degradable polymer or a metal. The non-degradable polymers that can be used to manufacture the atraumatic tip include but are not limited to polyethylene, polypropylene, polyethylene terephthalate (PET), nylon, polyurethane, polyetheretherketone (PEEK), polyaryletherketone (PAEK), fluorocarbon polymers such as polytetrafluoroethylene, silk and combinations thereof. The metals that can be used to prepare the atraumatic tip include but are not limited to stainless steel, titanium, nitinol, magnesium, alloys of Co-Cr-Mo, Cr-Ni-Cr-Mo, CP-Ti, Ti-AI-V, Ti-AI-Nb, Ti- 13Nb-13Zr, Ti-Mo-Zr-Fe or combinations thereof.
[00281] The atraumatic tip can be attached to the central core by a crimping process, a molding process, a process that uses an adhesive to bond the tip to the central core, or a thermal process.
[00282] The plug can comprise a hydrogel. In one aspect, the hydrogel is prepared using one or more crosslinked derivatized HA polymer and/or compositions of this disclosure. A hydrogel comprising a polyhydric polymer composition in the form a rod that is larger than the size of the fallopian tube is prepared. The hydrogel rod is then dried. The hydrogel can be dried at normal atmospheric pressures or under reduced atmospheric pressure. In one aspect, the hydrogel can be lyophilized. Once delivered to the desired site, the hydrogel plug would absorb moisture from the fallopian tube and swell. The swelling of the hydrogel plug will enable the hydrogel plug to be retained at the site where it was placed.
[00283] In one aspect, the hydrogel further comprises a porogen to facilitate the formation of pores within the hydrogel. The porogen can comprise particulates. The particulates can comprise a degradable polymer. Degradable polymers that can be used as porogens include but are not limited to degradable polyesters, polyanhydrides, polyurethanes, polyether-esters, polycarbonates, polyether-carbonates, polyether-ester carbonates, polkyhydroxyalkanoates, polyamides and polymers that are synthesized from one or more monomers from the group of I-
lactide, dl-lactide, glycolide, s-caprolactone, trimethylene carbonate, morpholine-dione, p- dioxanone and l,5-dioxapan-2-one.
[00284] In one aspect, the porogen can be leeched out of the hydrogel during the device manufacturing process. This can be accomplished by incubating the porogen containing hydrogen in a solvent in which the porogen will dissolve. The solvent is preferably a water miscible solvent. In another aspect, the porogen can remain in the device throughout the manufacturing process and will degrade and leech out once the hydrogel plug is inserted into the patient.
[00285] In one aspect the plug comprises a degradable polymer. Degradable polymers that can be used in the plug include but are not limited to degradable polyesters, polyanhydrides, polyurethanes, polyether-esters, polycarbonates, polyether-carbonates, polyether-ester carbonates, polkyhydroxyalkanoates, polyamides and polymers that are synthesized from one or more monomers from the group of l-lactide, dl-lactide, glycolide, s-caprolactone, trimethylene carbonate, morpholine-dione, p-dioxanone and l,5-dioxapan-2-one.
[00286] The plug can comprise a monofilament structure, a multifilament structure, or a braided structure. In one aspect, the plug can be prepared by taking particles or chopped fibers of the degradable polymer and compression mold them into a shape. Heat can be used to thermally fuse the particulates together such that a porous structure is obtained. In one aspect, the shape can be in the form of a rod. The porous rod can then be cut to a predetermined length. [00287] In one aspect, the plug can be made from an electrospun degradable polymer. In one aspect, the plug is made from a thin film of electrospun derivatized HA polymer and/or compositions. The plug can be cut directly from a sheet of the electrospun composition. In one aspect, the plug can be prepared by rolling an electrospun film into a roll. The electrospun plug or the rolled rod shaped structure can be coated with a second degradable polymer such that the rolled configuration is retained. In one aspect, the polymer used to prepare the rolled structure has a degradation time that is longer than the polymer used to coat the rolled structure. This can allow the plug to be more rigid which makes handling easier during manufacturing but upon delivery to the desired site, the faster degrading material will start degrading and facilitate tissue
ingrowth while the first longer lasting polymer provides a scaffold for the ingrowing tissue.
[00288] In another aspect, the electrospun plug can be coated or dipped into a solution of a water-soluble polymer. The plug is then dried at ambient pressure or at reduced pressure. The plug may also be dried by lyophilization. The presence of the water soluble polymer can make the electrospun composition more rigid and thus easier to handle during manufacturing and delivery to the intended site. Once positioned at the intended site, the polymer will start to dissolve and leech out of the electrospun composition. The tissue from the mechanically damaged fallopian tube can then grow into the electrospun composition. The electrospun composition will degrade over time leaving an occluded fallopian tube. In one aspect, the water soluble polymer can be selected from the group of polyethylene oxide, polyethylene glycol, block copolymers of polyethylene glycol and polypropylene glycol (e.g. Pluronics F126 and Pluronics F68, Sigma-Aldrich Corp., St. Louis, MO, USA), dextran, hyaluronic acid, or a hyaluronic acid derivative of this disclosure.
[00289] The degradable polymer used to form the plug can further comprise a porogen. The porogen can comprises an inorganic salt, an organic small molecule or a polymer. The porogen is selected such that it is soluble in a solvent in which the biodegradable polymer used to prepare the plug has limited solubility.
[00290] Inorganic salts that can be used as porogens include but not limited to sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts, copper salts, barium salts, iron salts. Examples of these salts include but are not limited to sodium chloride, sodium bromide, sodium iodide, sodium sulfate, sodium phosphate, sodium hydrogen phosphate, or combinations thereof.
[00291] A porous plug can be prepared by 3D-printing the plug. A degradable polymer can be used to 3D print the plug. In one aspect, the degradable polymer that can be used in the plug include but are not limited to degradable polyesters, polyanhydrides, polyurethanes, polyetheresters, polycarbonates, polyether-carbonates, polyether-ester carbonates, polkyhydroxyalkanoates, polyamides and polymers that are synthesized from one or more monomers from the group of l-lactide, dl-lactide, glycolide, 8-caprolactone, trimethylene
carbonate, morpholine-dione, p-dioxanone and l,5-dioxapan-2-one.
[00292] The plug can comprise position retaining features. These features can include non- symmetrical shapes, barbs, ridges, pores, slits, slots, or a combination thereof. The barbs can be unidirectional in that they all point in the same direction or the barbs could point in two or more different directions. The barbs could be uniformly spaced on the plug or they could be present in only specific portions of the plug.
[00293] In one aspect, plug can be dipped into a solution of the derivatized HA polymers of the disclosure. The solution can then be activated to allow the solution to crosslink such that the pores of the plug comprise the crosslinked derivatized HA polymer. The crosslinking process can be activated by adjusting pH of the solution, addition of a crosslinking agent, elevation of temperature, addition of an initiator or a combination of one or more of these.
[00294] In one aspect, the derivatized HA polymer compositions of the disclosure can be used as a scaffold to allow the ingrowth of tissue or bone. In one aspect, derivatized HA polymers of this disclosure can be prepared as a crosslinked matrix that is then lyophilized. The lyophilized derivatized HA polymer compositioncan then be rehydrated in the presence of cells such that the hydrated matrix acts as a scaffold that allows the growth of the cells on and into the scaffold. In another aspect, the derivatized HA polymers of this disclosure that have residual vinyl sulfone groups, can be electrospun to form a porous matrix. The electospun fibers can then be crosslinked using heat, ultraviolet, e-beam or gamma radiation. In another aspect, the derivatized HA polymer of the disclosure that contains residual vinyl sulfone groups can further comprise a photocrosslinker. A solution of this composition can be electrospun and then the electrospun matrix can be subjected to ultraviolet radiation such that the photocrosslinker results in crosslinking of the derivatized HA polymer. The resultant matrix can be rehydrated in the presence of cells such that it acts as a scaffold for tissue growth. In another aspect, carboxylic acid containing derivatized HA polymers of this disclosure can be electospun into a matrix by mixing a solution of the derivatized HA polymer of this disclosure with a solution of a multivalent cation just prior to electrospinning. In one aspect, a solution of a carboxylic acid containing composition of this disclosure could be placed in one syringe and a solution of a multivalent cation or a cationic polymer can be placed in another syringe. The syringes can be connected via
a y-connector and a needle can be connected to final arm of the y-connector. They two solutions can then be pumped through the needle and this mixture can be electrospun onto a surface such that the derivatized HA polymer of the disclosure is ionically crosslinked. Multivalent cations can include calcium magnesium, ferric ions, ferrous ions, aluminum and chromium.
[00295] Cationic polymers that can be used include but are not limited to chitosan and derivatives thereof, polyvinyl pyrollidone, peptides containing more than one lysine group and polyethyleneimine.
[00296] In another aspect, a solution of a derivatized HA polymer compositionsof this disclosure can be used to coat a degradable or non-degradable scaffold matrix. In one aspect, a derivatized HA polymer of this disclosure that has been modified with alkyl or aryl groups can be used to coat a scaffold for tissue growth. The alkyl or aryl groups will interact with the scaffold through hydrophobic bond while the hydrophilic portion of the derivatized HA polymer will allow for cell growth on the coated scaffold surface. In another aspect, the derivatized HA polymers of this disclosure that have residual vinyl sulfone groups, can be coated onto the scaffold. The coated scaffold can be subjected to heat which will result in the derivatized HA polymer transforming into a crosslinked derivatized HA polymer.
[00297] In another aspect, the derivatized HA polymers and/or compositions of the disclosure can comprise a sulfonate group. In another aspect, the derivatized HA polymers and/or compositions of the disclosure can comprise both hydrophobic groups and sulfonate groups. The hydrophobic groups can be alkyl or aromatic based.
[00298] In another aspect, tissue scaffold support structure can be 3D printed or electrospun using a degradable polymer. The degradable polymer that can be used can include but not limited to degradable polyesters, polyanhydrides, polyurethanes, polyether-esters, polycarbonates, polyether-carbonates, polyether-ester carbonates, polkyhydroxyalkanoates, polyamides and polymers that are synthesized from one or more monomers from the group of I- lactide, dl-lactide, glycolide, s-caprolactone, trimethylene carbonate, morpholine-dione, p- dioxanone and l,5-dioxapan-2-one.
[00299] In another aspect for the electrospun scaffold support structure, a single or
multiple polymer solutions can be prepared. The polymers used can be biodegradable polymers then include but are not limited to polyester, polyanhydride, polyorthoester, polycarbonate, poly-ester-co-carbonate), polyhydroxybutyrates or combinations thereof. Biodegradable polymers can include polylactice-co-glycolide copolymers, polydioxanone, polylactidetrimethylene carbonate copolymers as well as copolymers that comprise repeat units derived from at least one of the following monomers: l-lactide, dl-lactide, glycolide, trimethylene carbonate, epsilon-caprolactone, p-dioxanone and a morpholinedione
[00300] The solvents used can be an organic solvent, water or a combination thereof. For example, HFIP, DMSO, NMP, Chloroform, acetic acid, ethanol, dimethylformamide (DMF) solvents or mixtures of solvents can be used. Solutions with a concentration of 0.5 to 25% (w/v) can be prepared. The solution that is to be electrospun can be placed in a syringe with a needle. The syringe is then placed in a syringe pump. The needle can have a blunt end and an inner diameter in the range of 0.25 to 2.5 mm. The needle and collection plate are attached to a high voltage supply. In some applications, more than one needle can be used to prepare a single sheet. The needles can be arranged such that the same polymer solution flows through all the needles, different solutions flow through different needles or a combination thereof. The needles can be arranged such that adjacent needles allow different polymer solutions to flow through them. This alternation pattern can be repeated. A voltage is then applied to the system. The applied voltage can be in the lOkV to 45 kV. The syringe pump can extrude the solution. The flow rate of the syringe pump can be in the range of 0.0001 uL/min to 423 mL/min. The collector plate can be static, rotating or moving in a specific linear direction to give the fibers some directional orientation. The shape of the collector plate can be varied with the collector plate having but not limited to the following shapes: a flat surface, a textured surface, a curved surface, a square rod, a rectangular rod, a round mandrel, an oval mandrel, a semi-circular mandrel or a combination of these shapes. The distance of the needle tip to the collector plate can be altered. The distance of the needle tip to the collector plate can be in the 2-50 cm range. The collection plate can also be submerged in or sprayed with a solvent that assists in the precipitation of the newly spun fibers. For example, an ethanol bath may be used during the electrospinning of hyaluronic acid based derivatized HA polymers of this disclosure. The derivatized HA polymer of the disclosure
can be incorporated through a solution coating or submersion of an electrospun matrix.
[00301] In one aspect the polymer composition used to 3D print or electrospin the scaffold can further comprise an inorganic filler or a combination of inorganic fillers. In one aspect the inorganic filler can be selected from the group calcium carbonate, calcium phosphate, tricalcium phosphate, hydroxyapatite, bioglass, or a combination thereof.
[00302] In one aspect, 3D-printed or electrospun scaffold can be coated with a solution of the derivatized HA polymers of the disclosure. This derivatized HA polymer can be coated onto the scaffold through a dip coating or spray coating process. In another aspect, the derivatized HA polymer can be dispersed into the scaffold through compressive application. In another aspect, the derivatized HA polymer can be dispersed into the scaffold through submersion in solution which may or may not include sonication to aid in dispersion. In another aspect, the coated scaffold can be dried. The drying process can include drying at elevated temperature, drying at reduced pressure or lyophilization. In another aspect, the solution of the derivatized HA polymer compositions of the disclosure can further comprise a biologically active agent.
[00303] In another aspect, scaffold can be dipped into a solution of the derivatized HA polymers of the disclosure. The solution can then be activated to allow the solution to crosslink such that the pores of the scaffold comprise the crosslinked derivatized HA polymer. The crosslinking process can be activated by adjusting pH of the solution, addition of a crosslinked, elevation of temperature, addition of an initiator or a combination of one or more of these.
[00304] In another aspect, scaffold can be dipped into a solution of the derivatized HA polymers of the disclosure and allowed to dry or be lyophilized. The derivatized HA polymers within the substrate can then be dipped into a crosslinking solution to allow the solution to crosslink such that the pores of the scaffold comprise the crosslinked derivatized HA polymer. The crosslinking process can be activated by adjusting pH of the solution, addition of a crosslinked, elevation of temperature, addition of an initiator or a combination of one or more of these.
[00305] In another aspect, scaffold can be dipped into a solution of the derivatized HA polymers of the disclosure and a crosslinking agent. The rate of the crosslinking reaction can be controlled such that the scaffold can be coated with the derivatized HA polymer and/or
composition prior to complete crosslinking of the derivatized HA polymer. In one aspect a biologically active agent can be incorporated into the derivatized HA polymer and/or compositions before or immediately following the initiation of the crosslinking reaction. The scaffold can then be coated with this composition and once applied to the scaffold, the crosslinking reaction is completed such that the device comprises the crosslinked derivatized HA polymer with the biologically active agent essentially encapsulated by the crosslinked derivatized HA polymer composition.
[00306] In another aspect, the derivatized HA polymers and/or compositions of this disclosure are used to prepare a scaffold or to coat the scaffold can comprise a biologically active agent. In one aspect, the biologically active agent can enhance cell growth. In one aspect, the biologically active agent can be one or more growth factors or peptides that enhance cell growth and cell adhesion. In another aspect, the derivatized HA polymers and/or compositions of this disclosure used to prepare a scaffold or to coat the scaffold can further comprise an excipient. In one aspect, the derivatized HA polymer compositions of the disclosure can comprise one or more extracellular matrix components. The extracellular matrix component can include but are not limited to heparan sulfate, chondroitin sulfate, keratin sulfate, hyaluronic acid, collagen, elastin, fibronectin, and laminin.
[00307] In one aspect, the cells that can be added to the scaffolds that contain the derivatized HA polymer compositions of this disclosure include embryonic stem cells, mesenchymal stem cells, adipose-derived stem cell, endothelial stem cells, dental pulp stem cells, tumor cells, chondrocytes, osteoblasts, dermal fibroblasts, protomyofibroblasts, myofibroblasts, hepatocytes, smooth muscle cells, endothelial cells, epithelial cells, adipose tissue, adipose cells and cardiac cells
[00308] In one aspect, the derivatized HA polymers and compositions of the present disclosure comprise free vinyl sulfone functional groups and can be used to 3D print structures. The derivatized HA polymers can be prepared as solutions with viscosities that allow them to be 3d printed. In one aspect, a solution of the derivatized HA polymer with residual vinyl sulfone groups can be prepared. A second solution containing a derivatized HA polymer with at least two free thiol groups can be prepared. In one aspect, the first and second solution can be mixed
together. Just prior to printing, the pH of the mixture can be adjusted to a pH of greater than 8, preferably greater than 9, such that the mixture can be printed and then cure following printing. In one aspect, the pH can be adjusted by mixing the mixture with a buffer solution that has a pH of greater than 8. The mixing takes place just prior to the print head ensuring that the mixture does not gel up in the print head and thus clot the printer. In another aspect, the solution of the derivatized HA polymer that comprises the residual vinyl sulfone functional groups can has its pH adjusted to a pH of greater than 8 by mixing it with a buffer solution. This solution can then be mixed with solution 2 just prior to the print head such that the mixture is printed and then allowed to complete gelation once printed.
[00309] The viscosity of the mixture can be used to control the retention of the printed structure until gelation is completed. In another aspect, a thermogelling material can be added to either the first, second or buffer solution. Thus, the mixture can be printed and then the temperature of the printed environment can be different from the solution prior to printing such that following the printing process the printed solution undergoes thermal gelation to preserve the initial printed structure while the crosslinking process is moving towards completion.
[00310] Thermogelling materials can include but are not limited to polyethylene-block- polypropylene co polymers such as Pluronics F127 or F68 (Sigma-Aldrich Corp., St. Louis, MO, USA) or polyester-polyethylene glycol block co polymers. The polyester-polyethylene glycol copolymers can include deblock and triblock copolymers. The polyester component are polymers that are synthesized from at least one of the monomers from the group of l-lactide, dl-lactide, glycolide, s-caprolactone, morpholine-dione, p-dioxanone and l,5-dioxapan-2-one. In another aspect, a thermogelling polymer that comprises trimethylene carbonate can be used.
[00311] Following the completion of the gelation process, the printed construct can be rinsed to neutralize the pH of the printed gel. In another aspect the printed structure can be dried such that the residual water content is less than 10%. In another aspect, the printed structure can be lyophilized.
[00312] The printed structure can be used as a tissue scaffold, for wound healing applications, for occlusion of a lumen, a biopsy site or a needle tract.
[00313] For procedures such as neuroendoscopy, intracranial decompression, and treatment of chronic subdural hematoma, holes are often drilled into the skull. These are often referred to as burr holes. In many instances, these burr holes are left untreated following the surgical procedure and the scalp is replaced directly over these holes. This can lead to scalp depressions at the burr hole. These scalp depressions can lack mechanical strength. In order to prevent this, a burr hole plug can be inserted into the burr hole such that it can facilitate and support bone regrowth. Autologous bone can be used to fill the burr holes but this requires harvesting of the bone. Synthetic materials can be used as burr hole plugs. A degradable burr hole plug that degrades while facilitating bone ingrowth will allow the healing of the burr hole without leaving residual material. A polycaprolactone (PCL) burr hole plug has been commercialized. The challenge with PCL is that it is slow degrading and the interface between the polymer and the in-growing tissue is usually not the best due to the hydrophobicity of the polymer.
[00314] The derivatized HA polymers and compositions thereof of the disclosure can be made into a burr hole plug. A solution of a derivatized HA polymer can be placed in the mold and then the derivatized HA polymer compositioncan be lyophilized to produce a porous structure that can be inserted into the burr hole. In another aspect, the derivatized HA polymer compositions of the disclosure can be electrospun and then cut to form a plug that can be inserted into the burr hole. In another aspect, a solution of the derivatized HA polymer of the disclosure can be placed in a mold and the solution can be crosslinked. The crosslinked plug can be used directly. In another aspect, the crosslinked derivatized HA polymer compositions can be lyophilized to yield a porous crosslinked structure that can be used as a burr hole plug.
[00315] In another aspect, a burr hole plug can be 3D printed or electrospun using a degradable polymer. The degradable polymer that can be used can include but not limited to degradable polyesters, polyanhydrides, polyurethanes, polyether-esters, polycarbonates, polyether-carbonates, polyether-ester carbonates, polkyhydroxyalkanoates, polyamides and polymers that are synthesized from one or more monomers from the group of l-lactide, dl- lactide, glycolide, s-caprolactone, trimethylene carbonate, morpholine-dione, p-dioxanone and
l,5-dioxapan-2-one.
[00316] In one aspect the polymer used to 3D print or electrospin the burr hole plug can further comprise an inorganic filler or a combination of inorganic fillers. In one aspect the inorganic filler can be selected from the group calcium carbonate, calcium phosphate, tricalcium phosphate and hydroxyapatite.
[00317] In one aspect, the 3d-printed or electrospun burr plug can further comprise an extracellular matrix material. In one aspect, the extracellular matrix material can be selected from the group collagen, hyaluronic acid, chondroitin sulfate, heparan sulfate, keratin sulfate, elastin, fibronectin and laminin.
[00318] In one aspect, 3D-printed or electrospun plug can be coated with a solution of the derivatized HA polymers of the disclosure. This derivatized HA polymer compositioncan be coated onto the plug through a dip coating or spray coating process. In another aspect, the coated plug can be dried. The drying process can include drying at elevated temperature, drying at reduced pressure or lyophilization.
[00319] In another aspect, polymeric degradable plug can be dipped into a solution of the derivatized HA polymers of the disclosure. The solution can then be activated to allow the solution to crosslink such that the pores of the plug comprise the crosslinked derivatized HA polymer composition. The crosslinking process can be activated by adjusting pH of the solution, addition of a crosslinker, elevation of temperature, addition of an initiator or a combination of one or more of these.
[00320] In another aspect, polymeric degradable plug can be dipped into a solution of the derivatized HA polymers of the disclosure that contain residual vinyl sulfone groups. The coateddevice can be dried at elevated temperatures to remove the solvent and to allow crosslinking of the coating such that the pores of the plug comprise the crosslinked derivatized HA polymer composition.
[00321] In one aspect, the crosslinked forms of the derivatized HA polymers and/or compositions of this disclosure can be used to form nerve guides. Optionally, the nerve guides can be prepared by lyophilization. In one aspect, collagen, gelatin, chitosan heparan sulfate or a combination of these can be further added to the derivatized HA polymers and/or compositions
of the disclosure to form the nerve guides. In another aspect, Schwann cells can be incorporated into the derivatized HA polymer compositions during the formation of the nerve guide.
[00322] In one aspect, the derivatized HA polymers if this disclosure can be prepared as a solution that has a viscosity of greater than 50 cP. In one aspect, this solution can be applied to tissue to reduce the coefficient of friction with the tissue surface. In one aspect, the derivatized HA polymer compositioncan be used as a vaginal lubricant. In another aspect, the solution can be applied to a device that is to be inserted into an opening, orifice or cavity such that the solution act to lubricate the passage of the device through the opening, orifice or cavity. In one aspect the device could be an endoscope.
[00323] In one aspect, the derivatized HA polymer and compositions thereof of this disclosure can be used to coat a medical device. Medical devices that can be coated include but are not limited to a catheter, a needle, a biopsy needle, a tissue marker, a guide wire, and endoluminal sheath, a suture, a braid, a trocar, a hernia mesh, a surgical mesh, a contact lens, an intra-ocular lens, a stent (for example vascular stent, esophageal stent, biliary stent coronary stent, renal stent, peripheral vascular stent) , a nasal splint, a vascular graft, a stent-graft, aneurysm coils, introducer sheaths, balloon catheters, vascular closure devices, inferior vena cava filter, and Hydrocephalic shunts.
[00324] In one aspect, the derivatized HA polymer of the disclosure can be prepared as a solution which can then be applied by spray coating or dip coating. The solvent can then be removed to leave a coating of the derivatized HA polymer composition of the disclosure on the device surface. In one aspect, the solution can be an aqueous solution. In another aspect, the solution can comprise an organic solvent. In another aspect, the solution can comprise water and a water-miscible organic solvent. In one aspect the derivatized HA polymer of the disclosure can be functionalized with aliphatic or aromatic groups such that there is a hydrophobic interaction with these groups and the device surface. In one aspect, the derivatized HA polymer of this disclosure that has residual vinyl sulfone groups can be coated onto a medical device by dip coating or spray coating. The coating is dried. The coating can be exposed to heat, gamma, e- beam or ultraviolet radiation to crosslink the derivatized HA polymer. In another aspect, the coating can further comprise a biologically active agent. In another aspect, the coating when
hydrated, increase the lubricity of the coated device. The increased lubricity of the coated device can be measure by a decrease of the water contact angle by at least 20°. In another aspect, the increased lubricity can be measured as a decrease in the friction coefficient by at least 20%. In another aspect, the device can be partially coated with some part of the device remaining uncoated. In another aspect, the device can be precoated with binding polymer coating that enhances the binding of the coating derivatized HA polymer composition of this disclosure. In another aspect, the coating can further comprise heparin, to give the coating anti-thrombotic properties.
[00325] A process for making a derivative polymer of a polyhydric polymer, comprising: a) reacting hydroxyl groups of a polyhydric polymer, with divinyl sulfone (DVS) to provide a first polyhydric derivative; and b) reacting the first polyhydric polymer derivative with a nucleophile of a formula X'-l -Y, or X'-R2-Y7 or both to provide a second polyhydric polymer derivative; wherein R1 and R2 are different, and each is a substituted or unsubstituted C5-C20 aliphatic or aromatic moiety, , X' is a nucleophilic group of SH or NH2, and Y is the same or different, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group. This process, wherein the polyhydric polymer is hyaluronic acid (HA). This process may further further comprise step c) derivatizing the second polyhydric polymer derivative by repeating, one or more times, step a) or step a) and step b).
[00326] The following Examples are offered by way of illustration and not by way of limitation. In the Examples, DI stands for distilled water, PEG stands for polyethylene glycol and IV stands for intrinsic viscosity.
EXAMPLES
Example 1
DVS modified HA (DVS2)
[00327] 2.5 g sodium hyaluronate (900 KDa) was added to a glass 4L reaction kettle. The lid, overhead stirrer and anchor impellor were attached to the reaction kettle. The solution was then stirred at about 200 rpm. 250 g deionized water was added to the kettle. The solution was stirred for about 18 hrs. 166.5 g of a 0.25 M NaOH solution was added to the dissolved sodium
hyaluronate. The pH of the solution was measured after 2 min and was found to be 12.69. A freshly prepared solution of 10.6 g divinyl sulfone in 66g of DI water was then rapidly added to the stirring solution. After 75 seconds, 50 g of a IM HCI solution was added to the reaction mixture. 1 M NaOH was then added dropwise until the solution pH was between 5 and 7. 6 g NaCI was then added to the solution. Once the NaCI had dissolved, 1.25 L acetone was slowly added over a period of 20 minutes. The suspension was stirred for about 3 hours. 200 mL denatured ethanol was added and the solution was stirred for about 30 minutes. The precipitate was filtered under vacuum using a sintered glass funnel through a 0.22 pm PTFE filter membrane. Once all the solution had been filtered, the vacuum was disconnected and 100 mL ethanol was used to rinse the precipitate. The ethanol was then removed by vacuum filtration. This process was repeated an additional 3 times. The product was dried under vacuum at room temp in a vacuum oven.
[00328] Approx. 10-20 mg of the dried sample was added to a vial. D2O was added to the sample to make the final concentration of the solution about 6 mg/mL. The sample was shaken on an orbital shaker until dissolved. Once dissolved, the sample was transferred into a NMR tube and the 1H-NMR spectrum of the sample was recorded on a NMR spectrometer. The spectrum was printed out with the specific peaks in the 6.3-6.5 ppm (2 peaks from the 2 CH2= protons from the vinyl sulfone residue), the 6.8-7.0 ppm (CH peak of vinyl group) and 1.8-2.5 ppm (singlet from the 3 CH3 protons from the N-acetyl group of the HA) regions being integrated. The percent modification is calculated on molar ratio of the vinyl CH protons (6.8-7 ppm) to the acetamide (1.8-2.5 ppm) protons. The percent substitution was found to be about 8.9%.
Example 2
DVS modified HA (DVS13)
[00329] 3.5 g sodium hyaluronate (approx. SOOkDa; 1.4 m3/Kg IV) was added to a 4L glass reaction kettle. The lid, overhead stirrer and anchor impellor were attached to the reaction kettle. 350g deionized water was added to the kettle. The solution was then stirred at about 300 rpm. The solution was stirred for about 18 hrs. The stirring speed was then increased to 750 rpm and about 233 g of a 0.25 M NaOH solution was added to the dissolved sodium hyaluronate.
The pH of the solution was measured after 2min and was found to be 12.95. A freshly prepared solution of 15.5 g divinyl sulfone in 92.4 g of DI water was then rapidly added to the stirring solution. After 4.5 minutes, 63 g of a 1 M HCI solution was added to the reaction mixture. 1 M NaOH was then added dropwise until the solution pH was between 5 and 7. 8.4 g NaCI was then added to the solution. Once the NaCI had dissolved, 1.5 L acetone was slowly added over a period of 30 minutes. The suspension was stirred for about 3 hours. 300 mL denatured ethanol was added and the solution was stirred for about 30 minutes. The precipitate was filtered under vacuum using a sintered glass funnel through a 0.22 pm PTFE filter membrane. Once all the solution had been filtered, the vacuum was disconnected and 150 mL ethanol was used to rinse the precipitate. The ethanol was then removed by vacuum filtration. This process was repeated an additional 3 times. The product was dried under vacuum at room temp in a vacuum oven. The percent substitution, as determined by the procedure described in Example 1, was found to be about 25%.
Example 3
DVS modified HA (DVS14)
[00330] The reaction as described in Example 2 was performed using a reaction time of 6 minutes. The percent substitution, as determined according to the procedure described in Example 1, was found to be about 31%.
Example 4
HA-DVS reaction with 3-Mercaptopropionic acid (HA-DVS2-MPA)
[00331] 0.5 g vinyl sulfone derivatized HA (approx. 9%, as per Example 1) was added to 50 g DI water in a 250 mL round bottom flask. The solution was stirred overnight until the material had dissolved. The flask was then purged with nitrogen. 0.022 g 3-mercaptopropionic acid (MPA) was added to the solution. After the MPA had dissolved, the pH was adjusted to about 9 using 0.25 M NaOH. The solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCI. 1.25 g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. 150 mL cold acetone was slowly added to the solution. The reaction
mixture was stirred for 1.5 hours. 25 mL ethanol was added and the resultant mixture was stirred for 15 minutes. The precipitate was isolated using vacuum filtration. The precipitate was washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate was dried under vacuum at room temperature. A sample of the material was dissolved in D2O and the 1H-NMR spectrum was measured. The presence of MPA substitution was evidenced by peaks at 2.3-2.4 ppm (triplet) and 2.6-2.8 ppm (triplet). The MPA substitution, as calculated from the integrals at 2.3-2.4 ppm (MPA - CH2) and 1.7-2 ppm (HA - acetamide), was 7.6%.
Example 5
HA-DVS reaction with 1-octanethiol (HA-DVS2-oct)
[00332] 0.5 g vinyl sulfone derivatized HA (approx. 9%, as per Example 1) was added to 50 g DI water in a 250 mL round bottom flask. The solution was stirred for about 4 hours at room temperature. About 15.8 g denatured ethanol was added and the mixture was stirred for about 18 hrs at which point the material had dissolved. The flask was then purged with nitrogen. 0.023 g 1-octanethiol in 7.9 g ethanol was then added to the solution of derivatized HA. The pH of the reaction mixture was adjusted to about 9 using 0.25 M NaOH. The solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCL 0.5g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. 150 mL cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. The precipitate was isolated using vacuum filtration. The precipitate was washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate was dried under vacuum at room temperature. A sample of the material was dissolved in D2O and the 1H-NMR spectrum was measured. The presence of octanethiol substitution was evidenced by peaks at 0.8-0-9 ppm (-CH3), 1.2-1.6 ppm (-CH2-), 2.6-2.7 ppm (-CH2-S-) and 2.9-3.0 ppm (-S-CH2-). The octanethiol molar substitution, as calculated from the integrals at 2.6-2.7 ppm. (Oct - CH2-S-) and 1.7-2 ppm (HA - acetamide), was 5.4%.
Example 6
HA-DVS reaction with 1-octanethiol (HA-DVS2-oct-DMF)
[00333] 0.5 g vinyl sulfone derivatized HA (approx. 9%, as per Example 1) was added to 50 g DI water in a 250 mL round bottom flask. The solution was stirred for about 4 hours at room temperature. About 18.88 g dimethylformamide (DMF) was added and the mixture was stirred for about 18 hrs at which point the material had dissolved. The flask was then purged with nitrogen. 0.029 g 1-octanethiol in 9.4g DMF was then added to the derivatized HA solution. The pH of the reaction mixture was adjusted to about 9 using 0.25 M NaOH. The solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCI. About 0.25 g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. 150 mL cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. 25 mL ethanol was added and the resultant mixture was stirred for 15 minutes. The precipitate was isolated using vacuum filtration. The precipitate was washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate was dried under vacuum at room temperature. A sample of the material was dissolved in D2O and the 1H-NMR spectrum was measured. The octanethiol molar substitution, as calculated from the integrals at 2.4-2.5 ppm (Oct - CH2-S-) and 1.7-2 ppm (HA - acetamide), was 5.5%.
Example 7
HA-DVS reaction with 1-dodecanethiol (HA-DVS2-dod)
[00334] 0.5 g vinyl sulfone derivatized HA (approx. 9%, as per Example 1) was added to 50 g DI water in a 250 mL round bottom flask. The solution was stirred for about 4 hours at room temperature. About 15.8 g denatured ethanol was added and the mixture was stirred for about 18 hrs at which point the material had dissolved. The flask was then purged with nitrogen. 0.04 g 1-dodecanethiol in 7.9g ethanol was then added to the solution of derivatized HA. The pH of the reaction mixture was adjusted to about 9 using 0.25 M NaOH. The solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCI. 0.25g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. 150 mL cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. The precipitate was isolated using vacuum filtration. The precipitate was washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate was dried under vacuum at
room temperature. A sample of the material was dissolved in D2O and the 1H-NMR spectrum was measured. The presence of octanethiol substitution was evidenced by peaks at 0.8-0-9 ppm (CH3-), 1.2-1.6 ppm (-CH2-), 2.6-2.7 ppm (-CH2-S-) and 2.9-3.0ppm (-S-CH2-). The octanethiol molar substitution, as calculated from the integrals at 2.6-2.7 ppm (Oct - CH2-S-) and 1.7-2 ppm (HA - acetamide), was 5.2%.
Example 8
DVS modified HA - reaction 2 (DVS3)
[00335] 3.5 g sodium hyaluronate (approx. 900kDa, 17 dL/g) was added to a glass 4L reaction kettle. The lid, overhead stirrer and anchor impellor were attached to the reaction kettle. 350g deionized water was added to the kettle. The solution was stirred at about 200 rpm for about 18 hrs. 233 g of a 0.25 M NaOH solution was added to the dissolved sodium hyaluronate. The pH of the solution was measured after 2 min and was found to be 12.6. A freshly prepared solution of 14.8 g divinyl sulfone in 92.4g of DI water was then rapidly added to the stirring solution. After 1.25 minutes, 70 g of IM HCI was added to the reaction mixture. Either 1 M NaOH or IM HCI was then added dropwise as needed until the solution pH was between 5 and 7. About 6 g NaCI was then added to the solution. Once the NaCI had dissolved, 1.25 L acetone was slowly added over a period of 20 minutes. The suspension was stirred for about 3 hours. 200 mL ethanol was added and the solution was stirred for about 30 minutes. The precipitate was filtered under vacuum using a sintered glass funnel through a 0.22 pm PTFE filter membrane. 100 mL ethanol was used to rinse the precipitate. The ethanol was then removed by vacuum filtration. This process was repeated an additional 3 times. The product was dried under vacuum at room temp in a vacuum oven. The percent substitution, determined as described in Example 1, was found to be 8.6%.
Example 9
DVS modified HA - (DVS5 - 800kDa)
[00336] 3.5 g sodium hyaluronate (1.4 m3/kg, approx. 800kDa) was added to a glass 4L reaction kettle. The lid, overhead stirrer and anchor impellor were attached to the reaction kettle. 350g deionized water was added to the kettle. The solution was stirred at about 200 rpm for about 18 hrs. 233 g of a 0.25 M NaOH solution was added to the dissolved sodium hyaluronate. The pH of the solution was measured after 2 min and was found to be 12.85. A freshly prepared solution of 14.8 g divinyl sulfone in 92.4 g of DI water was then rapidly added to the stirring solution. After 75 seconds, 63 g of a IM HCI solution was added to the reaction mixture. Either IM NaOH or IM HCI was then added dropwise as needed until the solution pH was between 5 and 7. 8.4g NaCI was then added to the solution. Once the NaCI had dissolved, 1. 5 L acetone was slowly added over a period of 30 minutes. The suspension was stirred for about 3 hours. 200 mL ethanol (Ethanol, Alcohol Reagent, Denatured anhydrous 94-96%) was added and the solution was stirred for about 30 minutes. The precipitate was filtered under vacuum using a sintered glass funnel through a 0.22 pm PTFE filter membrane. 150 mL ethanol was used to rinse the precipitate. The ethanol was then removed by vacuum filtration. This process was repeated an additional 3 times. The product was dried under vacuum at room temp in a vacuum oven. The percent substitution, determined as described in Example 1, was found to be about 8.9%.
Example 10
HA-DVS reaction with 1-pentanethiol (HA-DVS5-pent2)
[00337] 0.5 g vinyl sulfone derivatized HA (approx. 9%, as per Example 9) was added to
27.5 g DI water in a 250 mL round bottom flask. The solution was stirred for about 4 hours at room temperature. About 16 g denatured ethanol was added and the mixture was stirred for about 18 hrs at which point the material had dissolved. The flask was then purged with nitrogen. 0.042 g 1-pentanethiol in about 1.8 g ethanol was then added to the solution of derivatized HA. The pH of the reaction mixture was adjusted to about 9 using 0.25 M NaOH. The solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCI. About 0.5 g NaCI
was added to the reaction solution. The solution was stirred until the NaCI had dissolved. 150 mL cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. The precipitate was isolated using vacuum filtration. The precipitate was washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate was dried under vacuum at room temperature. A sample was dissolved in D2O and the 1H-NMR spectrum was measured. The presence of pentanethiol substitution was evidenced by peaks at 0.6-0-8 ppm (CH3-), 1.2-1.6 ppm (-CH2-), 2.4-2.G ppm (-CH2-S-) and 2.7-2.9 ppm (-S-CH2-). The pentanethiol molar substitution, as calculated from the integrals at 2.3-2.7 ppm (pent- CH2-S-) and 1.7-2 ppm (HA - acetamide), was 7.3%.
Example 11
HA-DVS reaction with 1-decanethiol (HA-DVS5-dec)
[00338] 0.5 g vinyl sulfone derivatized HA (approx. 9%, as per Example 9) was added to 20
DI water in a 250 mL round bottom flask. The solution was stirred for about 4 hours at room temperature. 19.7 g denatured ethanol was added and the mixture was stirred for about 18 hrs at which point the material had dissolved. The flask was then purged with nitrogen. 0.035 g 1- decanethiol in 4 g ethanol was then added to the derivatized HA solution. The pH of the reaction mixture was adjusted to about 9 using 0.25 M NaOH. The solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCI. 0.25 g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. 150 mL cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. The precipitate was isolated using vacuum filtration. The precipitate was washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate was dried under vacuum at room temperature. A sample of the material was dissolved in D2O and the 1H-NMR spectrum was measured. The presence of decanethiol substitution was evidenced by peaks at 0.6-0-8 ppm (CH3-), 1.1-1.6 ppm (-CH2-), 2.4-2.6 ppm (-CH2-S-) and 2.7-2.9 ppm (-S-CH2-). The decanethiol molar substitution, as calculated from the integrals at 2.3-2.7 ppm (pent- CH2-S-) and 1.7-2 ppm (HA - acetamide), was 6.5%.
Example 12
DVS modified HA - reaction 5 (DVS10 - 800kDa)
[00339] 5 g sodium hyaluronate (1.4 m3/kg, approx. 800kDa) was added to a glass 4L reaction kettle. The lid, overhead stirrer and anchor impellor were attached to the reaction kettle. 500 g deionized water was added to the kettle. The solution was stirred for about at about 200 rpm for 18 hrs. 333 g of a 0.25 M NaOH solution was added to the dissolved sodium hyaluronate. The pH of the solution was measured after 2min and was found to be 12.93. A freshly prepared solution of 11 g divinyl sulfone in 66 g of DI water was then rapidly added to the stirring solution. After 2.5 minutes, 90 g of a IM HCI solution was added to the reaction mixture. Either IM NaOH or IM HCI as needed was then added dropwise until the solution pH was between 5 and 7. About 12 g NaCI was then added to the solution. Once the NaCI had dissolved, 1.75 L acetone was slowly added over a period of 30 minutes. The suspension was stirred for about 3 hours. 300 mL ethanol (Ethanol, Alcohol Reagent, Denatured anhydrous 94-96%) was added and the solution was stirred for about 30 minutes. The precipitate was filtered under vacuum using a sintered glass funnel through a 0.22 pm PTFE filter membrane. Once all the solution had been filtered, the vacuum was disconnected and 200 mL ethanol was used to rinse the precipitate. The ethanol was then removed by vacuum filtration. This process was repeated an additional 2 times. The product was dried under vacuum at room temp in a vacuum oven. The percent substitution, as determined according to the procedure described in Example 1, was found to be 8.1%.
Example 13
HA-DVS reaction with 2-mercaptobenzoic acid (HA-DVS10-MBA)
[00340] 0.5 g vinyl sulfone derivatized HA (approx. 8%, as per Example 14) was added to
27.5 g DI water in a 250 mL round bottom flask. The solution was stirred for about 4 hours at room temperature. 16 g denatured ethanol was added and the mixture was stirred for about 18 hrs at which point the material had dissolved. The flask was then purged with nitrogen and then placed in a water bath (temp = 30 ± 2 °C). 0.092 g 2-mercaptobenzoic acid (MBA) in 1.78 g ethanol was then added to the solution of derivatized HA. The pH of the reaction mixture was adjusted
to about 9 using 0.25 M NaOH. The solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCI. About 0.25 g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. 150 mL cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. The precipitate was isolated using vacuum filtration. The precipitate was washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate was dried under vacuum at room temperature. A sample of the material was dissolved in D2O and the 1H-NMR spectrum was measured. The presence of MBA substitution was evidenced by peaks at 7.1-7.5 ppm (Ar-H). The MBA molar substitution, as calculated from the integrals at 7.1-7.5 ppm (Ar-H) and 1.7-2 ppm (HA - acetamide), was 10%.
Example 14
HA-DVS reaction with 4-methylbenzenethiol (HA-DVS10-MBT)
[00341] 0.5 g vinyl sulfone derivatized HA (approx. 8%, as per Example 14) was added to
27.5 g DI water in a 250 mL round bottom flask. The solution was stirred for about 4 hours at room temperature. About 15.98 g denatured ethanol was added and the mixture was stirred for about 18 hrs at which point the material had dissolved. The flask was then purged with nitrogen and then placed in a water bath (temp = 30 ± 2 °C). 0.074 g 4-methylbenzenethiol (MBT) in about 1.78 g ethanol was then added to the solution of derivatized HA. The pH of the reaction mixture was adjusted to about 9.5 using 0.25 M NaOH. The solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCI. About 0.25g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. 150 mL cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. The precipitate was isolated using vacuum filtration. The precipitate was washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate was dried under vacuum at room temperature. A sample of the material was dissolved in D2O and the 1H-NMR spectrum was measured. The presence of MBT substitution was evidenced by peaks at 2.3-2.5 ppm (Ar-CH3), 7.2-7.6 ppm (Ar-H). The MBT molar substitution, as calculated from the integrals at 7.1-7.5 ppm (Ar-H) and 1.7-2 ppm (HA - acetamide), was 5.0%.
Example 15
HA-DVS reaction with 4-methoxy-a-toluenethiol (HA-DVS10-MTT)
[00342] 0.5 g vinyl sulfone derivatized HA (approx. 8%, as per Example 14) was added to
27.5 g DI water in a 250 mL round bottom flask. The solution was stirred for about 4 hours at room temperature. 16 g denatured ethanol was added and the mixture was stirred for about 18 hrs at which point the material had dissolved. The flask was then purged with nitrogen and then placed in a water bath (temp = 30 ± 2 °C). About 0.092 g 4-methoxy-a-toluenethiol (MTT) in 1.78 g ethanol was then added to the solution of derivatized HA. The pH of the reaction mixture was adjusted to about 9.5 using 0.25 M NaOH. The solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCI. 0.25g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. 150 mL cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. The precipitate was isolated using vacuum filtration. The precipitate was washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate was dried under vacuum at room temperature. A sample of the material was dissolved in D2O and the 1H-NMR spectrum was measured. The presence of MTT substitution was evidenced by peaks at 6.7-7.0 ppm (Ar-H), 7.1-7.3 ppm (Ar-H). The MTT molar substitution, as calculated from the integrals at 7.1-7.3 ppm (Ar-H) and 1.7-2 ppm (HA - acetamide), was 10.2%.
Example 16
HA-DVS reaction with thiophenol (HA-DVSIO-thiophenol)
[00343] 0.5 g vinyl sulfone derivatized HA (approx. 8%, as per Example 14) was added to
27.5 g DI water in a 250 mL round bottom flask. The solution was stirred for about 4 hours at room temperature. 16 g denatured ethanol was added and the mixture was stirred for about 18 hrs at which point the material had dissolved. The flask was then purged with nitrogen and then placed in a water bath (temp = 30 ± 2 °C). 0.066 g thiophenol in 1.78 g ethanol was then added to the solution of derivatized HA. The pH of the reaction mixture was adjusted to about 9.5 using 0.25 M NaOH. The solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCI. About 0.25 g NaCI was added to the reaction solution. The solution was stirred
until the NaCI had dissolved. 150 mLcold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. The precipitate was isolated using vacuum filtration. The precipitate was washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate was dried under vacuum at room temperature. A sample of the material was dissolved in D2O and the 1H-NMR spectrum was measured. The presence of thiophenol substitution was evidenced by peaks at 7.1-7.5 ppm (Ar-H). The thiophenol molar substitution, as calculated from the integrals at 7.1-7.5 ppm (Ar-H) and 1.7-2 ppm (HA - acetamide), was 7.6%.
[00344]
Example 17
DVS modified HA - (DVS12 - 800kDa)
[00345] 3.5 g sodium hyaluronate (1.4 m3/kg, approx. 800kDa) was added to a glass 4L reaction kettle. The lid, overhead stirrer and anchor impellor were attached to the reaction kettle. 350 g deionized water was added to the kettle. The solution was stirred at about 750 rpm for about 18 hrs. About 233 g of a 0.25 M NaOH solution was added to the dissolved sodium hyaluronate. The pH of the solution was measured after 2 min and was found to be 12.91. A freshly prepared solution of 15.5 g divinyl sulfone in 92 g of DI water was then rapidly added to the stirring solution. After 3.25 minutes, 63 g of a IM HCI solution was added to the reaction mixture. Either IM NaOH or IM HCI was then added dropwise as needed until the solution pH was between 5 and 7. About 8.4 g NaCI was then added to the solution. Once the NaCI had dissolved, 1.5 L acetone was slowly added over a period of 30 minutes. The suspension was stirred for about 3 hours. 300 mL ethanol (Ethanol, Alcohol Reagent, Denatured anhydrous 94- 96%) was added and the solution was stirred for about 30 minutes. The precipitate was filtered under vacuum using a sintered glass funnel through a 0.22 pm PTFE filter membrane. Once all the solution had been filtered, the vacuum was disconnected and 150 mL ethanol was used to rinse the precipitate. The ethanol was then removed by vacuum filtration. This process was repeated an additional 3 times. The product was dried under vacuum at room temp in a vacuum oven. The percent substitution, as determined according to the procedure described in Example
1, was found to be about 22.2%.
Example 18
DVS modified HA - (DVS14 - 800kDa)
[00346] 3.5 g sodium hyaluronate (1.4 m3/kg, approx. 800kDa) was added to a glass 4 L reaction kettle. The lid, overhead stirrer and anchor impellor were attached to the reaction kettle. 350 g deionized water was added to the kettle. The solution was stirred at about 750 rpm for about 18 hrs. 233 g of a 0.25 M NaOH solution was added to the dissolved sodium hyaluronate. The pH of the solution was measured after 2 min and was found to be 12.87. A freshly prepared solution of 15.5 g divinyl sulfone in 92 g of DI water was then rapidly added to the stirring solution. After 6 minutes, 63 g of a IM HCI solution was added to the reaction mixture. Either IM NaOH or IM HCI was then added dropwise as needed until the solution pH was between 5 and 7. About 8.4 g NaCI was then added to the solution. Once the NaCI had dissolved, 1.5 L acetone was slowly added over a period of 30 minutes. The suspension was stirred for about 3 hours. 3 00 m L ethanol (Ethanol, Alcohol Reagent, Denatured anhydrous 94- 96%) was added and the solution was stirred for about 30 minutes. The precipitate was filtered under vacuum using a sintered glass funnel through a 0.22 pm PTFE filter membrane. 150 mL ethanol was used to rinse the precipitate. The ethanol was then removed by vacuum filtration. This process was repeated an additional 3 times. The product was dried under vacuum at room temp in a vacuum oven. The percent substitution, as determined by the procedure described in Example 1, was found to be 31.4%.
Example 19
HA-DVS reaction with 2-mercaptobenzoic acid (HA-DVS14-MBA)
[00347] 1.0 g vinyl sulfone derivatized HA (approx. 31%, as per Example 22) was added to
55 g DI water in a 500 mL round bottom flask. The solution was stirred for about 1 hour at room temperature. 32 g denatured ethanol was added and the mixture was stirred for about 18 hrs at which point the material had dissolved. The flask was then purged with nitrogen and then placed in a water bath (temp = 30 ± 2 °C). 0.554 g 2-mercaptobenzoic acid (MBA) in 3.55 g ethanol was
then added to the derivatized HA solution. The pH of the reaction mixture was adjusted to about 9 using 0.25 M NaOH. The solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCL 1.32g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. 300 mL cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. The precipitate was isolated using vacuum filtration. The precipitate was washed 3 times with 50 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate was dried under vacuum at room temperature. A sample of the material was dissolved in D2O and the 1H-NMR spectrum was measured. The presence of MBA substitution was evidenced by peaks at 7.1-7.5 ppm (Ar-H). The MBA molar substitution, as calculated from the integrals at 7.1-7.5 ppm (Ar-H) and 1.7-2 ppm (HA - acetamide) was 35%.
[00348]
Example 20
HA-DVS reaction with 9-mercapto-l-nonanol (HA-DVS14-nonanol)
[00349] 1.0 g vinyl sulfone derivatized HA (approx. 31%, as per Example 22) was added to
55 g DI water in a 500 mL round bottom flask. The solution was stirred for about 1 hour at room temperature. 32 g denatured ethanol was added and the mixture was stirred for about 18 hrs at which point the material had dissolved. The flask was then purged with nitrogen and then placed in a water bath (temp = 30 ± 2 °C). 0.63 g 9-mercapto-l-nonanol in 3.55 g ethanol was then added to the solution of derivatized HA. The pH of the reaction mixture was adjusted to about 9 using 0.25 M NaOH. The solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCL 1.32 g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. 300 mL cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. The precipitate was isolated using vacuum filtration. The precipitate was washed 3 times with 50 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate was dried under vacuum at room temperature. A sample of the material was dissolved in D2O and the 1H-NMR spectrum was measured. The presence of nonanol substitution was evidenced by peaks at 1.1-1.8 ppm (-CH2-), 2.5-2.8ppm (-CH2-S-) and 2.9 - 3.1 ppm (-S-CH2-. The nonanol molar substitution, as calculated from the integrals at 2.5-2.8ppm (-
CH2-S-) and 1.7-2 ppm (HA - acetamide), was 37.5%.
Example 21
DVS modified HA - (DVS18 - 800kDa)
[00350] 3.5 g sodium hyaluronate (IV = 1.4 m3/kg, MW approx. 800 kD) was added to a glass 4 L reaction kettle. The lid, overhead stirrer and anchor impellor were attached to the reaction kettle. 350 g deionized water was added to the kettle. The solution was stirred at about 750 rpm for about 18 hrs. 233 g of a 0.25 M NaOH solution was added to the dissolved sodium hyaluronate. The pH of the solution was measured after 2 min and was found to be 12.92. A freshly prepared solution of 15.5 g divinyl sulfone in 92 g of DI water was then rapidly added to the stirring solution. After 15 minutes, 63 g of a IM HCI solution was added to the reaction mixture. Either IM NaOH or IM HCI was then added dropwise as needed until the solution pH was between 5 and 7. About 8.4 g NaCI was then added to the solution. Once the NaCI had dissolved, 1.5 L acetone was slowly added over a period of 30 minutes. The suspension was stirred for about 3 hours. 300 mL ethanol (Ethanol, Alcohol Reagent, Denatured anhydrous 94- 96%) was added and the solution was stirred for about 30 minutes. The precipitate was filtered under vacuum using a sintered glass funnel through a 0.22 pm PTFE filter membrane. Once all the solution had been filtered, the vacuum was disconnected and 150 mL ethanol was used to rinse the precipitate. The ethanol was then removed by vacuum filtration. This process was repeated an additional 3 times. The product was dried under vacuum at room temperature in a vacuum oven. The percent substitution, as determined by the procedure described in Example 1, was found to be 71.3%.
Example 22
HA-DVS reaction with 3-Mercaptopropionic acid (HA-DVS18-MPA)
[00351] 1.0 g vinyl sulfone derivatized HA (approx. 71%, as per Example 25) was added to
100 g DI water in a 500 mL round bottom flask. The solution was stirred at 300 rpm overnight so that all of the material had dissolved. The flask was then purged with nitrogen. 0.25 g 3- mercaptopropionic acid (MPA) was added to the solution. After the MPA had dissolved, the pH
was adjusted to about 9 using 0.25 M NaOH. The solution was stirred for 4 hours after which the pH was adjusted to about 7 using 0.25 M HCI. 2.4 g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. 300 mL cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. 50 mL ethanol was added and the resultant mixture was stirred for 15 minutes. The precipitate was isolated using vacuum filtration. The precipitate was washed 4 times with 50 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate was dried under vacuum at room temperature. A sample of the material was dissolved in D2O and the 1H-NMR spectrum was measured. The presence of MPA substitution was evidenced by peaks at 2.4-2.6 ppm (-CH2-COOH), 2.7-2.8 ppm (-CH2-S-) and 2.9-3.1 ppm (-S-CH2-). The MPA substitution, as calculated from the integrals at 2.4-2.6 ppm (MPA - CH2) and 1.7-2 ppm (HA - acetamide), was 79.4%.
Example 23
HA-DVS reaction with mercaptobenzoic acid (MBA) (HA-DVS-37-MBA)
[00352] The vinyl sulfone derivatized HA reaction (produced in the same manner as Example 25) was added to 660 g DI water in a 5L reaction kettle. The solution was stirred for about 1 hr at 300 rpm at 30°C. 426.06g Ethanol was then added and the solution was stirred for about 18 hrs at 300 rpm at 30°C. The stirring speed was then increased to 500 rpm. 8.305 g MBA was then added to the derivatized HA solution and allowed to stir for ten (10) minutes. The pH of the reaction mixture was monitored and adjusted to about 9 using 1 M NaOH. The solution was stirred for 2 hours after which the pH was adjusted to about 7 using IM HCI. About 9 g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. IL cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. The precipitate was isolated using vacuum filtration. Once all the solution had been filtered, the vacuum was disconnected and 200 mL ethanol was used to rinse the precipitate. The ethanol was then removed by vacuum filtration. This process was repeated an additional 3 times with each aliquot standing in static ethanol for five (5) minutes prior to applying vacuum. The product was dried under vacuum at room temp conditions. A sample of the material was dissolved in D2O and the TH-NMR spectrum was measured. The presence of MBA substitution was evidenced
by peaks at 7.1-7.5 ppm (Ar-H). The MBA molar substitution, as calculated from the integrals at 7.1-7.5 ppm (Ar-H) and 1.7-2 ppm (HA - acetamide), was 23.3%. Rheology results for a 2% (w/v) solution were as following for flow viscosity (0.1-1000 1/s) and frequency testing (1-10 Hz). See
Tables 1 and 2.
DVS modified HA - HA-DVS-36
[00355] 11.33 g sodium hyaluronate (1.4 m3/kg, approx. 800kDa) was added to a glass 5L reaction kettle. The lid, overhead stirrer and anchor impellor were attached to the reaction kettle. 1133 g deionized water was added to the kettle. The temperature controller for the Bioreactor heater (Chemglass CLS-1380-19V) was set to 25° C. The solution was stirred at about 300 rpm for approximately 18 hrs. The stirring speed was increased to 750 rpm. 35 g of a IM NaOH solution was then added to the dissolved sodium hyaluronate. The pH of the solution was measured after 2min and was found to be 12.5. The ph was adjusted to 12.32 using IM HCI solution. A freshly prepared solution of 50 g divinyl sulfone in 282.5 g of DI water was then rapidly added to the stirring solution. The pH was monitored and adjusted with IM NaOH to maintain pH range of 12.2-12.3 over the course of the reaction time of twenty (20) minutes. After 20 minutes, 35g of a IM HCI solution was added to the reaction mixture and pH was adjusted to a value between 5 and 7. About 19.5 g NaCI was then added to the solution. Once the NaCI had dissolved, 2 Lacetone was slowly added over a period of <30 minutes. The suspension was stirred for about 3 hours. 400 mL ethanol was added and the solution was stirred for about 30 minutes. The precipitate was filtered under vacuum using a sintered glass funnel. Once all the solution had been filtered, the vacuum was disconnected and 200 mL ethanol was used to rinse the precipitate. The ethanol was then removed by vacuum filtration. This process was repeated an additional 3 times with each aliquot standing in static ethanol for five (5) minutes prior to applying vacuum. The product was immediately dissolved for the reaction described in Example 58. The percent substitution was found to be 51.6% by the following NMR method. Approx. 10- 20 mg of the dried sample was added to a vial. D2O was added to the sample to make the final concentration of the solution about 6 mg/mL. The sample was shaken on an orbital shaker until dissolved. Once dissolved, the sample was transferred into a NMR tube and the 2H-NMR spectrum of the sample was recorded on a NMR spectrometer. The spectrum was printed out with the specific peaks in the 6.0-6.4 ppm (2 peaks from the 2 CH2= protons from the vinyl sulfone residue), the 6.6-7.0 ppm (CH peak of vinyl group) and 1.7-2.0 ppm (singlet from the 3 CH3
protons from the N-acetyl group of the HA) regions being integrated. The percent modification is calculated on molar ratio of the vinyl CH protons (6.8-7.0 ppm) to the acetamide (1.7-2.0 ppm) protons.
Example 25
HA-DVS reaction with Thiophenol (HA-DVS-36-THIO)
[00356] The vinyl sulfone derivatized HA reaction product (produced in the same manner as Example 28) was added to 660 g DI water in a 5L reaction kettle. The solution was stirred for about 1 hr at 300 rpm at 30°C. 426.06g Ethanol was then added and the solution was stirred for about 18 hrs at 300 rpm at 30°C. The stirring speed was then increased to 500 rpm. 10.881g Thiophenol was then added to the derivatized HA solution and allowed to stir for ten (10) minutes. The pH of the reaction mixture was monitored and adjusted to about 9 using 1 M NaOH. The solution was stirred for 2 hours after which the pH was adjusted to about 7 using IM HCL About 9 g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. IL cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. The precipitate was isolated using vacuum filtration. Once all the solution had been filtered, the vacuum was disconnected and 200 mL ethanol was used to rinse the precipitate. The ethanol was then removed by vacuum filtration. This process was repeated an additional 3 times with each aliquot standing in static ethanol for five (5) minutes prior to applying vacuum. The product was dried under vacuum at room temp conditions. A sample of the material was dissolved in D2O and the 1H-NMR spectrum was measured. The thiophenol peaks were observed in the 7.2-7.5 ppm. The thiophenol molar substitution was calculated at 50%. Rheology results for a 2% (w/v) solution were as following for flow viscosity (0.1-1000 1/s) and frequency testing (1-10 Hz). See Tables 3 and 4.
Example 26
HA-DVS reaction with mercaptobenzoic acid (MBA) (HA-DVS-36- BA)
[00359] The vinyl sulfone derivatized HA reaction product (produced in the same manner as Example 29) was added to 660 g DI water in a 5L reaction kettle. The solution was stirred for about 1 hr at 300 rpm at 30°C. 426.06g ethanol was then added and the solution was stirred for about 18 hrs at 300 rpm at 30°C. The stirring speed was then increased to 500 rpm. 15.227 g MBA was then added to the derivatized HA solution and allowed to stir for ten (10) minutes. The pH of the reaction mixture was monitored and adjusted to about 9 using 1 M NaOH. The solution was stirred for 2 hours after which the pH was adjusted to about 7 using IM HCI. About 9 g NaCI was added to the reaction solution. The solution was stirred until the NaCI had dissolved. IL cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. The precipitate was isolated using vacuum filtration. Once all the solution had been filtered, the vacuum was disconnected and 200 mL ethanol was used to rinse the precipitate. The ethanol was then removed by vacuum filtration. This process was repeated an additional 3 times with each aliquot standing in static ethanol for five (5) minutes prior to applying vacuum. The product
was dried under vacuum at room temp conditions. A sample of the material was dissolved in D2O and the 1H-NMR spectrum was measured. The presence of MBA substitution was evidenced by peaks at 7.1-7.5 ppm (Ar-H). The MBA molar substitution, as calculated from the integrals at 7.1-7.5 ppm (Ar-H) and 1.7-2 ppm (HA - acetamide), was 52.5%. Rheology results for a 2% (w/v) solution were as following for flow viscosity (0.1-1000 1/s) and frequency testing (1-10 Hz). See Table 5 .
Example 1
DVS modified HA - HA-DVS-37L lot 1 with lower MW Sodium Hyaluronate
[00361] 11.33 g sodium hyaluronate (0.62 m3/kg) was added to a glass 5L reaction kettle.
The lid, overhead stirrer and anchor impellor were attached to the reaction kettle. 1133 g deionized water was added to the kettle. The temperature controller for the Bioreactor heater (Chemglass CLS-1380-19V) was set to 25° C. The solution was stirred at about 300 rpm for approximately 18 hrs. The stirring speed was increased to 750 rpm. 30 g of a IM NaOH solution was then added to the dissolved sodium hyaluronate. The pH of the solution was measured after 2min and was found to be 12.26. The ph was adjusted to 12.30 using IM HCI solution. A freshly prepared solution of 50 g divinyl sulfone in 282.5 g of DI water was then rapidly added to the stirring solution. The pH was monitored and adjusted with IM NaOH to maintain pH range of 12.2-12.3 over the course of the reaction time of ten (10) minutes. After 10 minutes, 27g of a
IM HCI solution was added to the reaction mixture and pH was adjusted to a value between 5 and 7. About 19.5 g NaCI was then added to the solution. Once the NaCI had dissolved, 2 L acetone was slowly added over a period of <30 minutes. The suspension was stirred for about 3 hours. 500 mL ethanol was added and the solution was stirred for about 30 minutes. An additional 500 ml of cold acetone was added to ensure everything had precipitated. The precipitate was filtered under vacuum using a sintered glass funnel through a 0.22 pm PTFE filter membrane. Once all the solution had been filtered, the vacuum was disconnected and 200 mL ethanol was used to rinse the precipitate. The ethanol was then removed by vacuum filtration. This process was repeated an additional 3 times with each aliquot standing in static ethanol for five (5) minutes prior to applying vacuum. The product was immediately dissolved for the reaction described in Example 63. The percent substitution, as determined by the following NMR method, was found to be 25.1%. Approx. 10-20 mg of the dried sample was added to a vial. D2O was added to the sample to make the final concentration of the solution about 6 mg/mL. The sample was shaken on an orbital shaker until dissolved. Once dissolved, the sample was transferred into a NMR tube and the XH-NMR spectrum of the sample was recorded on a NMR spectrometer. The spectrum was printed out with the specific peaks in the 6.0-6.4 ppm (2 peaks from the 2 CH2= protons from the vinyl sulfone residue), the 6.6-7.0 ppm (CH peak of vinyl group) and 1.7-2.0 ppm (singlet from the 3 CH3 protons from the N-acetyl group of the HA) regions being integrated. The percent modification is calculated on molar ratio of the vinyl CH protons (6.8-7 ppm) to the acetamide (1.7-2.0 ppm) protons.
Example 28
HA-DVS reaction with Thiophenol (HA-DVS-37L-THIO)
[00362] The vinyl sulfone derivatized HA reaction product described in example 31 was added to 660 g DI water in a 5L reaction kettle. The solution was stirred for about 1 hr at 300 rpm at 30°C. 426.06g ethanol was then added and the solution was stirred for about 18 hrs at 300 rpm at 30°C. The stirring speed was then increased to 500 rpm. 5.935g Thiophenol was then added to the derivatized HA solution and allowed to stir for ten (10) minutes. The pH of the reaction mixture was monitored and adjusted to about 9 using 1 M NaOH. The solution was
stirred for 2 hours after which the pH was adjusted to about 7 using IM HCI. About 9 g NaCI was added to the reaction solution and stirred until the NaCI had dissolved. IL cold acetone was slowly added to the solution. The reaction mixture was stirred for 1.5 hours. The precipitate was isolated using vacuum filtration. Once all the solution had been filtered, the vacuum was disconnected and 200 mL ethanol was used to rinse the precipitate. The ethanol was then removed by vacuum filtration. This process was repeated an additional 3 times with each aliquot standing in static ethanol for five (5) minutes prior to applying vacuum. The product was dried under vacuum at room temp conditions. A sample of the material was dissolved in D2O and the TH-NMR spectrum was measured. The thiophenol peaks were observed in the 7.2-7.5 ppm. The thiophenol molar substitution was calculated at 24.4%. Rheology results for a 2% (w/v) solution were as following for flow viscosity (0.1-1000 1/s) and frequency testing (1-10 Hz). See Tables 6 and 7.
HA-DVS reaction with thiocholesterol
[00365] 0.5 g vinyl sulfone derivatized HA (approx. 8% substitution, as per Example 14) is added to 27.5 g DI water in a 250 mL round bottom flask. The solution is stirred for about 4 hours at room temperature. 16 g denatured ethanol is added and the mixture is stirred for about 18 hrs at which point the material had dissolved. The flask is then purged with nitrogen and then placed in a water bath (temp = 30 ± 2 °C). 0.25 g thiocholesterol (Sigma-Aldrich) in 3 g ethanol is then added to the solution of derivatized HA. The pH of the reaction mixture is adjusted to about 9.5 using 0.25 M NaOH. The solution is stirred for 24 hours after which the pH is adjusted to about 7 using 0.25 M HCL About 0.25 g NaCI is added to the reaction solution. The solution is stirred until the NaCI had dissolved. 150 mL cold acetone is slowly added to the solution. The reaction mixture is stirred for 1.5 hours. The precipitate is isolated using vacuum filtration. The precipitate is washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate is dried under vacuum at room temperature.
Example 30
HA-DVS reaction with lipid DSPE-SH
[00366] 0.5 g vinyl sulfone derivatized HA (approx. 8%, as per Example 14) is added to 27.5 g DI water in a 250 mL round bottom flask. The solution is stirred for about 4 hours at room temperature. 16 g denatured ethanol is added and the mixture is stirred for about 18 hrs at which point the material had dissolved. The flask is then purged with nitrogen and then placed in a water bath (temp = 30 ± 2 °C). 0.5 g DSPE-SH (BroadPharm) in 3 g ethanol is then added to the solution of derivatized HA. The pH of the reaction mixture is adjusted to about 9.5 using 0.25 M NaOH. The solution is stirred for 24 hours after which the pH is adjusted to about 7 using 0.25 M HCI. About 0.25 g NaCI is added to the reaction solution. The solution is stirred until the NaCI had dissolved. 150 mL cold acetone is slowly added to the solution. The reaction mixture is stirred for 1.5 hours. The precipitate is isolated using vacuum filtration. The precipitate is washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate is dried under vacuum at room temperature.
Ill
Example 31
HA-DVS reaction with Cholesterol-PEG-thiol
[00367] 0.5 g vinyl sulfone derivatized HA (approx. 8%, as per Example 14) is added to 27.5 g DI water in a 250 mL round bottom flask. The solution is stirred for about 4 hours at room temperature. 16 g denatured ethanol is added and the mixture is stirred for about 18 hrs at which point the material had dissolved. The flask is then purged with nitrogen and then placed in a water bath (temp = 30 ± 2 °C). 0.83 g Cholesterol-PEG-thiol (BroadPharm) in 5 g ethanol is then added to the solution of derivatized HA. The pH of the reaction mixture is adjusted to about 9.5 using 0.25 M NaOH. The solution is stirred for 24 hours after which the pH is adjusted to about 7 using 0.25 M HCL About 0.25 g NaCI is added to the reaction solution. The solution is stirred until the NaCI had dissolved. 150 mL cold acetone is slowly added to the solution. The reaction mixture is stirred for 1.5 hours. The precipitate is isolated using vacuum filtration. The precipitate is washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate is dried under vacuum at room temperature.
Example 32
HA-DVS reaction with DSPE-PEG-thiol
[00368] 0.5 g vinyl sulfone derivatized HA (approx. 8%, as per Example 14) is added to 27.5 g DI water in a 250 mL round bottom flask. The solution is stirred for about 4 hours at room temperature. 16 g denatured ethanol is added and the mixture is stirred for about 18 hrs at which point the material had dissolved. The flask is then purged with nitrogen and then placed in a water bath (temp - 30 ± 2 °C). 1.0 g DSPE-PEG-thiol (BroadPharm) in 6 g ethanol is then added to the solution of derivatized HA. The pH of the reaction mixture is adjusted to about 9.5 using 0.25 M NaOH. The solution is stirred for 24 hours after which the pH is adjusted to about 7 using 0.25 M HCL About 0.25 g NaCI is added to the reaction solution. The solution is stirred until the NaCI had dissolved. 150 mL cold acetone is slowly added to the solution. The reaction mixture is stirred for 1.5 hours. The precipitate is isolated using vacuum filtration. The precipitate is washed 4 times with 25 mL ethanol in such a manner that the filter funnel did not run dry. The precipitate is dried under vacuum at room temperature.
EXAMPLE 33
Liposomes
[00369] l,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) and 1,2-distearoyl-sn- glycero-3-phospho-(l'-rac-glycerol) (DSPG) are dissolved in a 65:35:8 mixture of chloroform, methanol and deionized water. Cholesterol and l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) is dissolved in chloroform. A lipid mixture composed of 31 mol% DSPC, 31 mol% cholesterol, 31 mol% DSPG and 6 mol% DSPE is prepared by adding the appropriate amounts of each solution in 50 mL round bottom flask and methanol is added dropwise until the solution becomes clear. The solvent is removed using a BUCHI rotovap system under heat (~60 -C) until dry (<16 mBarr) to make a thin lipid film. A Branson sonicator bath is filled with mi I liQ. water and heated until >65-C. A 0.01% (w/w) solution of the cholesterol HA derivative (above) is prepared using deionized water. The round bottom flask containing the lipid film is partially submerged in the water bath and cholesterol HA derivative solution is added to re-suspend the lipid film to a concentration of 2 mg lipid/mL solution. The solution is sonicated for 1 minute and then removed for 2 minute. This step is repeated three times and is then transferred to an Avestin LiposoFast LF-50 liposome extruder. The extruder is connected to a heated recirculator bath to maintain a temperature > 655C throughout the extruder. The liposome solution is extruded through sequentially smaller nucleopore membranes until a 50-100 nm liposome is obtained. This usually requires two passes through a stack of one 400 and one 200 nm membrane followed by two passes through one 100 nm membrane and two passes through a 50 nm membrane.
[00370] The liposome manufacturing process is repeated using the DSPE derivatized HA (above), the Cholesterol-PEG derivatized HA (abovr) and the DSPE-PEG derivatized HA (above). The liposome manufacturing process is repeated using each of the above HA derivatives with paclitaxel being added to the initial lipid chloroform solution such that the final paclitaxel concentration is 0.02 mg/mL. The liposome manufacturing process is repeated using each of the above HA derivatives with RNA being added to the HA derivative solution.
Example 34
[00371] A neutral lipid DOPE (l,2-dioleoyl-sn-glycero-3-phosphoethanolamine, Sigma, USA) and a cationic lipid DOTAP (N-[l-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride, Sigma, USA) are dissolved in chloroform. The lipid solutions are mixed in required ratios
to provide DOTAP:DOPE at a 1:1 weight ratio in a 50 mL round bottom flask. The solvent is removed using a rotavap and the lipid film is placed under vacuum overnight. A 0.1% (w/w) solution of the cholesterol HA derivative (above) is prepared using deionized water. The appropriate amount of HA derivative solution is added to dried lipid films to produce final lipid concentrations of 12 mg/mL. The solution is vortexed for 1 min and then sonicated at 40 °C for 20 min in a sonication bath. The liposome manufacturing process is repeated using the DSPE derivatized HA (above), the Cholesterol-PEG derivatized HA (above) and the DSPE-PEG derivatized HA (above). The liposome manufacturing process is repeated separately using each of the above HA derivatives with RNA being added to each of the HA derivative solution.
EXAMPLE 35
[00372] Lipid nanoparticles are prepared using ionizable lipid SM-102 (Heptadecan-9-yl 8- {(2-hydroxyethyl)[6-oxo-6-(undecyloxy)hexyl]amino}octa noate, BroadPharm), distearoylphosphatidylcholine (DSPC), and cholesterol at a molar ratio of 55:10:35. (SM- 102:DSPC:cholesterol). RNA is used at a lipid nitrogen to RNA phosphate ratio of 3 (approx, weight ratio of 10:1 of total lipid:RNA. A RNA solution at ~1 mg/ml is prepared in 10 mmol/l citrate buffer, pH 4. The lipids are dissolved in ethanol in the appropriate ratios. The syringes containing RNA solution and lipid solution are placed in a syringe pump and are connected to a union connector (0.05 in thru hole, #P-728; IDEX Health & Science, Oak Harbor, WA) with PEEK high-performance liquid chromatography tubing (0.02 in ID for siRNA solution and 0.01 in ID for lipid solution). The outlet of the union connector is connected to a length of PEEK high- performance liquid chromatography tubing (0.04 in ID). The end of the tubing is placed in a collection tube. The RNA solution and lipid solution are set at 15 and 5 ml/min, respectively and the two solutions are mixed and collected in the collection tube. A solution of the Cholesterol derivatized HA (Example 33) is added to the solution such that the HA cholesterol derivative to total lipid ratio is 40:1 on a weight basis. The resultant solution is vortexed for 10 minutes and left for 2hrs. The resultant solution is dialyzed (Spectra/Por MWCO 6000 to 8000) against phosphate-buffered saline (155 mmol/l NaCI, 3 mmol/l Na2HPO4, 1 mmol/l KH2PO4, pH 7.2). The lipid particle manufacturing process is repeated using the DSPE derivatized HA (above), the Cholesterol-PEG derivatized HA (Example 35) and the DSPE-PEG derivatized HA (above).
EXAMPLE 36
[00373] 0.3 g glycerin. 0.04 g mercaptobenzoic acid derivatized hyaluronic acid, 0.16 g d- panthenol, 0.1 g sharomix preservative were added together. 8.4 g deionized water was added to the mixture. The mixture was stirred for 24hr to generate a cosmetic HA containing serum solution. The process was repeated using the octane derivatized HA (above), the 9-mercapto-l- nonanol HA derivative (Example 25) and the lipid derivatized HA (above).
Example 37
[00374] Dissolve 0.15 g mercapto-l-nonanol HA derivative (above) in 45 g rose hydrosol and, 15 g distilled water. Once dissolved, heat the solution to about 65°C using a water bath. Heat 15 g avocado Oil, 10 g wheatgerm oil, 15 g emulsifying wax NF,1 g vitamin E oil to about 65°C using a water bath. Once the emulsifying wax has melted remove both containers from the water bath. Place a high-speed mixer impellor into the aqueous solution. Turn on the mixer to get a vigorous stir and then slowly add the warm oil phase. Mix it for at least 3 minutes. Reduce the speed and continue to stir until the cream cools to below 45C. Add 1 g phenoxyethanol to the cream and continue mixing for 3 minutes. Half of the cream is removed and 2 drops Rose Essential Oil and 1 drop Frankincense Essential Oil is added to the remaining cream. Stirring is continued for 3 minutes.
[00375] All references disclosed herein, including patent references and non-patent references, are hereby incorporated by reference in their entirety as if each was incorporated individually.
[00376] It is to be understood that the terminology used herein is for the purpose of describing specific aspects only and is not intended to be limiting. It is further to be understood that unless specifically defined herein, the terminology used herein is to be given its traditional meaning as known in the relevant art.
[00377] Reference throughout this specification to "one aspect" or "an aspect" and variations thereof means that a particular feature, structure, or characteristic described in connection with the aspect is included in at least one aspect. Thus, the appearances of the phrases "in one aspect" or "in an aspect" in various places throughout this specification are not necessarily all referring to the same aspect. Furthermore, the particular features, structures, or
characteristics may be combined in any suitable manner in one or more aspects.
[00378] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents, i.e., one or more, unless the content and context clearly dictates otherwise. It should also be noted that the conjunctive terms, "and" and "or" are generally employed in the broadest sense to include "and/or" unless the content and context clearly dictates inclusivity or exclusivity as the case may be. Thus, the use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives. In addition, the composition of "and" and "or" when recited herein as "and/or" is intended to encompass an aspect that includes all of the associated items or ideas and one or more other alternative aspects that include fewer than all of the associated items or ideas.
[00379] Unless the context requires otherwise, throughout the specification and claims that follow, the word "comprise" and synonyms and variants thereof such as "have" and "include", as well as variations thereof such as "comprises" and "comprising" are to be construed in an open, inclusive sense, e.g., "including, but not limited to." The term "consisting essentially of" limits the scope of a claim to the specified materials or steps, or to those that do not materially affect the basic and novel characteristics of the claimed disclosure.
[00380] Any headings used within this document are only being utilized to expedite its review by the reader, and should not be construed as limiting the disclosure or claims in any manner. Thus, the headings and Abstract of the Disclosure provided herein are for convenience only and do not interpret the scope or meaning of the aspects.
[00381] Where a range of values is provided herein, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.
[00382] For example, any concentration range, percentage range, ratio range, or integer
range provided herein is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. Also, any number range recited herein relating to any physical feature, such as polymer subunits, size or thickness, are to be understood to include any integer within the recited range, unless otherwise indicated. As used herein, the term "about" means ± 20% of the indicated range, value, or structure, unless otherwise indicated.
[00383] All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, are incorporated herein by reference, in their entirety. Such documents may be incorporated by reference for the purpose of describing and disclosing, for example, materials and methodologies described in the publications, which might be used in connection with the presently described disclosure. The publications discussed above and throughout the text are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate any referenced publication by virtue of prior disclosure.
[00384] All patents, publications, scientific articles, web sites, and other documents and materials referenced or mentioned herein are indicative of the levels of skill of those skilled in the art to which the disclosure pertains, and each such referenced document and material is hereby incorporated by reference to the same extent as if it had been incorporated by reference in its entirety individually or set forth herein in its entirety. Applicants reserve the right to physically incorporate into this specification any and all materials and information from any such patents, publications, scientific articles, web sites, electronically available information, and other referenced materials or documents.
[00385] In general, in the following claims, the terms used should not be construed to limit the claims to the specific aspects disclosed in the specification and the claims, but should be construed to include all possible aspects along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.
[00386] Furthermore, the written description portion of this patent includes all claims.
Furthermore, all claims, including all original claims as well as all claims from any and all priority documents, are hereby incorporated by reference in their entirety into the written description portion of the specification, and Applicants reserve the right to physically incorporate into the written description or any other portion of the application, any and all such claims. Thus, for example, under no circumstances may the patent be interpreted as allegedly not providing a written description for a claim on the assertion that the precise wording of the claim is not set forth in haec verba in written description portion of the patent.
[00387] The claims will be interpreted according to law. However, and notwithstanding the alleged or perceived ease or difficulty of interpreting any claim or portion thereof, under no circumstances may any adjustment or amendment of a claim or any portion thereof during prosecution of the application or applications leading to this patent be interpreted as having forfeited any right to any and all equivalents thereof that do not form a part of the prior art.
[00388] Other nonlimiting aspects are within the following claims. The patent may not be interpreted to be limited to the specific examples or nonlimiting aspects or methods specifically and/or expressly disclosed herein. Under no circumstances may the patent be interpreted to be limited by any statement made by any Examiner or any other official or employee of the Patent and Trademark Office unless such statement is specifically and without qualification or reservation expressly adopted in a responsive writing by Applicants.
Claims
1. A composition comprising a hyaluronic acid polymer derivative comprising one or more modified hydroxyl groups, wherein the hyaluronic acid polymer derivative has the formula:
A) HA-(OCH2CH2SO2CH2CH2-X-R1-Y)n, where HA is hyaluronic acid, X is S or NH, R1 is a substituted or unsubstituted C8-C20 aliphatic with at least four consecutive -CH2- groups, a cholesterol moiety, or a lipid moiety, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group, and n is the number of modified hydroxyl groups where n > 1; or
B) (Y-R2-X-CH2CH2SO2CH2CH2O)m-HA-(OCH2CH2SO2CH2CH2-X-R1-Y)n, where HA is hyaluronic acid, X is S or NH, R1 and R2 are each a substituted or unsubstituted C8-C20 aliphatic with at least four consecutive -CH2- groups, a cholesterol moiety, or a lipid moiety, wherein R1 and R2 are different from each other, Y may be the same or different, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group, or an amine group, and n > land m > 1; or
C) (CH2=CH-SO2CH2CH2O)m-HA-(OCH2CH2SO2CH2CH2-X-R1-Y)n, where HA is hyaluronic acid, X is S or NH, R1 is a substituted or unsubstituted C8-C2o aliphatic with at least four consecutive -CH2- groups, a cholesterol moiety, or a lipid moiety ,Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group, and n > 1 and m > 1; and a lipid.
2. The composition of Claim 1, wherein 0.25-50% of the hydroxyl groups of non-derivatized hyaluronic acid are a modified hydroxyl group.
3. The composition of Claim 1, wherein R1 is a lipid moiety.
4. The composition of Claim 1, wherein R1 is a lipid-polyethylene glycol moiety.
5. The composition of Claim 1, wherein the lipid is a phospholipid.
6. The composition of claim 1, wherein the lipid is an ionizable lipid.
7. The composition of Claim 1, wherein the composition comprises cholesterol.
8. The composition of Claim 1, wherein the composition is in the form of a liposome.
9. The composition of Claim 1, wherein the composition is in the form of a lipid nanoparticle.
10. The composition of Claim 1, wherein the composition further comprises a biologically active agent.
11. The composition of Claim 10, wherein the biologically active agent is RNA.
12. The composition of Claim 10, wherein the biologically active agent is a chemotherapeutic agent.
13. A composition comprising a hyaluronic acid polymer derivative comprising one or more modified hydroxyl groups, wherein the hyaluronic acid polymer derivative has the formula:
A) HA-(OCH2CH2SO2CH2CH2-X-R1-Y)n, where HA is hyaluronic acid, X is S or NH, R1 is a substituted or unsubstituted Cs-C2o aliphatic with at least four consecutive -CH2- groups, a cholesterol moiety, or a lipid moiety, Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group, and n is the number of modified hydroxyl groups where n > 1; or
B) (Y-R2-X-CH2CH2SO2CH2CH2O)m-HA-(OCH2CH2SO2CH2CH2-X-R1-Y)n, where HA is hyaluronic acid, X is S or NH, R1 and R2 are each a substituted or unsubstituted C8-C2o aliphatic with at least four consecutive -CH2- groups, a cholesterol moiety, or a lipid moiety, wherein R1 and R2 are different from each other, Y may be the same or different, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group, or an amine group, and n > land m > 1; or
C) (CH2=CH-SO2CH2CH2O)m-HA-(OCH2CH2SO2CH2CH2-X-R1-Y)n, where HA is hyaluronic acid, X is S or NH, R1 is a substituted or unsubstituted Cs-C2o aliphatic with at least four consecutive -CH2- groups, a cholesterol moiety, or a lipid moiety, Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group, and n > 1 and m > 1; and an oil phase.
14. A composition comprising a hyaluronic acid polymer derivative comprising one or more modified hydroxyl groups, wherein the hyaluronic acid polymer derivative has the formula:
A) HA-(OCH2CH2SO2CH2CH2-X-R1-Y)n, where HA is hyaluronic acid, X is S or NH, R1 is a substituted or unsubstituted C8-C20 aliphatic with at least four consecutive -CH2- groups, a
cholesterol moiety, or a lipid moiety, Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group, and n is the number of modified hydroxyl groups where n > 1; or
B) (y-R2-X-CH2CH2SO2CH2CH2O)m-HA-(OCH2CH2SO2CH2CH2-X-R1-Y)n, where HA is hyaluronic acid, X is S or NH, R1 and R2 are each a substituted or unsubstituted Cs-C2o aliphatic with at least four consecutive -CH2- groups, a cholesterol moiety, or a lipid moiety, wherein R1 and R2 are different from each other, Y may be the same or different, and Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group, or an amine group, and n > land m > 1; or
C) (CH2=CH-SO2CH2CH2O)m-HA-(OCH2CH2SO2CH2CH2-X-R1-Y)n, where HA is hyaluronic acid, X is S or NH, R1 is a substituted or unsubstituted C8-C20 aliphatic with at least four consecutive -CH2- groups, a cholesterol moiety, or a lipid moiety, Y is one or more of H, a carboxylic acid group or a salt or ester thereof, a hydroxyl group, a sulfonic acid group or a salt thereof, or an amine group, and n > 1 and m > 1; and a water phase.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202263394148P | 2022-08-01 | 2022-08-01 | |
US63/394,148 | 2022-08-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2024030437A1 true WO2024030437A1 (en) | 2024-02-08 |
Family
ID=89849608
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2023/029224 WO2024030437A1 (en) | 2022-08-01 | 2023-08-01 | Functionalized and crosslinked polymer methods and compositions |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2024030437A1 (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8790702B2 (en) * | 2009-07-30 | 2014-07-29 | Carbylan Therapeutics, Inc. | Modified hyaluronic acid polymer compositions and related methods |
US20200190225A1 (en) * | 2017-09-01 | 2020-06-18 | Pmidg, Llc | Functionalized and crosslinked polymers |
WO2022120097A1 (en) * | 2020-12-03 | 2022-06-09 | Pmidg, Llc | Functionalized and crosslinked polymers |
-
2023
- 2023-08-01 WO PCT/US2023/029224 patent/WO2024030437A1/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8790702B2 (en) * | 2009-07-30 | 2014-07-29 | Carbylan Therapeutics, Inc. | Modified hyaluronic acid polymer compositions and related methods |
US9192678B2 (en) * | 2009-07-30 | 2015-11-24 | Carbylan Therapeutics, Inc. | Modified hyaluronic acid polymer compositions and related methods |
US20200190225A1 (en) * | 2017-09-01 | 2020-06-18 | Pmidg, Llc | Functionalized and crosslinked polymers |
WO2022120097A1 (en) * | 2020-12-03 | 2022-06-09 | Pmidg, Llc | Functionalized and crosslinked polymers |
Non-Patent Citations (1)
Title |
---|
DATABASE PUBCHEM COMPOUND 21 August 2021 (2021-08-21), ANONYMOUS : "SCHEMBL23251210", XP093137211, retrieved from PUBCHEM Database accession no. 442480226 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20230312764A1 (en) | Functionalized and crosslinked polymers | |
KR102049124B1 (en) | Threads of cross-linked hyaluronic acid and methods of use thereof | |
JP6986758B2 (en) | Dendrimer-Bioadhesive Polymer Hydrogel Nano Adhesive and Its Use | |
CA2583561C (en) | Biocompatible protein particles, particle devices and methods thereof | |
CA2537315C (en) | Protein biomaterials and biocoacervates and methods of making and using thereof | |
US20070160647A1 (en) | Materials for medical implants and occlusive devices | |
CN106913902A (en) | Polysaccharide based aquagel | |
WO2008103045A1 (en) | A controlled release composition comprising a recombinant gelatin | |
EP2237770A2 (en) | Biocompatible protein particles, particle devices and methods thereof | |
EP3979947A1 (en) | Methods, devices and compositions for local delivery | |
US20200316265A1 (en) | Multiphase gel | |
US20240033283A1 (en) | Functionalized and crosslinked polymers | |
US20110182813A1 (en) | Amphiphilic copolymers and compositions containing such polymers | |
WO2024030437A1 (en) | Functionalized and crosslinked polymer methods and compositions | |
WO2020050779A1 (en) | Hydrogels with tunable electrostatic properties | |
AU2004279349B2 (en) | Protein biomaterials and biocoacervates and methods of making and using thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23850683 Country of ref document: EP Kind code of ref document: A1 |