US20230293344A1 - Punctal implants with controlled drug delivery features and methods of using same - Google Patents
Punctal implants with controlled drug delivery features and methods of using same Download PDFInfo
- Publication number
- US20230293344A1 US20230293344A1 US18/158,705 US202318158705A US2023293344A1 US 20230293344 A1 US20230293344 A1 US 20230293344A1 US 202318158705 A US202318158705 A US 202318158705A US 2023293344 A1 US2023293344 A1 US 2023293344A1
- Authority
- US
- United States
- Prior art keywords
- implant
- drug
- drugs
- eye
- agents
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000007943 implant Substances 0.000 title claims abstract description 310
- 238000000034 method Methods 0.000 title abstract description 25
- 238000012377 drug delivery Methods 0.000 title abstract description 20
- 239000000599 controlled substance Substances 0.000 title description 2
- 239000003814 drug Substances 0.000 claims abstract description 479
- 229940079593 drug Drugs 0.000 claims abstract description 416
- 238000010828 elution Methods 0.000 claims description 67
- 241000083513 Punctum Species 0.000 claims description 38
- 239000003826 tablet Substances 0.000 claims description 28
- 230000014759 maintenance of location Effects 0.000 claims description 26
- 238000003780 insertion Methods 0.000 claims description 12
- 230000037431 insertion Effects 0.000 claims description 12
- 210000000744 eyelid Anatomy 0.000 claims description 8
- 230000007423 decrease Effects 0.000 claims description 6
- 238000011282 treatment Methods 0.000 abstract description 15
- 208000022873 Ocular disease Diseases 0.000 abstract description 5
- 208000024891 symptom Diseases 0.000 abstract description 5
- 230000009467 reduction Effects 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 230000002265 prevention Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 description 96
- 210000001508 eye Anatomy 0.000 description 64
- -1 etc.) Substances 0.000 description 63
- 229940124597 therapeutic agent Drugs 0.000 description 59
- 239000003795 chemical substances by application Substances 0.000 description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- 229920000642 polymer Polymers 0.000 description 37
- 239000000203 mixture Substances 0.000 description 29
- 150000003839 salts Chemical class 0.000 description 23
- 210000001519 tissue Anatomy 0.000 description 20
- 239000012530 fluid Substances 0.000 description 19
- 239000000546 pharmaceutical excipient Substances 0.000 description 17
- 150000003431 steroids Chemical class 0.000 description 17
- 238000000576 coating method Methods 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 16
- 238000002513 implantation Methods 0.000 description 15
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical class 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 description 14
- 239000012528 membrane Substances 0.000 description 14
- 239000002105 nanoparticle Substances 0.000 description 14
- 230000001225 therapeutic effect Effects 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- 230000006870 function Effects 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000003112 inhibitor Substances 0.000 description 12
- 230000007170 pathology Effects 0.000 description 12
- 239000004094 surface-active agent Substances 0.000 description 12
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 11
- 108010036949 Cyclosporine Proteins 0.000 description 11
- 210000002159 anterior chamber Anatomy 0.000 description 11
- 229920001577 copolymer Polymers 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 11
- 229920001296 polysiloxane Polymers 0.000 description 11
- 229940126585 therapeutic drug Drugs 0.000 description 11
- 210000004083 nasolacrimal duct Anatomy 0.000 description 10
- 239000008188 pellet Substances 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 10
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 9
- 229960001265 ciclosporin Drugs 0.000 description 9
- 229930182912 cyclosporin Natural products 0.000 description 9
- 230000035699 permeability Effects 0.000 description 9
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 8
- 102000008186 Collagen Human genes 0.000 description 8
- 108010035532 Collagen Proteins 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 229930182558 Sterol Natural products 0.000 description 8
- 239000011248 coating agent Substances 0.000 description 8
- 229920001436 collagen Polymers 0.000 description 8
- 235000014113 dietary fatty acids Nutrition 0.000 description 8
- 239000000194 fatty acid Substances 0.000 description 8
- 229930195729 fatty acid Natural products 0.000 description 8
- 150000004665 fatty acids Chemical class 0.000 description 8
- 238000004108 freeze drying Methods 0.000 description 8
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 8
- 229920001223 polyethylene glycol Polymers 0.000 description 8
- 229920002635 polyurethane Polymers 0.000 description 8
- 239000004814 polyurethane Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 150000003432 sterols Chemical class 0.000 description 8
- 235000003702 sterols Nutrition 0.000 description 8
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 description 7
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 7
- 235000012000 cholesterol Nutrition 0.000 description 7
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical class C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 description 7
- 239000000017 hydrogel Substances 0.000 description 7
- 230000001965 increasing effect Effects 0.000 description 7
- 230000000670 limiting effect Effects 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- BQPPJGMMIYJVBR-UHFFFAOYSA-N (10S)-3c-Acetoxy-4.4.10r.13c.14t-pentamethyl-17c-((R)-1.5-dimethyl-hexen-(4)-yl)-(5tH)-Delta8-tetradecahydro-1H-cyclopenta[a]phenanthren Natural products CC12CCC(OC(C)=O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C BQPPJGMMIYJVBR-UHFFFAOYSA-N 0.000 description 6
- CHGIKSSZNBCNDW-UHFFFAOYSA-N (3beta,5alpha)-4,4-Dimethylcholesta-8,24-dien-3-ol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21 CHGIKSSZNBCNDW-UHFFFAOYSA-N 0.000 description 6
- XYTLYKGXLMKYMV-UHFFFAOYSA-N 14alpha-methylzymosterol Natural products CC12CCC(O)CC1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C XYTLYKGXLMKYMV-UHFFFAOYSA-N 0.000 description 6
- FPTJELQXIUUCEY-UHFFFAOYSA-N 3beta-Hydroxy-lanostan Natural products C1CC2C(C)(C)C(O)CCC2(C)C2C1C1(C)CCC(C(C)CCCC(C)C)C1(C)CC2 FPTJELQXIUUCEY-UHFFFAOYSA-N 0.000 description 6
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 6
- 206010013774 Dry eye Diseases 0.000 description 6
- 208000010412 Glaucoma Diseases 0.000 description 6
- BKLIAINBCQPSOV-UHFFFAOYSA-N Gluanol Natural products CC(C)CC=CC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(O)C(C)(C)C4CC3 BKLIAINBCQPSOV-UHFFFAOYSA-N 0.000 description 6
- LOPKHWOTGJIQLC-UHFFFAOYSA-N Lanosterol Natural products CC(CCC=C(C)C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 LOPKHWOTGJIQLC-UHFFFAOYSA-N 0.000 description 6
- 206010025421 Macule Diseases 0.000 description 6
- CAHGCLMLTWQZNJ-UHFFFAOYSA-N Nerifoliol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C CAHGCLMLTWQZNJ-UHFFFAOYSA-N 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- BHYOQNUELFTYRT-DPAQBDIFSA-N cholesterol sulfate Chemical compound C1C=C2C[C@@H](OS(O)(=O)=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 BHYOQNUELFTYRT-DPAQBDIFSA-N 0.000 description 6
- 210000004087 cornea Anatomy 0.000 description 6
- 238000009792 diffusion process Methods 0.000 description 6
- QBSJHOGDIUQWTH-UHFFFAOYSA-N dihydrolanosterol Natural products CC(C)CCCC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 QBSJHOGDIUQWTH-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
- 229940058690 lanosterol Drugs 0.000 description 6
- CAHGCLMLTWQZNJ-RGEKOYMOSA-N lanosterol Chemical compound C([C@]12C)C[C@@H](O)C(C)(C)[C@H]1CCC1=C2CC[C@]2(C)[C@H]([C@H](CCC=C(C)C)C)CC[C@@]21C CAHGCLMLTWQZNJ-RGEKOYMOSA-N 0.000 description 6
- 238000000465 moulding Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 239000000919 ceramic Substances 0.000 description 5
- 238000013329 compounding Methods 0.000 description 5
- 238000013270 controlled release Methods 0.000 description 5
- 239000003889 eye drop Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000011159 matrix material Substances 0.000 description 5
- 230000003204 osmotic effect Effects 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- 150000003180 prostaglandins Chemical class 0.000 description 5
- 210000001525 retina Anatomy 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000004489 tear production Effects 0.000 description 5
- 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 4
- 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 4
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 4
- 239000002033 PVDF binder Substances 0.000 description 4
- 239000004696 Poly ether ether ketone Substances 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 239000004743 Polypropylene Substances 0.000 description 4
- 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 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- 239000004599 antimicrobial Substances 0.000 description 4
- 210000001742 aqueous humor Anatomy 0.000 description 4
- 230000005540 biological transmission Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 210000004240 ciliary body Anatomy 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
- 238000006731 degradation reaction Methods 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- BFMKFCLXZSUVPI-UHFFFAOYSA-N ethyl but-3-enoate Chemical compound CCOC(=O)CC=C BFMKFCLXZSUVPI-UHFFFAOYSA-N 0.000 description 4
- 229940012356 eye drops Drugs 0.000 description 4
- 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 4
- 230000004410 intraocular pressure Effects 0.000 description 4
- 229960001160 latanoprost Drugs 0.000 description 4
- 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 4
- 239000002502 liposome Substances 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 229960002446 octanoic acid Drugs 0.000 description 4
- 210000001328 optic nerve Anatomy 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 4
- 229920002530 polyetherether ketone Polymers 0.000 description 4
- 239000004926 polymethyl methacrylate Substances 0.000 description 4
- 229920001155 polypropylene Polymers 0.000 description 4
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 4
- 239000004810 polytetrafluoroethylene Substances 0.000 description 4
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 229960002117 triamcinolone acetonide Drugs 0.000 description 4
- 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 4
- 150000003673 urethanes Chemical class 0.000 description 4
- 230000000007 visual effect Effects 0.000 description 4
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- BTEISVKTSQLKST-UHFFFAOYSA-N Haliclonasterol Natural products CC(C=CC(C)C(C)(C)C)C1CCC2C3=CC=C4CC(O)CCC4(C)C3CCC12C BTEISVKTSQLKST-UHFFFAOYSA-N 0.000 description 3
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 3
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 3
- 229920002562 Polyethylene Glycol 3350 Polymers 0.000 description 3
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 3
- 239000004642 Polyimide Substances 0.000 description 3
- 239000004721 Polyphenylene oxide Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000004098 Tetracycline Substances 0.000 description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 210000003484 anatomy Anatomy 0.000 description 3
- 230000001028 anti-proliverative effect Effects 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 229940121375 antifungal agent Drugs 0.000 description 3
- 239000003443 antiviral agent Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000003613 bile acid Chemical class 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 229940080277 cholesteryl sulfate Drugs 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 229960003957 dexamethasone Drugs 0.000 description 3
- 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 3
- 229940088598 enzyme Drugs 0.000 description 3
- 238000001125 extrusion Methods 0.000 description 3
- 239000003527 fibrinolytic agent Substances 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- 238000011010 flushing procedure Methods 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 229920000669 heparin Polymers 0.000 description 3
- 229960001680 ibuprofen Drugs 0.000 description 3
- 230000002519 immonomodulatory effect Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 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 3
- 208000014674 injury Diseases 0.000 description 3
- 229910010272 inorganic material Inorganic materials 0.000 description 3
- 239000011147 inorganic material Substances 0.000 description 3
- 239000004310 lactic acid Substances 0.000 description 3
- 235000014655 lactic acid Nutrition 0.000 description 3
- 150000002739 metals Chemical class 0.000 description 3
- 239000004005 microsphere Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 210000003205 muscle Anatomy 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
- 229910001000 nickel titanium Inorganic materials 0.000 description 3
- 229940068065 phytosterols Drugs 0.000 description 3
- 229920000747 poly(lactic acid) Polymers 0.000 description 3
- 229920000570 polyether Polymers 0.000 description 3
- 229920001721 polyimide Polymers 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 150000004671 saturated fatty acids Chemical class 0.000 description 3
- 210000003786 sclera Anatomy 0.000 description 3
- 229920002379 silicone rubber Polymers 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 235000019364 tetracycline Nutrition 0.000 description 3
- 150000003522 tetracyclines Chemical class 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 230000008733 trauma Effects 0.000 description 3
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 2
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 2
- MCKJPJYRCPANCC-XLXYOEISSA-N (8s,9s,10r,11s,13s,14s,17r)-11,17-dihydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthrene-17-carboxylic acid Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(O)=O)[C@@H]4[C@@H]3CCC2=C1 MCKJPJYRCPANCC-XLXYOEISSA-N 0.000 description 2
- YWWVWXASSLXJHU-AATRIKPKSA-N (9E)-tetradecenoic acid Chemical compound CCCC\C=C\CCCCCCCC(O)=O YWWVWXASSLXJHU-AATRIKPKSA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- BQCIDUSAKPWEOX-UHFFFAOYSA-N 1,1-Difluoroethene Chemical compound FC(F)=C BQCIDUSAKPWEOX-UHFFFAOYSA-N 0.000 description 2
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-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
- 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
- CNIIGCLFLJGOGP-UHFFFAOYSA-N 2-(1-naphthalenylmethyl)-4,5-dihydro-1H-imidazole Chemical compound C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 CNIIGCLFLJGOGP-UHFFFAOYSA-N 0.000 description 2
- CTPDSKVQLSDPLC-UHFFFAOYSA-N 2-(oxolan-2-ylmethoxy)ethanol Chemical compound OCCOCC1CCCO1 CTPDSKVQLSDPLC-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- SGNBVLSWZMBQTH-ZRUUVFCLSA-N 24-epicampesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@H](C)C(C)C)[C@@]1(C)CC2 SGNBVLSWZMBQTH-ZRUUVFCLSA-N 0.000 description 2
- VHRSUDSXCMQTMA-PJHHCJLFSA-N 6alpha-methylprednisolone 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@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 description 2
- WLCZTRVUXYALDD-IBGZPJMESA-N 7-[[(2s)-2,6-bis(2-methoxyethoxycarbonylamino)hexanoyl]amino]heptoxy-methylphosphinic acid Chemical compound COCCOC(=O)NCCCC[C@H](NC(=O)OCCOC)C(=O)NCCCCCCCOP(C)(O)=O WLCZTRVUXYALDD-IBGZPJMESA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical class [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=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-KKGHZKTASA-N 0.000 description 2
- 108010001478 Bacitracin Proteins 0.000 description 2
- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- SGNBVLSWZMBQTH-FGAXOLDCSA-N Campesterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]([C@H](CC[C@H](C(C)C)C)C)CC4)CC3)CC=2)CC1 SGNBVLSWZMBQTH-FGAXOLDCSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 108091006146 Channels Proteins 0.000 description 2
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 2
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 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
- 229930105110 Cyclosporin A Natural products 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-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
- 108010008165 Etanercept Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 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 2
- 229930182566 Gentamicin Natural products 0.000 description 2
- 108010026389 Gramicidin Proteins 0.000 description 2
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229920006370 Kynar Polymers 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 2
- 229930193140 Neomycin Natural products 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 description 2
- 229920001244 Poly(D,L-lactide) Polymers 0.000 description 2
- 229920012266 Poly(ether sulfone) PES Polymers 0.000 description 2
- 229920002614 Polyether block amide Polymers 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 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 2
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 description 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 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
- 239000004433 Thermoplastic polyurethane Substances 0.000 description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
- AVTXVDFKYBVTKR-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]phenanthren-3-yl] dihydrogen phosphate Chemical compound C1C=C2C[C@@H](OP(O)(O)=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 AVTXVDFKYBVTKR-DPAQBDIFSA-N 0.000 description 2
- CCORPVHYPHHRKB-NXUCFJMCSA-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]phenanthren-3-yl] propanoate 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](OC(=O)CC)C1 CCORPVHYPHHRKB-NXUCFJMCSA-N 0.000 description 2
- 229960004150 aciclovir Drugs 0.000 description 2
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 2
- 239000003732 agents acting on the eye Substances 0.000 description 2
- 108700025316 aldesleukin Proteins 0.000 description 2
- 229960005310 aldesleukin Drugs 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 description 2
- 239000000956 alloy Substances 0.000 description 2
- 229910045601 alloy Inorganic materials 0.000 description 2
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 2
- 229940126575 aminoglycoside Drugs 0.000 description 2
- 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 2
- 229960003942 amphotericin b Drugs 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 229940127090 anticoagulant agent Drugs 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 239000003096 antiparasitic agent Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000008135 aqueous vehicle Substances 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 239000000607 artificial tear Substances 0.000 description 2
- 229960002274 atenolol Drugs 0.000 description 2
- 229960003159 atovaquone Drugs 0.000 description 2
- KUCQYCKVKVOKAY-CTYIDZIISA-N atovaquone Chemical compound C1([C@H]2CC[C@@H](CC2)C2=C(C(C3=CC=CC=C3C2=O)=O)O)=CC=C(Cl)C=C1 KUCQYCKVKVOKAY-CTYIDZIISA-N 0.000 description 2
- 229960003071 bacitracin Drugs 0.000 description 2
- 229930184125 bacitracin Natural products 0.000 description 2
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 description 2
- 239000002876 beta blocker Substances 0.000 description 2
- 229940097320 beta blocking agent Drugs 0.000 description 2
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 description 2
- 229960002537 betamethasone Drugs 0.000 description 2
- 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 2
- 229960004324 betaxolol Drugs 0.000 description 2
- NWIUTZDMDHAVTP-UHFFFAOYSA-N betaxolol Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1CCOCC1CC1 NWIUTZDMDHAVTP-UHFFFAOYSA-N 0.000 description 2
- 229960000397 bevacizumab Drugs 0.000 description 2
- 239000003833 bile salt Substances 0.000 description 2
- 239000000560 biocompatible material Substances 0.000 description 2
- 238000006065 biodegradation reaction Methods 0.000 description 2
- 229920013641 bioerodible polymer Polymers 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000000480 calcium channel blocker Substances 0.000 description 2
- SGNBVLSWZMBQTH-PODYLUTMSA-N campesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](C)C(C)C)[C@@]1(C)CC2 SGNBVLSWZMBQTH-PODYLUTMSA-N 0.000 description 2
- 235000000431 campesterol Nutrition 0.000 description 2
- 230000001413 cellular effect 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
- 238000006243 chemical reaction Methods 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
- 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 2
- 229960003291 chlorphenamine Drugs 0.000 description 2
- WLNARFZDISHUGS-MIXBDBMTSA-N cholesteryl hemisuccinate Chemical compound C1C=C2C[C@@H](OC(=O)CCC(O)=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 WLNARFZDISHUGS-MIXBDBMTSA-N 0.000 description 2
- 210000003161 choroid Anatomy 0.000 description 2
- 229960000724 cidofovir Drugs 0.000 description 2
- 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 2
- 229960003405 ciprofloxacin Drugs 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 229960002896 clonidine Drugs 0.000 description 2
- 238000013267 controlled drug release Methods 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
- 229960001334 corticosteroids Drugs 0.000 description 2
- 229960004544 cortisone Drugs 0.000 description 2
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 description 2
- 238000011461 current therapy Methods 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 2
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 2
- 238000000151 deposition Methods 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 239000004205 dimethyl polysiloxane Substances 0.000 description 2
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- UKMSUNONTOPOIO-UHFFFAOYSA-N docosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229960003933 dorzolamide Drugs 0.000 description 2
- 229940068204 drug implant Drugs 0.000 description 2
- 239000003844 drug implant Substances 0.000 description 2
- 229960003276 erythromycin Drugs 0.000 description 2
- 229960005309 estradiol Drugs 0.000 description 2
- 229930182833 estradiol Natural products 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
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 230000004438 eyesight Effects 0.000 description 2
- 229960002390 flurbiprofen Drugs 0.000 description 2
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 2
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 150000002334 glycols Chemical class 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 229960004905 gramicidin Drugs 0.000 description 2
- ZWCXYZRRTRDGQE-SORVKSEFSA-N gramicidina Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CC=3C4=CC=CC=C4NC=3)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CC=3C4=CC=CC=C4NC=3)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CC=3C4=CC=CC=C4NC=3)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](C(C)C)NC(=O)[C@H](C)NC(=O)[C@H](NC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](NC=O)C(C)C)CC(C)C)C(=O)NCCO)=CNC2=C1 ZWCXYZRRTRDGQE-SORVKSEFSA-N 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 229960000890 hydrocortisone Drugs 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 150000002443 hydroxylamines Chemical class 0.000 description 2
- WDKXLLJDNUBYCY-UHFFFAOYSA-N ibopamine Chemical compound CNCCC1=CC=C(OC(=O)C(C)C)C(OC(=O)C(C)C)=C1 WDKXLLJDNUBYCY-UHFFFAOYSA-N 0.000 description 2
- VKOBVWXKNCXXDE-UHFFFAOYSA-N icosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCC(O)=O VKOBVWXKNCXXDE-UHFFFAOYSA-N 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection 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
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 229960001798 loteprednol Drugs 0.000 description 2
- DMKSVUSAATWOCU-HROMYWEYSA-N loteprednol etabonate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)OCCl)(OC(=O)OCC)[C@@]1(C)C[C@@H]2O DMKSVUSAATWOCU-HROMYWEYSA-N 0.000 description 2
- 229960003744 loteprednol etabonate Drugs 0.000 description 2
- 208000002780 macular degeneration Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- 229960004584 methylprednisolone Drugs 0.000 description 2
- 229960004857 mitomycin Drugs 0.000 description 2
- 229960004270 nabumetone Drugs 0.000 description 2
- 239000002077 nanosphere Substances 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
- 229960004927 neomycin Drugs 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-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
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 229940023490 ophthalmic product Drugs 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- SECPZKHBENQXJG-FPLPWBNLSA-N palmitoleic acid Chemical compound CCCCCC\C=C/CCCCCCCC(O)=O SECPZKHBENQXJG-FPLPWBNLSA-N 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 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
- 229960001802 phenylephrine Drugs 0.000 description 2
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 2
- 108091008695 photoreceptors Proteins 0.000 description 2
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 2
- 229960001697 physostigmine Drugs 0.000 description 2
- 210000001127 pigmented epithelial cell Anatomy 0.000 description 2
- 229960001416 pilocarpine Drugs 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 2
- 229920001610 polycaprolactone Polymers 0.000 description 2
- 229920000728 polyester Polymers 0.000 description 2
- 229920000098 polyolefin Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 229960005205 prednisolone Drugs 0.000 description 2
- 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 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 229960003387 progesterone Drugs 0.000 description 2
- 239000000186 progesterone Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-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
- 210000001747 pupil Anatomy 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
- 239000002516 radical scavenger Substances 0.000 description 2
- 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 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin 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\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 2
- 229960001225 rifampicin Drugs 0.000 description 2
- 229960001860 salicylate Drugs 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 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
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- LIVNPJMFVYWSIS-UHFFFAOYSA-N silicon monoxide Chemical class [Si-]#[O+] LIVNPJMFVYWSIS-UHFFFAOYSA-N 0.000 description 2
- 229910052814 silicon oxide Inorganic materials 0.000 description 2
- 229910052709 silver Inorganic materials 0.000 description 2
- 239000004332 silver Substances 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- 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 2
- NLQLSVXGSXCXFE-UHFFFAOYSA-N sitosterol Natural products CC=C(/CCC(C)C1CC2C3=CCC4C(C)C(O)CCC4(C)C3CCC2(C)C1)C(C)C NLQLSVXGSXCXFE-UHFFFAOYSA-N 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 210000005070 sphincter Anatomy 0.000 description 2
- 239000003381 stabilizer Substances 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
- 239000000126 substance Substances 0.000 description 2
- SKIVFJLNDNKQPD-UHFFFAOYSA-N sulfacetamide Chemical compound CC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 SKIVFJLNDNKQPD-UHFFFAOYSA-N 0.000 description 2
- 229960002673 sulfacetamide Drugs 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 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 2
- 229960002180 tetracycline Drugs 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229920002803 thermoplastic polyurethane Polymers 0.000 description 2
- 229910052719 titanium Inorganic materials 0.000 description 2
- 239000010936 titanium 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
- 238000011200 topical administration Methods 0.000 description 2
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 2
- 229960003962 trifluridine Drugs 0.000 description 2
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 2
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- 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 1
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 1
- HMJIYCCIJYRONP-UHFFFAOYSA-N (+-)-Isradipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC2=NON=C12 HMJIYCCIJYRONP-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
- KZJWDPNRJALLNS-VPUBHVLGSA-N (-)-beta-Sitosterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]([C@H](CC[C@@H](C(C)C)CC)C)CC4)CC3)CC=2)CC1 KZJWDPNRJALLNS-VPUBHVLGSA-N 0.000 description 1
- RWTQCZGAMKTBRV-PTHRTHQKSA-N (1s,2r,5s,10s,11s,14r,15r)-2,15-dimethyl-14-[(2r)-6-methylheptan-2-yl]tetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadec-7-en-5-yl pentanoate 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](OC(=O)CCCC)C1 RWTQCZGAMKTBRV-PTHRTHQKSA-N 0.000 description 1
- CSVWWLUMXNHWSU-UHFFFAOYSA-N (22E)-(24xi)-24-ethyl-5alpha-cholest-22-en-3beta-ol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(CC)C(C)C)C1(C)CC2 CSVWWLUMXNHWSU-UHFFFAOYSA-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
- LHBOGKKAOIZYKX-SVYNMNNPSA-N (2r,3r,4r,5r)-2-(6-aminopurin-9-yl)-5-(hydroxymethyl)-3-phenyl-2-propan-2-yloxolane-3,4-diol Chemical compound C1([C@@]2(O)[C@H](O)[C@@H](CO)O[C@@]2(C(C)C)N2C3=NC=NC(N)=C3N=C2)=CC=CC=C1 LHBOGKKAOIZYKX-SVYNMNNPSA-N 0.000 description 1
- WQKLGQXWHKQTPO-UXRZSMILSA-N (2r,3s,4s,5r,6r)-2-(hydroxymethyl)-6-methoxyoxane-3,4,5-triol;2-(2-hydroxypropoxy)propan-1-ol Chemical compound CC(O)COC(C)CO.CC(O)COC(C)CO.CC(O)COC(C)CO.CC(O)COC(C)CO.CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O WQKLGQXWHKQTPO-UXRZSMILSA-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
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- OQANPHBRHBJGNZ-FYJGNVAPSA-N (3e)-6-oxo-3-[[4-(pyridin-2-ylsulfamoyl)phenyl]hydrazinylidene]cyclohexa-1,4-diene-1-carboxylic acid Chemical compound C1=CC(=O)C(C(=O)O)=C\C1=N\NC1=CC=C(S(=O)(=O)NC=2N=CC=CC=2)C=C1 OQANPHBRHBJGNZ-FYJGNVAPSA-N 0.000 description 1
- 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 1
- 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 1
- WDLWHQDACQUCJR-ZAMMOSSLSA-N (6r,7r)-7-[[(2r)-2-azaniumyl-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 WDLWHQDACQUCJR-ZAMMOSSLSA-N 0.000 description 1
- 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 1
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 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
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- NWIUTZDMDHAVTP-KRWDZBQOSA-N (S)-betaxolol Chemical compound C1=CC(OC[C@@H](O)CNC(C)C)=CC=C1CCOCC1CC1 NWIUTZDMDHAVTP-KRWDZBQOSA-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
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 1
- 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 1
- JQSAYKKFZOSZGJ-UHFFFAOYSA-N 1-[bis(4-fluorophenyl)methyl]-4-[(2,3,4-trimethoxyphenyl)methyl]piperazine Chemical compound COC1=C(OC)C(OC)=CC=C1CN1CCN(C(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 JQSAYKKFZOSZGJ-UHFFFAOYSA-N 0.000 description 1
- ZQCIPRGNRQXXSK-UHFFFAOYSA-N 1-octadecoxypropan-2-ol Chemical compound CCCCCCCCCCCCCCCCCCOCC(C)O ZQCIPRGNRQXXSK-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-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
- DBPWSSGDRRHUNT-CEGNMAFCSA-N 17α-hydroxyprogesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DBPWSSGDRRHUNT-CEGNMAFCSA-N 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
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical compound CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 description 1
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- 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 1
- 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 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
- 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
- KLEXDBGYSOIREE-UHFFFAOYSA-N 24xi-n-propylcholesterol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CCC)C(C)C)C1(C)CC2 KLEXDBGYSOIREE-UHFFFAOYSA-N 0.000 description 1
- NZJKEVWTYMOYOR-UHFFFAOYSA-N 3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanylidene-1h-quinazolin-4-one Chemical compound C1=C(Cl)C(OC)=CC(N2C(C3=CC=CC=C3NC2=S)=O)=C1Cl NZJKEVWTYMOYOR-UHFFFAOYSA-N 0.000 description 1
- RMTFNDVZYPHUEF-XZBKPIIZSA-N 3-O-methyl-D-glucose Chemical compound O=C[C@H](O)[C@@H](OC)[C@H](O)[C@H](O)CO RMTFNDVZYPHUEF-XZBKPIIZSA-N 0.000 description 1
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 1
- LZENMJMJWQSSNJ-UHFFFAOYSA-N 3H-1,2-dithiole-3-thione Chemical compound S=C1C=CSS1 LZENMJMJWQSSNJ-UHFFFAOYSA-N 0.000 description 1
- XUGISPSHIFXEHZ-UHFFFAOYSA-N 3beta-acetoxy-cholest-5-ene Natural products C1C=C2CC(OC(C)=O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 XUGISPSHIFXEHZ-UHFFFAOYSA-N 0.000 description 1
- GJOHLWZHWQUKAU-UHFFFAOYSA-N 5-azaniumylpentan-2-yl-(6-methoxyquinolin-8-yl)azanium;dihydrogen phosphate Chemical compound OP(O)(O)=O.OP(O)(O)=O.N1=CC=CC2=CC(OC)=CC(NC(C)CCCN)=C21 GJOHLWZHWQUKAU-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
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-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
- 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 1
- YWWVWXASSLXJHU-UHFFFAOYSA-N 9E-tetradecenoic acid Natural products CCCCC=CCCCCCCCC(O)=O YWWVWXASSLXJHU-UHFFFAOYSA-N 0.000 description 1
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- QYPPJABKJHAVHS-UHFFFAOYSA-N Agmatine Natural products NCCCCNC(N)=N QYPPJABKJHAVHS-UHFFFAOYSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 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
- 239000005995 Aluminium silicate Substances 0.000 description 1
- YUWPMEXLKGOSBF-GACAOOTBSA-N Anecortave acetate Chemical compound O=C1CC[C@]2(C)C3=CC[C@]4(C)[C@](C(=O)COC(=O)C)(O)CC[C@H]4[C@@H]3CCC2=C1 YUWPMEXLKGOSBF-GACAOOTBSA-N 0.000 description 1
- 102400000068 Angiostatin Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 235000019737 Animal fat Nutrition 0.000 description 1
- 108010058207 Anistreplase Proteins 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
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 description 1
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- MBUVEWMHONZEQD-UHFFFAOYSA-N Azeptin Chemical compound C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 MBUVEWMHONZEQD-UHFFFAOYSA-N 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 235000021357 Behenic acid Nutrition 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 1
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 1
- OILXMJHPFNGGTO-NRHJOKMGSA-N Brassicasterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@](C)([C@H]([C@@H](/C=C/[C@H](C(C)C)C)C)CC4)CC3)CC=2)CC1 OILXMJHPFNGGTO-NRHJOKMGSA-N 0.000 description 1
- DPUOLQHDNGRHBS-UHFFFAOYSA-N Brassidinsaeure Natural products CCCCCCCCC=CCCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-UHFFFAOYSA-N 0.000 description 1
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 1
- CKDZWMVGDHGMFR-UHFFFAOYSA-N Buttersaeure-cholesterylester Natural products C12CCC3(C)C(C(C)CCCC(C)C)CCC3C2CC=C2C1(C)CCC(OC(=O)CCC)C2 CKDZWMVGDHGMFR-UHFFFAOYSA-N 0.000 description 1
- 102100032912 CD44 antigen Human genes 0.000 description 1
- QAGYKUNXZHXKMR-UHFFFAOYSA-N CPD000469186 Natural products CC1=C(O)C=CC=C1C(=O)NC(C(O)CN1C(CC2CCCCC2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-UHFFFAOYSA-N 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 102000018208 Cannabinoid Receptor Human genes 0.000 description 1
- 108050007331 Cannabinoid receptor Proteins 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229940122072 Carbonic anhydrase inhibitor Drugs 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 108010020326 Caspofungin Proteins 0.000 description 1
- 229930186147 Cephalosporin Natural products 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
- 229920001661 Chitosan Polymers 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- 239000004099 Chlortetracycline Substances 0.000 description 1
- 239000005148 Cholesterol Benzoate Substances 0.000 description 1
- 239000005151 Cholesterol Decanoate Substances 0.000 description 1
- 239000005155 Cholesterol Propionate Substances 0.000 description 1
- BHYOQNUELFTYRT-UHFFFAOYSA-N Cholesterol sulfate Natural products C1C=C2CC(OS(O)(=O)=O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 BHYOQNUELFTYRT-UHFFFAOYSA-N 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 208000024304 Choroidal Effusions Diseases 0.000 description 1
- 208000005590 Choroidal Neovascularization Diseases 0.000 description 1
- 206010060823 Choroidal neovascularisation Diseases 0.000 description 1
- 108010005939 Ciliary Neurotrophic Factor Proteins 0.000 description 1
- 102100031614 Ciliary neurotrophic factor Human genes 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- LPZCCMIISIBREI-MTFRKTCUSA-N Citrostadienol Natural products CC=C(CC[C@@H](C)[C@H]1CC[C@H]2C3=CC[C@H]4[C@H](C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C LPZCCMIISIBREI-MTFRKTCUSA-N 0.000 description 1
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 1
- 101710152347 Cochlin Proteins 0.000 description 1
- 102100040996 Cochlin Human genes 0.000 description 1
- 102000015225 Connective Tissue Growth Factor Human genes 0.000 description 1
- 108010039419 Connective Tissue Growth Factor Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 102100034126 Cytoglobin Human genes 0.000 description 1
- 108010053020 Cytoglobin Proteins 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
- 108020004414 DNA Proteins 0.000 description 1
- ARVGMISWLZPBCH-UHFFFAOYSA-N Dehydro-beta-sitosterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)CCC(CC)C(C)C)CCC33)C)C3=CC=C21 ARVGMISWLZPBCH-UHFFFAOYSA-N 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 206010012305 Demyelination Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 206010012688 Diabetic retinal oedema Diseases 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 101150006098 Dnm1l gene Proteins 0.000 description 1
- 206010052805 Drug tolerance decreased Diseases 0.000 description 1
- 102100024827 Dynamin-1-like protein Human genes 0.000 description 1
- 101710109538 Dynamin-1-like protein Proteins 0.000 description 1
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 1
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 1
- 108010041308 Endothelial Growth Factors Proteins 0.000 description 1
- 102400001368 Epidermal growth factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- URXZXNYJPAJJOQ-UHFFFAOYSA-N Erucic acid Natural products CCCCCCC=CCCCCCCCCCCCC(O)=O URXZXNYJPAJJOQ-UHFFFAOYSA-N 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
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 102000021523 FK506 binding proteins Human genes 0.000 description 1
- 108091011114 FK506 binding proteins Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 229940123457 Free radical scavenger Drugs 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-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
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical compound [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 235000008100 Ginkgo biloba Nutrition 0.000 description 1
- 244000194101 Ginkgo biloba Species 0.000 description 1
- 241000223783 Glaucoma Species 0.000 description 1
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 description 1
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 1
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 description 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 1
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 1
- 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 1
- 108010007979 Glycocholic Acid Proteins 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- 229920001499 Heparinoid Polymers 0.000 description 1
- 108010007267 Hirudins Proteins 0.000 description 1
- 102000007625 Hirudins Human genes 0.000 description 1
- ZTVIKZXZYLEVOL-MCOXGKPRSA-N Homatropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(O)C1=CC=CC=C1 ZTVIKZXZYLEVOL-MCOXGKPRSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 1
- 101000932178 Homo sapiens Peptidyl-prolyl cis-trans isomerase FKBP4 Proteins 0.000 description 1
- 101000878253 Homo sapiens Peptidyl-prolyl cis-trans isomerase FKBP5 Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- SHBUUTHKGIVMJT-UHFFFAOYSA-N Hydroxystearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OO SHBUUTHKGIVMJT-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
- 208000001953 Hypotension 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
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 102000012355 Integrin beta1 Human genes 0.000 description 1
- 108010022222 Integrin beta1 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound 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 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 description 1
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 1
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 1
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 description 1
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 description 1
- 102000010638 Kinesin Human genes 0.000 description 1
- 108010063296 Kinesin Proteins 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 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 1
- XUIIKFGFIJCVMT-LBPRGKRZSA-N L-thyroxine Chemical compound IC1=CC(C[C@H]([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-LBPRGKRZSA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 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
- 206010023642 Lacrimation decreased Diseases 0.000 description 1
- 206010023644 Lacrimation increased Diseases 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 102000004058 Leukemia inhibitory factor Human genes 0.000 description 1
- 108090000581 Leukemia inhibitory factor Proteins 0.000 description 1
- 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 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 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
- 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 1
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-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
- 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
- 229920000168 Microcrystalline cellulose Polymers 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
- 229930192392 Mitomycin Natural products 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 102000006386 Myelin Proteins Human genes 0.000 description 1
- 108010083674 Myelin Proteins Proteins 0.000 description 1
- SJDMTGSQPOFVLR-UHFFFAOYSA-N Myristinsaeure-cholesterylester Natural products C12CCC3(C)C(C(C)CCCC(C)C)CCC3C2CC=C2C1(C)CCC(OC(=O)CCCCCCCCCCCCC)C2 SJDMTGSQPOFVLR-UHFFFAOYSA-N 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-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
- 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
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- RFDAIACWWDREDC-UHFFFAOYSA-N Na salt-Glycocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCC(O)=O)C)C1(C)C(O)C2 RFDAIACWWDREDC-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
- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- 102100035411 Neuroglobin Human genes 0.000 description 1
- 108010026092 Neuroglobin Proteins 0.000 description 1
- 108700042240 NgR(310) Ecto-Fc Proteins 0.000 description 1
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 1
- FAIIFDPAEUKBEP-UHFFFAOYSA-N Nilvadipine Chemical compound COC(=O)C1=C(C#N)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC([N+]([O-])=O)=C1 FAIIFDPAEUKBEP-UHFFFAOYSA-N 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
- 239000000006 Nitroglycerin Substances 0.000 description 1
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 206010030043 Ocular hypertension Diseases 0.000 description 1
- RJECHNNFRHZQKU-UHFFFAOYSA-N Oelsaeurecholesterylester Natural products C12CCC3(C)C(C(C)CCCC(C)C)CCC3C2CC=C2C1(C)CCC(OC(=O)CCCCCCCC=CCCCCCCCC)C2 RJECHNNFRHZQKU-UHFFFAOYSA-N 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 239000005480 Olmesartan Substances 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 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
- 239000004100 Oxytetracycline Substances 0.000 description 1
- 102400000050 Oxytocin Human genes 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
- 101800000989 Oxytocin Proteins 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 235000021319 Palmitoleic acid Nutrition 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- 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 1
- 102100020739 Peptidyl-prolyl cis-trans isomerase FKBP4 Human genes 0.000 description 1
- QZVCTJOXCFMACW-UHFFFAOYSA-N Phenoxybenzamine Chemical compound C=1C=CC=CC=1CN(CCCl)C(C)COC1=CC=CC=C1 QZVCTJOXCFMACW-UHFFFAOYSA-N 0.000 description 1
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 1
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 1
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 108010093965 Polymyxin B Proteins 0.000 description 1
- 108010040201 Polymyxins Proteins 0.000 description 1
- 229920002675 Polyoxyl Polymers 0.000 description 1
- LRJOMUJRLNCICJ-JZYPGELDSA-N Prednisolone acetate Chemical compound C1CC2=CC(=O)C=C[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 LRJOMUJRLNCICJ-JZYPGELDSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- KCLANYCVBBTKTO-UHFFFAOYSA-N Proparacaine Chemical compound CCCOC1=CC=C(C(=O)OCCN(CC)CC)C=C1N KCLANYCVBBTKTO-UHFFFAOYSA-N 0.000 description 1
- 229940127361 Receptor Tyrosine Kinase Inhibitors Drugs 0.000 description 1
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 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
- 241000283984 Rodentia Species 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 102000054727 Serum Amyloid A Human genes 0.000 description 1
- 108700028909 Serum Amyloid A Proteins 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 229920002385 Sodium hyaluronate Polymers 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 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
- 108010023197 Streptokinase Proteins 0.000 description 1
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 239000000150 Sympathomimetic Substances 0.000 description 1
- 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 1
- WBWWGRHZICKQGZ-UHFFFAOYSA-N Taurocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)C(O)C2 WBWWGRHZICKQGZ-UHFFFAOYSA-N 0.000 description 1
- 108010039185 Tenecteplase Proteins 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
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- 102000002938 Thrombospondin Human genes 0.000 description 1
- 108060008245 Thrombospondin Proteins 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 1
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- BGDKAVGWHJFAGW-UHFFFAOYSA-N Tropicamide Chemical compound C=1C=CC=CC=1C(CO)C(=O)N(CC)CC1=CC=NC=C1 BGDKAVGWHJFAGW-UHFFFAOYSA-N 0.000 description 1
- OILXMJHPFNGGTO-ZRUUVFCLSA-N UNPD197407 Natural products C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)C=C[C@H](C)C(C)C)[C@@]1(C)CC2 OILXMJHPFNGGTO-ZRUUVFCLSA-N 0.000 description 1
- HZYXFRGVBOPPNZ-UHFFFAOYSA-N UNPD88870 Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)=CCC(CC)C(C)C)C1(C)CC2 HZYXFRGVBOPPNZ-UHFFFAOYSA-N 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 description 1
- WPVFJKSGQUFQAP-GKAPJAKFSA-N Valcyte Chemical compound N1C(N)=NC(=O)C2=C1N(COC(CO)COC(=O)[C@@H](N)C(C)C)C=N2 WPVFJKSGQUFQAP-GKAPJAKFSA-N 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 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
- 206010047163 Vasospasm Diseases 0.000 description 1
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 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
- 241000700605 Viruses Species 0.000 description 1
- 206010047513 Vision blurred Diseases 0.000 description 1
- 229930003427 Vitamin E Natural products 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
- XUXXPLDKUZSGKH-OHPSOFBHSA-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]phenanthren-3-yl] 2-chloroacetate Chemical compound C1C=C2C[C@@H](OC(=O)CCl)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 XUXXPLDKUZSGKH-OHPSOFBHSA-N 0.000 description 1
- CKDZWMVGDHGMFR-GTPODGLVSA-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]phenanthren-3-yl] butanoate 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](OC(=O)CCC)C1 CKDZWMVGDHGMFR-GTPODGLVSA-N 0.000 description 1
- LJGMGXXCKVFFIS-IATSNXCDSA-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]phenanthren-3-yl] decanoate 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](OC(=O)CCCCCCCCC)C1 LJGMGXXCKVFFIS-IATSNXCDSA-N 0.000 description 1
- KXWDMNPRHKRGKB-DYQRUOQXSA-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]phenanthren-3-yl] heptanoate 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](OC(=O)CCCCCC)C1 KXWDMNPRHKRGKB-DYQRUOQXSA-N 0.000 description 1
- FPBODWXATDKICU-FLFWOSPYSA-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]phenanthren-3-yl] hexanoate 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](OC(=O)CCCCC)C1 FPBODWXATDKICU-FLFWOSPYSA-N 0.000 description 1
- ZWBTYMGEBZUQTK-PVLSIAFMSA-N [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,32-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-1'-(2-methylpropyl)-6,23-dioxospiro[8,33-dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1(32),2,4,9,19,21,24,26,30-nonaene-28,4'-piperidine]-13-yl] acetate Chemical compound CO[C@H]1\C=C\O[C@@]2(C)Oc3c(C2=O)c2c4NC5(CCN(CC(C)C)CC5)N=c4c(=NC(=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]1C)c(O)c2c(O)c3C ZWBTYMGEBZUQTK-PVLSIAFMSA-N 0.000 description 1
- 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 1
- JTLGKFXVWNCJGW-UHFFFAOYSA-N [I].P1=CCCC1 Chemical compound [I].P1=CCCC1 JTLGKFXVWNCJGW-UHFFFAOYSA-N 0.000 description 1
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 1
- 229960004748 abacavir Drugs 0.000 description 1
- 229960000446 abciximab Drugs 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- GOEMGAFJFRBGGG-UHFFFAOYSA-N acebutolol Chemical compound CCCC(=O)NC1=CC=C(OCC(O)CNC(C)C)C(C(C)=O)=C1 GOEMGAFJFRBGGG-UHFFFAOYSA-N 0.000 description 1
- 229960002122 acebutolol Drugs 0.000 description 1
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 1
- JUGOREOARAHOCO-UHFFFAOYSA-M acetylcholine chloride Chemical compound [Cl-].CC(=O)OCC[N+](C)(C)C JUGOREOARAHOCO-UHFFFAOYSA-M 0.000 description 1
- 229960004266 acetylcholine chloride Drugs 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 229960002964 adalimumab Drugs 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 229960002833 aflibercept Drugs 0.000 description 1
- 108010081667 aflibercept Proteins 0.000 description 1
- 206010064930 age-related macular degeneration Diseases 0.000 description 1
- 230000004931 aggregating effect Effects 0.000 description 1
- QYPPJABKJHAVHS-UHFFFAOYSA-P agmatinium(2+) Chemical compound NC(=[NH2+])NCCCC[NH3+] QYPPJABKJHAVHS-UHFFFAOYSA-P 0.000 description 1
- 239000000556 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
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 description 1
- 239000002160 alpha blocker Substances 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 1
- 229960000711 alprostadil Drugs 0.000 description 1
- 229960003318 alteplase Drugs 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 229960004821 amikacin Drugs 0.000 description 1
- 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 1
- 229960000528 amlodipine Drugs 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
- 229960003022 amoxicillin Drugs 0.000 description 1
- 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 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
- 229960001830 amprenavir Drugs 0.000 description 1
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 1
- 206010002022 amyloidosis Diseases 0.000 description 1
- 238000004873 anchoring Methods 0.000 description 1
- 229960001232 anecortave Drugs 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229960000983 anistreplase Drugs 0.000 description 1
- 229960002469 antazoline Drugs 0.000 description 1
- REYFJDPCWQRWAA-UHFFFAOYSA-N antazoline Chemical compound N=1CCNC=1CN(C=1C=CC=CC=1)CC1=CC=CC=C1 REYFJDPCWQRWAA-UHFFFAOYSA-N 0.000 description 1
- 230000003527 anti-angiogenesis Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001384 anti-glaucoma Effects 0.000 description 1
- 230000003602 anti-herpes Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000416 anti-micotic effect Effects 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 230000001355 anti-mycobacterial effect Effects 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 230000003431 anti-prostaglandin Effects 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 230000002137 anti-vascular effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229940125687 antiparasitic agent Drugs 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 229940121357 antivirals Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 229940114079 arachidonic acid Drugs 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
- 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
- 125000003118 aryl group Chemical group 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
- 208000003464 asthenopia Diseases 0.000 description 1
- 229960003277 atazanavir Drugs 0.000 description 1
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 description 1
- 238000000231 atomic layer deposition Methods 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 229940120638 avastin Drugs 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
- 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
- 229960004574 azelastine Drugs 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
- 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
- 230000004888 barrier function Effects 0.000 description 1
- 229920005601 base polymer Polymers 0.000 description 1
- 229960004669 basiliximab Drugs 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 1
- 229940092705 beclomethasone Drugs 0.000 description 1
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 1
- 229940116226 behenic acid Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960003665 bepridil Drugs 0.000 description 1
- UIEATEWHFDRYRU-UHFFFAOYSA-N bepridil Chemical compound C1CCCN1C(COCC(C)C)CN(C=1C=CC=CC=1)CC1=CC=CC=C1 UIEATEWHFDRYRU-UHFFFAOYSA-N 0.000 description 1
- 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 1
- MJVXAPPOFPTTCA-UHFFFAOYSA-N beta-Sistosterol Natural products CCC(CCC(C)C1CCC2C3CC=C4C(C)C(O)CCC4(C)C3CCC12C)C(C)C MJVXAPPOFPTTCA-UHFFFAOYSA-N 0.000 description 1
- NJKOMDUNNDKEAI-UHFFFAOYSA-N beta-sitosterol Natural products CCC(CCC(C)C1CCC2(C)C3CC=C4CC(O)CCC4C3CCC12C)C(C)C NJKOMDUNNDKEAI-UHFFFAOYSA-N 0.000 description 1
- 229940093761 bile salts 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
- 230000003115 biocidal effect Effects 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- VHYCDWMUTMEGQY-UHFFFAOYSA-N bisoprolol Chemical compound CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 VHYCDWMUTMEGQY-UHFFFAOYSA-N 0.000 description 1
- 229960002781 bisoprolol Drugs 0.000 description 1
- 108010055460 bivalirudin Proteins 0.000 description 1
- 229960001500 bivalirudin Drugs 0.000 description 1
- OIRCOABEOLEUMC-GEJPAHFPSA-N bivalirudin 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(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 OIRCOABEOLEUMC-GEJPAHFPSA-N 0.000 description 1
- 238000005422 blasting Methods 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229940077737 brain-derived neurotrophic factor Drugs 0.000 description 1
- OILXMJHPFNGGTO-ZAUYPBDWSA-N brassicasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@H](C)C(C)C)[C@@]1(C)CC2 OILXMJHPFNGGTO-ZAUYPBDWSA-N 0.000 description 1
- 235000004420 brassicasterol Nutrition 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
- ZBPLOVFIXSTCRZ-UHFFFAOYSA-N bromfenac Chemical compound NC1=C(CC(O)=O)C=CC=C1C(=O)C1=CC=C(Br)C=C1 ZBPLOVFIXSTCRZ-UHFFFAOYSA-N 0.000 description 1
- 229960003655 bromfenac Drugs 0.000 description 1
- 229960004436 budesonide Drugs 0.000 description 1
- CDQSJQSWAWPGKG-UHFFFAOYSA-N butane-1,1-diol Chemical compound CCCC(O)O CDQSJQSWAWPGKG-UHFFFAOYSA-N 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
- 229960004015 calcitonin Drugs 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229960002713 calcium chloride Drugs 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960004484 carbachol Drugs 0.000 description 1
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000002041 carbon nanotube Substances 0.000 description 1
- 229910021393 carbon nanotube Inorganic materials 0.000 description 1
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 1
- DLJKPYFALUEJCK-MRVZPHNRSA-N carboprost Chemical compound CCCCC[C@](C)(O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C\CCCC(O)=O DLJKPYFALUEJCK-MRVZPHNRSA-N 0.000 description 1
- 229960003395 carboprost Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 239000000969 carrier Substances 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
- 229960004195 carvedilol Drugs 0.000 description 1
- NPAKNKYSJIDKMW-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=NC3=CC=C[CH]C3=C12 NPAKNKYSJIDKMW-UHFFFAOYSA-N 0.000 description 1
- JYIKNQVWKBUSNH-WVDDFWQHSA-N caspofungin Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CCN)=CC=C(O)C=C1 JYIKNQVWKBUSNH-WVDDFWQHSA-N 0.000 description 1
- 229960003034 caspofungin 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
- 229960005361 cefaclor Drugs 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
- 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
- KMIPKYQIOVAHOP-YLGJWRNMSA-N cefditoren 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=1\C=C/C=1SC=NC=1C KMIPKYQIOVAHOP-YLGJWRNMSA-N 0.000 description 1
- 229960004069 cefditoren Drugs 0.000 description 1
- 229960002100 cefepime Drugs 0.000 description 1
- HVFLCNVBZFFHBT-ZKDACBOMSA-O cefepime(1+) 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=1C[N+]1(C)CCCC1 HVFLCNVBZFFHBT-ZKDACBOMSA-O 0.000 description 1
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound 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 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 description 1
- 229960004682 cefoperazone Drugs 0.000 description 1
- 229960004261 cefotaxime Drugs 0.000 description 1
- GPRBEKHLDVQUJE-VINNURBNSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 description 1
- 229960005495 cefotetan Drugs 0.000 description 1
- SRZNHPXWXCNNDU-RHBCBLIFSA-N cefotetan Chemical compound N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CS[C@@H]21)C(O)=O)=O)C(=O)C1SC(=C(C(N)=O)C(O)=O)S1 SRZNHPXWXCNNDU-RHBCBLIFSA-N 0.000 description 1
- WZOZEZRFJCJXNZ-ZBFHGGJFSA-N cefoxitin Chemical compound N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)CC1=CC=CS1 WZOZEZRFJCJXNZ-ZBFHGGJFSA-N 0.000 description 1
- 229960002682 cefoxitin Drugs 0.000 description 1
- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 description 1
- 229960005090 cefpodoxime Drugs 0.000 description 1
- 229960002580 cefprozil Drugs 0.000 description 1
- 229960004086 ceftibuten Drugs 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
- 229960001991 ceftizoxime Drugs 0.000 description 1
- NNULBSISHYWZJU-LLKWHZGFSA-N ceftizoxime Chemical compound N([C@@H]1C(N2C(=CCS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 NNULBSISHYWZJU-LLKWHZGFSA-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
- 210000004027 cell Anatomy 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 229960001803 cetirizine Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 1
- 229960001091 chenodeoxycholic acid 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
- 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
- 150000001840 cholesterol esters Chemical class 0.000 description 1
- XUGISPSHIFXEHZ-VEVYEIKRSA-N cholesteryl acetate Chemical compound C1C=C2C[C@@H](OC(C)=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 XUGISPSHIFXEHZ-VEVYEIKRSA-N 0.000 description 1
- UVZUFUGNHDDLRQ-LLHZKFLPSA-N cholesteryl benzoate Chemical compound O([C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)C(=O)C1=CC=CC=C1 UVZUFUGNHDDLRQ-LLHZKFLPSA-N 0.000 description 1
- SJDMTGSQPOFVLR-ZPQCIJQQSA-N cholesteryl myristate 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](OC(=O)CCCCCCCCCCCCC)C1 SJDMTGSQPOFVLR-ZPQCIJQQSA-N 0.000 description 1
- WCLNGBQPTVENHV-MKQVXYPISA-N cholesteryl nonanoate 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](OC(=O)CCCCCCCC)C1 WCLNGBQPTVENHV-MKQVXYPISA-N 0.000 description 1
- RJECHNNFRHZQKU-RMUVNZEASA-N cholesteryl oleate 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](OC(=O)CCCCCCC\C=C/CCCCCCCC)C1 RJECHNNFRHZQKU-RMUVNZEASA-N 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- SECPZKHBENQXJG-UHFFFAOYSA-N cis-palmitoleic acid Natural products CCCCCCC=CCCCCCCCC(O)=O SECPZKHBENQXJG-UHFFFAOYSA-N 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
- 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 1
- 210000000078 claw Anatomy 0.000 description 1
- 229960002881 clemastine 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
- 229960002227 clindamycin Drugs 0.000 description 1
- 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 1
- 229960003608 clomifene Drugs 0.000 description 1
- 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 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 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
- 229910052681 coesite Inorganic materials 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 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 1
- 229910052593 corundum Inorganic materials 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 229960000265 cromoglicic acid Drugs 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- SKYSRIRYMSLOIN-UHFFFAOYSA-N cyclopentolate Chemical compound C1CCCC1(O)C(C(=O)OCCN(C)C)C1=CC=CC=C1 SKYSRIRYMSLOIN-UHFFFAOYSA-N 0.000 description 1
- 229960001815 cyclopentolate Drugs 0.000 description 1
- 229940124570 cycloplegic agent Drugs 0.000 description 1
- 239000000634 cycloplegic agent Substances 0.000 description 1
- 229960001140 cyproheptadine Drugs 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
- 229960000684 cytarabine Drugs 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 229960002806 daclizumab Drugs 0.000 description 1
- 229960004969 dalteparin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin 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(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 239000000850 decongestant Substances 0.000 description 1
- 229940124581 decongestants Drugs 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 229960005319 delavirdine Drugs 0.000 description 1
- YHKBUDZECQDYBR-UHFFFAOYSA-L demecarium bromide Chemical compound [Br-].[Br-].C=1C=CC([N+](C)(C)C)=CC=1OC(=O)N(C)CCCCCCCCCCN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 YHKBUDZECQDYBR-UHFFFAOYSA-L 0.000 description 1
- 229960003715 demecarium bromide Drugs 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 108010073652 desirudin Proteins 0.000 description 1
- XYWBJDRHGNULKG-OUMQNGNKSA-N desirudin 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(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 XYWBJDRHGNULKG-OUMQNGNKSA-N 0.000 description 1
- 229960000296 desirudin Drugs 0.000 description 1
- 229960001271 desloratadine Drugs 0.000 description 1
- 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 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
- 229960001985 dextromethorphan Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 201000011190 diabetic macular edema Diseases 0.000 description 1
- 229940099238 diamox Drugs 0.000 description 1
- GDLBFKVLRPITMI-UHFFFAOYSA-N diazoxide Chemical compound ClC1=CC=C2NC(C)=NS(=O)(=O)C2=C1 GDLBFKVLRPITMI-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
- 229960005081 diclofenamide Drugs 0.000 description 1
- GJQPMPFPNINLKP-UHFFFAOYSA-N diclofenamide Chemical compound NS(=O)(=O)C1=CC(Cl)=C(Cl)C(S(N)(=O)=O)=C1 GJQPMPFPNINLKP-UHFFFAOYSA-N 0.000 description 1
- 229960001585 dicloxacillin Drugs 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
- 230000004069 differentiation Effects 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
- 229960000616 diflunisal Drugs 0.000 description 1
- MUCZHBLJLSDCSD-UHFFFAOYSA-N diisopropyl fluorophosphate Chemical compound CC(C)OP(F)(=O)OC(C)C MUCZHBLJLSDCSD-UHFFFAOYSA-N 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
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- OCUJLLGVOUDECM-UHFFFAOYSA-N dipivefrin Chemical compound CNCC(O)C1=CC=C(OC(=O)C(C)(C)C)C(OC(=O)C(C)(C)C)=C1 OCUJLLGVOUDECM-UHFFFAOYSA-N 0.000 description 1
- 229960000966 dipivefrine Drugs 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- 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 1
- 238000007907 direct compression Methods 0.000 description 1
- 229960004100 dirithromycin Drugs 0.000 description 1
- WLOHNSSYAXHWNR-NXPDYKKBSA-N dirithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H]2O[C@H](COCCOC)N[C@H]([C@@H]2C)[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 WLOHNSSYAXHWNR-NXPDYKKBSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 229940090949 docosahexaenoic acid Drugs 0.000 description 1
- 235000020669 docosahexaenoic acid Nutrition 0.000 description 1
- 229940052760 dopamine agonists Drugs 0.000 description 1
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- RUZYUOTYCVRMRZ-UHFFFAOYSA-N doxazosin Chemical compound C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 RUZYUOTYCVRMRZ-UHFFFAOYSA-N 0.000 description 1
- 229960001389 doxazosin Drugs 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 102000013035 dynein heavy chain Human genes 0.000 description 1
- 108060002430 dynein heavy chain Proteins 0.000 description 1
- 229960003804 efavirenz Drugs 0.000 description 1
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 1
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 description 1
- 235000020673 eicosapentaenoic acid Nutrition 0.000 description 1
- 229960005135 eicosapentaenoic acid Drugs 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000000806 elastomer Substances 0.000 description 1
- 239000013536 elastomeric material Substances 0.000 description 1
- 230000004406 elevated intraocular pressure Effects 0.000 description 1
- 229960000325 emedastine Drugs 0.000 description 1
- KBUZBQVCBVDWKX-UHFFFAOYSA-N emedastine Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N1CCCN(C)CC1 KBUZBQVCBVDWKX-UHFFFAOYSA-N 0.000 description 1
- 229960000366 emtricitabine Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229940073621 enbrel Drugs 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229960000610 enoxaparin Drugs 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 1
- 229960002770 ertapenem Drugs 0.000 description 1
- DPUOLQHDNGRHBS-KTKRTIGZSA-N erucic acid Chemical compound CCCCCCCC\C=C/CCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-KTKRTIGZSA-N 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229960003399 estrone 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
- 229940081345 estropipate 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
- 229960003199 etacrynic acid Drugs 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- 238000005530 etching Methods 0.000 description 1
- 229960000285 ethambutol Drugs 0.000 description 1
- 229950005098 ethoxzolamide Drugs 0.000 description 1
- OUZWUKMCLIBBOG-UHFFFAOYSA-N ethoxzolamide Chemical compound CCOC1=CC=C2N=C(S(N)(=O)=O)SC2=C1 OUZWUKMCLIBBOG-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 229960004667 ethyl cellulose Drugs 0.000 description 1
- 229960005293 etodolac Drugs 0.000 description 1
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-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
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 229960005167 everolimus Drugs 0.000 description 1
- 208000030533 eye disease Diseases 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
- 229960003580 felodipine Drugs 0.000 description 1
- 229960002724 fenoldopam Drugs 0.000 description 1
- TVURRHSHRRELCG-UHFFFAOYSA-N fenoldopam Chemical compound C1=CC(O)=CC=C1C1C2=CC(O)=C(O)C(Cl)=C2CCNC1 TVURRHSHRRELCG-UHFFFAOYSA-N 0.000 description 1
- 229960001419 fenoprofen Drugs 0.000 description 1
- 229960003592 fexofenadine Drugs 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 229940126864 fibroblast growth factor Drugs 0.000 description 1
- 230000001497 fibrovascular Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 230000004992 fission Effects 0.000 description 1
- 229930182486 flavonoid glycoside Natural products 0.000 description 1
- 150000007955 flavonoid glycosides Chemical class 0.000 description 1
- 230000009969 flowable effect Effects 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
- 229960004884 fluconazole Drugs 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 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 1
- 229960002011 fludrocortisone Drugs 0.000 description 1
- 229960000676 flunisolide Drugs 0.000 description 1
- 229960001347 fluocinolone acetonide Drugs 0.000 description 1
- 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 1
- 229960001048 fluorometholone Drugs 0.000 description 1
- 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 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 229960005051 fluostigmine 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
- 229960002714 fluticasone Drugs 0.000 description 1
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone 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)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 description 1
- KANJSNBRCNMZMV-ABRZTLGGSA-N fondaparinux Chemical compound O[C@@H]1[C@@H](NS(O)(=O)=O)[C@@H](OC)O[C@H](COS(O)(=O)=O)[C@H]1O[C@H]1[C@H](OS(O)(=O)=O)[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O[C@@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O4)NS(O)(=O)=O)[C@H](O3)C(O)=O)O)[C@@H](COS(O)(=O)=O)O2)NS(O)(=O)=O)[C@H](C(O)=O)O1 KANJSNBRCNMZMV-ABRZTLGGSA-N 0.000 description 1
- 229960001318 fondaparinux Drugs 0.000 description 1
- 229960005102 foscarnet 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
- 229960003980 galantamine Drugs 0.000 description 1
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 1
- 229910052733 gallium Inorganic materials 0.000 description 1
- 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 1
- 229960002963 ganciclovir Drugs 0.000 description 1
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 1
- 229960003923 gatifloxacin Drugs 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 230000002518 glial effect Effects 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 description 1
- 229940099347 glycocholic acid Drugs 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- 229940094892 gonadotropins Drugs 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000002554 heparinoid Substances 0.000 description 1
- 229940025770 heparinoids Drugs 0.000 description 1
- 230000004402 high myopia Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940006607 hirudin Drugs 0.000 description 1
- 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 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 229960000857 homatropine Drugs 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940048921 humira Drugs 0.000 description 1
- 229960002474 hydralazine Drugs 0.000 description 1
- 229960001067 hydrocortisone acetate Drugs 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 229960004171 hydroxychloroquine 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
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 229960002899 hydroxyprogesterone Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229940072106 hydroxystearate Drugs 0.000 description 1
- 229960000930 hydroxyzine Drugs 0.000 description 1
- 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 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 239000002303 hypothalamus releasing factor Substances 0.000 description 1
- 229960004370 ibopamine Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960004716 idoxuridine Drugs 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 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
- 230000001900 immune effect Effects 0.000 description 1
- 229960001438 immunostimulant agent Drugs 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229960001936 indinavir 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
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 229960000598 infliximab 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
- 238000011221 initial treatment Methods 0.000 description 1
- 238000001746 injection moulding Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 210000001153 interneuron Anatomy 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 231100001032 irritation of the eye Toxicity 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
- 229960004427 isradipine Drugs 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- 229960002418 ivermectin Drugs 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229960000829 kaolin Drugs 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 239000003835 ketolide antibiotic agent Substances 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
- 229960004752 ketorolac Drugs 0.000 description 1
- 229960004958 ketotifen Drugs 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 229960001632 labetalol Drugs 0.000 description 1
- 210000004561 lacrimal apparatus Anatomy 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 238000010030 laminating Methods 0.000 description 1
- 238000003475 lamination Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229930193708 latrunculin Natural products 0.000 description 1
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([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 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- OTQCKZUSUGYWBD-BRHMIFOHSA-N lepirudin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)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](CS)C(=O)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)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)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(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)C(C)C)[C@@H](C)O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)[C@@H](C)O)C1=CC=C(O)C=C1 OTQCKZUSUGYWBD-BRHMIFOHSA-N 0.000 description 1
- 229960004408 lepirudin Drugs 0.000 description 1
- 229960004771 levobetaxolol Drugs 0.000 description 1
- 229960000831 levobunolol Drugs 0.000 description 1
- IXHBTMCLRNMKHZ-LBPRGKRZSA-N levobunolol Chemical compound O=C1CCCC2=C1C=CC=C2OC[C@@H](O)CNC(C)(C)C IXHBTMCLRNMKHZ-LBPRGKRZSA-N 0.000 description 1
- 229960001120 levocabastine Drugs 0.000 description 1
- ZCGOMHNNNFPNMX-KYTRFIICSA-N levocabastine Chemical compound C1([C@@]2(C(O)=O)CCN(C[C@H]2C)[C@@H]2CC[C@@](CC2)(C#N)C=2C=CC(F)=CC=2)=CC=CC=C1 ZCGOMHNNNFPNMX-KYTRFIICSA-N 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 229960004400 levonorgestrel Drugs 0.000 description 1
- 229950008325 levothyroxine 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
- 229960004488 linolenic acid Drugs 0.000 description 1
- 229960004305 lodoxamide Drugs 0.000 description 1
- RVGLGHVJXCETIO-UHFFFAOYSA-N lodoxamide Chemical compound OC(=O)C(=O)NC1=CC(C#N)=CC(NC(=O)C(O)=O)=C1Cl RVGLGHVJXCETIO-UHFFFAOYSA-N 0.000 description 1
- 229950007692 lomerizine Drugs 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960004525 lopinavir Drugs 0.000 description 1
- 229960001977 loracarbef Drugs 0.000 description 1
- JAPHQRWPEGVNBT-UTUOFQBUSA-N loracarbef Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CC[C@@H]32)C([O-])=O)=O)[NH3+])=CC=CC=C1 JAPHQRWPEGVNBT-UTUOFQBUSA-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
- 239000000314 lubricant Substances 0.000 description 1
- 229940076783 lucentis Drugs 0.000 description 1
- 238000003754 machining Methods 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 229940092110 macugen Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 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 1
- 229960003439 mebendazole Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229940013798 meclofenamate 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
- 229960001011 medrysone Drugs 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
- 229960001962 mefloquine Drugs 0.000 description 1
- 229960001786 megestrol Drugs 0.000 description 1
- JBVNBBXAMBZTMQ-CEGNMAFCSA-N megestrol Chemical compound C1=CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 JBVNBBXAMBZTMQ-CEGNMAFCSA-N 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 1
- 229960004640 memantine Drugs 0.000 description 1
- 229960000582 mepyramine Drugs 0.000 description 1
- YECBIJXISLIIDS-UHFFFAOYSA-N mepyramine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 YECBIJXISLIIDS-UHFFFAOYSA-N 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine 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
- 229960002260 meropenem Drugs 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 229910052976 metal sulfide Inorganic materials 0.000 description 1
- HNJJXZKZRAWDPF-UHFFFAOYSA-N methapyrilene Chemical compound C=1C=CC=NC=1N(CCN(C)C)CC1=CC=CS1 HNJJXZKZRAWDPF-UHFFFAOYSA-N 0.000 description 1
- FLOSMHQXBMRNHR-DAXSKMNVSA-N methazolamide Chemical compound CC(=O)\N=C1/SC(S(N)(=O)=O)=NN1C FLOSMHQXBMRNHR-DAXSKMNVSA-N 0.000 description 1
- 229960004083 methazolamide Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- VKQFCGNPDRICFG-UHFFFAOYSA-N methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC=C1[N+]([O-])=O VKQFCGNPDRICFG-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 229960001566 methyltestosterone Drugs 0.000 description 1
- 229960002704 metipranolol Drugs 0.000 description 1
- BLWNYSZZZWQCKO-UHFFFAOYSA-N metipranolol hydrochloride Chemical compound [Cl-].CC(C)[NH2+]CC(O)COC1=CC(C)=C(OC(C)=O)C(C)=C1C BLWNYSZZZWQCKO-UHFFFAOYSA-N 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 229960002509 miconazole Drugs 0.000 description 1
- 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 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 231100000782 microtubule inhibitor Toxicity 0.000 description 1
- VKHAHZOOUSRJNA-GCNJZUOMSA-N mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 description 1
- 229960003248 mifepristone Drugs 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- 229960003632 minoxidil 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
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 150000002763 monocarboxylic acids Chemical class 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000000921 morphogenic effect Effects 0.000 description 1
- 229960003702 moxifloxacin Drugs 0.000 description 1
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 1
- 230000003551 muscarinic effect Effects 0.000 description 1
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
- 229960004866 mycophenolate mofetil Drugs 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- 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 1
- 210000005012 myelin Anatomy 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 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
- 229960000515 nafcillin 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
- 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
- 239000002088 nanocapsule Substances 0.000 description 1
- 229960005016 naphazoline Drugs 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 1
- 229960000884 nelfinavir Drugs 0.000 description 1
- 229960001002 nepafenac Drugs 0.000 description 1
- QEFAQIPZVLVERP-UHFFFAOYSA-N nepafenac Chemical compound NC(=O)CC1=CC=CC(C(=O)C=2C=CC=CC=2)=C1N QEFAQIPZVLVERP-UHFFFAOYSA-N 0.000 description 1
- 239000004090 neuroprotective agent Substances 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 229960001783 nicardipine Drugs 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 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 1
- 229960005366 nilvadipine Drugs 0.000 description 1
- 229960000715 nimodipine Drugs 0.000 description 1
- 229960000227 nisoldipine Drugs 0.000 description 1
- 239000000236 nitric oxide synthase inhibitor Substances 0.000 description 1
- IAIWVQXQOWNYOU-FPYGCLRLSA-N nitrofural Chemical compound NC(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 IAIWVQXQOWNYOU-FPYGCLRLSA-N 0.000 description 1
- 229960000564 nitrofurantoin Drugs 0.000 description 1
- 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 1
- 229960001907 nitrofurazone Drugs 0.000 description 1
- SENUTBBWBZZNRT-LVEBTZEWSA-N nitromemantine Chemical compound C([C@](C1)(N)C2)[C@@]3(CC)C[C@]2(CC)C[C@]1(O[N+]([O-])=O)C3 SENUTBBWBZZNRT-LVEBTZEWSA-N 0.000 description 1
- 229960002460 nitroprusside Drugs 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 229940053934 norethindrone 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
- 229960001180 norfloxacin Drugs 0.000 description 1
- 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 1
- 230000004493 normal intraocular pressure Effects 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 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
- 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
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 230000008397 ocular pathology Effects 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 1
- 229960005117 olmesartan Drugs 0.000 description 1
- 229960004114 olopatadine Drugs 0.000 description 1
- JBIMVDZLSHOPLA-LSCVHKIXSA-N olopatadine Chemical compound C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCN(C)C)\C2=CC=CC=C21 JBIMVDZLSHOPLA-LSCVHKIXSA-N 0.000 description 1
- 229940125702 ophthalmic agent Drugs 0.000 description 1
- 210000003733 optic disk Anatomy 0.000 description 1
- 239000002357 osmotic agent Substances 0.000 description 1
- 229960003552 other antineoplastic agent in atc Drugs 0.000 description 1
- 229960001019 oxacillin 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
- 229960000464 oxandrolone Drugs 0.000 description 1
- OFPXSFXSNFPTHF-UHFFFAOYSA-N oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 description 1
- 229960002739 oxaprozin Drugs 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000019039 oxygen homeostasis Effects 0.000 description 1
- 238000006213 oxygenation reaction Methods 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
- 229940094443 oxytocics prostaglandins Drugs 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
- 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 1
- 238000012856 packing Methods 0.000 description 1
- 239000000734 parasympathomimetic agent Substances 0.000 description 1
- 230000001499 parasympathomimetic effect Effects 0.000 description 1
- 229940005542 parasympathomimetics Drugs 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 229960001319 parathyroid hormone Drugs 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 229960003407 pegaptanib Drugs 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 229960002035 penbutolol Drugs 0.000 description 1
- KQXKVJAGOJTNJS-HNNXBMFYSA-N penbutolol Chemical compound CC(C)(C)NC[C@H](O)COC1=CC=CC=C1C1CCCC1 KQXKVJAGOJTNJS-HNNXBMFYSA-N 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 229960001190 pheniramine Drugs 0.000 description 1
- 229960003418 phenoxybenzamine Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 238000002428 photodynamic therapy Methods 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
- IVBHGBMCVLDMKU-GXNBUGAJSA-N piperacillin Chemical compound 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 IVBHGBMCVLDMKU-GXNBUGAJSA-N 0.000 description 1
- 229960002292 piperacillin 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
- ZEMIJUDPLILVNQ-ZXFNITATSA-N pivampicillin 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)OCOC(=O)C(C)(C)C)=CC=CC=C1 ZEMIJUDPLILVNQ-ZXFNITATSA-N 0.000 description 1
- 229960003342 pivampicillin Drugs 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229920001691 poly(ether urethane) Polymers 0.000 description 1
- 229940065514 poly(lactide) Drugs 0.000 description 1
- 229920001857 poly(tyrosine carbonate) Polymers 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920006149 polyester-amide block copolymer Polymers 0.000 description 1
- 229920000024 polymyxin B Polymers 0.000 description 1
- 229960005266 polymyxin b Drugs 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 229920003225 polyurethane elastomer Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 229940078491 ppg-15 stearyl ether Drugs 0.000 description 1
- 229940116393 ppg-20 methyl glucose ether Drugs 0.000 description 1
- 229960002957 praziquantel Drugs 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
- 238000001556 precipitation Methods 0.000 description 1
- 229960002800 prednisolone acetate Drugs 0.000 description 1
- 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 1
- 229960005179 primaquine Drugs 0.000 description 1
- 230000009290 primary effect Effects 0.000 description 1
- 229960000624 procarbazine 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
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229960003910 promethazine Drugs 0.000 description 1
- 229960003981 proparacaine Drugs 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 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 1
- PXGPLTODNUVGFL-UHFFFAOYSA-N prostaglandin F2alpha Natural products CCCCCC(O)C=CC1C(O)CC(O)C1CC=CCCCC(O)=O PXGPLTODNUVGFL-UHFFFAOYSA-N 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 239000012521 purified sample Substances 0.000 description 1
- 239000003379 purinergic P1 receptor agonist Substances 0.000 description 1
- 239000000296 purinergic P1 receptor antagonist Substances 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
- 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
- 229960001404 quinidine Drugs 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 229950001037 quinpirole Drugs 0.000 description 1
- FTSUPYGMFAPCFZ-ZWNOBZJWSA-N quinpirole Chemical compound C([C@H]1CCCN([C@@H]1C1)CCC)C2=C1C=NN2 FTSUPYGMFAPCFZ-ZWNOBZJWSA-N 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000003439 radiotherapeutic effect Effects 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- 229960003876 ranibizumab Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 229940116176 remicade Drugs 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 235000021283 resveratrol Nutrition 0.000 description 1
- 229940016667 resveratrol Drugs 0.000 description 1
- 108010051412 reteplase Proteins 0.000 description 1
- 229960002917 reteplase Drugs 0.000 description 1
- 210000003994 retinal ganglion cell Anatomy 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000003590 rho kinase inhibitor Substances 0.000 description 1
- 102000000568 rho-Associated Kinases Human genes 0.000 description 1
- 108010041788 rho-Associated Kinases Proteins 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 229960000885 rifabutin Drugs 0.000 description 1
- 229960004181 riluzole Drugs 0.000 description 1
- 229960001487 rimexolone Drugs 0.000 description 1
- QTTRZHGPGKRAFB-OOKHYKNYSA-N rimexolone 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)CC)(C)[C@@]1(C)C[C@@H]2O QTTRZHGPGKRAFB-OOKHYKNYSA-N 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
- 229960004641 rituximab Drugs 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 239000011435 rock Substances 0.000 description 1
- 229960000371 rofecoxib Drugs 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
- 229920002631 room-temperature vulcanizate silicone Polymers 0.000 description 1
- CSYSULGPHGCBQD-UHFFFAOYSA-N s-ethylisothiouronium diethylphosphate Chemical compound CCSC(N)=N.CCOP(O)(=O)OCC CSYSULGPHGCBQD-UHFFFAOYSA-N 0.000 description 1
- 229960000953 salsalate Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229960001852 saquinavir Drugs 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
- 229960002646 scopolamine Drugs 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound 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 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 239000000565 sealant Substances 0.000 description 1
- 210000000697 sensory organ Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000952 serotonin receptor agonist Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 1
- 235000015500 sitosterol Nutrition 0.000 description 1
- 229950005143 sitosterol Drugs 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 239000004055 small Interfering RNA Substances 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229960005480 sodium caprylate Drugs 0.000 description 1
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- 229940082004 sodium laurate Drugs 0.000 description 1
- 229940045845 sodium myristate Drugs 0.000 description 1
- BYKRNSHANADUFY-UHFFFAOYSA-M sodium octanoate Chemical compound [Na+].CCCCCCCC([O-])=O BYKRNSHANADUFY-UHFFFAOYSA-M 0.000 description 1
- 229940045870 sodium palmitate Drugs 0.000 description 1
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
- 229960003212 sodium propionate Drugs 0.000 description 1
- 235000010334 sodium propionate Nutrition 0.000 description 1
- 239000004324 sodium propionate Substances 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(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- Chemical compound [Na+].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 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- DDMGAAYEUNWXSI-XVSDJDOKSA-M sodium;(5z,8z,11z,14z)-icosa-5,8,11,14-tetraenoate Chemical compound [Na+].CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC([O-])=O DDMGAAYEUNWXSI-XVSDJDOKSA-M 0.000 description 1
- GGXKEBACDBNFAF-UHFFFAOYSA-M sodium;hexadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCC([O-])=O GGXKEBACDBNFAF-UHFFFAOYSA-M 0.000 description 1
- JUQGWKYSEXPRGL-UHFFFAOYSA-M sodium;tetradecanoate Chemical compound [Na+].CCCCCCCCCCCCCC([O-])=O JUQGWKYSEXPRGL-UHFFFAOYSA-M 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 229940032091 stigmasterol Drugs 0.000 description 1
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 description 1
- 235000016831 stigmasterol Nutrition 0.000 description 1
- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 239000002731 stomach secretion inhibitor Substances 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- CIOAGBVUUVVLOB-OUBTZVSYSA-N strontium-89 Chemical compound [89Sr] CIOAGBVUUVVLOB-OUBTZVSYSA-N 0.000 description 1
- 229940006509 strontium-89 Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- AXOIZCJOOAYSMI-UHFFFAOYSA-N succinylcholine Chemical compound C[N+](C)(C)CCOC(=O)CCC(=O)OCC[N+](C)(C)C AXOIZCJOOAYSMI-UHFFFAOYSA-N 0.000 description 1
- 229940032712 succinylcholine Drugs 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
- 229960000654 sulfafurazole 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
- 229960005158 sulfamethizole Drugs 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 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
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- RJVBVECTCMRNFG-ANKJNSLFSA-N swinholide a Chemical compound C1[C@H](OC)C[C@H](C)O[C@H]1CC[C@H](C)[C@H](O)[C@H](C)[C@@H]1[C@@H](C)[C@H](O)C[C@H](O)[C@H](C)[C@@H](OC)C[C@H](CC=C2)O[C@@H]2C[C@@H](O)C/C=C(\C)/C=C/C(=O)O[C@H]([C@@H](C)[C@@H](O)[C@@H](C)CC[C@@H]2O[C@@H](C)C[C@H](C2)OC)[C@@H](C)[C@H](O)C[C@H](O)[C@H](C)[C@@H](OC)C[C@H](CC=C2)O[C@@H]2C[C@@H](O)C/C=C(\C)/C=C/C(=O)O1 RJVBVECTCMRNFG-ANKJNSLFSA-N 0.000 description 1
- GDACDJNQZCXLNU-UHFFFAOYSA-N swinholide-A Natural products C1C(OC)CC(C)OC1CCC(C)C(O)C(C)C1C(C)C(O)CC(O)C(C)C(OC)CC(CC=C2)OC2CC(O)CC=C(C)C=CC(=O)O1 GDACDJNQZCXLNU-UHFFFAOYSA-N 0.000 description 1
- 229940127230 sympathomimetic drug Drugs 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- 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 1
- 229960000835 tadalafil Drugs 0.000 description 1
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 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
- 229960003250 telithromycin Drugs 0.000 description 1
- 229960000216 tenecteplase Drugs 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 description 1
- 229960001693 terazosin 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
- 229960002722 terbinafine Drugs 0.000 description 1
- 150000003505 terpenes Chemical class 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
- 150000003511 tertiary amides Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 description 1
- 229960002372 tetracaine Drugs 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)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)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 238000003856 thermoforming Methods 0.000 description 1
- 239000012815 thermoplastic material Substances 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 229960000103 thrombolytic agent 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
- 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 1
- 229960004659 ticarcillin 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
- 229960005001 ticlopidine Drugs 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 229960005062 tinzaparin 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
- JIVZKJJQOZQXQB-UHFFFAOYSA-N tolazoline Chemical compound C=1C=CC=CC=1CC1=NCCN1 JIVZKJJQOZQXQB-UHFFFAOYSA-N 0.000 description 1
- 229960002312 tolazoline 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
- 239000003860 topical agent Substances 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 229960005267 tositumomab Drugs 0.000 description 1
- 210000001585 trabecular meshwork Anatomy 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 230000032258 transport 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
- 238000011269 treatment regimen Methods 0.000 description 1
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 description 1
- 229960005032 treprostinil Drugs 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- 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 1
- 229910052905 tridymite Inorganic materials 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
- 229960001082 trimethoprim Drugs 0.000 description 1
- 229960004791 tropicamide Drugs 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 229960004317 unoprostone Drugs 0.000 description 1
- TVHAZVBUYQMHBC-SNHXEXRGSA-N unoprostone Chemical compound CCCCCCCC(=O)CC[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(O)=O TVHAZVBUYQMHBC-SNHXEXRGSA-N 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 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 1
- 229960005356 urokinase Drugs 0.000 description 1
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 1
- 229960001661 ursodiol Drugs 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 229940093257 valacyclovir Drugs 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- 229960002149 valganciclovir 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
- 238000007740 vapor deposition Methods 0.000 description 1
- 229960002381 vardenafil Drugs 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 229960003895 verteporfin Drugs 0.000 description 1
- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 1
- 229960003636 vidarabine 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
- 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
- 229960004528 vincristine Drugs 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
- 239000013603 viral vector Substances 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- 229960004740 voriconazole Drugs 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- 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 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- ZXIBCJHYVWYIKI-PZJWPPBQSA-N ximelagatran Chemical compound C1([C@@H](NCC(=O)OCC)C(=O)N2[C@@H](CC2)C(=O)NCC=2C=CC(=CC=2)C(\N)=N\O)CCCCC1 ZXIBCJHYVWYIKI-PZJWPPBQSA-N 0.000 description 1
- 229960001522 ximelagatran Drugs 0.000 description 1
- 229910001845 yogo sapphire 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
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
- A61F9/0008—Introducing ophthalmic products into the ocular cavity or retaining products therein
- A61F9/0017—Introducing ophthalmic products into the ocular cavity or retaining products therein implantable in, or in contact with, the eye, e.g. ocular inserts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
- A61F9/007—Methods or devices for eye surgery
- A61F9/00772—Apparatus for restoration of tear ducts
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2210/0004—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2210/0014—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof using shape memory or superelastic materials, e.g. nitinol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2220/00—Fixations or connections for prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2220/0008—Fixation appliances for connecting prostheses to the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2220/00—Fixations or connections for prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2220/0008—Fixation appliances for connecting prostheses to the body
- A61F2220/0016—Fixation appliances for connecting prostheses to the body with sharp anchoring protrusions, e.g. barbs, pins, spikes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
- A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
- A61F2250/0068—Means for introducing or releasing pharmaceutical products into the body the pharmaceutical product being in a reservoir
Definitions
- This disclosure relates to implantable drug delivery devices structured to provide targeted and/or controlled release of a drug to a desired ocular target tissue and methods of using such devices for the treatment of ocular diseases and disorders.
- this disclosure relates to devices for insertion into the punctum and for delivery of a therapeutic agent or agents to the eye in a controlled manner.
- the mammalian eye is a specialized sensory organ capable of light reception and is able to receive visual images.
- the retina of the eye consists of photoreceptors that are sensitive to various levels of light, interneurons that relay signals from the photoreceptors to the retinal ganglion cells, which transmit the light-induced signals to the brain.
- the iris is an intraocular membrane that is involved in controlling the amount of light reaching the retina.
- the iris consists of two layers (arranged from anterior to posterior), the pigmented fibrovascular tissue known as a stroma and pigmented epithelial cells.
- the stroma connects a sphincter muscle (sphincter pupillae), which contracts the pupil, and a set of dilator muscles (dilator pupillae) which open it.
- the pigmented epithelial cells block light from passing through the iris and thereby restrict light passage to the pupil.
- the central portion of the retina is known as the macula.
- the macula which is responsible for central vision, fine visualization and color differentiation, may be affected by age related macular degeneration (wet or dry), diabetic macular edema, idiopathic choroidal neovascularization, or high myopia macular degeneration, among other pathologies.
- Aqueous humor is a transparent liquid that fills at least the region between the cornea, at the front of the eye, and the lens and is responsible for producing a pressure within the ocular cavity.
- Normal intraocular pressure is maintained by drainage of aqueous humor from the anterior chamber by way of a trabecular meshwork which is located in an anterior chamber angle, lying between the iris and the cornea or by way of the “uveoscleral outflow pathway.”
- the “uveoscleral outflow pathway” is the space or passageway whereby aqueous exits the eye by passing through the ciliary muscle bundles located in the angle of the anterior chamber and into the tissue planes between the choroid and the sclera, which extend posteriorly to the optic nerve.
- About two percent of people in the United States have glaucoma, which is a group of eye diseases encompassing a broad spectrum of clinical presentations and etiologies but unified by increased intraocular pressure.
- Glaucoma causes pathological changes in the optic nerve, visible on the optic disk, and it causes corresponding visual field loss, which can result in blindness if untreated.
- Increased intraocular pressure is the only risk factor associated with glaucoma that can be treated, thus lowering intraocular pressure is the major treatment goal in all glaucomas, and can be achieved by drug therapy, surgical therapy, or combinations thereof.
- the implants disclosed herein operate to provide a therapeutic effect in the eye of a subject based, at least in part, on a physical arrangement of drugs within the implant.
- the implants comprise a punctual plug and the physical arrangement of the drugs within the implant provides advantageous timing of delivery of the drugs.
- the punctal implants disclosed herein are placed into the punctum and reside at least partially in a lacrimal canaliculus of an eye. Such an approach is useful, in several embodiments, such as when steroid and cyclosporine are combined to treat dry eye.
- Many current therapies for dry eye employ an initial treatment with steroid eye drops for a first time period (e.g., two weeks). After the initial period cyclosporine eye drops are added to the treatment regimen.
- a punctal implant can deliver steroid and cyclosporine with appropriate timing to achieve a near constant, zero order administration of drug.
- Such a dosing profile is generally considered more efficient than bolus delivery, such as occurs with eye drops.
- the second (or third, etc.) agent results in synergistic effects when combined with the first agent.
- the second agent reduces one or more side effects associated with the first agent. It is understood, however, that any embodiment of implant disclosed herein may contain only one drug.
- implants for insertion into a punctum of the eye of a subject comprising an outer shell having a proximal end, a distal end, the outer shell being shaped to define an interior lumen, the outer shell dimensioned for insertion into the punctum of the eye of a subject, at least a first drug positioned within the interior lumen, at least one region of drug release the proximal portion of outer shell, and a distal occlusive member within the inner lumen, the distal occlusive member preventing elution of the first drug from the distal end of the implant.
- the first drug elutes from the lumen to the tear film of the eye of the subject by passing through the at least one region of drug release.
- the implant is dimensioned to be implanted with the distal end of the outer shell positioned in the lacrimal duct. In some embodiments, the implant is dimensioned to be implanted with the distal end of the outer shell positioned in the lacrimal sac. In several embodiments, the implant is dimensioned to be implanted with the distal end of the outer shell positioned in the nasolacrimal duct.
- a punctal implant for insertion into a punctum of the eye of a subject and configured to deliver two or more drugs to the eye of the subject, the implant comprising an outer shell comprising (i) a proximal end comprising at least one region of drug release and a flange, (ii) a closed distal end, and (iii) an interior lumen comprising at least two drugs positioned within the lumen.
- a punctal implant for insertion into a punctum of the eye of a subject and configured to deliver two or more drugs to the eye of the subject
- the implant comprising an outer shell comprising (i) a proximal end comprising at least one region of drug release and a flange, (ii) a closed distal end, and (iii) an interior lumen comprising at least two drugs positioned within the lumen, wherein the region of drug release comprises aperture through an annular ring positioned at the proximal-most portion of the interior lumen, wherein said aperture allows elution of the two or more drugs to occur only through the occlusive member, wherein the dimensions of the aperture at least partially defines the elution rate of the two or more drugs, wherein the flange is configured to rest on the surface of the eyelid when the implant is inserted into the punctum, and wherein the first and second drug elute from the lumen to the tear film of the eye of the subject by passing through the at least one
- the at least one region of drug release comprises at least one aperture.
- the implant further comprises at least one membrane that occludes the at least one aperture, wherein the membrane is permeable to the at least a first drug, wherein the membrane allows elution of the at least a first drug to occur only through the at least one membrane.
- the at least one region of drug release comprises a plurality of apertures through the outer shell and positioned randomly or in a patterned array throughout the proximal portion of the implant. As above, at least a portion of the plurality of apertures is occluded by a membrane permeable to the first drug.
- Some embodiments provided for herein result in elution of drug (or drugs) from the implant with zero-order or pseudo zero-order kinetics.
- the intraocular target is the posterior chamber of the eye, the anterior chamber of the eye, both the anterior chamber and posterior of the eye, or the macula, the retina, the optic nerve, the ciliary body, and the intraocular vasculature.
- the drug acts on the intraocular target tissue to generate a therapeutic effect for an extended period.
- the drug comprises a steroid.
- the implant contains a total load of steroid ranging from about 10 to about 1000 micrograms, steroid is released from the implant at a rate ranging from about 0.05 to about 10 micrograms per day and/or the steroid acts on the diseased or damaged target tissue at a concentration ranging from about 1 to about 100 nanomolar.
- the steroid additionally generates side effects associated with accumulation of physiologic fluid, and an optional shunt transports the accumulated fluid from the first location to the remote second location (such as, for example, from the anterior chamber to an existing physiological outflow pathway, such as Schlemm's canal or the naso-lacrimal duct).
- an optional shunt transports the accumulated fluid from the first location to the remote second location (such as, for example, from the anterior chamber to an existing physiological outflow pathway, such as Schlemm's canal or the naso-lacrimal duct).
- the at least one region of drug release comprises an occlusive member that is permeable to said two or more drugs, and the occlusive member allows elution of the two or more drugs to occur through the occlusive member.
- the thickness of the occlusive member at least partially defines the elution rate of the drug (or drugs).
- having a flange the flange is configured to rest on the surface of the eyelid when the implant is inserted into the punctum.
- the drug (or drugs) elute from the lumen to the tear film of the eye of the subject by passing through the at least one region of drug release.
- the occlusive member is an occlusive membrane is dimensioned based on the permeability of said occlusive member to said first drug (and second or more) and the desired relative timing and duration of elution of said first and second drugs.
- the occlusive member has a thickness of between about 0.0001 and 0.0005 inches.
- the occlusive member is integrally formed with the outer shell of the implant.
- the occlusive member further comprises randomly or patterned holes through the occlusive membrane.
- a first drug is placed in a more proximal position within the interior lumen relative to the position of a second drug.
- a third drug is included, and in certain such embodiments, the first drug and second drug are positioned adjacent to one another and both the first and second drugs are placed in a more proximal position within the interior lumen relative to the position of the third drug.
- the drug is formulated as tablets, as a nanodispersion, or a combination thereof.
- a first drug is formed as a discontinuous first phase and a second drug is formulated as dispersion of solid of liquid particles into which the first drug is dispersed.
- the outer shell of the implant comprises a bulge in the distal region in order to anchor the implant in the punctum.
- a first drug elutes from an implant for a period of between 1 and 75 days, and a second drug elutes for a period of time ranging from about 1 to about 24 months after the first drug is eluted.
- the implants disclosed herein have a length of between about 0.5 and about 2.5 mm. Some embodiments of the implants have a length of about 1.4 to about 1.6 mm. Some embodiments of the implant have a diameter of about 0.2 to about 1.5 mm. Some embodiments of the implant have a diameter of about 0.2 to about 0.6 mm.
- the first drug may be a steroid.
- the steroid is selected from the group consisting of loteprednol etabonate, dexamethasone, and triamcinolone acetonide.
- a second drug is cyclosporine and is optionally formulated as a nanodispersion.
- the first drug is cyclosporine A.
- the first drug facilitates tear production.
- a retention protrusion configured to anchor the implant in an implantation site (e.g., the punctum).
- Such retention protrusions optionally comprise one or more of bulges, ridges, claws, threads, flexible ribs, rivet-like shapes, flexible barbs, barbed tips, expanding material (such as a hydrogel), and biocompatible adhesives.
- the expanding material is placed on an exterior surface of the outer shell of the implant and expands after contact with a solvent, such as, for example, intraocular fluid or tear film.
- FIG. 1 A illustrates a schematic cross section of an implant in accordance with embodiments disclosed herein.
- FIGS. 1 B- 1 D illustrate additional embodiments of an implant in accordance with embodiments disclosed herein.
- FIGS. 2 A- 2 D illustrate schematic cross sections of additional embodiments of implants in accordance with embodiment disclosed herein.
- FIG. 3 illustrates a schematic cross section of an additional embodiment of an implant in accordance with disclosure herein.
- FIG. 4 illustrates a schematic cross section of an additional embodiment of an implant in accordance with disclosure herein.
- FIG. 5 illustrates a schematic cross section of an additional embodiment of an implant in accordance with disclosure herein.
- FIG. 6 illustrates a schematic cross section of an additional embodiment of an implant in accordance with disclosure herein.
- FIG. 7 illustrates a schematic cross section of an additional embodiment of an implant in accordance with disclosure herein.
- FIG. 8 is a schematic graph showing the elution profile of two therapeutic agents eluted from an implant according to an embodiment disclosed herein.
- FIG. 9 is a schematic graph showing an alternative elution profile of two therapeutic agents eluted from an additional implant according to an embodiment disclosed herein.
- FIG. 10 illustrates the anatomy of an eye.
- FIG. 11 illustrates an embodiment of an implant in which the implant is rechargeable in that an additional, or substitute, drug payload can be added to implant without requiring removal of the implant.
- FIG. 12 illustrates an embodiment of an implant delivery system comprising a plunger for use with a preloaded drug implant.
- FIGS. 13 A- 13 C illustrate schematic cross sections of embodiments of inserter tools in accordance with disclosure provided herein.
- FIGS. 14 A- 14 B illustrate schematic cross sections of additional embodiments of implants in accordance with disclosure herein.
- FIGS. 15 A- 15 B illustrate schematic cross sections of additional embodiments of implants in accordance with disclosure herein.
- FIGS. 16 A- 16 B illustrate schematic cross sections of additional embodiments of implants in accordance with disclosure herein.
- FIGS. 17 A- 17 B illustrate schematic cross sections of additional embodiments of implants in accordance with disclosure herein.
- FIGS. 18 A- 18 B illustrate schematic cross sections of additional embodiments of implants in accordance with disclosure herein.
- FIGS. 19 A- 19 B illustrate schematic cross sections of additional embodiments of implants in accordance with disclosure herein.
- Achieving local ocular administration of a drug may require direct injection or application, but could also include the use of a drug eluting implant, a portion of which, could be positioned in close proximity to the target site of action within the eye or within the chamber of the eye where the target site is located (e.g., anterior chamber, posterior chamber, or both simultaneously).
- Use of a drug eluting implant could also allow the targeted delivery of a drug to a specific ocular tissue, such as, for example, the macula, the retina, the ciliary body, the optic nerve, or the vascular supply to certain regions of the eye.
- Use of a drug eluting implant could also provide the opportunity to administer a controlled amount of drug for a desired amount of time, depending on the pathology.
- implants may serve additional functions once the delivery of the drug is complete. Implants may maintain the patency of a fluid flow passageway within an ocular cavity, they may function as a reservoir for future administration of the same or a different therapeutic agent, or may also function to maintain the patency of a fluid flow pathway or passageway from a first location to a second location, e.g. function as a stent. Conversely, should a drug be required only acutely, an implant may also be made completely biodegradable.
- the implants are configured specifically for use (e.g., implantation) in the punctum of the eye of a subject (e.g., the upper and/or lower punctum of the upper and/or lower canaliculus, respectively).
- the puncta function to collect tears that are released onto the surface of the eye by the lacrimal glands.
- tear production is reduced, blocked, decreased, or otherwise insufficient to maintain an adequate level of moisture on the eye (or eyes). Damage to the corneal surface of the eye can result if the moisture on the eye remains reduced.
- the puncta convey the tear fluid to the lacrimal sac, which then allows it to drain through the nasolacrimal duct to the inner nose.
- One treatment for dry eye or similar syndromes is implantation of punctual plugs. Once implanted the plugs function to block the drainage of tear fluid, thereby increasing the retention of tear fluid on the eye.
- the implant embodiments disclosed herein advantageously allow the supplementation of the physical blockage of tear drainage with the delivery of one or more therapeutic agents to the eye in order to treat one or more aspects of reduced tear production.
- one or more therapeutic agents are positioned in the implant in order to increase tear production and/or treat a symptom of dry eye, including, but not limited to, reduction in swelling, irritation of the eye and surrounding tissues and/or inflammation.
- Additional symptoms that are reduced, ameliorated, and in some cases eliminated include stinging or burning of the eye, a sandy or gritty feeling as if something is in the eye, episodes of excess tears following very dry eye periods, a stringy discharge from the eye, pain and redness of the eye, temporary or extended episodes of blurred vision, heavy eyelids, reduced ability to cry, discomfort when wearing contact lenses, decreased tolerance of reading, working on the computer, or any activity that requires sustained visual attention, and eye fatigue.
- the implants advantageously obviate the need for additional topical agents (e.g., ointments, artificial tears, etc.).
- the implants are configured (e.g., have a particular drug release profile) to work synergistically with one or more of such agents.
- the implant is configured to deliver a constant dosage of a therapeutic agent over time to treat a damaged or diseased eye, and a subject with them implants in place can also use artificial tears, for example, to further enhance the efficacy of the agent delivered from the implant.
- the agents delivered from the implant are used for treatment of another ocular disorder, such as glaucoma, ocular hypertension, and/or elevated intraocular pressure.
- implants configured for punctual placement allows metered delivery of one or more therapeutic agents; that is, delivery at a constant rate, thereby reducing the peaks and valleys of therapeutic agent concentration as occurs with topical administration (e.g., via eye drop).
- the dimensions of the implants, their shape, their drug release characteristics, and the like can be configured for use in the punctum.
- the plugs can be tailored to the punctal dimensions of a particular subject.
- the plugs can be configured to be removable or, in several embodiments, permanent (e.g., capable of being recharged).
- the punctal implants comprise at least a first active agent that is loaded, at least in part, preferentially in the proximal region of the implant (e.g., such that the agent is released to the tear film of the subject) with the distal region of the implant positioned within the within the lacrimal ducts.
- the implant is specifically adapted to prevent unintended release of the active agent (or agents) from the distal portion of the implant.
- a plug e.g., an impermeable occlusive member
- a membrane e.g., a membrane with little to no permeability to the active agent/agents
- a valve e.g., a one-way valve
- the use of a valve or plug enables flushing of the implant.
- the plug can be removed and the implant flushed from a proximal to distal direction, allowing the therapeutic agent remaining in the implant to be flushed down the nasolacrimal duct. Thereafter the implant can be reloaded with another dose, another agent, and the like.
- flushing the implant can be performed when a valve is positioned in the distal region of the implant, the valve being opened by pressure exerted on it from the flushing procedure and preventing backflow of the flushed agent into the implant.
- an implant and method for treating an eye with latanoprost or other therapeutic agent(s) comprising inserting a distal end of an implant into at least one punctum of the eye and positioning the implant such that the proximal portion of the implant delivers latanoprost or other therapeutic agent(s) to the tear fluid adjacent the eye. In several embodiments, delivery of the latanoprost or other therapeutic agent(s) is inhibited distally of the proximal end.
- Implants according to the embodiments disclosed herein preferably do not require an osmotic or ionic gradient to release the drug(s), are implanted with a device that minimizes trauma to the healthy tissues of the eye which thereby reduces ocular morbidity, and/or may be used to deliver one or more drugs in a targeted and controlled release fashion to treat multiple ocular pathologies or a single pathology and its symptoms.
- an osmotic or ionic gradient is used to initiate, control (in whole or in part), or adjust the release of a drug (or drugs) from an implant.
- osmotic pressure is balanced between the interior portion(s) of the implant and the ocular fluid, resulting in no appreciable gradient (either osmotic or ionic).
- variable amounts of solute are added to the drug within the device in order to balance the pressures.
- drug refers generally to one or more drugs that may be administered alone, in combination and/or compounded with one or more pharmaceutically acceptable excipients (e.g. binders, disintegrants, fillers, diluents, lubricants, drug release control polymers or other agents, etc.), auxiliary agents or compounds as may be housed within the implants as described herein.
- pharmaceutically acceptable excipients e.g. binders, disintegrants, fillers, diluents, lubricants, drug release control polymers or other agents, etc.
- drug is a broad term that may be used interchangeably with “therapeutic agent” and “pharmaceutical” or “pharmacological agent” and includes not only so-called small molecule drugs, but also macromolecular drugs, and biologics, including but not limited to proteins, nucleic acids, antibodies and the like, regardless of whether such drug is natural, synthetic, or recombinant.
- Drug may refer to the drug alone or in combination with the excipients described above.
- “Drug” may also refer to an active drug itself or a prodrug or salt of an active drug.
- the drug diffuses through the implant itself and into the intraocular environment.
- the outer material of the implant is permeable or semi-permeable to the drug (or drugs) positioned within an interior lumen, and therefore, at least some portion of the total elution of the drug occurs through the shell itself.
- the shell of the implant is impermeable to the drug (or drugs) in the interior lumen, and the implant comprises one or more specific regions of drug release.
- impermeable or “semi permeable”) are used herein to refer to a material being permeable to some degree (or not permeable) to one or more drugs or therapeutic agents and/or ocular fluids.
- the term “impermeable” does not necessarily mean that there is no elution or transmission of a drug through a material, instead such elution or other transmission is negligible or very slight, e.g. less than about 3% of the total amount, including less than about 2% and less than about 1%.
- an impermeable outer shell permits no elution of drug through the shell.
- patient shall be given its ordinary meaning and shall also refer to mammals generally.
- mammal includes, but is not limited to, humans, dogs, cats, rabbits, rodents, swine, ovine, and primates, among others. Additionally, throughout the specification ranges of values are given along with lists of values for a particular parameter. In these instances, it should be noted that such disclosure includes not only the values listed, but also ranges of values that include whole and fractional values between any two of the listed values.
- the drug delivery implants disclosed herein are configured to delivery drug to the eye via a topical delivery route.
- the implant is configured to deliver one or more drugs to anterior region of the eye in a controlled fashion while in other embodiments the implant is configured to deliver one or more drugs to the posterior region of the eye in a controlled fashion.
- the implant is configured to simultaneously deliver drugs to both the anterior and posterior region of the eye in a controlled fashion.
- the configuration of the implant is such that drug is released in a targeted fashion to a particular intraocular tissue, for example, the macula or the ciliary body.
- each of the embodiments described herein may target one or more of these regions and, optionally, reaches the site and achieves a therapeutic effect after being administered topically.
- drug is released from the implant in a targeted and controlled fashion, based on the design of the various aspects of the implant, preferably for an extended period of time.
- the implant and associated methods disclosed herein may be used in the treatment of pathologies requiring drug administration to the surface of the eye (e.g., topical), the posterior chamber of the eye, the anterior chamber of the eye, or to specific tissues within the eye.
- the present disclosure relates to ophthalmic drug delivery implants which, following implantation at an implantation site, such as the punctum, provide controlled release of one or more drugs to a desired target region within the eye, the controlled release optionally being for an extended, period of time.
- implantation site such as the punctum
- controlled release optionally being for an extended, period of time.
- a biocompatible drug delivery ocular implant comprising an outer shell that is shaped to define at least one interior lumen that houses a drug for release into an ocular space.
- the implant comprises a body 10 having an interior lumen 12 .
- the shell is formed to have at least two interior lumens.
- the upper portion of the implant in several embodiments, comprises a flange 14 that extends radially and sits on the surface of the eyelid after the plug is implanted into the punctum. Opposite the flange 14 is a closed end 16 .
- an open end or open lateral portion may also be used, for example to provide drainage to the naso-lacrimal duct.
- the implant comprises a radial bulge 18 from a long axis LA of the body in order to provide an anchor within the punctum.
- the bulge is parallel (or substantially parallel to a short axis SA of the implant).
- the bulge (or other pattern) need not be uniform.
- the bulge can comprise a raised ridge (or series of ridges encircling the body).
- the bulge is similar to threads on a screw.
- a bulge for example, a ridge, groove, relief, hole, or annular groove, barbs, barbs with holes, screw-like elements, knurled elements, suture, friction or wedge fit, and/or expandable materials.
- the upper portion of the implant comprises a flange with a diameter configured to ensure reduced, limited, or in some embodiments, no corneal or scleral contact.
- the flange preferably has a generally flattened lower surface to allow it to rest upon the lower eyelid immediately adjacent to the punctum.
- FIG. 1 B illustrates a flange 14 that is circular in shape
- FIG. 1 C illustrates an asymmetrical flange
- FIG. 1 D illustrates an ovoid flange. Attributes of the flange, such as area, shape, and thickness may be varied as desired such as to aid in positioning of the uppermost end of the implant at the surface of the punctum.
- the flange may be round, ovoid, or any geometric or asymmetric shape.
- the flange is asymmetrical to provide reduced, limited, or in some embodiments, no corneal or scleral contact. Illustrations of non-limiting embodiments of an asymmetric flange can also be seen in FIGS. 15 A and 18 A .
- the implant optionally comprises at least one retention protrusion configured to anchor the implant in an implantation site.
- these retention features are non-occlusive, for example, they allow tear or other fluid flow through the canaliculus toward the nasolacrimal duct while holding the tissue of the canaliculus away from the implant body.
- the at least one retention feature optionally comprises a bulge, protuberance, or other change in shape (relative to the long axis of the implant body) that extends axially from the body and that holds the implant in position.
- the implant further comprises an inner tubular passageway of any size and shape. For example, FIGS.
- FIGS. 14 A and 14 B illustrate a non-limiting embodiment comprising two retention features extending axially from the body of the implant, each further comprising a straight tubular passageway that passes through the feature.
- the at least one retention feature optionally comprises a bulge that extends axially from the body of the implant and comprises an inner relief, as illustrated in FIGS. 17 A, 17 B .
- FIGS. 18 A and 18 B illustrate another embodiment of an implant comprising three retention features, each further comprising an inner relief, and an asymmetric flange.
- the inner relief can be of any shape and size, advantageously facilitating an optionally greater tear or other fluid flow as compared to retention features comprising a tubular passageway.
- the relief features may also provide a point through which a securing suture can be fastened to secure the implant into position. Additionally, some such embodiments are used in conjunction with therapeutic agents having a side effect of increased tear production.
- the retention features optionally comprise an erodible material.
- the retention protrusions extend from the proximal end of the implant to a position approximately or more than halfway down the (long axis of the) implant towards the distal end.
- the retention protrusions extend from the proximal end of the implant to less than halfway to the distal end of the implant.
- the retention protrusion comprises a ring positioned at any point along the body of the implant, as shown, for example, in FIG. 19 A .
- the ring optionally contains spoke features, occluding some, but not all, fluid flow, as shown, for example, in FIG. 19 B .
- these retention features and flange shapes may be incorporated into any of the embodiments of FIGS. 1 - 7 .
- the dimension of the at least one retention feature ranges from about 0.01 mm to about 0.15 mm as measured from the outer surface of the implant body to an edge of retention feature.
- the thickness of the retention feature ranges from about 0.01 mm to about 0.02 mm, about 0.02 mm to about 0.03 mm, about 0.03 mm to about 0.04 mm, about 0.04 mm to about 0.05 mm, about 0.05 mm to about 0.06 mm, about 0.06 mm to about 0.07 mm, about 0.07 mm to about 0.08 mm, about 0.08 mm to about 0.09 mm, about 0.09 mm to about 0.10 mm, about 0.10 mm to about 0.11 mm, about 0.11 mm to about 0.12 mm, about 0.12 mm to about 0.13 mm, about 0.13 mm to about 0.14 mm, about 0.14 mm to about 0.15 mm, and overlapping ranges therebetween and/or any other dimensions sufficient to secure the implant in the punctum of a particular patient
- the long axis of the implant is greater than the short axis of the implant.
- the ratio of the long axis to the short axis ranges from about 1:1 to about 2:1, about 2:1 to about 3:1, about 3:1 to about 4:1, about 4:1 to about 5:1, about 5:1 to about 6:1, about 6:1 to about 7:1, about 7:1 to about 8:1, about 8:1 to about 9:1, about 9:1 to about 10:1, about 10:1 to about 20:1, or ratios between (or greater) than those listed.
- the punctal implant ranges between about 0.5 and about 2.5 mm long (e.g., from the proximal end to the distal end).
- the length of the implant in some embodiments, ranges from about 0.5 mm to about 0.7 mm, about 0.7 mm to about 0.9 mm, about 0.9 mm to about 1.0 mm, about 1.0 mm to about 1.1 mm, about 1.1 mm to about 1.2 mm, about 1.2 mm to about 1.3 mm, about 1.3 mm to about 1.35 mm, about 1.35 mm to about 1.4 mm, about 1.4 mm to about 1.45 mm, about 1.45 mm to about 1.5 mm, about 1.5 mm to about 1.55 mm, about 1.55 mm to about 1.6 mm, about 1.6 mm to about 1.65 mm, about 1.65 mm to about 1.7 mm, about 1.7 mm to about 1.9 mm, about 1.9 mm to about 2.1 mm, about 2.1 mm to about 2.3 mm
- implants configured for implantation into the punctum have a diameter between about 0.2 mm and 2.0 mm, including about 0.2 mm to about 0.3 mm, about 0.3 mm to about 0.4 mm, about 0.4 mm to about 0.5 mm, about 0.5 mm to about 0.6 mm, about 0.5 mm to about 0.6 mm, about 0.6 mm to about 0.7 mm, about 0.7 mm to about 0.8 mm, about 0.8 mm to about 0.9 mm, about 0.9 mm to about 1.0 mm, about 1.0 mm to about 1.1 mm, about 1.1 mm to about 1.2 mm, about 1.2 mm to about 1.3 mm, about 1.3 mm to about 1.4 mm, about 1.4 mm to about 1.5 mm, about 1.5 mm to about 1.6 mm, about 1.6 mm to about 1.7 mm, about 1.7 mm to about 1.8 mm, about 1.8 mm to about 1.9 mm, about 1.9 mm to about 2.0 mm and
- FIGS. 1 - 7 The characteristics of the implant shown in FIG. 1 are carried through FIGS. 1 - 7 , however it shall be appreciated that any of the features of the implants disclosed herein can be used in combination with any other features disclosed herein (unless otherwise expressly noted).
- all Figures are presently shown with a bulge 18 as a retention feature; the bulge may be replaced with any retention feature such as those disclosed herein.
- any type of drug arrangement may be used with any type of drug elution element.
- the two phase drug of FIG. 5 may be included in a device having elution elements between the drug and the exterior such as in FIG. 2 A or 2 C .
- a region of a first therapeutic drug 20 is shown near the flange and a region of a second therapeutic drug 30 is shown in the lumen 12 .
- One or both regions of drug may comprise pure drug, or drug plus excipients, or drug within a bioerodible or non-bioerodible matrix, as discussed in more detail below. Additionally, one or both regions may comprise packed powder formulation or pure drug, or tableted formulation or pure drug, or microspheres, nanospheres, liposomes, or the like of pure drug.
- the drug (or drugs) comprises drug-containing pellets, while in other embodiments, the drug is a liquid, a slurry, micro-pellets (e.g., micro-tablets) or powder.
- the drug (or drugs) may also be in the form of nanodispersions, depending on the embodiment. Combinations of any of these forms can also be used.
- one region can be of one form while the other region can be in another form (e.g., the drug of the first region is pure drug and the drug of the second region is drug plus excipient).
- the drug of the first region is pure drug and the drug of the second region is drug plus excipient.
- any combinations of form, composition, etc. may be used in any of the drug regions, as is needed to tailor the drug elution to a desired profile.
- the drug elution is controlled, depending on the embodiment, to allow drug release over a desired time frame.
- the duration drug release ranges from several months to several years, e.g., about 6 to about 12 months, about 12 to about 18 months, about 18 to about 24 months, about 24 to about 30 months, about 30 to about 36 months, etc.
- the first therapeutic drug 20 is steroid, such as loteprednol etabonate, dexamethasone, or triamcinolone acetonide (or a combination of any of these); and the second therapeutic drug 30 is cyclosporine.
- the first therapeutic drug e.g., the steroid(s)
- the first drug will tend to dissolve first, and thus, may be exhausted first (though in some embodiments the first drug is not exhausted at the time the release of the second drug is initiated).
- the second drug e.g., cyclosporine
- the second drug will tend to dissolve at or near the conclusion of the dissolution of the first drug, and thus, will have a more prolonged time course.
- this “tail-to-nose” overlapping elution results in an advantageously therapeutic elution profile that provides a therapeutic level of the first and second drugs, but reduces the peaks and valleys in drug concentration that can be result from current therapies (such as eye drops).
- FIG. 8 shows a sample non-limiting schematic of a time course of drug elution that may result from implants configured similar to the embodiment shown in FIG. 1 .
- Element 130 is the time course of the first drug
- element 140 is the time course of the second drug. While FIG. 1 depicts one lumen that is exposed to the ocular environment through which drug(s) is released, it shall also be understood that, depending on the embodiment, one, two, or more drug regions may be utilized in a punctal plug delivery device as disclosed herein.
- the in vivo environment into which several embodiments of the implants disclosed herein are positioned may be comprised of a water-based solution (such as aqueous humor or tear film) or gel (such as vitreous humor).
- a water-based solution such as aqueous humor or tear film
- gel such as vitreous humor
- Water from the surrounding in vivo environment may, in some embodiments, diffuse into one or more of the interior lumens, depending on the embodiment, and begin dissolving a small amount of the tablet or drug-excipient powder. The dissolution process continues until a solution is formed within the lumen that is in osmotic equilibrium with the in vivo environment.
- osmotic agents such as saccharides or salts are added to the drug to facilitate ingress of water and formation of the isosmotic solution.
- relatively insoluble drugs for example corticosteroids
- the isosmotic solution may become saturated with respect to the drug in certain embodiments.
- saturation can be maintained until the drug supply is almost exhausted.
- maintaining a saturated condition is particularly advantageous because the elution rate will tend to be essentially constant, according to Fick's Law.
- the outer shell comprises one or more orifices to allow ocular fluid to contact the drug within the lumen (or lumens) of the implant and result in drug release.
- a layer or layers of a permeable or semi-permeable material is used to cover the implant (wholly or partially) and the orifice(s) (wholly or partially), thereby allowing control of the rate of drug release from the implant.
- combinations of one or more orifices, a layer or layers covering the one or more orifices are used to tailor the rate of drug release from the implant.
- FIG. 2 A shows an embodiment wherein an additional component 40 , representing a semi-permeable membrane or layer is included in the implant and obstructs (wholly or partially) the opening from the lumen of the implant to the ocular space external to the implant.
- component 40 may comprise a bioerodible or non-bioerodible hydrogel, or a semi-permeable polymer, or a polymeric, metallic, or ceramic screen or filter.
- the elution rate of the therapeutic drug (or drugs) within the implant is regulated according to the drug's permeability through component 40 .
- the regulation of permeability can be altered by changing one or more characteristics of the component 40 (e.g., thickness, chemical makeup, porosity, etc.). It shall also be appreciated that elution regulation component 40 (or its equivalents) may be incorporated into any subsequent example, including those shown in any of the additional figure or any embodiment described herein.
- FIG. 2 B depicts another embodiment of an implant that provides an advantageous drug elution profile.
- Item 10 is the body of the punctal plug, as discussed above, with a flange that rests in apposition to the surface of the eyelid after the plug is implanted into the punctum.
- the punctal plug 10 is molded of a soft elastomeric material, such as silicone, polyurethane or a copolymer (such as PurSil®).
- these materials allow the plug to conform to the punctum of a specific patient, thereby increasing the comfort of the implant over the life of implantation.
- these materials (or combinations thereof) also facilitate the consistent manufacture of the implants.
- the size of the implant may optionally vary depending on the patient.
- silicone (or other similar material) implants are personalized to an individual patient or a segment of possible patients and their anatomical characteristics.
- the implants are designed as a “one size fits all patients” implant. In alternative embodiments, however other materials disclosed herein may be used to construct the implant (either in whole or in part).
- the outer shell is not biodegradable, while in others, the shell is optionally biodegradable.
- the implant is made of a flexible material.
- a portion of the implant is made from flexible material (e.g., the body) while another portion of the implant is made from rigid or semi-rigid material (e.g., the body or the bulge).
- the implant comprises one or more flexures (e.g., hinges).
- the drug delivery implant is pre-flexed, yet flexible enough to be contained within the straight lumen of a delivery device.
- At least a portion of the implant is made of a material capable of shape memory.
- a material capable of shape memory may be compressed and, upon release, may expand axially or radially, or both axially and radially, to assume a particular shape.
- at least a portion of the implant has a preformed shape.
- at least a portion of the implant is made of a superelastic material.
- at least a portion of the implant is made up of nitinol.
- at least a portion of the implant is made of a deformable material.
- the punctal plug comprise a lumen 103 that is molded with an opening at the bottom of the plug.
- a thin-walled region (or plurality of regions) 104 extending across the upper end of lumen 103 .
- the thin-walled regions 104 function to retain solid or dissolved drug housed within plug 10 as shown in FIG. 2 C (e.g., they function as a large scale sieve), while also providing a diffusion path between the drug and the tear film external to plug 10 .
- region 104 comprises the same material as the rest of plug 10 , or alternatively, comprises a different material (for example, manufactured as an insert molded with the rest of the plug).
- Region 104 allows diffusion of drug into the tear film according to the drug permeability of the region 104 material, the cross-sectional dimension of region 104 , and the optional addition of holes or fenestrations 102 . Control of drug elution rates is discussed in more detail below. Depending on the embodiment, region 104 ranges in thickness between about 0.0005 inches to about 0.05 inches.
- region 104 ranges in thickness from about 0.0005 inches to about 0.00075 inches, about 0.00075 inches to about 0.001 inches, about 0.001 inches to about 0.00125 inches, about 0.00125 inches to about 0.0015 inches, about 0.0015 inches to about 0.00175 inches, about 0.00175 inches to about 0.002 inches, about 0.002 inches to about 0.00225 inches, about 0.00225 inches to about 0.0025 inches, about 0.0025 inches to about 0.00275 inches, about 0.00275 inches to about 0.003 inches, about 0.003 inches to about 0.00325 inches, about 0.00325 inches to about 0.0035 inches, about 0.0035 inches to about 0.00375 inches, about 0.00375 inches to about 0.004 inches, about 0.004 inches to about 0.0045 inches, about 0.0045 inches to about 0.005 inches, about 0.005 inches to about 0.006 inches, about 0.006 inches to about 0.006 inches, about 0.006 inches to about 0.007 inches, about 0.007 inches to about 0.008 inches,
- the holes or fenestrations may be of any shape, including but not limited to square, round, irregular-shaped. In each case, an individual fenestration or hole has a diameter less than that of lumen 103 .
- the holes or fenestrations are located in any geometrical pattern (or randomly positioned) within region 104 . In those embodiments having more than one region 104 , the holes or fenestrations may be positioned differentially between each region (e.g., patterned positioning in a first region and random positioning in a second region).
- Holes or fenestrations 102 may be formed during molding of plug 10 , or may be laser machined after molding, such as by ablation, stretching, etching, grinding, molding, femtosecond laser exposure, particle blasting, machining, or other methods.
- the implant allows for drug elution proximally toward the tear film, as well as distally toward the nasolacrimal duct.
- the active agent is released into the tear film, the nasolacrimal duct, or both the tear film and the nasolacrimal duct.
- Distal drug elution is useful, in several embodiments, for intranasal and/or systemic drug delivery.
- Embodiments comprising holes or fenestrations 102 also optionally comprise at least one non-occlusive retention feature, as discussed above, rendering the implant non-occlusive and comprising a design solution for overall distal drug delivery.
- a therapeutic agent eluted from either a proximal end or distal end of the implant will ultimately drain distally toward the nasolacrimal duct.
- agents eluted from a proximal end of the implant results in only proximal drug delivery as delivery of the therapeutic agent is inhibited distally of the proximal end.
- the implant shown in FIG. 2 C is assembled by first obtaining tablets or powder (or other form) of at least a first and second drug. In reverse order of release from the implant, the drugs are loaded through the open end of lumen 103 shown in FIG. 2 B .
- FIG. 2 C shows the assembled delivery device, where item 20 is a region of a first therapeutic drug, and item 30 is a region of a second therapeutic drug.
- one or both regions may comprise pure drug, or drug plus excipients, or drug within a bioerodible or non-bioerodible matrix.
- One or both regions may comprise packed powder formulation or pure drug, or tableted formulation or pure drug, or microspheres, nanospheres, liposomes, or the like of pure drug.
- the plug comprises a flowable material that acts as a sealant by filling the remaining space in the lumen 103 .
- the plug 101 comprises, RTV silicone injected into the open end of lumen 103 .
- the plug 101 is preformed of silicone elastomer, another polymer (or polymers), or another biocompatible material, and press fit into lumen 103 .
- plug 101 comprises a thermoplastic material such as PurSil®, which is then thermoformed in place to seal the end of the implant.
- the drug load is isolated from the plug material with a drug sleeve (e.g., a sleeve body).
- a drug sleeve e.g., a sleeve body
- FIG. 2 D shows a cross-sectional view of an implant 1 comprising a drug core 35 and surrounding drug sleeve 45 , according to several embodiments.
- the sleeve body comprises appropriate shapes, dimensions, and/or materials to regulate, adjust, or otherwise control elution of the therapeutic agent from the drug core.
- the drug sleeve comprises a material that is substantially impermeable (e.g., less than 50% permeable) to the therapeutic agent so that the rate of migration of the therapeutic agent is primarily (or at least in part) controlled by the exposed surface area of the drug core that is not covered by the drug sleeve.
- suitable materials for the drug sleeve include, but are not limited to, polypropylene, polyimide, glass, nitinol, polyvinyl alcohol, polyvinyl pyrolidone, collagen, chemically-treated collagen, polyethersulfone (PES), poly(styrene-isobutyl-styrene), polyurethane, ethyl vinyl acetate (EVA), polyetherether ketone (PEEK), Kynar (Polyvinylidene Fluoride; PVDF), Polytetrafluoroethylene (PTFE), Polymethylmethacrylate (PMMA), Pebax, acrylic, polyolefin, polydimethylsiloxane and other silicone elastomers, polypropylene, hydroxyapetite, titanium, gold, silver, platinum, other metals and alloys, ceramics, plastics and mixtures or combinations thereof.
- the drug sleeve allows for an exchangeable drug core if the therapeutic agent needs to be replenished, replaced, or supplemented by the same or different agent. Accordingly, the implant body can remain implanted in the patient. In some embodiments, the drug sleeve remains in the implant while only the drug core is replaced. In these embodiments, the drug sleeve may be provided, for example, with external protrusions that apply force to the drug sleeve when squeezed and eject the core from the drug sleeve. In some embodiments, the drug sleeve is removed with the drug core.
- the drug sleeve ranges between about 0.5 and 2.4 mm long (e.g., from the proximal end to the distal end).
- the length of the drug sleeve in some embodiments, ranges from about 0.5 mm to about 0.7 mm, about 0.7 mm to about 0.9 mm, about 0.9 mm to about 1.0 mm, about 1.0 mm to about 1.1 mm, about 1.1 mm to about 1.2 mm, about 1.2 mm to about 1.3 mm, about 1.3 mm to about 1.35 mm, about 1.35 mm to about 1.4 mm, about 1.4 mm to about 1.45 mm, about 1.45 mm to about 1.5 mm, about 1.5 mm to about 1.55 mm, about 1.55 mm to about 1.6 mm, about 1.6 mm to about 1.65 mm, about 1.65 mm to about 1.7 mm, about 1.7 mm to about 1.9 mm, about 1.9 mm to about 2.1 mm, about 2.1 mm,
- drug sleeves have an inner diameter between about 0.2 mm and 1.9 mm, including about 0.2 mm to about 0.3 mm, about 0.3 mm to about 0.4 mm, about 0.4 mm to about 0.5 mm, about 0.5 mm to about 0.6 mm, about 0.5 mm to about 0.6 mm, about 0.6 mm to about 0.7 mm, about 0.7 mm to about 0.8 mm, about 0.8 mm to about 0.9 mm, about 0.9 mm to about 1.0 mm, about 1.0 mm to about 1.1 mm, about 1.1 mm to about 1.2 mm, about 1.2 mm to about 1.3 mm, about 1.3 mm to about 1.4 mm, about 1.4 mm to about 1.5 mm, about 1.5 mm to about 1.6 mm, about 1.6 mm to about 1.7 mm, about 1.7 mm to about 1.8 mm, about 1.8 mm to about 1.9 mm and any diameters in between or overlapping with these ranges.
- FIG. 3 shows an embodiment where two drug regions, depicted as 22 and 24 , respectively are loaded in parallel within the punctual plug. In such embodiments, both drug regions 22 and 24 begin eluting at the same time.
- the elution profiles of 22 and 24 are substantially similar, for example when drug 24 reduces the potential for side effects of administration of drug 22 .
- the elution profiles of drug 22 and drug 24 are offset.
- drug 22 and 24 are completely or substantially eluted at such time as a third drug region 30 begins elution. While shown effectively as equal proportions, it shall be appreciated that drug 22 and drug 24 can be placed in the punctal plug in any ratio with respect to one another that produces a desired therapeutic effect.
- drug 22 may make up about 10%, about 20%, about 25%, about 30% or more of the total amount of drugs 22 and 24 present in the implant.
- drug 22 may make up about 60%, about 70%, about 80%, about 90% or more of the total amount of drugs 22 and 24 present in the implant. Any combination of drug 22 and 24 can be used, depending on the embodiment.
- the drugs may be loaded at an angle with respect to one another, in order to control the surface area of the drug that is exposed to tear file at a given time post implantation.
- an angular gradient could be used to start with a high percentage of release of drug 22 as compared to release of drug 24 , with an inverse elution profile being generated as the drugs are eluted (e.g., as elution of the drugs proceeds, the proportion of drug 22 being released, versus the total, decreases, while the proportion of drug 24 increases.
- FIG. 4 shows an embodiment in which multiple drug regions 50 , 60 , 70 , and 80 are preformed into tablets (or micropellets) to facilitate control of drug formulation, and to facilitate manufacturing assembly of the punctal plug delivery device.
- the preformation of the drugs into tablets advantageously enables the placement of the drugs sequentially into the implant with reduced complications during assembly (e.g., mis-ordering of the drugs, damage to the implant, etc.).
- pre-formation allows the specific tailoring of a drug profile for a particular patient.
- an option may be to reformulate the drugs within the implant (e.g., drug regions 50 , 80 , 60 , and 70 , or 50 , 50 , 60 , 70 ).
- This advantageously allows customization of a drug treatment regime for the therapeutic needs of a specific patient.
- Alternative methods for loading an implant as disclosed herein are provided in U.S. Pat. No. 7,117,870, the entire contents of which are incorporated by reference herein.
- FIG. 5 shows an arrangement used in several embodiments, wherein drug region 90 comprises a discontinuous first phase which is distributed within drug region 100 , which forms a second phase.
- drug region 90 may comprise microparticles, nanoparticles, liposomes, or the like, any or all of which may carry a first therapeutic drug.
- Drug region 100 depending on the embodiment, comprises a dispersion of solid or liquid particles or droplets of a second therapeutic drug dispersed within a hydrogel matrix, or some other semi-permeable polymer matrix.
- Such embodiments are advantageous in that small and predictable boluses of drug 90 can be intermixed with a second (or more) drug in different phases. This allows a further degree of tailoring the release profiles of the drug or drugs.
- the second region of drug 100 can complement the first region 90 , for example in providing an environment that improves the stability of drug 90 , which may otherwise be relatively volatile.
- FIG. 6 shows an additional embodiment of a punctal plug comprising a ring-shaped component 110 comprising an aperture 112 , the aperture being sized in diameter and thickness to regulate elution rate according to Fick's Law of diffusion (discussed in more detail below).
- the ring-shaped component can be used to further refine and tailor the release of a drug (or drugs) from the implant, while having the implant be “off the shelf”.
- the implant shell can be one of several stock sizes (e.g., small, medium, large, etc.), each size having a particular size lumen.
- the ring-shaped component 110 can thus be used to adjust the rate of elution of the drug (or drugs) from the implant by re-sizing the opening of the lumen according to the needs of a particular patient.
- the ring-shaped component 110 in several embodiments, is made of a material that is generally impermeable to the drug (or drugs) in the lumen. Control of drug release is then calculated by the dimensions of aperture 112 , and any membrane or other controlling material (e.g., component 40 of FIG. 2 ) placed within, or over, the aperture.
- the ring-shaped component 110 can comprise a material that is semi-permeable material to one or more of the drugs within the lumen of the implant. In such embodiments, the combination of the ring-shaped component 110 , its dimensions, and its interaction with the aperture and/or component 40 work in concert to define the release rates of the drugs from the implant.
- FIGS. 8 and 9 Such elution profiles are shown in FIGS. 8 and 9 . These profiles can advantageously be modified to meet the needs of a particular patient, not only in terms of the drugs that are administered and at what time, but in what amount compared with one another, so as to reduce (or treat) side effects.
- FIG. 7 shows an additional component 120 , which is a separator placed between the first drug region 20 and the second drug region 30 .
- Separator 120 depending on the embodiment, comprises a bioerodible, non-bioerodible; hydrogel; semi-permeable polymer; or a porous element comprising ceramic or metal. Separator 120 serves to create a separation in time between the elution of the drug in region 20 and the drug in region 30 .
- FIG. 9 depicts a schematic elution profile resulting from an embodiment such as the implant of FIG. 7 .
- 130 is the time course of drug elution from the first region 20
- 140 is the time course of elution from the second drug region 30 .
- the two drug regions may contain the same drug, and the purpose of separator 120 is to create a “drug holiday”, a time interval during which little or no drug is being eluted (compare the elution profile of FIG. 8 with that of FIG. 9 ).
- the implants according to the embodiments disclosed herein allow a highly flexible approach for drug delivery to the eye as well as the ability to customize the drugs used, release timing and concentration (vis-à-vis other drugs in the implant) and thereby create a personalized overall therapeutic regime.
- the drug delivery implant may contain one or more drugs which may or may not be compounded with a bioerodible polymer or a bioerodible polymer and at least one additional agent, the release profiles of each can be managed independently, further adding to the flexibility of the overall treatment plant.
- the drug delivery implant is used to sequentially deliver multiple drugs. Some embodiments elute one or more drugs at a constant rate, with other embodiments release one or more drugs with a zero-order release profile.
- Still other embodiments yield variable elution profiles. Still other embodiments are designed to stop elution completely or nearly completely for a predetermined period of time (e.g., a “drug holiday”) and later resume elution at the same or a different elution rate or elution concentration. Some such embodiments elute the same therapeutic agent before and after the drug holiday while other embodiments elute different therapeutic agents before and after the drug holiday.
- a predetermined period of time e.g., a “drug holiday”
- Some such embodiments elute the same therapeutic agent before and after the drug holiday while other embodiments elute different therapeutic agents before and after the drug holiday.
- FIG. 10 illustrates the anatomy of an eye, which includes the sclera 11 , which joins the cornea 12 at the limbus 21 , the iris 13 and the anterior chamber 20 between the iris 13 and the cornea 12 .
- the eye also includes the lens 26 disposed behind the iris 13 , the ciliary body 16 and Schlemm's canal 22 .
- the eye also includes a uveoscleral outflow pathway, which functions to remove a portion of fluid from the anterior chamber, and a suprachoroidal space positioned between the choroid 28 and the sclera 11 .
- the eye also includes the posterior region 30 of the eye which includes the macula 32 .
- the drug delivery implants as described herein function to house a drug and provide drug elution from the implant in a controlled fashion, based on the design of the various components of the implant, for an extended period of time.
- Various elements of the implant composition, implant physical characteristics, and the composition of the drug work in combination to produce the desired drug release profile.
- the drug delivery implant may be made from any biological inert and biocompatible materials having desired characteristics. Desirable characteristics, in some embodiments, include permeability to liquid water or water vapor, allowing for an implant to be manufactured, loaded with drug, and sterilized in a dry state, with subsequent rehydration of the drug upon implantation. Also desirable for certain portions of the implant, depending on the embodiment, is use of a material comprising microscopic porosities between polymer chains. These porosities may interconnect, which forms channels of water through the implant material. In several embodiments, the resultant channels are convoluted and thereby form a tortuous path which solubilized drug travels during the elution process.
- Implant materials advantageously also possess sufficient permeability to a drug such that the implant may be a practical size for implantation.
- portions of the implant e.g., the membrane material
- Implant material also ideally possesses sufficient elasticity, flexibility and potential elongation to not only conform to the target anatomy during and after implantation, but also remain unkinked, untorn, unpunctured, and with a patent lumen during and after implantation.
- implant material would advantageously processable in a practical manner, such as, for example, by molding, extrusion, thermoforming, and the like.
- implants are manufactured via injection molding.
- suitable materials for the outer shell include, but are not limited to, polypropylene, polyimide, glass, nitinol, polyvinyl alcohol, polyvinyl pyrolidone, collagen, chemically-treated collagen, polyethersulfone (PES), poly(styrene-isobutyl-styrene), polyurethane, ethyl vinyl acetate (EVA), polyetherether ketone (PEEK), Kynar (Polyvinylidene Fluoride; PVDF), Polytetrafluoroethylene (PTFE), Polymethylmethacrylate (PMMA), Pebax, acrylic, polyolefin, polydimethylsiloxane and other silicone elastomers, polypropylene, hydroxyapetite, titanium, gold, silver, platinum, other metals and alloys, ceramics, plastics and mixtures or combinations thereof.
- Additional suitable materials used to construct certain embodiments of the implant include, but are not limited to, poly(lactic acid), poly(tyrosine carbonate), polyethylene-vinyl acetate, poly(L-lactic acid), poly(D,L-lactic-co-glycolic acid), poly(D,L-lactide), poly(D,L-lactide-co-trimethylene carbonate), collagen, heparinized collagen, poly(caprolactone), poly(glycolic acid), and/or other polymer, copolymers, or block co-polymers, polyester urethanes, polyester amides, polyester ureas, polythioesters, thermoplastic polyurethanes, silicone-modified polyether urethanes, poly(carbonate urethane), or polyimide.
- poly(lactic acid), poly(tyrosine carbonate), polyethylene-vinyl acetate poly(L-lactic acid), poly(D,L-lactic-co-glycolic acid), poly(D,L-lactide
- Thermoplastic polyurethanes are polymers or copolymers which may comprise aliphatic polyurethanes, aromatic polyurethanes, polyurethane hydrogel-forming materials, hydrophilic polyurethanes (such as those described in U.S. Pat. No. 5,428,123, which is incorporated in its entirety by reference herein), or combinations thereof.
- Non-limiting examples include elasthane (poly(ether urethane)) such as ElasthaneTM 80A, Lubrizol, TecophilicTM, PellethaneTM, CarbothaneTM, TecothaneTM, TecoplastTM, and EstaneTM.
- polysiloxane-containing polyurethane elastomers are used, which include CarbosilTM 20 or PursilTM 20 80A, Elast-EonTM, and the like. Hydrophilic and/or hydrophobic materials may be used. Non-limiting examples of such elastomers are provided in U.S. Pat. No. 6,627,724, which is incorporated in its entirety by reference herein.
- Poly(carbonate urethane) may include BionateTM 80A or similar polymers.
- such silicone modified polyether urethanes are particularly advantageous based on improved biostability of the polymer imparted by the inclusion of silicone.
- oxidative stability and thrombo-resistance is also improved as compared to non-modified polyurethanes.
- the degree of silicone (or other modifier) may be adjusted accordingly.
- silicone modification reduces the coefficient of friction of the polymer, which reduces trauma during implantation of devices described herein.
- silicone modification in addition to the other mechanisms described herein, is another variable that can be used to tailor the permeability of the polymer. Further, in some embodiments, silicone modification of a polymer is accomplished through the addition of silicone-containing surface modifying endgroups to the base polymer. In other embodiments, flurorocarbon or polyethylene oxide surface modifying endgroups are added to a based polymer. In several embodiments, one or more biodegradable materials are used to construct all or a portion of the implant, or any other device disclosed herein. Such materials include any suitable material that degrades or erodes over time when placed in the human or animal body, whether due to a particular chemical reaction or enzymatic process or in the absence of such a reaction or process.
- biodegradable material includes bioerodible materials. Such materials can optionally biodegrade or bioerode at a predictable rate so that the plugs expire after the treatment time is over or are easily flushed out for replacement.
- the degradation rate of the biodegradable outer shell is another variable (of many) that may be used to tailor the drug elution rate from an implant.
- the drug may be sensitive to moisture (e.g. liquid water, water vapor, humidity) or where the drug's long term stability may be adversely affected by exposure to moisture
- a material for the implant or at least a portion of the implant which is water resistant, water impermeable or waterproof such that it presents a significant barrier to the intrusion of liquid water and/or water vapor, especially at or around human body temperature (e.g. about 35-40° C. or 37° C.). This may be accomplished by using a material that is, itself, water resistant, water impermeable or waterproof.
- materials that are generally considered water impermeable may still allow in enough water to adversely affect the drug within an implant.
- the water resistance or water impermeability of a material may be increased by any suitable method.
- Such methods of treatment include providing a coating for a material (including by lamination) or by compounding a material with a component that adds water resistance or increases impermeability.
- such treatment may be performed on the implant (or portion of the implant) itself, it may be done on the material prior to fabrication (e.g. coating a polymeric tube), or it may be done in the formation of the material itself (e.g. by compounding a resin with a material prior to forming the resin into a tube or sheet).
- Such treatment may include, without limitation, one or more of the following: coating or laminating the material with a hydrophobic polymer or other material to increase water resistance or impermeability; compounding the material with hydrophobic or other material to increase water resistance or impermeability; compounding or treating the material with a substance that fills microscopic gaps or pores within the material that allow for ingress of water or water vapor; coating and/or compounding the material with a water scavenger or hygroscopic material that can absorb, adsorb or react with water so as to increase the water resistance or impermeability of the material.
- Inorganic materials include, but are not limited to, metals, metal oxides and other metal compounds (e.g. metal sulfides, metal hydrides), ceramics, and main group materials and their compounds (e.g. carbon (e.g. carbon nanotubes), silicon, silicon oxides).
- suitable materials include aluminum oxides (e.g. Al 2 O 3 ) and silicon oxides (e.g. SiO 2 ).
- Inorganic materials may be advantageously coated onto a material (at any stage of manufacture of the material or implant) using techniques such as are known in the art to create extremely thin coatings on a substrate, including by vapor deposition, atomic layer deposition, plasma deposition, and the like.
- Such techniques can provide for the deposition of very thin coatings (e.g. about 20 nm-40 nm thick, including about 25 nm thick, about 30 nm thick, and about 35 nm thick) on substrates, including polymeric substrates, and can provide a coating on the exterior and/or interior luminal surfaces of small tubing, including that of the size suitable for use in implants disclosed herein.
- Such coatings can provide excellent resistance to the permeation of water or water vapor while still being at least moderately flexible so as not to undesirably compromise the performance of an implant in which flexibility is desired.
- the drugs carried by the drug delivery implant may be in any form that can be reasonably retained within the device and results in controlled elution of the resident drug or drugs over a period of time lasting at least several days and in some embodiments up to several weeks, and in certain preferred embodiments, up to several years. Certain embodiments utilize drugs that are readily soluble in ocular fluid, while other embodiments utilize drugs that are partially soluble in ocular fluid.
- the therapeutic agent may be in any form, including but not limited to a compressed pellet, a solid, a capsule, multiple particles, a liquid, a gel, a suspension, slurry, emulsion, and the like.
- drug particles are in the form of micro-pellets (e.g., micro-tablets), fine powders, or slurries, each of which has fluid-like properties, allowing for recharging by injection into the inner lumen(s).
- the implants can be recharged, which in several embodiments, is accomplished with a syringe/needle, through which a therapeutic agent is delivered.
- micro-tablets are delivered through a needle of about 23 gauge to about 32 gauge, including 23-25 gauge, 25 to 27 gauge, 27-29 gauge, 29-30 gauge, 30-32 gauge, and overlapping ranges thereof.
- the needle is 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 gauge.
- a drug sleeve surrounding a drug core is used to recharge an implant, as shown, for example, in FIG. 11 . As shown in FIG.
- the drug core and drug sleeve can be removed together by drawing drug core proximally, and then a replacement core within a replacement drug sleeve can be inserted together by advancing the replacement core and sleeve 45 attached to an inserter tool 55 into the lumen or cavity of the implant.
- implants comprised of hydrogel utilize the drug load inserter with the exchangeable drug core and drug sleeve.
- one size of a hydrogel plug will fit all patients.
- FIG. 12 shows the terminal aspect of an inserter tool 215 used to insert an implant into an implant site, the inserter comprising a plunger 220 that can be depressed and a preloaded drug implant 1 held within the terminus of the inserter prior to insertion, according to some embodiments. It is to be understood that the forceps and other insertion tools may be used to place an implant in the punctum and into the lacrimal canaliculus.
- the distal edge of the inserter tool is parallel with the implant, as illustrated in FIG. 13 A .
- the inserter tool can optionally have a straight cut tip.
- the inserter tool contains at least one additional gripping component 225 that guides and supports the implant into the implant site, as shown, for example, in FIG. 13 B .
- Such a gripper may be movably connected to a handpiece that allows for engagement and disengagement of the gripper.
- the distal edge of the inserter tool is asymmetric in relation to the implant, as shown in FIG. 13 C .
- the distal end of the inserter tool 230 may optionally have a beveled or angled cut tip, which can act as a lead-in. Testing has shown beveled cut tip allowed easier entry of the inserter into the punctum over the straight cut tip.
- the lead-in may also be used as a dilator to pre-dilate the area prior to insertion of an implant.
- a portion of the insertion tool may be made of clear material, for example, such as an acrylic material, so that the physician can visualize the tissue through the insertion tool and see the punctum.
- the optionally clear material may also allow viewing of an implant while it is being implanted, and may also confirm that the implant is implanted properly.
- the clear material may be a magnifying material and/or have a magnifying geometry, such as a spherical lens or angled lens, so that the punctum is more easily visualized.
- some embodiments may utilize two agents of the same form. In other embodiments, agents in different form may be used.
- one or more drugs utilize an adjuvant, excipient, or auxiliary compound, for example to enhance stability or tailor the elution profile, that compound or compounds may also be in any form that is compatible with the drug and can be reasonably retained with the implant.
- treatment of particular pathology with a drug released from the implant may not only treat the pathology, but also induce certain undesirable side effects.
- embodiments as described herein may include a drug mixed or compounded with a biodegradable material, excipient, or other agent modifying the release characteristics of the drug.
- biodegradable materials include copolymers of lactic acid and glycolic acid, also known as poly (lactic-co-glycolic acid) or PLGA.
- PLGA poly (lactic-co-glycolic acid)
- PLGA poly (lactic-co-glycolic acid)
- PLGA poly (lactic-co-glycolic acid)
- the drug positioned within the lumen of the implant is not compounded or mixed with any other compound or material, thereby maximizing the volume of drug that is positioned within the lumen.
- control of the degradation rate provides a means for control of the delivery rate of the drug contained within the therapeutic agent.
- Variation of the average molecular weight of the polymer or copolymer chains which make up the PLGA copolymer or other polymer may be used to control the degradation rate of the copolymer, thereby achieving a desired duration or other release profile of therapeutic agent delivery to the eye.
- rate of biodegradation of the PLGA copolymer may be controlled by varying the ratio of lactic acid to glycolic acid units in a copolymer.
- Still other embodiments may utilize combinations of varying the average molecular weights of the constituents of the copolymer and varying the ratio of lactic acid to glycolic acid in the copolymer to achieve a desired biodegradation rate.
- the outer shell of the implant comprises a polymer in some embodiments. Additionally, the shell may further comprise one or more polymeric coatings in various locations on or within the implant.
- the outer shell and any polymeric coatings are optionally biodegradable.
- the biodegradable outer shell and biodegradable polymer coating may be any suitable material including, but not limited to, poly(lactic acid), polyethylene-vinyl acetate, poly(lactic-co-glycolic acid), poly(D,L-lactide), poly(D,L-lactide-co-trimethylene carbonate), collagen, heparinized collagen, poly(caprolactone), poly(glycolic acid), and/or other polymer or copolymer.
- some embodiments of the implants comprise a release material that is permeable to the drug (or drugs) and allows passage of the drug (or drugs) through the material in a controlled fashion. Control of the release of the drug can further be controlled by coatings in or on the implant (e.g., a coating over the release material that slows the rate of release of a drug).
- a given combination of drug and release material will yield a characteristic diffusion coefficient D, such that:
- Elution ⁇ rate [ D ⁇ A ⁇ ( C i - C o ) ] d
- D diffusion coefficient (cm 2 /sec)
- A area of the region of drug release material
- Ci ⁇ Co difference in drug concentration between the inside and outside of the device.
- d thickness of the region of release material
- the area and thickness of the region of drug release are variables that determine, in part, the rate of elution of the drug from the implant, and are also variables that can be controlled during the process of manufacturing the implant.
- the release material could be manufactured to be thin (d is small) or with a large overall area (A is large) or a combination of the two (as dictated by the structural sufficiency of the outer shell). In either case, the end result is that the elution rate of the drug can be increased to compensate for the low solubility of the drug based on the structure and design of the implant.
- the drug release material can be made thicker, more dense, or more concentrated, thereby adjusting the rate of release of the drug from the implant.
- additional polymer coatings to either (i) increase the effective thickness (d) of the drug release material or (ii) decrease the overall permeability of the drug release material, resulting in a reduction in drug elution.
- multiple additional polymer coatings are used. By covering either distinct or overlapping portions of the implant and the drug release material, a controlled pattern of drug release from the implant overall can be achieved.
- the drug release material also serves a safety function.
- an implant in accordance with embodiments described herein is capable of delivering a drug at a controlled rate to a target tissue for a period of several (i.e. at least three) months.
- implants can deliver drugs at a controlled rate to target tissues for about 6 months or longer, including 3, 4, 5, 6, 7, 8, 9, 12, 15, 18, and 24 months, without requiring recharging.
- the duration of controlled drug release (without recharging of the implant) exceeds 2 years (e.g., 3, 4, 5, or more years). It shall be appreciated that additional time frames including ranges bordering, overlapping or inclusive of two or more of the values listed above are also used in certain embodiments.
- the total drug load for example the total load of a steroid, delivered to a target tissue over the lifetime of an implant ranges from about 10 to about 1000 ⁇ g. In certain embodiments the total drug load ranges from about 100 to about 900 ⁇ g, from about 200 to about 800 ⁇ g, from about 300 to about 700 ⁇ g, or from about 400 to about 600 ⁇ g. In some embodiments, the total drug load ranges from about 10 to about 300 ⁇ g, from about 10 to about 500 ⁇ g, or about 10 to about 700 ⁇ g.
- total drug load ranges from about 200 to about 500 ⁇ g, from 400 to about 700 ⁇ g or from about 600 to about 1000 ⁇ g. In still other embodiments, total drug load ranges from about 200 to about 1000 ⁇ g, from about 400 to about 1000 ⁇ g, or from about 700 to about 1000 ⁇ g. In some embodiments total drug load ranges from about 500 to about 700 ⁇ g, about 550 to about 700 ⁇ g, or about 550 to about 650 ⁇ g, including 575, 590, 600, 610, and 625 ⁇ g. It shall be appreciated that additional ranges of drugs bordering, overlapping or inclusive of the ranges listed above are also used in certain embodiments.
- controlled drug delivery is calculated based on the elution rate of the drug from the implant.
- an elution rate of a drug for example, a steroid, is about 0.05 ⁇ g/day to about 10 ⁇ g/day is achieved. In other embodiments an elution rate of about 0.05 ⁇ g/day to about 5 ⁇ g/day, about 0.05 ⁇ g/day to about 3 ⁇ g/day, or about 0.05 ⁇ g/day to about 2 ⁇ g/day is achieved.
- an elution rate of about 2 ⁇ g/day to about 5 ⁇ g/day, about 4 ⁇ g/day to about 7 ⁇ g/day, or about 6 ⁇ g/day to about 10 ⁇ g/day is achieved. In other embodiments, an elution rate of about 1 ⁇ g/day to about 4 ⁇ g/day, about 3 ⁇ g/day to about 6 ⁇ g/day, or about 7 ⁇ g/day to about 10 ⁇ g/day is achieved.
- an elution rate of about 0.05 ⁇ g/day to about 1 ⁇ g/day, including 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 ⁇ g/day is achieved. It shall be appreciated that additional ranges of drugs bordering, overlapping or inclusive of the ranges listed above are also used in certain embodiments.
- the release of drug from an implant may be controlled based on the desired concentration of the drug at target tissues.
- the desired concentration of a drug for example, a steroid, at the target tissue, ranges from about 1 nM to about 100 nM.
- the desired concentration of a drug at the site of action ranges from about 10 nM to about 90 nM, from about 20 nM to about 80 nM, from about 30 nM to about 70 nM, or from about 40 nM to about 60 nM.
- the desired concentration of a drug at the site of action ranges from about 1 nM to about 40 nM, from about 20 nM to about 60 nM, from about 50 nM to about 70 nM, or from about 60 nM to about 90 nM. In yet other embodiments the desired concentration of a drug at the site of action ranges from about 1 nM to about 30 nM, from about 10 nM to about 50 nM, from about 30 nM to about 70 nM, or from about 60 nM to about 100 nM.
- the desired concentration of a drug at the site of action ranges from about 45 nM to about 55 nM, including 46, 47, 48, 49, 50, 51, 52, 53, and 54 nM. It shall be appreciated that additional ranges of drugs bordering, overlapping or inclusive of the ranges listed above are also used in certain embodiments.
- the drug or drugs employed may take one or more forms.
- multiple pellets of single or multiple drug(s) are placed within an interior lumen of the implant (see, e.g., FIG. 4 ).
- the therapeutic agent is formulated as micro-pellets or micro-tablets. Additionally, in some embodiments, micro-tablets allow a greater amount of the therapeutic agent to be used in an implant. This is because, in some embodiments, tabletting achieves a greater density in a pellet than can be achieved by packing a device. Greater amounts of drug in a given volume may also be achieved by decreasing the amount of excipient used as a percentage by weight of the whole tablet, which has been found by the inventors to be possible when creating tablets of a very small size while retaining the integrity of the tablet. In some embodiments, the percentage of active therapeutic (by weight) is about 70% or higher.
- the therapeutic agent can be combined with excipients or binders that are known in the art.
- the percentage of therapeutic agent ranges from about 70% to about 95%, from about 75 to 85%, from about 75 to 90%, from about 70 to 75%, from about 75% to about 80% from about 80% to about 85%, from about 85% to about 90%, from about 90% to about 95%, from about 95% to about 99%, from about 99% to about 99.9%, and overlapping ranges thereof.
- the percentage of therapeutic agent ranges from about 80% to about 85%, including 81, 82, 83, and 84% by weight.
- micro-tablets provide an advantage with respect to the amount of an agent that can be packed, tamped, or otherwise placed into an implant disclosed herein.
- the resultant implant comprising micro-tablets thus comprises therapeutic agent at a higher density than can be achieved with non-micro-tablet forms.
- the density of the micro-pellet form of an agent within an implant ranges from about 0.7 g/cc to about 1.6 g/cc.
- the density used in an implant ranges from about 0.7 g/cc to about 0.9 g/cc, from about 0.9 g/cc to about 1.1 g/cc, from about 1.1 g/cc to about 1.3 g/cc, from about 1.1 g/cc to about 1.5 g./cc, from about 1.3 g/cc to about 1.5 g/cc, from about 1.5 g/cc to about 1.6 g/cc, and overlapping ranges thereof.
- densities of therapeutic agent that are greater than 1.6 g/cc are used.
- micro-tablets with the above properties, or any combination thereof are made using known techniques in the art including tableting, lyophilization, granulation (wet or dry), flaking, direct compression, molding, extrusion, and the like. Moreover, as discussed below, alterations in the above-discussed characteristics can be used to tailor the release profile of the micro-tableted therapeutic agent from an implant.
- lyophilization of a therapeutic agent is used prior to the micro-pelleting process. In some embodiments, lyophilization improves the stability of the therapeutic agent once incorporated into a micro-tablet. In some embodiments, lyophilization allows for a greater concentration of therapeutic to be obtained prior to micro-pelleting, thereby enhancing the ability to achieve the high percentages of active therapeutic agents that are desirable in some embodiments. For example, many commercially available therapeutic agents useful to treat ocular diseases are developed as first-line agents for other diseases. As such, their original formulation may not be suitable or ideal for micro-pelleting or for administration to an ocular target via an ocular implant such as those disclosed herein.
- anti-VEGF compounds are supplied as sterile liquid in single use vials meant to be administered intravenously (e.g., bevacizumab).
- a liquid formulation is less preferred for formation of micro-pellets as compared to a solid, though a liquid therapeutic agent may optionally be used in some embodiments.
- a liquid therapeutic agent may optionally be used in some embodiments.
- such liquid formulations may be frozen (e.g., stored at temperatures between ⁇ 20° C. and ⁇ 80° C. for 16 to 24 hours or longer) and then subject to lyophilization until dry. Alternatively, air spraying, crystallization, or other means may optionally be used to dry the therapeutic agent.
- the lyophilized (or otherwise dried) therapeutic agent is optionally tested for purity.
- solvents may be added to a liquid (or solid) formulation in order to dissolve and remove (via evaporation) non-therapeutic components (e.g., excipients or inert binding agents).
- a therapeutic agent is purified by conventional methods (e.g., antibody-based chromatography, HPLC, etc.) prior to lyophilization. In such embodiments, lyophilization often functions to increase the concentration of the therapeutic agent in the recovered purified sample.
- the dried therapeutic agent (which, for efficiency purposes is optionally dried in bulk) is ground, sieved, macerated, freeze-fractured, or subdivided into known quantities by other means, and then micro-pelleted.
- the therapeutic agent is fed into a micro-pelleting process.
- standard techniques e.g., compression, extrusion, molding, or other means
- more specialized techniques are used.
- the therapeutic agent is a protein
- drying and/or tabletization should be completed under conditions (e.g., temperature, acid/base, etc.) that do not adversely affect the biological activity of the therapeutic agent.
- protein therapeutics are formulated with a stabilizing agent (e.g., mannitol, trehalose, starch, or other poly-hydroxy polymer) to maintain the structure (and therefore activity) of the therapeutic protein.
- a stabilizing agent e.g., mannitol, trehalose, starch, or other poly-hydroxy polymer
- the drug or drugs to be administered via the drug delivery implant may be in the form of a nanodispersion.
- Nanodispersions are particularly advantageous when the drug (or drugs) to be administered is poorly soluble or insoluble in aqueous solutions, which can lead to instability and/or reduced bioavailability.
- nanodispersion shall be given its ordinary meaning and shall refer to a composition comprising nanoparticles comprising a drug and/or an aqueous vehicle.
- the aqueous vehicle comprises a water miscible solvent and water.
- the nanoparticles may comprise a drug, a polymer and a surfactant comprising a mixture of fatty acids or its salts and sterol or its derivatives or its salts, in some embodiments.
- nanoparticle as used herein shall be given its ordinary meaning and shall also refer to particles having controlled dimensions of the order of nanometers.
- the nanoparticles in several embodiments, are a polymeric nanoparticle (matrix of polymer entrapping the drug) and/or a polymeric nanovesicle (polymer stabilized nano sized vesicle encapsulating the drug.) and/or a polymeric nanocapsule (polymeric membrane surrounding drug in core) and/or nano sized particles of the drug stabilized by surfactants, and the like the nanoparitcles having mean size less than about 300 nm (e.g., ranging from about 10 nm to about 275 nm, or in the range of about 10 nm to about 200 nm.
- the water miscible solvent used in the nanodispersion comprises one or more of alcohols, glycols and its derivatives, polyalkylene glycols and its derivatives, glycerol, glycofurol and combinations thereof.
- additional non-limiting examples include, but are not limited to, alcohols such as ethanol, n-propanol, isopropanol; glycols such as ethylene glycol, propylene glycol, butylene glycol and its derivatives; polyethylene glycols like PEG 400 or PEG 3350; polypropylene glycol and its derivatives such as PPG-10 butanediol, PPG-10 methyl glucose ether, PPG-20 methyl glucose ether, PPG-15 stearyl ether; glycerol; glycofurol and the like and mixtures thereof.
- the non-aqueous solvent is selected from the group consisting of alcohols, polyethylene glycols and/or mixtures thereof, such as, for example, a mixture of ethanol and PEG (polyethylene glycol).
- ethanol in which ethanol is used in the nanodispersion, ethanol is present in an amount ranging from about 0.001% w/v to about 5% w/v, more preferably from about 0.05% w/v to about 0.5% w/v and most preferably from about 0.1% w/v to about 0.25% w/v.
- Polyethylene glycols which are used preferably, include PEG-400 and PEG-3350.
- PEG-400 is used, depending on the embodiment, in an amount ranging from about 0.01% w/v to about 20.0% w/v, more preferably from about 0.05% w/v to about 5.0% w/v and most preferably from about 1.0% w/v to about 2.5% w/v.
- PEG-3350 is used, depending on the embodiment, in an amount ranging from about 0.001% w/v to about 10.0% w/v, more preferably from about 0.05% w/v to about 5.0% w/v and most preferably from about 0.1% w/v to about 3% w/v.
- the nanoparticles comprise one or more polymers.
- the polymer(s) used in several embodiments are preferably, water soluble.
- Polyvinylpyrrolidone one such water soluble polymer used in several embodiments, is a tertiary amide polymer having linearly arranged monomer units of 1-vinyl-2-pyrrolidone. It has mean molecular weights ranging from about 10,000 to about 700,000.
- Other grades of polyvinylpyrrolidone are used in some embodiments, with molecular weights ranging from about 2000 to about 3000, about 7000 to about 11,000, about 28,000 to about 34,000, or about 1,000,000 to about 1,5000,000.
- polyvinylpyrrolidone use for the polymer have molecular weight in the range from about 1,000 to about 45,000, preferably, from about 4,000 to about 30,000. According several embodiments, the amount of polymer used in the nanodispersion ranges from about 0.001% w/v to about 20% w/v, including preferably about 0.01% w/v to about 5.0% w/v and also about 0.01% w/v to about 1.0% w/v.
- Polyethylene glycol is used in several embodiments, either in addition or in place of polyvinylpyrrolidone.
- the amount of polymer used in the nanodispersion ranges from about 0.001% w/v to about 20% w/v, including about 0.01% w/v to about 5.0% w/v, and in some embodiments, about 0.01% w/v to about 1.0% w/v.
- Surfactants are used in some embodiments of the nanodispersions for drug(s).
- the surfactants comprise a mixture of fatty acid or its salts and sterol or its derivatives or its salts.
- fatty acids shall be given its ordinary meaning and shall also include aliphatic (saturated or unsaturated) monocarboxylic acids derived from or contained in esterified form, in an animal or vegetable fat, oil or wax.
- Non-limiting examples of fatty acids (or its salts) that may be used in in several embodiments include, but are not limited to, fatty acids or its salts having ‘n’ number of carbon atoms wherein ‘n’ ranges from about 4 to about 28.
- the fatty acid may be a saturated fatty acid or an unsaturated fatty acid, and their salt and combinations thereof.
- the saturated fatty acid and its salts may be selected from butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, sodium caprylate, sodium laurate, sodium myristate, sodium palmitate and the like and/or mixtures thereof.
- the unsaturated fatty acid and its salts may be selected from myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, alpha linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, sodium oleate, sodium arachidonate and the like and/or mixtures thereof.
- sterol or its derivative or its salts that may be used in the nanodispersion or nanoparticles may be acid esters of sterols.
- Acid salts of cholesterol include, but are not limited to, cholesteryl sulfate, cholesterol acetate, cholesterol chloroacetate, cholesterol benzoate, cholesterol myristate, cholesterol hemisuccinate, cholesterol phosphate, cholesterol phosphate, phosphonate, borate, nitrate, cholesterol cinnamate, cholesterol crotanoate, cholesterol butyrate, cholesterol heptanoate, cholesterol hexanoate, cholesterol octanoate, cholesterol nonanoate, cholesterol decanoate, cholesterol oleate, cholesterol propionate, cholesterol valerate, dicholesteryl carbonate and the like and mixtures thereof.
- Phytosterols that may be used in the compositions include sitosterol, campesterol, stigmasterol, brassicasterol and its derivatives, salts and mixture thereof.
- Bile acids include cholic acid, chenodeoxycholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, ursodeoxycholic acid and its derivatives, salts and mixture thereof.
- the sterols can also be esters of cholesterol including cholesterol hemi-succinate, salts of cholesterol including cholesterol hydrogen sulfate and cholesterol sulfate, ergosterol, esters of ergosterol including ergosterol hemi-succinate, salts of ergosterol including ergosterol hydrogen sulfate and ergosterol sulfate, lanosterol, esters of lanosterol including lanosterol hemi-succinate, salts of lanosterol including lanosterol hydrogen sulfate and lanosterol sulfate.
- the nanoparticles comprise a surfactant which is a mixture of sterol or its derivatives or its salts and fatty acids or its salts.
- the nanoparticles comprise of cholesterol ester of polar acids.
- the surfactant used in the nanodispersion is a mixture of caprylic acid and cholesteryl sulfate.
- Caprylic acid, also known as octanoic acid may be used in such embodiments in an amount ranging from about 0.001% w/v to about 5.0% w/v, more preferably from about 0.01% w/v to about 1.0% w/v and most preferably from about 0.01% w/v to about 0.5% w/v.
- Cholesteryl sulfate is used in certain embodiments in an amount ranging from about 0.001% w/v to about 5.0% w/v, more preferably from about 0.01% w/v to about 1.0% w/v and most preferably from about 0.01% w/v to about 0.5% w/v.
- the surfactant used is selected from oleic acid and cholesteryl sulphate and/or mixtures thereof. In some embodiments, the surfactant used is selected from saturated fatty acid and bile acid or bile salt and/or mixtures thereof.
- Bile salts when used according to some embodiments, are present in an amount ranging from about 0.001% w/v to about 5.0% w/v, more preferably from about 0.01% w/v to about 1.0% w/v and most preferably from about 0.01% w/v to about 0.75% w/v. Other amounts may be used in conjunction with other embodiments disclosed herein.
- Nanodispersions can be generated by methods appreciated in the art, such as those methods (and the resulting nanodispersions) disclosed in U.S. Pat. No. 8,778,364, which is incorporated by reference in its entirety herein.
- one or more of the therapeutic drug regions may comprise drug-cyclodextrin inclusion complexes; liposome encapsulation; micelles based on polymers such as polysaccharide, poly (ethylene glycol)-poly(lactide), methoxy poly(ethylene glycol)-poly(hexyl-lactide), or hydrophobically-modified hydroxypropylcellulose; nanoparticles of amorphous drug formed by antisolvent precipitation and stabilized with surfactant such as poysorbate 80 or polyoxyl 15 hydroxystearate; nanoparticles having a mean size less than 500 nm containing one or more drugs, a polymer, and a surfactant, where the surfactant may include a mixture of fatty acids or its salts and sterol or its derivitatives or its salts; drug co-processed or granulated with excipients such as microcrystalline cellulose, lactose, hydroxypropyl methyl cellulose, or povidone; added polymers such
- the therapeutic agents utilized with the drug delivery implant may include one or more drugs provided below, either alone or in combination.
- the drugs utilized may also be the equivalent of, derivatives of, or analogs of one or more of the drugs provided below.
- the drugs may include but are not limited to pharmaceutical agents including anti-glaucoma medications, ocular agents, antimicrobial agents (e.g., antibiotic, antiviral, antiparasitic, antifungal agents), anti-inflammatory agents (including steroids or non-steroidal anti-inflammatory), biological agents including hormones, enzymes or enzyme-related components, antibodies or antibody-related components, oligonucleotides (including DNA, RNA, short-interfering RNA, antisense oligonucleotides, and the like), DNA/RNA vectors, viruses (either wild type or genetically modified) or viral vectors, peptides, proteins, enzymes, extracellular matrix components, and live cells configured to produce one or more biological components.
- pharmaceutical agents including anti-glaucoma medications, ocular agents, antimicrobial agents
- any particular drug is not limited to its primary effect or regulatory body-approved treatment indication or manner of use.
- Drugs also include compounds or other materials that reduce or treat one or more side effects of another drug or therapeutic agent.
- the listing of any particular drug within any one therapeutic class below is only representative of one possible use of the drug and is not intended to limit the scope of its use with the ophthalmic implant system.
- the therapeutic agents may be combined with any number of excipients as is known in the art.
- excipients including, but not limited to, benzyl alcohol, ethylcellulose, methylcellulose, hydroxymethylcellulose, cetyl alcohol, croscarmellose sodium, dextrans, dextrose, fructose, gelatin, glycerin, monoglycerides, diglycerides, kaolin, calcium chloride, lactose, lactose monohydrate, maltodextrins, polysorbates, pregelatinized starch, calcium stearate, magnesium stearate, silicon dioxide, cornstarch, talc, and the like.
- the one or more excipients may be included in total amounts as low as about 1%, 5%, or 10% and in other embodiments may be included in total amounts as high as 50%, 70% or 90%.
- drugs may include various anti-secretory agents; antimitotics and other anti-proliferative agents, including among others, anti-angiogenesis agents such as angiostatin, anecortave acetate, thrombospondin, VEGF receptor tyrosine kinase inhibitors and anti-vascular endothelial growth factor (anti-VEGF) drugs such as ranibizumab (LUCENTIS®) and bevacizumab (AVASTIN®), pegaptanib (MACUGEN®), aflibercept (EYELEA®), sunitinib and sorafenib and any of a variety of known small-molecule and transcription inhibitors having anti-angiogenesis effect; classes of known ophthalmic drugs, including: glaucoma agents, such as adrenergic antagonists, including for example, beta-blocker agents such as atenolol propranolol, metipranolol, betaxolol, carteolol, le
- drugs may also include anti-inflammatory agents including for example glucocorticoids and corticosteroids such as betamethasone, cortisone, dexamethasone, dexamethasone 21-phosphate, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, prednisolone, fluroometholone, loteprednol, medrysone, fluocinolone acetonide, triamcinolone acetonide, triamcinolone, triamcinolone acetonide, beclomethasone, budesonide, flunisolide, fluorometholone, fluticasone, hydrocortisone, hydrocortisone acetate, loteprednol, rimexolone and non-steroidal anti-inflammatory agents including, for example, diclofenac, flurbiprofen, ibuprofen, bromfenac, ne
- Other therapeutic agents may include neuroprotective agents such as lubezole, nimodipine and related compounds, and including blood flow enhancers such as dorzolamide or betaxolol; compounds that promote blood oxygenation such as erythropoeitin; sodium channels blockers; calcium channel blockers such as nilvadipine or lomerizine; glutamate inhibitors such as memantine nitromemantine, riluzole, dextromethorphan or agmatine; acetylcholinsterase inhibitors such as galantamine; hydroxylamines or derivatives thereof, such as the water soluble hydroxylamine derivative OT-440; synaptic modulators such as hydrogen sulfide compounds containing flavonoid glycosides and/or terpenoids, such as Ginkgo biloba ; neurotrophic factors such as glial cell-line derived neutrophic factor, brain derived neurotrophic factor; cytokines of the IL-6 family of proteins such as ciliary
- Other therapeutic agents include: other beta-blocker agents such as acebutolol, atenolol, bisoprolol, carvedilol, asmolol, labetalol, nadolol, penbutolol, and pindolol; other corticosteroidal and non-steroidal anti-inflammatory agents such aspirin, betamethasone, cortisone, diflunisal, etodolac, fenoprofen, fludrocortisone, flurbiprofen, hydrocortisone, ibuprofen, indomethacine, ketoprofen, meclofenamate, mefenamic acid, meloxicam, methylprednisolone, nabumetone, naproxen, oxaprozin, prednisolone, prioxicam, salsalate, sulindac and tolmetin; COX-2 inhibitors like celecoxib, rofe
- Valdecoxib other immune-modulating agents such as aldesleukin, adalimumab (HUMIRA®), azathioprine, basiliximab, daclizumab, etanercept (ENBREL®), hydroxychloroquine, infliximab (REMICADE®), leflunomide, methotrexate, mycophenolate mofetil, and sulfasalazine; other anti-histamine agents such as loratadine, desloratadine, cetirizine, diphenhydramine, chlorpheniramine, dexchlorpheniramine, clemastine, cyproheptadine, fexofenadine, hydroxyzine and promethazine; other anti-infective agents such as aminoglycosides such as amikacin and streptomycin; anti-fungal agents such as amphotericin B, caspofungin, clotrimazole, fluconazole
Abstract
Disclosed herein are drug delivery punctal implants and methods of using the implants for the treatment of ocular disorders requiring targeted and controlled administration of a drug to an interior portion of the eye for reduction or prevention of symptoms of the disorder. The physical arrangement of drugs within the punctal plugs disclosed herein results, in several embodiments, in advantageous controlled delivery of one or more drugs to the eye of a patient.
Description
- This application is a continuation of U.S. patent application Ser. No. 15/762,969, filed on Mar. 23, 2018, which is the U.S. National Phase application under 35 U.S.C. § 371 of International Application No. PCT/US2016/053570, filed on Sep. 23, 2016, which claims the benefit of U.S. Provisional Application No. 62/233,259, filed on Sep. 25, 2015, the entire disclosure of each which is incorporated by reference herein.
- This disclosure relates to implantable drug delivery devices structured to provide targeted and/or controlled release of a drug to a desired ocular target tissue and methods of using such devices for the treatment of ocular diseases and disorders. In certain embodiments, this disclosure relates to devices for insertion into the punctum and for delivery of a therapeutic agent or agents to the eye in a controlled manner.
- The mammalian eye is a specialized sensory organ capable of light reception and is able to receive visual images. The retina of the eye consists of photoreceptors that are sensitive to various levels of light, interneurons that relay signals from the photoreceptors to the retinal ganglion cells, which transmit the light-induced signals to the brain. The iris is an intraocular membrane that is involved in controlling the amount of light reaching the retina. The iris consists of two layers (arranged from anterior to posterior), the pigmented fibrovascular tissue known as a stroma and pigmented epithelial cells. The stroma connects a sphincter muscle (sphincter pupillae), which contracts the pupil, and a set of dilator muscles (dilator pupillae) which open it. The pigmented epithelial cells block light from passing through the iris and thereby restrict light passage to the pupil.
- Numerous pathologies can compromise or entirely eliminate an individual's ability to perceive visual images, including trauma to the eye, infection, degeneration, vascular irregularities, and inflammatory problems. The central portion of the retina is known as the macula. The macula, which is responsible for central vision, fine visualization and color differentiation, may be affected by age related macular degeneration (wet or dry), diabetic macular edema, idiopathic choroidal neovascularization, or high myopia macular degeneration, among other pathologies.
- Other pathologies, such as abnormalities in intraocular pressure, can affect vision as well. Aqueous humor is a transparent liquid that fills at least the region between the cornea, at the front of the eye, and the lens and is responsible for producing a pressure within the ocular cavity. Normal intraocular pressure is maintained by drainage of aqueous humor from the anterior chamber by way of a trabecular meshwork which is located in an anterior chamber angle, lying between the iris and the cornea or by way of the “uveoscleral outflow pathway.” The “uveoscleral outflow pathway” is the space or passageway whereby aqueous exits the eye by passing through the ciliary muscle bundles located in the angle of the anterior chamber and into the tissue planes between the choroid and the sclera, which extend posteriorly to the optic nerve. About two percent of people in the United States have glaucoma, which is a group of eye diseases encompassing a broad spectrum of clinical presentations and etiologies but unified by increased intraocular pressure. Glaucoma causes pathological changes in the optic nerve, visible on the optic disk, and it causes corresponding visual field loss, which can result in blindness if untreated. Increased intraocular pressure is the only risk factor associated with glaucoma that can be treated, thus lowering intraocular pressure is the major treatment goal in all glaucomas, and can be achieved by drug therapy, surgical therapy, or combinations thereof.
- Many pathologies of the eye progress due to the difficulty in administering therapeutic agents to the eye in sufficient quantities and/or duration necessary to ameliorate symptoms of the pathology. Often, uptake and processing of the drug component of the therapeutic agent occurs prior to the drug reaching an ocular target site. Due to this metabolism, systemic administration may require undesirably high concentrations of the drug to reach therapeutic levels at an ocular target site. This can not only be impractical or expensive, but may also result in a higher incidence of side effects. Topical administration is potentially limited by limited diffusion across the cornea, or dilution of a topically applied drug by tear-action. Even those drugs that cross the cornea may be unacceptably depleted from the eye by the flow of ocular fluids and transfer into the general circulation. Thus, a means for ocular administration of a therapeutic agent in a controlled and targeted fashion would address the limitations of other delivery routes.
- In several embodiments, the implants disclosed herein operate to provide a therapeutic effect in the eye of a subject based, at least in part, on a physical arrangement of drugs within the implant. In several embodiments, the implants comprise a punctual plug and the physical arrangement of the drugs within the implant provides advantageous timing of delivery of the drugs. The punctal implants disclosed herein are placed into the punctum and reside at least partially in a lacrimal canaliculus of an eye. Such an approach is useful, in several embodiments, such as when steroid and cyclosporine are combined to treat dry eye. Many current therapies for dry eye employ an initial treatment with steroid eye drops for a first time period (e.g., two weeks). After the initial period cyclosporine eye drops are added to the treatment regimen. Thereafter the steroid is then tapered off, ending at day 60 and cyclosporine therapy is continued alone, as long as needed. However, according to one embodiment disclosed herein, a punctal implant can deliver steroid and cyclosporine with appropriate timing to achieve a near constant, zero order administration of drug. Such a dosing profile is generally considered more efficient than bolus delivery, such as occurs with eye drops.
- In several embodiments employing multiple drugs, the second (or third, etc.) agent results in synergistic effects when combined with the first agent. In other embodiments, the second agent reduces one or more side effects associated with the first agent. It is understood, however, that any embodiment of implant disclosed herein may contain only one drug.
- As such, several embodiments provide for implants for insertion into a punctum of the eye of a subject, comprising an outer shell having a proximal end, a distal end, the outer shell being shaped to define an interior lumen, the outer shell dimensioned for insertion into the punctum of the eye of a subject, at least a first drug positioned within the interior lumen, at least one region of drug release the proximal portion of outer shell, and a distal occlusive member within the inner lumen, the distal occlusive member preventing elution of the first drug from the distal end of the implant.
- In several such embodiments, the first drug elutes from the lumen to the tear film of the eye of the subject by passing through the at least one region of drug release. In some embodiments, the implant is dimensioned to be implanted with the distal end of the outer shell positioned in the lacrimal duct. In some embodiments, the implant is dimensioned to be implanted with the distal end of the outer shell positioned in the lacrimal sac. In several embodiments, the implant is dimensioned to be implanted with the distal end of the outer shell positioned in the nasolacrimal duct.
- In several embodiments, there is also provided a punctal implant for insertion into a punctum of the eye of a subject and configured to deliver two or more drugs to the eye of the subject, the implant comprising an outer shell comprising (i) a proximal end comprising at least one region of drug release and a flange, (ii) a closed distal end, and (iii) an interior lumen comprising at least two drugs positioned within the lumen.
- In several embodiments, there is also provided a punctal implant for insertion into a punctum of the eye of a subject and configured to deliver two or more drugs to the eye of the subject, the implant comprising an outer shell comprising (i) a proximal end comprising at least one region of drug release and a flange, (ii) a closed distal end, and (iii) an interior lumen comprising at least two drugs positioned within the lumen, wherein the region of drug release comprises aperture through an annular ring positioned at the proximal-most portion of the interior lumen, wherein said aperture allows elution of the two or more drugs to occur only through the occlusive member, wherein the dimensions of the aperture at least partially defines the elution rate of the two or more drugs, wherein the flange is configured to rest on the surface of the eyelid when the implant is inserted into the punctum, and wherein the first and second drug elute from the lumen to the tear film of the eye of the subject by passing through the at least one region of drug release.
- In several embodiments, the at least one region of drug release comprises at least one aperture. Additionally, in some embodiments, the implant further comprises at least one membrane that occludes the at least one aperture, wherein the membrane is permeable to the at least a first drug, wherein the membrane allows elution of the at least a first drug to occur only through the at least one membrane.
- In several embodiments, the at least one region of drug release comprises a plurality of apertures through the outer shell and positioned randomly or in a patterned array throughout the proximal portion of the implant. As above, at least a portion of the plurality of apertures is occluded by a membrane permeable to the first drug.
- Some embodiments provided for herein result in elution of drug (or drugs) from the implant with zero-order or pseudo zero-order kinetics.
- In some embodiments, the intraocular target is the posterior chamber of the eye, the anterior chamber of the eye, both the anterior chamber and posterior of the eye, or the macula, the retina, the optic nerve, the ciliary body, and the intraocular vasculature.
- In several embodiments, the drug acts on the intraocular target tissue to generate a therapeutic effect for an extended period. In one embodiment, the drug comprises a steroid. In such embodiments, the implant contains a total load of steroid ranging from about 10 to about 1000 micrograms, steroid is released from the implant at a rate ranging from about 0.05 to about 10 micrograms per day and/or the steroid acts on the diseased or damaged target tissue at a concentration ranging from about 1 to about 100 nanomolar. In some embodiments, the steroid additionally generates side effects associated with accumulation of physiologic fluid, and an optional shunt transports the accumulated fluid from the first location to the remote second location (such as, for example, from the anterior chamber to an existing physiological outflow pathway, such as Schlemm's canal or the naso-lacrimal duct).
- In several embodiments, the at least one region of drug release comprises an occlusive member that is permeable to said two or more drugs, and the occlusive member allows elution of the two or more drugs to occur through the occlusive member. In several embodiments, the thickness of the occlusive member at least partially defines the elution rate of the drug (or drugs). In several embodiments, having a flange, the flange is configured to rest on the surface of the eyelid when the implant is inserted into the punctum. In several embodiments, the drug (or drugs) elute from the lumen to the tear film of the eye of the subject by passing through the at least one region of drug release.
- In several embodiments, the occlusive member is an occlusive membrane is dimensioned based on the permeability of said occlusive member to said first drug (and second or more) and the desired relative timing and duration of elution of said first and second drugs. In several embodiments, the occlusive member has a thickness of between about 0.0001 and 0.0005 inches. In certain embodiments, the occlusive member is integrally formed with the outer shell of the implant. In some embodiments, the occlusive member further comprises randomly or patterned holes through the occlusive membrane.
- In some embodiments, a first drug is placed in a more proximal position within the interior lumen relative to the position of a second drug. In some embodiments, a third drug is included, and in certain such embodiments, the first drug and second drug are positioned adjacent to one another and both the first and second drugs are placed in a more proximal position within the interior lumen relative to the position of the third drug.
- In several embodiments, the drug (or drugs) is formulated as tablets, as a nanodispersion, or a combination thereof. In some embodiments, a first drug is formed as a discontinuous first phase and a second drug is formulated as dispersion of solid of liquid particles into which the first drug is dispersed.
- In several embodiments, the outer shell of the implant comprises a bulge in the distal region in order to anchor the implant in the punctum.
- In several embodiments, a first drug elutes from an implant for a period of between 1 and 75 days, and a second drug elutes for a period of time ranging from about 1 to about 24 months after the first drug is eluted.
- In several embodiments, the implants disclosed herein have a length of between about 0.5 and about 2.5 mm. Some embodiments of the implants have a length of about 1.4 to about 1.6 mm. Some embodiments of the implant have a diameter of about 0.2 to about 1.5 mm. Some embodiments of the implant have a diameter of about 0.2 to about 0.6 mm.
- Depending on the embodiment, the first drug may be a steroid. In some such embodiments, the steroid is selected from the group consisting of loteprednol etabonate, dexamethasone, and triamcinolone acetonide. In some embodiments, a second drug is cyclosporine and is optionally formulated as a nanodispersion. In several embodiments, the first drug is cyclosporine A. In several embodiments, the first drug facilitates tear production.
- Several embodiments optionally comprise a retention protrusion configured to anchor the implant in an implantation site (e.g., the punctum). Such retention protrusions optionally comprise one or more of bulges, ridges, claws, threads, flexible ribs, rivet-like shapes, flexible barbs, barbed tips, expanding material (such as a hydrogel), and biocompatible adhesives. In some embodiments, the expanding material is placed on an exterior surface of the outer shell of the implant and expands after contact with a solvent, such as, for example, intraocular fluid or tear film.
- These and other features, aspects, and advantages of the present disclosure will now be described with reference to the drawings of embodiments, which embodiments are intended to illustrate and not to limit the disclosure. One of ordinary skill in the art would readily appreciated that the features depicted in the illustrative embodiments are capable of combination in manners that are not explicitly depicted, but are both envisioned and disclosed herein.
-
FIG. 1A illustrates a schematic cross section of an implant in accordance with embodiments disclosed herein. -
FIGS. 1B-1D illustrate additional embodiments of an implant in accordance with embodiments disclosed herein. -
FIGS. 2A-2D illustrate schematic cross sections of additional embodiments of implants in accordance with embodiment disclosed herein. -
FIG. 3 illustrates a schematic cross section of an additional embodiment of an implant in accordance with disclosure herein. -
FIG. 4 illustrates a schematic cross section of an additional embodiment of an implant in accordance with disclosure herein. -
FIG. 5 illustrates a schematic cross section of an additional embodiment of an implant in accordance with disclosure herein. -
FIG. 6 illustrates a schematic cross section of an additional embodiment of an implant in accordance with disclosure herein. -
FIG. 7 illustrates a schematic cross section of an additional embodiment of an implant in accordance with disclosure herein. -
FIG. 8 is a schematic graph showing the elution profile of two therapeutic agents eluted from an implant according to an embodiment disclosed herein. -
FIG. 9 is a schematic graph showing an alternative elution profile of two therapeutic agents eluted from an additional implant according to an embodiment disclosed herein. -
FIG. 10 illustrates the anatomy of an eye. -
FIG. 11 illustrates an embodiment of an implant in which the implant is rechargeable in that an additional, or substitute, drug payload can be added to implant without requiring removal of the implant. -
FIG. 12 illustrates an embodiment of an implant delivery system comprising a plunger for use with a preloaded drug implant. -
FIGS. 13A-13C illustrate schematic cross sections of embodiments of inserter tools in accordance with disclosure provided herein. -
FIGS. 14A-14B illustrate schematic cross sections of additional embodiments of implants in accordance with disclosure herein. -
FIGS. 15A-15B illustrate schematic cross sections of additional embodiments of implants in accordance with disclosure herein. -
FIGS. 16A-16B illustrate schematic cross sections of additional embodiments of implants in accordance with disclosure herein. -
FIGS. 17A-17B illustrate schematic cross sections of additional embodiments of implants in accordance with disclosure herein. -
FIGS. 18A-18B illustrate schematic cross sections of additional embodiments of implants in accordance with disclosure herein. -
FIGS. 19A-19B illustrate schematic cross sections of additional embodiments of implants in accordance with disclosure herein. - Achieving local ocular administration of a drug may require direct injection or application, but could also include the use of a drug eluting implant, a portion of which, could be positioned in close proximity to the target site of action within the eye or within the chamber of the eye where the target site is located (e.g., anterior chamber, posterior chamber, or both simultaneously). Use of a drug eluting implant could also allow the targeted delivery of a drug to a specific ocular tissue, such as, for example, the macula, the retina, the ciliary body, the optic nerve, or the vascular supply to certain regions of the eye. Use of a drug eluting implant could also provide the opportunity to administer a controlled amount of drug for a desired amount of time, depending on the pathology. For instance, some pathologies may require drugs to be released at a constant rate for just a few days, others may require drug release at a constant rate for up to several months, still others may need periodic or varied release rates over time, and even others may require periods of no release (e.g., a “drug holiday”). Further, implants may serve additional functions once the delivery of the drug is complete. Implants may maintain the patency of a fluid flow passageway within an ocular cavity, they may function as a reservoir for future administration of the same or a different therapeutic agent, or may also function to maintain the patency of a fluid flow pathway or passageway from a first location to a second location, e.g. function as a stent. Conversely, should a drug be required only acutely, an implant may also be made completely biodegradable.
- In several embodiments, the implants are configured specifically for use (e.g., implantation) in the punctum of the eye of a subject (e.g., the upper and/or lower punctum of the upper and/or lower canaliculus, respectively). The puncta function to collect tears that are released onto the surface of the eye by the lacrimal glands. However, in some individuals tear production is reduced, blocked, decreased, or otherwise insufficient to maintain an adequate level of moisture on the eye (or eyes). Damage to the corneal surface of the eye can result if the moisture on the eye remains reduced. When functioning normally (e.g., in a patient with normal tear production), the puncta convey the tear fluid to the lacrimal sac, which then allows it to drain through the nasolacrimal duct to the inner nose. One treatment for dry eye or similar syndromes is implantation of punctual plugs. Once implanted the plugs function to block the drainage of tear fluid, thereby increasing the retention of tear fluid on the eye. However, several of the implant embodiments disclosed herein advantageously allow the supplementation of the physical blockage of tear drainage with the delivery of one or more therapeutic agents to the eye in order to treat one or more aspects of reduced tear production. Thus, in several embodiments, one or more therapeutic agents are positioned in the implant in order to increase tear production and/or treat a symptom of dry eye, including, but not limited to, reduction in swelling, irritation of the eye and surrounding tissues and/or inflammation. Additional symptoms that are reduced, ameliorated, and in some cases eliminated include stinging or burning of the eye, a sandy or gritty feeling as if something is in the eye, episodes of excess tears following very dry eye periods, a stringy discharge from the eye, pain and redness of the eye, temporary or extended episodes of blurred vision, heavy eyelids, reduced ability to cry, discomfort when wearing contact lenses, decreased tolerance of reading, working on the computer, or any activity that requires sustained visual attention, and eye fatigue.
- In several embodiments, the implants advantageously obviate the need for additional topical agents (e.g., ointments, artificial tears, etc.). In several embodiments, however, the implants are configured (e.g., have a particular drug release profile) to work synergistically with one or more of such agents. For example, in several embodiments, the implant is configured to deliver a constant dosage of a therapeutic agent over time to treat a damaged or diseased eye, and a subject with them implants in place can also use artificial tears, for example, to further enhance the efficacy of the agent delivered from the implant.
- In several embodiments, the agents delivered from the implant are used for treatment of another ocular disorder, such as glaucoma, ocular hypertension, and/or elevated intraocular pressure.
- Advantageously, as discussed herein, several embodiments of the implants configured for punctual placement allows metered delivery of one or more therapeutic agents; that is, delivery at a constant rate, thereby reducing the peaks and valleys of therapeutic agent concentration as occurs with topical administration (e.g., via eye drop).
- Any of the relevant features disclosed herein can be applied to the embodiments configured for use in the punctum. For example, the dimensions of the implants, their shape, their drug release characteristics, and the like can be configured for use in the punctum. In several embodiments, the plugs can be tailored to the punctal dimensions of a particular subject. Moreover, the plugs can be configured to be removable or, in several embodiments, permanent (e.g., capable of being recharged). In several embodiments, the punctal implants comprise at least a first active agent that is loaded, at least in part, preferentially in the proximal region of the implant (e.g., such that the agent is released to the tear film of the subject) with the distal region of the implant positioned within the within the lacrimal ducts. In several such embodiments, the implant is specifically adapted to prevent unintended release of the active agent (or agents) from the distal portion of the implant. In some such embodiments, a plug (e.g., an impermeable occlusive member), a membrane (e.g., a membrane with little to no permeability to the active agent/agents), and/or a valve (e.g., a one-way valve) prevent elution in a distal region of the device.
- In several embodiments, the use of a valve or plug enables flushing of the implant. For example, if there is a need to replace the therapeutic agent (e.g., with a different agent or a different dose of the same agent) it may be beneficial to substantially remove any remaining agent within the implant. In such instances, the plug can be removed and the implant flushed from a proximal to distal direction, allowing the therapeutic agent remaining in the implant to be flushed down the nasolacrimal duct. Thereafter the implant can be reloaded with another dose, another agent, and the like. Similarly, flushing the implant can be performed when a valve is positioned in the distal region of the implant, the valve being opened by pressure exerted on it from the flushing procedure and preventing backflow of the flushed agent into the implant.
- In several embodiments, an implant and method for treating an eye with latanoprost or other therapeutic agent(s) is provided, the method comprising inserting a distal end of an implant into at least one punctum of the eye and positioning the implant such that the proximal portion of the implant delivers latanoprost or other therapeutic agent(s) to the tear fluid adjacent the eye. In several embodiments, delivery of the latanoprost or other therapeutic agent(s) is inhibited distally of the proximal end.
- Implants according to the embodiments disclosed herein preferably do not require an osmotic or ionic gradient to release the drug(s), are implanted with a device that minimizes trauma to the healthy tissues of the eye which thereby reduces ocular morbidity, and/or may be used to deliver one or more drugs in a targeted and controlled release fashion to treat multiple ocular pathologies or a single pathology and its symptoms. However, in certain embodiments, an osmotic or ionic gradient is used to initiate, control (in whole or in part), or adjust the release of a drug (or drugs) from an implant. In some embodiments, osmotic pressure is balanced between the interior portion(s) of the implant and the ocular fluid, resulting in no appreciable gradient (either osmotic or ionic). In such embodiments, variable amounts of solute are added to the drug within the device in order to balance the pressures.
- As used herein, “drug” refers generally to one or more drugs that may be administered alone, in combination and/or compounded with one or more pharmaceutically acceptable excipients (e.g. binders, disintegrants, fillers, diluents, lubricants, drug release control polymers or other agents, etc.), auxiliary agents or compounds as may be housed within the implants as described herein. The term “drug” is a broad term that may be used interchangeably with “therapeutic agent” and “pharmaceutical” or “pharmacological agent” and includes not only so-called small molecule drugs, but also macromolecular drugs, and biologics, including but not limited to proteins, nucleic acids, antibodies and the like, regardless of whether such drug is natural, synthetic, or recombinant. Drug may refer to the drug alone or in combination with the excipients described above. “Drug” may also refer to an active drug itself or a prodrug or salt of an active drug.
- In some embodiments, the drug diffuses through the implant itself and into the intraocular environment. In several embodiments, the outer material of the implant is permeable or semi-permeable to the drug (or drugs) positioned within an interior lumen, and therefore, at least some portion of the total elution of the drug occurs through the shell itself. In other embodiments, however, the shell of the implant is impermeable to the drug (or drugs) in the interior lumen, and the implant comprises one or more specific regions of drug release. The term “permeable” and related terms (e.g. “impermeable” or “semi permeable”) are used herein to refer to a material being permeable to some degree (or not permeable) to one or more drugs or therapeutic agents and/or ocular fluids. The term “impermeable” does not necessarily mean that there is no elution or transmission of a drug through a material, instead such elution or other transmission is negligible or very slight, e.g. less than about 3% of the total amount, including less than about 2% and less than about 1%. However, in some embodiments, an impermeable outer shell permits no elution of drug through the shell.
- As used herein, “patient” shall be given its ordinary meaning and shall also refer to mammals generally. The term “mammal”, in turn, includes, but is not limited to, humans, dogs, cats, rabbits, rodents, swine, ovine, and primates, among others. Additionally, throughout the specification ranges of values are given along with lists of values for a particular parameter. In these instances, it should be noted that such disclosure includes not only the values listed, but also ranges of values that include whole and fractional values between any two of the listed values.
- In several embodiments, the drug delivery implants disclosed herein are configured to delivery drug to the eye via a topical delivery route. In some embodiments, the implant is configured to deliver one or more drugs to anterior region of the eye in a controlled fashion while in other embodiments the implant is configured to deliver one or more drugs to the posterior region of the eye in a controlled fashion. In still other embodiments, the implant is configured to simultaneously deliver drugs to both the anterior and posterior region of the eye in a controlled fashion. In yet other embodiments, the configuration of the implant is such that drug is released in a targeted fashion to a particular intraocular tissue, for example, the macula or the ciliary body. It will be appreciated that each of the embodiments described herein may target one or more of these regions and, optionally, reaches the site and achieves a therapeutic effect after being administered topically. Following implantation at the desired site within the eye, such as the punctum, drug is released from the implant in a targeted and controlled fashion, based on the design of the various aspects of the implant, preferably for an extended period of time. The implant and associated methods disclosed herein may be used in the treatment of pathologies requiring drug administration to the surface of the eye (e.g., topical), the posterior chamber of the eye, the anterior chamber of the eye, or to specific tissues within the eye.
- The present disclosure relates to ophthalmic drug delivery implants which, following implantation at an implantation site, such as the punctum, provide controlled release of one or more drugs to a desired target region within the eye, the controlled release optionally being for an extended, period of time. Various embodiments of the implants are shown in the accompanying figures and will be referred to herein.
- In several embodiments, a biocompatible drug delivery ocular implant is provided that comprises an outer shell that is shaped to define at least one interior lumen that houses a drug for release into an ocular space.
- As shown in
FIG. 1 , which is a cross-section of a punctal plug drug delivery system according to several embodiments, disclosed herein, the implant comprises abody 10 having aninterior lumen 12. In several embodiments, the shell is formed to have at least two interior lumens. The upper portion of the implant, in several embodiments, comprises aflange 14 that extends radially and sits on the surface of the eyelid after the plug is implanted into the punctum. Opposite theflange 14 is aclosed end 16. However, in some embodiments, an open end (or open lateral portion) may also be used, for example to provide drainage to the naso-lacrimal duct. In several embodiments, the implant comprises aradial bulge 18 from a long axis LA of the body in order to provide an anchor within the punctum. In several embodiments, the bulge is parallel (or substantially parallel to a short axis SA of the implant). In additional embodiments, the bulge (or other pattern) need not be uniform. For example, in several embodiments, the bulge can comprise a raised ridge (or series of ridges encircling the body). In one embodiment, the bulge is similar to threads on a screw. Other surface irregularities may be used in place of, or in combination with a bulge, for example, a ridge, groove, relief, hole, or annular groove, barbs, barbs with holes, screw-like elements, knurled elements, suture, friction or wedge fit, and/or expandable materials. - In several embodiments, the upper portion of the implant comprises a flange with a diameter configured to ensure reduced, limited, or in some embodiments, no corneal or scleral contact. The flange preferably has a generally flattened lower surface to allow it to rest upon the lower eyelid immediately adjacent to the punctum.
FIG. 1B illustrates aflange 14 that is circular in shape, whileFIG. 1C illustrates an asymmetrical flange, andFIG. 1D illustrates an ovoid flange. Attributes of the flange, such as area, shape, and thickness may be varied as desired such as to aid in positioning of the uppermost end of the implant at the surface of the punctum. The flange may be round, ovoid, or any geometric or asymmetric shape. In several embodiments, the flange is asymmetrical to provide reduced, limited, or in some embodiments, no corneal or scleral contact. Illustrations of non-limiting embodiments of an asymmetric flange can also be seen inFIGS. 15A and 18A . - Several embodiments optionally comprise at least one retention protrusion configured to anchor the implant in an implantation site. In several embodiments, these retention features are non-occlusive, for example, they allow tear or other fluid flow through the canaliculus toward the nasolacrimal duct while holding the tissue of the canaliculus away from the implant body. In several embodiments, the at least one retention feature optionally comprises a bulge, protuberance, or other change in shape (relative to the long axis of the implant body) that extends axially from the body and that holds the implant in position. In several embodiments, the implant further comprises an inner tubular passageway of any size and shape. For example,
FIGS. 14A and 14B illustrate a non-limiting embodiment comprising two retention features extending axially from the body of the implant, each further comprising a straight tubular passageway that passes through the feature.FIGS. 15A and 15B depict an additional embodiment, further comprising an asymmetric flange.FIGS. 16A and 16B illustrates another embodiment of an implant comprising three retention features, each further comprising an elbow-shaped inner tubular passageway. In several embodiments, the at least one retention feature optionally comprises a bulge that extends axially from the body of the implant and comprises an inner relief, as illustrated inFIGS. 17A, 17B .FIGS. 18A and 18B illustrate another embodiment of an implant comprising three retention features, each further comprising an inner relief, and an asymmetric flange. In such embodiments, the inner relief can be of any shape and size, advantageously facilitating an optionally greater tear or other fluid flow as compared to retention features comprising a tubular passageway. In several embodiments, the relief features may also provide a point through which a securing suture can be fastened to secure the implant into position. Additionally, some such embodiments are used in conjunction with therapeutic agents having a side effect of increased tear production. In several embodiments, the retention features optionally comprise an erodible material. In several embodiments, the retention protrusions extend from the proximal end of the implant to a position approximately or more than halfway down the (long axis of the) implant towards the distal end. In some embodiments, the retention protrusions extend from the proximal end of the implant to less than halfway to the distal end of the implant. In some embodiments, the retention protrusion comprises a ring positioned at any point along the body of the implant, as shown, for example, inFIG. 19A . In such embodiments, the ring optionally contains spoke features, occluding some, but not all, fluid flow, as shown, for example, inFIG. 19B . Again, these retention features and flange shapes may be incorporated into any of the embodiments ofFIGS. 1-7 . - In several embodiments, the dimension of the at least one retention feature ranges from about 0.01 mm to about 0.15 mm as measured from the outer surface of the implant body to an edge of retention feature. The thickness of the retention feature, in some embodiments, ranges from about 0.01 mm to about 0.02 mm, about 0.02 mm to about 0.03 mm, about 0.03 mm to about 0.04 mm, about 0.04 mm to about 0.05 mm, about 0.05 mm to about 0.06 mm, about 0.06 mm to about 0.07 mm, about 0.07 mm to about 0.08 mm, about 0.08 mm to about 0.09 mm, about 0.09 mm to about 0.10 mm, about 0.10 mm to about 0.11 mm, about 0.11 mm to about 0.12 mm, about 0.12 mm to about 0.13 mm, about 0.13 mm to about 0.14 mm, about 0.14 mm to about 0.15 mm, and overlapping ranges therebetween and/or any other dimensions sufficient to secure the implant in the punctum of a particular patient.
- In several embodiments, the long axis of the implant is greater than the short axis of the implant. In several embodiments, the ratio of the long axis to the short axis ranges from about 1:1 to about 2:1, about 2:1 to about 3:1, about 3:1 to about 4:1, about 4:1 to about 5:1, about 5:1 to about 6:1, about 6:1 to about 7:1, about 7:1 to about 8:1, about 8:1 to about 9:1, about 9:1 to about 10:1, about 10:1 to about 20:1, or ratios between (or greater) than those listed.
- In several embodiments, the punctal implant ranges between about 0.5 and about 2.5 mm long (e.g., from the proximal end to the distal end). The length of the implant, in some embodiments, ranges from about 0.5 mm to about 0.7 mm, about 0.7 mm to about 0.9 mm, about 0.9 mm to about 1.0 mm, about 1.0 mm to about 1.1 mm, about 1.1 mm to about 1.2 mm, about 1.2 mm to about 1.3 mm, about 1.3 mm to about 1.35 mm, about 1.35 mm to about 1.4 mm, about 1.4 mm to about 1.45 mm, about 1.45 mm to about 1.5 mm, about 1.5 mm to about 1.55 mm, about 1.55 mm to about 1.6 mm, about 1.6 mm to about 1.65 mm, about 1.65 mm to about 1.7 mm, about 1.7 mm to about 1.9 mm, about 1.9 mm to about 2.1 mm, about 2.1 mm to about 2.3 mm, about 2.3 mm to about 2.5 mm, or lengths in between these ranges. In several embodiments, implants configured for implantation into the punctum have a diameter between about 0.2 mm and 2.0 mm, including about 0.2 mm to about 0.3 mm, about 0.3 mm to about 0.4 mm, about 0.4 mm to about 0.5 mm, about 0.5 mm to about 0.6 mm, about 0.5 mm to about 0.6 mm, about 0.6 mm to about 0.7 mm, about 0.7 mm to about 0.8 mm, about 0.8 mm to about 0.9 mm, about 0.9 mm to about 1.0 mm, about 1.0 mm to about 1.1 mm, about 1.1 mm to about 1.2 mm, about 1.2 mm to about 1.3 mm, about 1.3 mm to about 1.4 mm, about 1.4 mm to about 1.5 mm, about 1.5 mm to about 1.6 mm, about 1.6 mm to about 1.7 mm, about 1.7 mm to about 1.8 mm, about 1.8 mm to about 1.9 mm, about 1.9 mm to about 2.0 mm and diameters in between these ranges.
- The characteristics of the implant shown in
FIG. 1 are carried throughFIGS. 1-7 , however it shall be appreciated that any of the features of the implants disclosed herein can be used in combination with any other features disclosed herein (unless otherwise expressly noted). For example, all Figures are presently shown with abulge 18 as a retention feature; the bulge may be replaced with any retention feature such as those disclosed herein. Furthermore, any type of drug arrangement may be used with any type of drug elution element. For example, the two phase drug ofFIG. 5 may be included in a device having elution elements between the drug and the exterior such as inFIG. 2A or 2C . A region of a firsttherapeutic drug 20 is shown near the flange and a region of a secondtherapeutic drug 30 is shown in thelumen 12. One or both regions of drug may comprise pure drug, or drug plus excipients, or drug within a bioerodible or non-bioerodible matrix, as discussed in more detail below. Additionally, one or both regions may comprise packed powder formulation or pure drug, or tableted formulation or pure drug, or microspheres, nanospheres, liposomes, or the like of pure drug. Depending on the embodiment, the drug (or drugs) comprises drug-containing pellets, while in other embodiments, the drug is a liquid, a slurry, micro-pellets (e.g., micro-tablets) or powder. The drug (or drugs) may also be in the form of nanodispersions, depending on the embodiment. Combinations of any of these forms can also be used. - In several embodiments, one region can be of one form while the other region can be in another form (e.g., the drug of the first region is pure drug and the drug of the second region is drug plus excipient). Thus, any combinations of form, composition, etc. may be used in any of the drug regions, as is needed to tailor the drug elution to a desired profile.
- The drug elution is controlled, depending on the embodiment, to allow drug release over a desired time frame. For example, in several embodiments, the duration drug release, depending on the embodiment, ranges from several months to several years, e.g., about 6 to about 12 months, about 12 to about 18 months, about 18 to about 24 months, about 24 to about 30 months, about 30 to about 36 months, etc.
- As a non-limiting example, in one embodiment, the first
therapeutic drug 20 is steroid, such as loteprednol etabonate, dexamethasone, or triamcinolone acetonide (or a combination of any of these); and the secondtherapeutic drug 30 is cyclosporine. In some embodiments, because of the physical location and volume of the drugs, the first therapeutic drug (e.g., the steroid(s)) will tend to dissolve first, and thus, may be exhausted first (though in some embodiments the first drug is not exhausted at the time the release of the second drug is initiated). In several embodiments, the second drug (e.g., cyclosporine) will tend to dissolve at or near the conclusion of the dissolution of the first drug, and thus, will have a more prolonged time course. In several embodiments, this “tail-to-nose” overlapping elution (or in some embodiments, serial elution) results in an advantageously therapeutic elution profile that provides a therapeutic level of the first and second drugs, but reduces the peaks and valleys in drug concentration that can be result from current therapies (such as eye drops).FIG. 8 shows a sample non-limiting schematic of a time course of drug elution that may result from implants configured similar to the embodiment shown inFIG. 1 .Element 130 is the time course of the first drug, andelement 140 is the time course of the second drug. WhileFIG. 1 depicts one lumen that is exposed to the ocular environment through which drug(s) is released, it shall also be understood that, depending on the embodiment, one, two, or more drug regions may be utilized in a punctal plug delivery device as disclosed herein. - The in vivo environment into which several embodiments of the implants disclosed herein are positioned may be comprised of a water-based solution (such as aqueous humor or tear film) or gel (such as vitreous humor). Water from the surrounding in vivo environment may, in some embodiments, diffuse into one or more of the interior lumens, depending on the embodiment, and begin dissolving a small amount of the tablet or drug-excipient powder. The dissolution process continues until a solution is formed within the lumen that is in osmotic equilibrium with the in vivo environment.
- In additional embodiments, osmotic agents such as saccharides or salts are added to the drug to facilitate ingress of water and formation of the isosmotic solution. With relatively insoluble drugs, for example corticosteroids, the isosmotic solution may become saturated with respect to the drug in certain embodiments. In certain such embodiments, saturation can be maintained until the drug supply is almost exhausted. In several embodiments, maintaining a saturated condition is particularly advantageous because the elution rate will tend to be essentially constant, according to Fick's Law.
- In some embodiments, the outer shell comprises one or more orifices to allow ocular fluid to contact the drug within the lumen (or lumens) of the implant and result in drug release. In some embodiments, as discussed in more detail below, a layer or layers of a permeable or semi-permeable material is used to cover the implant (wholly or partially) and the orifice(s) (wholly or partially), thereby allowing control of the rate of drug release from the implant. Additionally, in some embodiments, combinations of one or more orifices, a layer or layers covering the one or more orifices are used to tailor the rate of drug release from the implant.
-
FIG. 2A shows an embodiment wherein anadditional component 40, representing a semi-permeable membrane or layer is included in the implant and obstructs (wholly or partially) the opening from the lumen of the implant to the ocular space external to the implant. Depending on the embodiment,component 40 may comprise a bioerodible or non-bioerodible hydrogel, or a semi-permeable polymer, or a polymeric, metallic, or ceramic screen or filter. In any of such embodiments, the elution rate of the therapeutic drug (or drugs) within the implant is regulated according to the drug's permeability throughcomponent 40. As discussed in more detail below, the regulation of permeability can be altered by changing one or more characteristics of the component 40 (e.g., thickness, chemical makeup, porosity, etc.). It shall also be appreciated that elution regulation component 40 (or its equivalents) may be incorporated into any subsequent example, including those shown in any of the additional figure or any embodiment described herein. -
FIG. 2B depicts another embodiment of an implant that provides an advantageous drug elution profile.Item 10 is the body of the punctal plug, as discussed above, with a flange that rests in apposition to the surface of the eyelid after the plug is implanted into the punctum. In several embodiments, thepunctal plug 10 is molded of a soft elastomeric material, such as silicone, polyurethane or a copolymer (such as PurSil®). In several embodiments, these materials (or combinations) allow the plug to conform to the punctum of a specific patient, thereby increasing the comfort of the implant over the life of implantation. In several embodiments, these materials (or combinations thereof) also facilitate the consistent manufacture of the implants. In several embodiments in which the punctual plug is molded of silicone, the size of the implant may optionally vary depending on the patient. In other words, some embodiments of silicone (or other similar material) implants are personalized to an individual patient or a segment of possible patients and their anatomical characteristics. In some embodiments in which the punctual plug is comprised of hydrogel, the implants are designed as a “one size fits all patients” implant. In alternative embodiments, however other materials disclosed herein may be used to construct the implant (either in whole or in part). In certain embodiments, the outer shell is not biodegradable, while in others, the shell is optionally biodegradable. - In some embodiments, the implant is made of a flexible material. In other embodiments, a portion of the implant is made from flexible material (e.g., the body) while another portion of the implant is made from rigid or semi-rigid material (e.g., the body or the bulge). In some embodiments, the implant comprises one or more flexures (e.g., hinges). In some embodiments, the drug delivery implant is pre-flexed, yet flexible enough to be contained within the straight lumen of a delivery device.
- In other embodiments, at least a portion of the implant (e.g., an internal spine or an anchor) is made of a material capable of shape memory. A material capable of shape memory may be compressed and, upon release, may expand axially or radially, or both axially and radially, to assume a particular shape. In some embodiments, at least a portion of the implant has a preformed shape. In other embodiments, at least a portion of the implant is made of a superelastic material. In some embodiments, at least a portion of the implant is made up of nitinol. In other embodiments, at least a portion of the implant is made of a deformable material.
- As shown in
FIG. 2B , several embodiments of the punctal plug comprise alumen 103 that is molded with an opening at the bottom of the plug. At the top of the plug is a thin-walled region (or plurality of regions) 104, extending across the upper end oflumen 103. In several embodiments, the thin-walled regions 104 function to retain solid or dissolved drug housed withinplug 10 as shown inFIG. 2C (e.g., they function as a large scale sieve), while also providing a diffusion path between the drug and the tear film external to plug 10. Depending on the embodiment,region 104 comprises the same material as the rest ofplug 10, or alternatively, comprises a different material (for example, manufactured as an insert molded with the rest of the plug).Region 104 allows diffusion of drug into the tear film according to the drug permeability of theregion 104 material, the cross-sectional dimension ofregion 104, and the optional addition of holes orfenestrations 102. Control of drug elution rates is discussed in more detail below. Depending on the embodiment,region 104 ranges in thickness between about 0.0005 inches to about 0.05 inches. For example,region 104 ranges in thickness from about 0.0005 inches to about 0.00075 inches, about 0.00075 inches to about 0.001 inches, about 0.001 inches to about 0.00125 inches, about 0.00125 inches to about 0.0015 inches, about 0.0015 inches to about 0.00175 inches, about 0.00175 inches to about 0.002 inches, about 0.002 inches to about 0.00225 inches, about 0.00225 inches to about 0.0025 inches, about 0.0025 inches to about 0.00275 inches, about 0.00275 inches to about 0.003 inches, about 0.003 inches to about 0.00325 inches, about 0.00325 inches to about 0.0035 inches, about 0.0035 inches to about 0.00375 inches, about 0.00375 inches to about 0.004 inches, about 0.004 inches to about 0.0045 inches, about 0.0045 inches to about 0.005 inches, about 0.005 inches to about 0.006 inches, about 0.006 inches to about 0.006 inches, about 0.006 inches to about 0.007 inches, about 0.007 inches to about 0.008 inches, about 0.008 inches to about 0.009 inches, about 0.009 inches to about 0.01 inches and any thickness between those listed. - In those embodiments comprising holes or
fenestrations 102, the holes or fenestrations may be of any shape, including but not limited to square, round, irregular-shaped. In each case, an individual fenestration or hole has a diameter less than that oflumen 103. Depending on the embodiment, the holes or fenestrations are located in any geometrical pattern (or randomly positioned) withinregion 104. In those embodiments having more than oneregion 104, the holes or fenestrations may be positioned differentially between each region (e.g., patterned positioning in a first region and random positioning in a second region). Holes orfenestrations 102 may be formed during molding ofplug 10, or may be laser machined after molding, such as by ablation, stretching, etching, grinding, molding, femtosecond laser exposure, particle blasting, machining, or other methods. - In certain embodiments comprising holes or
fenestrations 102, the implant allows for drug elution proximally toward the tear film, as well as distally toward the nasolacrimal duct. In these embodiments, the active agent is released into the tear film, the nasolacrimal duct, or both the tear film and the nasolacrimal duct. Distal drug elution is useful, in several embodiments, for intranasal and/or systemic drug delivery. Embodiments comprising holes orfenestrations 102 also optionally comprise at least one non-occlusive retention feature, as discussed above, rendering the implant non-occlusive and comprising a design solution for overall distal drug delivery. In these non-occlusive embodiments, for example, a therapeutic agent eluted from either a proximal end or distal end of the implant will ultimately drain distally toward the nasolacrimal duct. In contrast, in occlusive embodiments, for example, agents eluted from a proximal end of the implant results in only proximal drug delivery as delivery of the therapeutic agent is inhibited distally of the proximal end. - In one embodiment, the implant shown in
FIG. 2C , is assembled by first obtaining tablets or powder (or other form) of at least a first and second drug. In reverse order of release from the implant, the drugs are loaded through the open end oflumen 103 shown inFIG. 2B .FIG. 2C shows the assembled delivery device, whereitem 20 is a region of a first therapeutic drug, anditem 30 is a region of a second therapeutic drug. As discussed above, one or both regions may comprise pure drug, or drug plus excipients, or drug within a bioerodible or non-bioerodible matrix. One or both regions may comprise packed powder formulation or pure drug, or tableted formulation or pure drug, or microspheres, nanospheres, liposomes, or the like of pure drug. Upon completion of drug loading into the lumen, the open end oflumen 103 is sealed with aplug 101. Depending on the embodiments, the plug comprises a flowable material that acts as a sealant by filling the remaining space in thelumen 103. For example, in one embodiment, theplug 101 comprises, RTV silicone injected into the open end oflumen 103. In other embodiments, theplug 101 is preformed of silicone elastomer, another polymer (or polymers), or another biocompatible material, and press fit intolumen 103. In still additional embodiments, plug 101 comprises a thermoplastic material such as PurSil®, which is then thermoformed in place to seal the end of the implant. - In several embodiments, as shown in
FIG. 2D , the drug load is isolated from the plug material with a drug sleeve (e.g., a sleeve body).FIG. 2D shows a cross-sectional view of an implant 1 comprising adrug core 35 and surroundingdrug sleeve 45, according to several embodiments. In several such embodiments, the sleeve body comprises appropriate shapes, dimensions, and/or materials to regulate, adjust, or otherwise control elution of the therapeutic agent from the drug core. In several embodiments, the drug sleeve comprises a material that is substantially impermeable (e.g., less than 50% permeable) to the therapeutic agent so that the rate of migration of the therapeutic agent is primarily (or at least in part) controlled by the exposed surface area of the drug core that is not covered by the drug sleeve. Illustrative and non-limiting examples of suitable materials for the drug sleeve include, but are not limited to, polypropylene, polyimide, glass, nitinol, polyvinyl alcohol, polyvinyl pyrolidone, collagen, chemically-treated collagen, polyethersulfone (PES), poly(styrene-isobutyl-styrene), polyurethane, ethyl vinyl acetate (EVA), polyetherether ketone (PEEK), Kynar (Polyvinylidene Fluoride; PVDF), Polytetrafluoroethylene (PTFE), Polymethylmethacrylate (PMMA), Pebax, acrylic, polyolefin, polydimethylsiloxane and other silicone elastomers, polypropylene, hydroxyapetite, titanium, gold, silver, platinum, other metals and alloys, ceramics, plastics and mixtures or combinations thereof. - In several such embodiments, the drug sleeve allows for an exchangeable drug core if the therapeutic agent needs to be replenished, replaced, or supplemented by the same or different agent. Accordingly, the implant body can remain implanted in the patient. In some embodiments, the drug sleeve remains in the implant while only the drug core is replaced. In these embodiments, the drug sleeve may be provided, for example, with external protrusions that apply force to the drug sleeve when squeezed and eject the core from the drug sleeve. In some embodiments, the drug sleeve is removed with the drug core.
- In many embodiments, the drug sleeve ranges between about 0.5 and 2.4 mm long (e.g., from the proximal end to the distal end). The length of the drug sleeve, in some embodiments, ranges from about 0.5 mm to about 0.7 mm, about 0.7 mm to about 0.9 mm, about 0.9 mm to about 1.0 mm, about 1.0 mm to about 1.1 mm, about 1.1 mm to about 1.2 mm, about 1.2 mm to about 1.3 mm, about 1.3 mm to about 1.35 mm, about 1.35 mm to about 1.4 mm, about 1.4 mm to about 1.45 mm, about 1.45 mm to about 1.5 mm, about 1.5 mm to about 1.55 mm, about 1.55 mm to about 1.6 mm, about 1.6 mm to about 1.65 mm, about 1.65 mm to about 1.7 mm, about 1.7 mm to about 1.9 mm, about 1.9 mm to about 2.1 mm, about 2.1 mm to about 2.3 mm, about 2.3 mm to about 2.5 mm, or lengths in between these ranges. In several embodiments, drug sleeves have an inner diameter between about 0.2 mm and 1.9 mm, including about 0.2 mm to about 0.3 mm, about 0.3 mm to about 0.4 mm, about 0.4 mm to about 0.5 mm, about 0.5 mm to about 0.6 mm, about 0.5 mm to about 0.6 mm, about 0.6 mm to about 0.7 mm, about 0.7 mm to about 0.8 mm, about 0.8 mm to about 0.9 mm, about 0.9 mm to about 1.0 mm, about 1.0 mm to about 1.1 mm, about 1.1 mm to about 1.2 mm, about 1.2 mm to about 1.3 mm, about 1.3 mm to about 1.4 mm, about 1.4 mm to about 1.5 mm, about 1.5 mm to about 1.6 mm, about 1.6 mm to about 1.7 mm, about 1.7 mm to about 1.8 mm, about 1.8 mm to about 1.9 mm and any diameters in between or overlapping with these ranges.
-
FIG. 3 shows an embodiment where two drug regions, depicted as 22 and 24, respectively are loaded in parallel within the punctual plug. In such embodiments, bothdrug regions drug 24 reduces the potential for side effects of administration ofdrug 22. In additional embodiments, the elution profiles ofdrug 22 anddrug 24 are offset. In some embodiments,drug third drug region 30 begins elution. While shown effectively as equal proportions, it shall be appreciated thatdrug 22 anddrug 24 can be placed in the punctal plug in any ratio with respect to one another that produces a desired therapeutic effect. For example,drug 22 may make up about 10%, about 20%, about 25%, about 30% or more of the total amount ofdrugs drug 22 may make up about 60%, about 70%, about 80%, about 90% or more of the total amount ofdrugs drug FIG. 3 as parallel to one another, different physical configurations ofdrug drug 22 as compared to release ofdrug 24, with an inverse elution profile being generated as the drugs are eluted (e.g., as elution of the drugs proceeds, the proportion ofdrug 22 being released, versus the total, decreases, while the proportion ofdrug 24 increases. -
FIG. 4 shows an embodiment in whichmultiple drug regions drug regions drug regions -
FIG. 5 shows an arrangement used in several embodiments, whereindrug region 90 comprises a discontinuous first phase which is distributed withindrug region 100, which forms a second phase. For example,drug region 90 may comprise microparticles, nanoparticles, liposomes, or the like, any or all of which may carry a first therapeutic drug.Drug region 100, depending on the embodiment, comprises a dispersion of solid or liquid particles or droplets of a second therapeutic drug dispersed within a hydrogel matrix, or some other semi-permeable polymer matrix. Such embodiments, are advantageous in that small and predictable boluses ofdrug 90 can be intermixed with a second (or more) drug in different phases. This allows a further degree of tailoring the release profiles of the drug or drugs. Moreover, in several embodiments, the second region ofdrug 100 can complement thefirst region 90, for example in providing an environment that improves the stability ofdrug 90, which may otherwise be relatively volatile. -
FIG. 6 shows an additional embodiment of a punctal plug comprising a ring-shapedcomponent 110 comprising anaperture 112, the aperture being sized in diameter and thickness to regulate elution rate according to Fick's Law of diffusion (discussed in more detail below). Such embodiments are advantageous at least in that the ring-shaped component can be used to further refine and tailor the release of a drug (or drugs) from the implant, while having the implant be “off the shelf”. For example, the implant shell can be one of several stock sizes (e.g., small, medium, large, etc.), each size having a particular size lumen. The ring-shapedcomponent 110 can thus be used to adjust the rate of elution of the drug (or drugs) from the implant by re-sizing the opening of the lumen according to the needs of a particular patient. The ring-shapedcomponent 110, in several embodiments, is made of a material that is generally impermeable to the drug (or drugs) in the lumen. Control of drug release is then calculated by the dimensions ofaperture 112, and any membrane or other controlling material (e.g.,component 40 ofFIG. 2 ) placed within, or over, the aperture. Alternatively, or in combination, the ring-shapedcomponent 110 can comprise a material that is semi-permeable material to one or more of the drugs within the lumen of the implant. In such embodiments, the combination of the ring-shapedcomponent 110, its dimensions, and its interaction with the aperture and/orcomponent 40 work in concert to define the release rates of the drugs from the implant. - As discussed above, the various implant embodiments result in characteristic elution profiles. Such elution profiles are shown in
FIGS. 8 and 9 . These profiles can advantageously be modified to meet the needs of a particular patient, not only in terms of the drugs that are administered and at what time, but in what amount compared with one another, so as to reduce (or treat) side effects. -
FIG. 7 shows anadditional component 120, which is a separator placed between thefirst drug region 20 and thesecond drug region 30.Separator 120, depending on the embodiment, comprises a bioerodible, non-bioerodible; hydrogel; semi-permeable polymer; or a porous element comprising ceramic or metal.Separator 120 serves to create a separation in time between the elution of the drug inregion 20 and the drug inregion 30.FIG. 9 depicts a schematic elution profile resulting from an embodiment such as the implant ofFIG. 7 . InFIG. 9, 130 is the time course of drug elution from thefirst region second drug region 30. In some cases, the two drug regions may contain the same drug, and the purpose ofseparator 120 is to create a “drug holiday”, a time interval during which little or no drug is being eluted (compare the elution profile ofFIG. 8 with that ofFIG. 9 ). - Thus, the implants according to the embodiments disclosed herein allow a highly flexible approach for drug delivery to the eye as well as the ability to customize the drugs used, release timing and concentration (vis-à-vis other drugs in the implant) and thereby create a personalized overall therapeutic regime. Because in certain embodiments, the drug delivery implant may contain one or more drugs which may or may not be compounded with a bioerodible polymer or a bioerodible polymer and at least one additional agent, the release profiles of each can be managed independently, further adding to the flexibility of the overall treatment plant. In still other embodiments, the drug delivery implant is used to sequentially deliver multiple drugs. Some embodiments elute one or more drugs at a constant rate, with other embodiments release one or more drugs with a zero-order release profile. Yet other embodiments yield variable elution profiles. Still other embodiments are designed to stop elution completely or nearly completely for a predetermined period of time (e.g., a “drug holiday”) and later resume elution at the same or a different elution rate or elution concentration. Some such embodiments elute the same therapeutic agent before and after the drug holiday while other embodiments elute different therapeutic agents before and after the drug holiday.
-
FIG. 10 illustrates the anatomy of an eye, which includes thesclera 11, which joins thecornea 12 at thelimbus 21, theiris 13 and theanterior chamber 20 between theiris 13 and thecornea 12. The eye also includes thelens 26 disposed behind theiris 13, theciliary body 16 and Schlemm'scanal 22. The eye also includes a uveoscleral outflow pathway, which functions to remove a portion of fluid from the anterior chamber, and a suprachoroidal space positioned between the choroid 28 and thesclera 11. The eye also includes theposterior region 30 of the eye which includes themacula 32. - The drug delivery implants as described herein, function to house a drug and provide drug elution from the implant in a controlled fashion, based on the design of the various components of the implant, for an extended period of time. Various elements of the implant composition, implant physical characteristics, and the composition of the drug work in combination to produce the desired drug release profile.
- As described above the drug delivery implant may be made from any biological inert and biocompatible materials having desired characteristics. Desirable characteristics, in some embodiments, include permeability to liquid water or water vapor, allowing for an implant to be manufactured, loaded with drug, and sterilized in a dry state, with subsequent rehydration of the drug upon implantation. Also desirable for certain portions of the implant, depending on the embodiment, is use of a material comprising microscopic porosities between polymer chains. These porosities may interconnect, which forms channels of water through the implant material. In several embodiments, the resultant channels are convoluted and thereby form a tortuous path which solubilized drug travels during the elution process. Implant materials advantageously also possess sufficient permeability to a drug such that the implant may be a practical size for implantation. Thus, in several embodiments, portions of the implant (e.g., the membrane material) are sufficiently permeable to the drug to be delivered that the implant is dimensioned to reside wholly contained within the eye of a subject. Implant material also ideally possesses sufficient elasticity, flexibility and potential elongation to not only conform to the target anatomy during and after implantation, but also remain unkinked, untorn, unpunctured, and with a patent lumen during and after implantation. In several embodiments, implant material would advantageously processable in a practical manner, such as, for example, by molding, extrusion, thermoforming, and the like. In particular, in some embodiments, implants are manufactured via injection molding.
- Illustrative, examples of suitable materials for the outer shell include, but are not limited to, polypropylene, polyimide, glass, nitinol, polyvinyl alcohol, polyvinyl pyrolidone, collagen, chemically-treated collagen, polyethersulfone (PES), poly(styrene-isobutyl-styrene), polyurethane, ethyl vinyl acetate (EVA), polyetherether ketone (PEEK), Kynar (Polyvinylidene Fluoride; PVDF), Polytetrafluoroethylene (PTFE), Polymethylmethacrylate (PMMA), Pebax, acrylic, polyolefin, polydimethylsiloxane and other silicone elastomers, polypropylene, hydroxyapetite, titanium, gold, silver, platinum, other metals and alloys, ceramics, plastics and mixtures or combinations thereof. Additional suitable materials used to construct certain embodiments of the implant include, but are not limited to, poly(lactic acid), poly(tyrosine carbonate), polyethylene-vinyl acetate, poly(L-lactic acid), poly(D,L-lactic-co-glycolic acid), poly(D,L-lactide), poly(D,L-lactide-co-trimethylene carbonate), collagen, heparinized collagen, poly(caprolactone), poly(glycolic acid), and/or other polymer, copolymers, or block co-polymers, polyester urethanes, polyester amides, polyester ureas, polythioesters, thermoplastic polyurethanes, silicone-modified polyether urethanes, poly(carbonate urethane), or polyimide. Thermoplastic polyurethanes are polymers or copolymers which may comprise aliphatic polyurethanes, aromatic polyurethanes, polyurethane hydrogel-forming materials, hydrophilic polyurethanes (such as those described in U.S. Pat. No. 5,428,123, which is incorporated in its entirety by reference herein), or combinations thereof. Non-limiting examples include elasthane (poly(ether urethane)) such as Elasthane™ 80A, Lubrizol, Tecophilic™, Pellethane™, Carbothane™, Tecothane™, Tecoplast™, and Estane™. In some embodiments, polysiloxane-containing polyurethane elastomers are used, which include
Carbosil™ 20 orPursil™ 20 80A, Elast-Eon™, and the like. Hydrophilic and/or hydrophobic materials may be used. Non-limiting examples of such elastomers are provided in U.S. Pat. No. 6,627,724, which is incorporated in its entirety by reference herein. Poly(carbonate urethane) may include Bionate™ 80A or similar polymers. In several embodiments, such silicone modified polyether urethanes are particularly advantageous based on improved biostability of the polymer imparted by the inclusion of silicone. In addition, in some embodiments, oxidative stability and thrombo-resistance is also improved as compared to non-modified polyurethanes. In some embodiments, there is a reduction in angiogenesis, cellular adhesion, inflammation, and/or protein adsorption with silicone-modified polyether urethanes. In other embodiments, should angiogenesis, cellular adhesion or protein adsorption (e.g., for assistance in anchoring an implant) is preferable, the degree of silicone (or other modifier) may be adjusted accordingly. Moreover, in some embodiments, silicone modification reduces the coefficient of friction of the polymer, which reduces trauma during implantation of devices described herein. In some embodiments, silicone modification, in addition to the other mechanisms described herein, is another variable that can be used to tailor the permeability of the polymer. Further, in some embodiments, silicone modification of a polymer is accomplished through the addition of silicone-containing surface modifying endgroups to the base polymer. In other embodiments, flurorocarbon or polyethylene oxide surface modifying endgroups are added to a based polymer. In several embodiments, one or more biodegradable materials are used to construct all or a portion of the implant, or any other device disclosed herein. Such materials include any suitable material that degrades or erodes over time when placed in the human or animal body, whether due to a particular chemical reaction or enzymatic process or in the absence of such a reaction or process. Accordingly, as the term is used herein, biodegradable material includes bioerodible materials. Such materials can optionally biodegrade or bioerode at a predictable rate so that the plugs expire after the treatment time is over or are easily flushed out for replacement. In such biodegradable embodiments, the degradation rate of the biodegradable outer shell is another variable (of many) that may be used to tailor the drug elution rate from an implant. - In some embodiments, such as where the drug is sensitive to moisture (e.g. liquid water, water vapor, humidity) or where the drug's long term stability may be adversely affected by exposure to moisture, it may be desirable to utilize a material for the implant or at least a portion of the implant, which is water resistant, water impermeable or waterproof such that it presents a significant barrier to the intrusion of liquid water and/or water vapor, especially at or around human body temperature (e.g. about 35-40° C. or 37° C.). This may be accomplished by using a material that is, itself, water resistant, water impermeable or waterproof.
- In some circumstances, however, even materials that are generally considered water impermeable may still allow in enough water to adversely affect the drug within an implant. For example, it may be desirable to have 5% by weight of the drug or less water intrusion over the course of a year. In one embodiment of implant, this would equate to a water vapor transmission rate for a material of about 1×10−3 g/m2/day or less. This may be as much as one-tenth of the water transmission rate of some polymers generally considered to be water resistant or water impermeable. Therefore, it may be desirable to increase the water resistance or water impermeability of a material.
- The water resistance or water impermeability of a material may be increased by any suitable method. Such methods of treatment include providing a coating for a material (including by lamination) or by compounding a material with a component that adds water resistance or increases impermeability. For example, such treatment may be performed on the implant (or portion of the implant) itself, it may be done on the material prior to fabrication (e.g. coating a polymeric tube), or it may be done in the formation of the material itself (e.g. by compounding a resin with a material prior to forming the resin into a tube or sheet). Such treatment may include, without limitation, one or more of the following: coating or laminating the material with a hydrophobic polymer or other material to increase water resistance or impermeability; compounding the material with hydrophobic or other material to increase water resistance or impermeability; compounding or treating the material with a substance that fills microscopic gaps or pores within the material that allow for ingress of water or water vapor; coating and/or compounding the material with a water scavenger or hygroscopic material that can absorb, adsorb or react with water so as to increase the water resistance or impermeability of the material.
- One type of material that may be employed as a coating to increase water resistance and/or water impermeability is an inorganic material. Inorganic materials include, but are not limited to, metals, metal oxides and other metal compounds (e.g. metal sulfides, metal hydrides), ceramics, and main group materials and their compounds (e.g. carbon (e.g. carbon nanotubes), silicon, silicon oxides). Examples of suitable materials include aluminum oxides (e.g. Al2O3) and silicon oxides (e.g. SiO2). Inorganic materials may be advantageously coated onto a material (at any stage of manufacture of the material or implant) using techniques such as are known in the art to create extremely thin coatings on a substrate, including by vapor deposition, atomic layer deposition, plasma deposition, and the like. Such techniques can provide for the deposition of very thin coatings (e.g. about 20 nm-40 nm thick, including about 25 nm thick, about 30 nm thick, and about 35 nm thick) on substrates, including polymeric substrates, and can provide a coating on the exterior and/or interior luminal surfaces of small tubing, including that of the size suitable for use in implants disclosed herein. Such coatings can provide excellent resistance to the permeation of water or water vapor while still being at least moderately flexible so as not to undesirably compromise the performance of an implant in which flexibility is desired.
- The drugs carried by the drug delivery implant may be in any form that can be reasonably retained within the device and results in controlled elution of the resident drug or drugs over a period of time lasting at least several days and in some embodiments up to several weeks, and in certain preferred embodiments, up to several years. Certain embodiments utilize drugs that are readily soluble in ocular fluid, while other embodiments utilize drugs that are partially soluble in ocular fluid.
- For example, the therapeutic agent may be in any form, including but not limited to a compressed pellet, a solid, a capsule, multiple particles, a liquid, a gel, a suspension, slurry, emulsion, and the like. In certain embodiments, drug particles are in the form of micro-pellets (e.g., micro-tablets), fine powders, or slurries, each of which has fluid-like properties, allowing for recharging by injection into the inner lumen(s).
- As discussed above, in some embodiments, the implants can be recharged, which in several embodiments, is accomplished with a syringe/needle, through which a therapeutic agent is delivered. In some embodiments, micro-tablets are delivered through a needle of about 23 gauge to about 32 gauge, including 23-25 gauge, 25 to 27 gauge, 27-29 gauge, 29-30 gauge, 30-32 gauge, and overlapping ranges thereof. In some embodiments, the needle is 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 gauge. In some embodiments, as described above, a drug sleeve surrounding a drug core is used to recharge an implant, as shown, for example, in
FIG. 11 . As shown inFIG. 11 , for example, the drug core and drug sleeve can be removed together by drawing drug core proximally, and then a replacement core within a replacement drug sleeve can be inserted together by advancing the replacement core andsleeve 45 attached to aninserter tool 55 into the lumen or cavity of the implant. In some embodiments, implants comprised of hydrogel utilize the drug load inserter with the exchangeable drug core and drug sleeve. In some embodiments, one size of a hydrogel plug will fit all patients. - In several embodiments, however, recharging of the implant is not performed, in favor of replacing the implant with a new, drug-preloaded implant, based at least in part on the ease of access to the implant site (e.g., the punctum). In these embodiments, an inserter tool is used to insert the implant into the implant site.
FIG. 12 shows the terminal aspect of aninserter tool 215 used to insert an implant into an implant site, the inserter comprising aplunger 220 that can be depressed and a preloaded drug implant 1 held within the terminus of the inserter prior to insertion, according to some embodiments. It is to be understood that the forceps and other insertion tools may be used to place an implant in the punctum and into the lacrimal canaliculus. In some embodiments, the distal edge of the inserter tool is parallel with the implant, as illustrated inFIG. 13A . In other words, as illustrated inFIG. 13A , the inserter tool can optionally have a straight cut tip. In some embodiments, the inserter tool contains at least one additionalgripping component 225 that guides and supports the implant into the implant site, as shown, for example, inFIG. 13B . Such a gripper may be movably connected to a handpiece that allows for engagement and disengagement of the gripper. In some embodiments, the distal edge of the inserter tool is asymmetric in relation to the implant, as shown inFIG. 13C . In other words, in some embodiments, the distal end of theinserter tool 230 may optionally have a beveled or angled cut tip, which can act as a lead-in. Testing has shown beveled cut tip allowed easier entry of the inserter into the punctum over the straight cut tip. In some embodiments, the lead-in may also be used as a dilator to pre-dilate the area prior to insertion of an implant. - In one embodiment, a portion of the insertion tool may be made of clear material, for example, such as an acrylic material, so that the physician can visualize the tissue through the insertion tool and see the punctum. The optionally clear material may also allow viewing of an implant while it is being implanted, and may also confirm that the implant is implanted properly. In another embodiment, the clear material may be a magnifying material and/or have a magnifying geometry, such as a spherical lens or angled lens, so that the punctum is more easily visualized.
- When more than one drug is desired for treatment of a particular pathology or when a second drug is administered such as to counteract a side effect of the first drug, some embodiments may utilize two agents of the same form. In other embodiments, agents in different form may be used. Likewise, should one or more drugs utilize an adjuvant, excipient, or auxiliary compound, for example to enhance stability or tailor the elution profile, that compound or compounds may also be in any form that is compatible with the drug and can be reasonably retained with the implant.
- In some embodiments, treatment of particular pathology with a drug released from the implant may not only treat the pathology, but also induce certain undesirable side effects.
- It will be understood that embodiments as described herein may include a drug mixed or compounded with a biodegradable material, excipient, or other agent modifying the release characteristics of the drug. In several embodiments, such biodegradable materials include copolymers of lactic acid and glycolic acid, also known as poly (lactic-co-glycolic acid) or PLGA. It will be understood by one skilled in the art that although some disclosure herein specifically describes use of PLGA, other suitable biodegradable materials may be substituted for PLGA or used in combination with PLGA in such embodiments. It will also be understood that in certain embodiments as described herein, the drug positioned within the lumen of the implant is not compounded or mixed with any other compound or material, thereby maximizing the volume of drug that is positioned within the lumen.
- It may be desirable, in some embodiments, to provide for a particular rate of release of drug from a PLGA copolymer, other polymeric material, or other excipient. As the release rate of a drug from a polymer correlates with the degradation rate of that polymer, control of the degradation rate provides a means for control of the delivery rate of the drug contained within the therapeutic agent. Variation of the average molecular weight of the polymer or copolymer chains which make up the PLGA copolymer or other polymer may be used to control the degradation rate of the copolymer, thereby achieving a desired duration or other release profile of therapeutic agent delivery to the eye.
- In certain other embodiments employing PLGA copolymers, rate of biodegradation of the PLGA copolymer may be controlled by varying the ratio of lactic acid to glycolic acid units in a copolymer.
- Still other embodiments may utilize combinations of varying the average molecular weights of the constituents of the copolymer and varying the ratio of lactic acid to glycolic acid in the copolymer to achieve a desired biodegradation rate.
- As described above, the outer shell of the implant comprises a polymer in some embodiments. Additionally, the shell may further comprise one or more polymeric coatings in various locations on or within the implant. The outer shell and any polymeric coatings are optionally biodegradable. The biodegradable outer shell and biodegradable polymer coating may be any suitable material including, but not limited to, poly(lactic acid), polyethylene-vinyl acetate, poly(lactic-co-glycolic acid), poly(D,L-lactide), poly(D,L-lactide-co-trimethylene carbonate), collagen, heparinized collagen, poly(caprolactone), poly(glycolic acid), and/or other polymer or copolymer.
- As described above, some embodiments of the implants comprise a release material that is permeable to the drug (or drugs) and allows passage of the drug (or drugs) through the material in a controlled fashion. Control of the release of the drug can further be controlled by coatings in or on the implant (e.g., a coating over the release material that slows the rate of release of a drug).
- For example, a given combination of drug and release material will yield a characteristic diffusion coefficient D, such that:
-
where D = diffusion coefficient (cm2/sec) A = area of the region of drug release material (Ci − Co) = difference in drug concentration between the inside and outside of the device. d = thickness of the region of release material - Thus, the area and thickness of the region of drug release are variables that determine, in part, the rate of elution of the drug from the implant, and are also variables that can be controlled during the process of manufacturing the implant. In some embodiments using a highly insoluble drug, the release material could be manufactured to be thin (d is small) or with a large overall area (A is large) or a combination of the two (as dictated by the structural sufficiency of the outer shell). In either case, the end result is that the elution rate of the drug can be increased to compensate for the low solubility of the drug based on the structure and design of the implant.
- In contrast, in some embodiments using a highly soluble drug, the drug release material can be made thicker, more dense, or more concentrated, thereby adjusting the rate of release of the drug from the implant.
- Additionally, certain embodiments use additional polymer coatings to either (i) increase the effective thickness (d) of the drug release material or (ii) decrease the overall permeability of the drug release material, resulting in a reduction in drug elution. In still other embodiments, multiple additional polymer coatings are used. By covering either distinct or overlapping portions of the implant and the drug release material, a controlled pattern of drug release from the implant overall can be achieved.
- In several embodiments as described herein, there are no direct through holes or penetrating apertures needed or utilized to specifically facilitate or control drug elution. As such, in those embodiments, there is no direct contact between the drug core (which may be of very high concentration) and the ocular tissue where adjacent to the site where the implant is positioned. In some cases, direct contact of ocular tissue with high concentrations of drug residing within the implant could lead to local cell toxicity and possible local cell death. Thus, in several embodiments, the drug release material also serves a safety function.
- As described above, duration of drug release is desired over an extended period of time. In some embodiments, an implant in accordance with embodiments described herein is capable of delivering a drug at a controlled rate to a target tissue for a period of several (i.e. at least three) months. In certain embodiments, implants can deliver drugs at a controlled rate to target tissues for about 6 months or longer, including 3, 4, 5, 6, 7, 8, 9, 12, 15, 18, and 24 months, without requiring recharging. In still other embodiments, the duration of controlled drug release (without recharging of the implant) exceeds 2 years (e.g., 3, 4, 5, or more years). It shall be appreciated that additional time frames including ranges bordering, overlapping or inclusive of two or more of the values listed above are also used in certain embodiments.
- In conjunction with the controlled release of a drug to a target tissue, certain doses of a drug (or drugs) are desirable over time, in certain embodiments. As such, in some embodiments, the total drug load, for example the total load of a steroid, delivered to a target tissue over the lifetime of an implant ranges from about 10 to about 1000 μg. In certain embodiments the total drug load ranges from about 100 to about 900 μg, from about 200 to about 800 μg, from about 300 to about 700 μg, or from about 400 to about 600 μg. In some embodiments, the total drug load ranges from about 10 to about 300 μg, from about 10 to about 500 μg, or about 10 to about 700 μg. In other embodiments, total drug load ranges from about 200 to about 500 μg, from 400 to about 700 μg or from about 600 to about 1000 μg. In still other embodiments, total drug load ranges from about 200 to about 1000 μg, from about 400 to about 1000 μg, or from about 700 to about 1000 μg. In some embodiments total drug load ranges from about 500 to about 700 μg, about 550 to about 700 μg, or about 550 to about 650 μg, including 575, 590, 600, 610, and 625 μg. It shall be appreciated that additional ranges of drugs bordering, overlapping or inclusive of the ranges listed above are also used in certain embodiments.
- Similarly, in other embodiments, controlled drug delivery is calculated based on the elution rate of the drug from the implant. In certain such embodiments, an elution rate of a drug, for example, a steroid, is about 0.05 μg/day to about 10 μg/day is achieved. In other embodiments an elution rate of about 0.05 μg/day to about 5 μg/day, about 0.05 μg/day to about 3 μg/day, or about 0.05 μg/day to about 2 μg/day is achieved. In other embodiment, an elution rate of about 2 μg/day to about 5 μg/day, about 4 μg/day to about 7 μg/day, or about 6 μg/day to about 10 μg/day is achieved. In other embodiments, an elution rate of about 1 μg/day to about 4 μg/day, about 3 μg/day to about 6 μg/day, or about 7 μg/day to about 10 μg/day is achieved. In still other embodiments, an elution rate of about 0.05 μg/day to about 1 μg/day, including 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 μg/day is achieved. It shall be appreciated that additional ranges of drugs bordering, overlapping or inclusive of the ranges listed above are also used in certain embodiments.
- Alternatively, or in addition to one or more of the parameters above, the release of drug from an implant may be controlled based on the desired concentration of the drug at target tissues. In some embodiments, the desired concentration of a drug, for example, a steroid, at the target tissue, ranges from about 1 nM to about 100 nM. In other embodiments the desired concentration of a drug at the site of action ranges from about 10 nM to about 90 nM, from about 20 nM to about 80 nM, from about 30 nM to about 70 nM, or from about 40 nM to about 60 nM. In still other embodiments the desired concentration of a drug at the site of action ranges from about 1 nM to about 40 nM, from about 20 nM to about 60 nM, from about 50 nM to about 70 nM, or from about 60 nM to about 90 nM. In yet other embodiments the desired concentration of a drug at the site of action ranges from about 1 nM to about 30 nM, from about 10 nM to about 50 nM, from about 30 nM to about 70 nM, or from about 60 nM to about 100 nM. In some embodiments, the desired concentration of a drug at the site of action ranges from about 45 nM to about 55 nM, including 46, 47, 48, 49, 50, 51, 52, 53, and 54 nM. It shall be appreciated that additional ranges of drugs bordering, overlapping or inclusive of the ranges listed above are also used in certain embodiments.
- In some embodiments, as discussed above, the drug or drugs employed may take one or more forms. For example, multiple pellets of single or multiple drug(s) are placed within an interior lumen of the implant (see, e.g.,
FIG. 4 ). - In some embodiments, the therapeutic agent (or agents) is formulated as micro-pellets or micro-tablets. Additionally, in some embodiments, micro-tablets allow a greater amount of the therapeutic agent to be used in an implant. This is because, in some embodiments, tabletting achieves a greater density in a pellet than can be achieved by packing a device. Greater amounts of drug in a given volume may also be achieved by decreasing the amount of excipient used as a percentage by weight of the whole tablet, which has been found by the inventors to be possible when creating tablets of a very small size while retaining the integrity of the tablet. In some embodiments, the percentage of active therapeutic (by weight) is about 70% or higher. As discussed herein, the therapeutic agent can be combined with excipients or binders that are known in the art. In some embodiments, the percentage of therapeutic agent ranges from about 70% to about 95%, from about 75 to 85%, from about 75 to 90%, from about 70 to 75%, from about 75% to about 80% from about 80% to about 85%, from about 85% to about 90%, from about 90% to about 95%, from about 95% to about 99%, from about 99% to about 99.9%, and overlapping ranges thereof. In some embodiments, the percentage of therapeutic agent ranges from about 80% to about 85%, including 81, 82, 83, and 84% by weight.
- In several embodiments, micro-tablets provide an advantage with respect to the amount of an agent that can be packed, tamped, or otherwise placed into an implant disclosed herein. The resultant implant comprising micro-tablets, in some embodiments, thus comprises therapeutic agent at a higher density than can be achieved with non-micro-tablet forms. For example, in some embodiments, the density of the micro-pellet form of an agent within an implant ranges from about 0.7 g/cc to about 1.6 g/cc. In some embodiments, the density used in an implant ranges from about 0.7 g/cc to about 0.9 g/cc, from about 0.9 g/cc to about 1.1 g/cc, from about 1.1 g/cc to about 1.3 g/cc, from about 1.1 g/cc to about 1.5 g./cc, from about 1.3 g/cc to about 1.5 g/cc, from about 1.5 g/cc to about 1.6 g/cc, and overlapping ranges thereof. In some embodiments, densities of therapeutic agent that are greater than 1.6 g/cc are used.
- In one embodiment, micro-tablets with the above properties, or any combination thereof, are made using known techniques in the art including tableting, lyophilization, granulation (wet or dry), flaking, direct compression, molding, extrusion, and the like. Moreover, as discussed below, alterations in the above-discussed characteristics can be used to tailor the release profile of the micro-tableted therapeutic agent from an implant.
- In several embodiments, lyophilization of a therapeutic agent is used prior to the micro-pelleting process. In some embodiments, lyophilization improves the stability of the therapeutic agent once incorporated into a micro-tablet. In some embodiments, lyophilization allows for a greater concentration of therapeutic to be obtained prior to micro-pelleting, thereby enhancing the ability to achieve the high percentages of active therapeutic agents that are desirable in some embodiments. For example, many commercially available therapeutic agents useful to treat ocular diseases are developed as first-line agents for other diseases. As such, their original formulation may not be suitable or ideal for micro-pelleting or for administration to an ocular target via an ocular implant such as those disclosed herein. For example, several anti-VEGF compounds are supplied as sterile liquid in single use vials meant to be administered intravenously (e.g., bevacizumab). As a result, such a liquid formulation is less preferred for formation of micro-pellets as compared to a solid, though a liquid therapeutic agent may optionally be used in some embodiments. To achieve micro-pelleting at high percentages of therapeutic agent, such liquid formulations may be frozen (e.g., stored at temperatures between −20° C. and −80° C. for 16 to 24 hours or longer) and then subject to lyophilization until dry. Alternatively, air spraying, crystallization, or other means may optionally be used to dry the therapeutic agent.
- Once dry, the lyophilized (or otherwise dried) therapeutic agent is optionally tested for purity. In some embodiments, solvents may be added to a liquid (or solid) formulation in order to dissolve and remove (via evaporation) non-therapeutic components (e.g., excipients or inert binding agents). In some embodiments, a therapeutic agent is purified by conventional methods (e.g., antibody-based chromatography, HPLC, etc.) prior to lyophilization. In such embodiments, lyophilization often functions to increase the concentration of the therapeutic agent in the recovered purified sample.
- In some embodiments, the dried therapeutic agent (which, for efficiency purposes is optionally dried in bulk) is ground, sieved, macerated, freeze-fractured, or subdivided into known quantities by other means, and then micro-pelleted.
- After lyophilization and or subdivision, the therapeutic agent is fed into a micro-pelleting process. In some embodiments, standard techniques (e.g., compression, extrusion, molding, or other means) are used. However, in several embodiments employing high percentages of active therapeutic agent, more specialized techniques are used.
- In several embodiments, the therapeutic agent is a protein, and in such embodiments, drying and/or tabletization should be completed under conditions (e.g., temperature, acid/base, etc.) that do not adversely affect the biological activity of the therapeutic agent. To assist in maintenance of biological activity of micro-pelleted therapeutic agents, in some embodiments, protein therapeutics are formulated with a stabilizing agent (e.g., mannitol, trehalose, starch, or other poly-hydroxy polymer) to maintain the structure (and therefore activity) of the therapeutic protein.
- As mentioned above, depending on the embodiment, the drug or drugs to be administered via the drug delivery implant may be in the form of a nanodispersion. Nanodispersions are particularly advantageous when the drug (or drugs) to be administered is poorly soluble or insoluble in aqueous solutions, which can lead to instability and/or reduced bioavailability.
- As used herein, the term “nanodispersion” shall be given its ordinary meaning and shall refer to a composition comprising nanoparticles comprising a drug and/or an aqueous vehicle. In several embodiments, the aqueous vehicle comprises a water miscible solvent and water. In several embodiments, the nanoparticles may comprise a drug, a polymer and a surfactant comprising a mixture of fatty acids or its salts and sterol or its derivatives or its salts, in some embodiments.
- The term “nanoparticle” as used herein shall be given its ordinary meaning and shall also refer to particles having controlled dimensions of the order of nanometers. For example the nanoparticles, in several embodiments, are a polymeric nanoparticle (matrix of polymer entrapping the drug) and/or a polymeric nanovesicle (polymer stabilized nano sized vesicle encapsulating the drug.) and/or a polymeric nanocapsule (polymeric membrane surrounding drug in core) and/or nano sized particles of the drug stabilized by surfactants, and the like the nanoparitcles having mean size less than about 300 nm (e.g., ranging from about 10 nm to about 275 nm, or in the range of about 10 nm to about 200 nm.
- In several embodiments, the water miscible solvent used in the nanodispersion comprises one or more of alcohols, glycols and its derivatives, polyalkylene glycols and its derivatives, glycerol, glycofurol and combinations thereof. Additional non-limiting examples include, but are not limited to, alcohols such as ethanol, n-propanol, isopropanol; glycols such as ethylene glycol, propylene glycol, butylene glycol and its derivatives; polyethylene glycols like PEG 400 or PEG 3350; polypropylene glycol and its derivatives such as PPG-10 butanediol, PPG-10 methyl glucose ether, PPG-20 methyl glucose ether, PPG-15 stearyl ether; glycerol; glycofurol and the like and mixtures thereof. In still additional embodiments, the non-aqueous solvent is selected from the group consisting of alcohols, polyethylene glycols and/or mixtures thereof, such as, for example, a mixture of ethanol and PEG (polyethylene glycol). In some embodiments, in which ethanol is used in the nanodispersion, ethanol is present in an amount ranging from about 0.001% w/v to about 5% w/v, more preferably from about 0.05% w/v to about 0.5% w/v and most preferably from about 0.1% w/v to about 0.25% w/v. Polyethylene glycols which are used preferably, include PEG-400 and PEG-3350. PEG-400 is used, depending on the embodiment, in an amount ranging from about 0.01% w/v to about 20.0% w/v, more preferably from about 0.05% w/v to about 5.0% w/v and most preferably from about 1.0% w/v to about 2.5% w/v. PEG-3350 is used, depending on the embodiment, in an amount ranging from about 0.001% w/v to about 10.0% w/v, more preferably from about 0.05% w/v to about 5.0% w/v and most preferably from about 0.1% w/v to about 3% w/v.
- In some embodiments, the nanoparticles comprise one or more polymers. The polymer(s) used in several embodiments are preferably, water soluble. Polyvinylpyrrolidone, one such water soluble polymer used in several embodiments, is a tertiary amide polymer having linearly arranged monomer units of 1-vinyl-2-pyrrolidone. It has mean molecular weights ranging from about 10,000 to about 700,000. Other grades of polyvinylpyrrolidone are used in some embodiments, with molecular weights ranging from about 2000 to about 3000, about 7000 to about 11,000, about 28,000 to about 34,000, or about 1,000,000 to about 1,5000,000. In still additional embodiments, polyvinylpyrrolidone use for the polymer have molecular weight in the range from about 1,000 to about 45,000, preferably, from about 4,000 to about 30,000. According several embodiments, the amount of polymer used in the nanodispersion ranges from about 0.001% w/v to about 20% w/v, including preferably about 0.01% w/v to about 5.0% w/v and also about 0.01% w/v to about 1.0% w/v.
- Polyethylene glycol is used in several embodiments, either in addition or in place of polyvinylpyrrolidone. In several embodiments, the amount of polymer used in the nanodispersion ranges from about 0.001% w/v to about 20% w/v, including about 0.01% w/v to about 5.0% w/v, and in some embodiments, about 0.01% w/v to about 1.0% w/v.
- Surfactants are used in some embodiments of the nanodispersions for drug(s). In several embodiments, the surfactants comprise a mixture of fatty acid or its salts and sterol or its derivatives or its salts.
- As used herein, the term “fatty acids” shall be given its ordinary meaning and shall also include aliphatic (saturated or unsaturated) monocarboxylic acids derived from or contained in esterified form, in an animal or vegetable fat, oil or wax. Non-limiting examples of fatty acids (or its salts) that may be used in in several embodiments include, but are not limited to, fatty acids or its salts having ‘n’ number of carbon atoms wherein ‘n’ ranges from about 4 to about 28. The fatty acid may be a saturated fatty acid or an unsaturated fatty acid, and their salt and combinations thereof. Depending on the embodiment, the saturated fatty acid and its salts may be selected from butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, sodium caprylate, sodium laurate, sodium myristate, sodium palmitate and the like and/or mixtures thereof. The unsaturated fatty acid and its salts may be selected from myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, alpha linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, sodium oleate, sodium arachidonate and the like and/or mixtures thereof.
- Additionally, non-limiting examples, of sterol or its derivative or its salts that may be used in the nanodispersion or nanoparticles may be acid esters of sterols. The sterols that may be suitable, but are not limited to, cholesterol, phytosterols, ergosterol, bile acids salts and mixtures thereof. Acid salts of cholesterol that may be used include, but are not limited to, cholesteryl sulfate, cholesterol acetate, cholesterol chloroacetate, cholesterol benzoate, cholesterol myristate, cholesterol hemisuccinate, cholesterol phosphate, cholesterol phosphate, phosphonate, borate, nitrate, cholesterol cinnamate, cholesterol crotanoate, cholesterol butyrate, cholesterol heptanoate, cholesterol hexanoate, cholesterol octanoate, cholesterol nonanoate, cholesterol decanoate, cholesterol oleate, cholesterol propionate, cholesterol valerate, dicholesteryl carbonate and the like and mixtures thereof. Phytosterols that may be used in the compositions include sitosterol, campesterol, stigmasterol, brassicasterol and its derivatives, salts and mixture thereof. For example, Phytosterols marketed by Sigma, U.S.A. containing bsitosterol, campesterol and dihydrobrassicasterol. Bile acids include cholic acid, chenodeoxycholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, ursodeoxycholic acid and its derivatives, salts and mixture thereof. The sterols can also be esters of cholesterol including cholesterol hemi-succinate, salts of cholesterol including cholesterol hydrogen sulfate and cholesterol sulfate, ergosterol, esters of ergosterol including ergosterol hemi-succinate, salts of ergosterol including ergosterol hydrogen sulfate and ergosterol sulfate, lanosterol, esters of lanosterol including lanosterol hemi-succinate, salts of lanosterol including lanosterol hydrogen sulfate and lanosterol sulfate.
- According to one embodiment, the nanoparticles comprise a surfactant which is a mixture of sterol or its derivatives or its salts and fatty acids or its salts. In an additional embodiment, the nanoparticles comprise of cholesterol ester of polar acids. In still further embodiments, the surfactant used in the nanodispersion is a mixture of caprylic acid and cholesteryl sulfate. Caprylic acid, also known as octanoic acid may be used in such embodiments in an amount ranging from about 0.001% w/v to about 5.0% w/v, more preferably from about 0.01% w/v to about 1.0% w/v and most preferably from about 0.01% w/v to about 0.5% w/v. Cholesteryl sulfate is used in certain embodiments in an amount ranging from about 0.001% w/v to about 5.0% w/v, more preferably from about 0.01% w/v to about 1.0% w/v and most preferably from about 0.01% w/v to about 0.5% w/v. In one embodiment, the surfactant used is selected from oleic acid and cholesteryl sulphate and/or mixtures thereof. In some embodiments, the surfactant used is selected from saturated fatty acid and bile acid or bile salt and/or mixtures thereof. Bile salts, when used according to some embodiments, are present in an amount ranging from about 0.001% w/v to about 5.0% w/v, more preferably from about 0.01% w/v to about 1.0% w/v and most preferably from about 0.01% w/v to about 0.75% w/v. Other amounts may be used in conjunction with other embodiments disclosed herein. Nanodispersions can be generated by methods appreciated in the art, such as those methods (and the resulting nanodispersions) disclosed in U.S. Pat. No. 8,778,364, which is incorporated by reference in its entirety herein.
- In addition, one or more of the therapeutic drug regions may comprise drug-cyclodextrin inclusion complexes; liposome encapsulation; micelles based on polymers such as polysaccharide, poly (ethylene glycol)-poly(lactide), methoxy poly(ethylene glycol)-poly(hexyl-lactide), or hydrophobically-modified hydroxypropylcellulose; nanoparticles of amorphous drug formed by antisolvent precipitation and stabilized with surfactant such as
poysorbate 80 or polyoxyl 15 hydroxystearate; nanoparticles having a mean size less than 500 nm containing one or more drugs, a polymer, and a surfactant, where the surfactant may include a mixture of fatty acids or its salts and sterol or its derivitatives or its salts; drug co-processed or granulated with excipients such as microcrystalline cellulose, lactose, hydroxypropyl methyl cellulose, or povidone; added polyethylene glycol chains to the drug, polymer, or surfactant (PEGylation); solid dispersions in polymeric carriers such as hypromellose acetate succinate, copolymers based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, poly(vinylpyrrolidone-vinyl acetate), or lauroyl macrogolglycerides; or microspheres (for example, based on PLGA or chitosan). - The therapeutic agents utilized with the drug delivery implant, may include one or more drugs provided below, either alone or in combination. The drugs utilized may also be the equivalent of, derivatives of, or analogs of one or more of the drugs provided below. The drugs may include but are not limited to pharmaceutical agents including anti-glaucoma medications, ocular agents, antimicrobial agents (e.g., antibiotic, antiviral, antiparasitic, antifungal agents), anti-inflammatory agents (including steroids or non-steroidal anti-inflammatory), biological agents including hormones, enzymes or enzyme-related components, antibodies or antibody-related components, oligonucleotides (including DNA, RNA, short-interfering RNA, antisense oligonucleotides, and the like), DNA/RNA vectors, viruses (either wild type or genetically modified) or viral vectors, peptides, proteins, enzymes, extracellular matrix components, and live cells configured to produce one or more biological components. The use of any particular drug is not limited to its primary effect or regulatory body-approved treatment indication or manner of use. Drugs also include compounds or other materials that reduce or treat one or more side effects of another drug or therapeutic agent. As many drugs have more than a single mode of action, the listing of any particular drug within any one therapeutic class below is only representative of one possible use of the drug and is not intended to limit the scope of its use with the ophthalmic implant system.
- As discussed above, the therapeutic agents may be combined with any number of excipients as is known in the art. In addition to the biodegradable polymeric excipients discussed above, other excipients may be used, including, but not limited to, benzyl alcohol, ethylcellulose, methylcellulose, hydroxymethylcellulose, cetyl alcohol, croscarmellose sodium, dextrans, dextrose, fructose, gelatin, glycerin, monoglycerides, diglycerides, kaolin, calcium chloride, lactose, lactose monohydrate, maltodextrins, polysorbates, pregelatinized starch, calcium stearate, magnesium stearate, silicon dioxide, cornstarch, talc, and the like. The one or more excipients may be included in total amounts as low as about 1%, 5%, or 10% and in other embodiments may be included in total amounts as high as 50%, 70% or 90%.
- Examples of drugs may include various anti-secretory agents; antimitotics and other anti-proliferative agents, including among others, anti-angiogenesis agents such as angiostatin, anecortave acetate, thrombospondin, VEGF receptor tyrosine kinase inhibitors and anti-vascular endothelial growth factor (anti-VEGF) drugs such as ranibizumab (LUCENTIS®) and bevacizumab (AVASTIN®), pegaptanib (MACUGEN®), aflibercept (EYELEA®), sunitinib and sorafenib and any of a variety of known small-molecule and transcription inhibitors having anti-angiogenesis effect; classes of known ophthalmic drugs, including: glaucoma agents, such as adrenergic antagonists, including for example, beta-blocker agents such as atenolol propranolol, metipranolol, betaxolol, carteolol, levobetaxolol, levobunolol and timolol; adrenergic agonists or sympathomimetic agents such as epinephrine, dipivefrin, clonidine, aparclonidine, and brimonidine; parasympathomimetics or cholingeric agonists such as pilocarpine, carbachol, phospholine iodine, and physostigmine, salicylate, acetylcholine chloride, eserine, diisopropyl fluorophosphate, demecarium bromide); muscarinics; carbonic anhydrase inhibitor agents, including topical and/or systemic agents, for example acetozolamide, brinzolamide, dorzolamide and methazolamide, ethoxzolamide, diamox, and dichlorphenamide; mydriatic-cycloplegic agents such as atropine, cyclopentolate, succinylcholine, homatropine, phenylephrine, scopolamine and tropicamide; prostaglandins such as prostaglandin F2 alpha, antiprostaglandins, prostaglandin precursors, or prostaglandin analog agents such as bimatoprost, latanoprost, travoprost and unoprostone.
- Other examples of drugs may also include anti-inflammatory agents including for example glucocorticoids and corticosteroids such as betamethasone, cortisone, dexamethasone, dexamethasone 21-phosphate, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, prednisolone, fluroometholone, loteprednol, medrysone, fluocinolone acetonide, triamcinolone acetonide, triamcinolone, triamcinolone acetonide, beclomethasone, budesonide, flunisolide, fluorometholone, fluticasone, hydrocortisone, hydrocortisone acetate, loteprednol, rimexolone and non-steroidal anti-inflammatory agents including, for example, diclofenac, flurbiprofen, ibuprofen, bromfenac, nepafenac, and ketorolac, salicylate, indomethacin, ibuprofen, naxopren, piroxicam and nabumetone; anti-infective or antimicrobial agents such as antibiotics including, for example, tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, rifampicin, ciprofloxacin, tobramycin, gentamycin, erythromycin, penicillin, sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole, sulfisoxazole, nitrofurazone, sodium propionate, aminoglycosides such as gentamicin and tobramycin; fluoroquinolones such as ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin; bacitracin, erythromycin, fusidic acid, neomycin, polymyxin B, gramicidin, trimethoprim and sulfacetamide; antifungals such as amphotericin B and miconazole; antivirals such as idoxuridine trifluorothymidine, acyclovir, gancyclovir, interferon; antimicotics; immune-modulating agents such as antiallergenics, including, for example, sodium chromoglycate, antazoline, methapyriline, chlorpheniramine, cetrizine, pyrilamine, prophenpyridamine; anti-histamine agents such as azelastine, emedastine and levocabastine; immunological drugs (such as vaccines, immune stimulants, and/or immunosuppressants); MAST cell stabilizer agents such as cromolyn sodium, ketotifen, lodoxamide, nedocrimil, olopatadine and pemirolastciliary body ablative agents, such as gentimicin and cidofovir; and other ophthalmic agents such as verteporfin, proparacaine, tetracaine, cyclosporine and pilocarpine; inhibitors of cell-surface glycoprotein receptors; decongestants such as phenylephrine, naphazoline, tetrahydrazoline; lipids or hypotensive lipids; dopaminergic agonists and/or antagonists such as quinpirole, fenoldopam, and ibopamine; vasospasm inhibitors; vasodilators; antihypertensive agents; angiotensin converting enzyme (ACE) inhibitors; angiotensin-1 receptor antagonists such as olmesartan; microtubule inhibitors; molecular motor (dynein and/or kinesin) inhibitors; actin cytoskeleton regulatory agents such as cyctchalasin, latrunculin, swinholide A, ethacrynic acid, H-7, and Rho-kinase (ROCK) inhibitors; remodeling inhibitors; modulators of the extracellular matrix such as tert-butylhydro-quinolone and AL-3037A; adenosine receptor agonists and/or antagonists such as N-6-cylclophexyladenosine and (R)-phenylisopropyladenosine; serotonin agonists; hormonal agents such as estrogens, estradiol, progestational hormones, progesterone, insulin, calcitonin, parathyroid hormone, peptide and vasopressin hypothalamus releasing factor; growth factor antagonists or growth factors, including, for example, epidermal growth factor, fibroblast growth factor, platelet derived growth factor or antagonists thereof (such as those disclosed in U.S. Pat. No. 7,759,472 or U.S. patent application Ser. Nos. 12/465,051, 12/564,863, or 12/641,270, each of which is incorporated in its entirety by reference herein), transforming growth factor beta, somatotrapin, fibronectin, connective tissue growth factor, bone morphogenic proteins (BMPs); cytokines such as interleukins, CD44, cochlin, and serum amyloids, such as serum amyloid A.
- Other therapeutic agents may include neuroprotective agents such as lubezole, nimodipine and related compounds, and including blood flow enhancers such as dorzolamide or betaxolol; compounds that promote blood oxygenation such as erythropoeitin; sodium channels blockers; calcium channel blockers such as nilvadipine or lomerizine; glutamate inhibitors such as memantine nitromemantine, riluzole, dextromethorphan or agmatine; acetylcholinsterase inhibitors such as galantamine; hydroxylamines or derivatives thereof, such as the water soluble hydroxylamine derivative OT-440; synaptic modulators such as hydrogen sulfide compounds containing flavonoid glycosides and/or terpenoids, such as Ginkgo biloba; neurotrophic factors such as glial cell-line derived neutrophic factor, brain derived neurotrophic factor; cytokines of the IL-6 family of proteins such as ciliary neurotrophic factor or leukemia inhibitory factor; compounds or factors that affect nitric oxide levels, such as nitric oxide, nitroglycerin, or nitric oxide synthase inhibitors; cannabinoid receptor agonsists such as WIN55-212-2; free radical scavengers such as methoxypolyethylene glycol thioester (MPDTE) or methoxypolyethlene glycol thiol coupled with EDTA methyl triester (MPSEDE); anti-oxidants such as astaxathin, dithiolethione, vitamin E, or metallocorroles (e.g., iron, manganese or gallium corroles); compounds or factors involved in oxygen homeostasis such as neuroglobin or cytoglobin; inhibitors or factors that impact mitochondrial division or fission, such as Mdivi-1 (a selective inhibitor of dynamin related protein 1 (Drp1)); kinase inhibitors or modulators such as the Rho-kinase inhibitor H-1152 or the tyrosine kinase inhibitor AG1478; compounds or factors that affect integrin function, such as the Beta 1-integrin activating antibody HUTS-21; N-acyl-ethanaolamines and their precursors, N-acyl-ethanolamine phospholipids; stimulators of glucagon-like peptide 1 receptors (e.g., glucagon-like peptide 1); polyphenol containing compounds such as resveratrol; chelating compounds; apoptosis-related protease inhibitors; compounds that reduce new protein synthesis; radiotherapeutic agents; photodynamic therapy agents; gene therapy agents; genetic modulators; auto-immune modulators that prevent damage to nerves or portions of nerves (e.g., demyelination) such as glatimir; myelin inhibitors such as anti-NgR Blocking Protein, NgR(310)ecto-Fc; other immune modulators such as FK506 binding proteins (e.g., FKBP51); and dry eye medications such as cyclosporine, cyclosporine A, delmulcents, and sodium hyaluronate.
- Other therapeutic agents that may be used include: other beta-blocker agents such as acebutolol, atenolol, bisoprolol, carvedilol, asmolol, labetalol, nadolol, penbutolol, and pindolol; other corticosteroidal and non-steroidal anti-inflammatory agents such aspirin, betamethasone, cortisone, diflunisal, etodolac, fenoprofen, fludrocortisone, flurbiprofen, hydrocortisone, ibuprofen, indomethacine, ketoprofen, meclofenamate, mefenamic acid, meloxicam, methylprednisolone, nabumetone, naproxen, oxaprozin, prednisolone, prioxicam, salsalate, sulindac and tolmetin; COX-2 inhibitors like celecoxib, rofecoxib and. Valdecoxib; other immune-modulating agents such as aldesleukin, adalimumab (HUMIRA®), azathioprine, basiliximab, daclizumab, etanercept (ENBREL®), hydroxychloroquine, infliximab (REMICADE®), leflunomide, methotrexate, mycophenolate mofetil, and sulfasalazine; other anti-histamine agents such as loratadine, desloratadine, cetirizine, diphenhydramine, chlorpheniramine, dexchlorpheniramine, clemastine, cyproheptadine, fexofenadine, hydroxyzine and promethazine; other anti-infective agents such as aminoglycosides such as amikacin and streptomycin; anti-fungal agents such as amphotericin B, caspofungin, clotrimazole, fluconazole, itraconazole, ketoconazole, voriconazole, terbinafine and nystatin; anti-malarial agents such as chloroquine, atovaquone, mefloquine, primaquine, quinidine and quinine; anti-mycobacterium agents such as ethambutol, isoniazid, pyrazinamide, rifampin and rifabutin; anti-parasitic agents such as albendazole, mebendazole, thiobendazole, metronidazole, pyrantel, atovaquone, iodoquinaol, ivermectin, paromycin, praziquantel, and trimatrexate; other anti-viral agents, including anti-CMV or anti-herpetic agents such as acyclovir, cidofovir, famciclovir, gangciclovir, valacyclovir, valganciclovir, vidarabine, trifluridine and foscarnet; protease inhibitors such as ritonavir, saquinavir, lopinavir, indinavir, atazanavir, amprenavir and nelfinavir; nucleotide/nucleoside/non-nucleoside reverse transcriptase inhibitors such as abacavir, ddI, 3TC, d4T, ddC, tenofovir and emtricitabine, delavirdine, efavirenz and nevirapine; other anti-viral agents such as interferons, ribavirin and trifluridiene; other anti-bacterial agents, including cabapenems like ertapenem, imipenem and meropenem; cephalosporins such as cefadroxil, cefazolin, cefdinir, cefditoren, cephalexin, cefaclor, cefepime, cefoperazone, cefotaxime, cefotetan, cefoxitin, cefpodoxime, cefprozil, ceftaxidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime and loracarbef; other macrolides and ketolides such as azithromycin, clarithromycin, dirithromycin and telithromycin; penicillins (with and without clavulanate) including amoxicillin, ampicillin, pivampicillin, dicloxacillin, nafcillin, oxacillin, piperacillin, and ticarcillin; tetracyclines such as doxycycline, minocycline and tetracycline; other anti-bacterials such as aztreonam, chloramphenicol, clindamycin, linezolid, nitrofurantoin and vancomycin; alpha blocker agents such as doxazosin, prazosin and terazosin; calcium-channel blockers such as amlodipine, bepridil, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine and verapamil; other anti-hypertensive agents such as clonidine, diazoxide, fenoldopan, hydralazine, minoxidil, nitroprus side, phenoxybenzamine, epoprostenol, tolazoline, treprostinil and nitrate-based agents; anti-coagulant agents, including heparins and heparinoids such as heparin, dalteparin, enoxaparin, tinzaparin and fondaparinux; other anti-coagulant agents such as hirudin, aprotinin, argatroban, bivalirudin, desirudin, lepirudin, warfarin and ximelagatran; anti-platelet agents such as abciximab, clopidogrel, dipyridamole, optifibatide, ticlopidine and tirofiban; prostaglandin PDE-5 inhibitors and other prostaglandin agents such as alprostadil, carboprost, sildenafil, tadalafil and vardenafil; thrombin inhibitors; antithrombogenic agents; anti-platelet aggregating agents; thrombolytic agents and/or fibrinolytic agents such as alteplase, anistreplase, reteplase, streptokinase, tenecteplase and urokinase; anti-proliferative agents such as sirolimus, tacrolimus, everolimus, zotarolimus, paclitaxel and mycophenolic acid; hormonal-related agents including levothyroxine, fluoxymestrone, methyltestosterone, nandrolone, oxandrolone, testosterone, estradiol, estrone, estropipate, clomiphene, gonadotropins, hydroxyprogesterone, levonorgestrel, medroxyprogesterone, megestrol, mifepristone, norethindrone, oxytocin, progesterone, raloxifene and tamoxifen; anti-neoplastic agents, including alkylating agents such as carmustine lomustine, melphalan, cisplatin, fluorouracil3, and procarbazine antibiotic-like agents such as bleomycin, daunorubicin, doxorubicin, idarubicin, mitomycin and plicamycin; anti proliferative agents (such as 1,3-cis retinoic acid, 5-fluorouracil, taxol, rapamycin, mitomycin C and cisplatin); antimetabolite agents such as cytarabine, fludarabine, hydroxyurea, mercaptopurine and 5-fluorouracil (5-FU); immune modulating agents such as aldesleukin, imatinib, rituximab and tositumomab; mitotic inhibitors docetaxel, etoposide, vinblastine and vincristine; radioactive agents such as strontium-89; and other anti-neoplastic agents such as irinotecan, topotecan and mitotane.
- While certain embodiments of the disclosure have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of the disclosure. Indeed, the novel methods, systems, and devices described herein may be embodied in a variety of other forms. For example, embodiments of one illustrated or described implant may be combined with embodiments of another illustrated or described shunt. Moreover, the implants described above may be utilized for other purposes. For example, the implants may be used to drain fluid from the anterior chamber to other locations of the eye or outside the eye. Furthermore, various omissions, substitutions and changes in the form of the methods, systems, and devices described herein may be made without departing from the spirit of the disclosure.
Claims (21)
1. (canceled)
2. A punctal implant for insertion into a punctum of the eye of a subject, the implant comprising:
an outer shell comprising:
a first end comprising a plurality of holes or fenestrations,
a closed second end;
an interior lumen extending from the first end to the closed second end; and
a first drug and a second drug within the interior lumen, wherein the first and second drugs are individually shaped into tablets, wherein the tablets are sized and physically arranged within the interior lumen to allow the first drug to be closer to the region of drug release and initially elute prior to an initial elution of the second drug, and
wherein the first drug and the second drug elute from the lumen by passing through the plurality of holes or fenestrations.
3. The implant of claim 2 , further comprising at least one retention feature configured to anchor the implant in the punctum.
4. The implant of claim 3 , wherein the at least one retention feature is non-occlusive.
5. The implant of claim 2 , further comprising an asymmetrical flange having a length extending in a first direction that exceeds a width extending in a second direction.
6. The implant of claim 5 , wherein the asymmetrical flange is configured to rest on the surface of the eyelid when the implant is inserted into the punctum.
7. The implant of claim 2 , wherein the first drug is shaped into a first tablet and the second drug is shaped into a second tablet, the first tablet positioned atop the second tablet.
8. The implant of claim 2 , wherein each of the plurality of holes or fenestrations have a diameter that is less than a diameter of the lumen.
9. The implant of claim 2 , wherein the outer shell comprises a radial bulge in a distal region in order to anchor the implant in the punctum.
10. The implant of claim 9 , wherein a width of the radial bulge gradually increases to a maximum width and gradually decreases from the maximum width.
11. The implant of claim 2 , wherein the outer shell has an outer diameter that gradually increases to a maximum outer diameter in a distal region and wherein the outer diameter gradually decreases between the maximum outer diameter and the closed second end.
12. A punctal implant for insertion into a punctum of the eye of a subject, the implant comprising:
an outer shell comprising:
a first end comprising a plurality of holes or fenestrations; and
an interior lumen extending from the first end to a second end; and
a first tablet comprising a first drug and a second tablet comprising a second drug positioned within the interior lumen, the first tablet positioned atop the second tablet, and
wherein the first and second drug elute from the lumen by passing through the plurality of holes or fenestrations.
13. The implant of claim 12 , further comprising at least one retention feature configured to anchor the implant in the punctum.
14. The implant of claim 13 , wherein the at least one retention feature is non-occlusive.
15. The implant of claim 12 , further comprising an asymmetrical flange having a length extending in a first direction that exceeds a width extending in a second direction.
16. The implant of claim 15 , wherein the asymmetrical flange is configured to rest on the surface of the eyelid when the implant is inserted into the punctum.
17. The implant of claim 12 , wherein each of the plurality of holes or fenestrations have a diameter that is less than a diameter of the lumen.
18. The implant of claim 12 , wherein the second end is a closed second end.
19. The implant of claim 12 , wherein the outer shell comprises a radial bulge in a distal region in order to anchor the implant in the punctum.
20. The implant of claim 19 , wherein a width of the radial bulge gradually increases to a maximum width and gradually decreases from the maximum width.
21. The implant of claim 20 , wherein the outer shell has an outer diameter that gradually increases to a maximum outer diameter in a distal region and wherein the outer diameter gradually decreases between the maximum outer diameter and the closed second end.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US18/158,705 US20230293344A1 (en) | 2015-09-25 | 2023-01-24 | Punctal implants with controlled drug delivery features and methods of using same |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562233259P | 2015-09-25 | 2015-09-25 | |
PCT/US2016/053570 WO2017053885A1 (en) | 2015-09-25 | 2016-09-23 | Punctal implants with controlled drug delivery features and methods of using same |
US201815762969A | 2018-03-23 | 2018-03-23 | |
US18/158,705 US20230293344A1 (en) | 2015-09-25 | 2023-01-24 | Punctal implants with controlled drug delivery features and methods of using same |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/762,969 Continuation US11564833B2 (en) | 2015-09-25 | 2016-09-23 | Punctal implants with controlled drug delivery features and methods of using same |
PCT/US2016/053570 Continuation WO2017053885A1 (en) | 2015-09-25 | 2016-09-23 | Punctal implants with controlled drug delivery features and methods of using same |
Publications (1)
Publication Number | Publication Date |
---|---|
US20230293344A1 true US20230293344A1 (en) | 2023-09-21 |
Family
ID=57184782
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/762,969 Active 2037-09-24 US11564833B2 (en) | 2015-09-25 | 2016-09-23 | Punctal implants with controlled drug delivery features and methods of using same |
US18/158,705 Pending US20230293344A1 (en) | 2015-09-25 | 2023-01-24 | Punctal implants with controlled drug delivery features and methods of using same |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/762,969 Active 2037-09-24 US11564833B2 (en) | 2015-09-25 | 2016-09-23 | Punctal implants with controlled drug delivery features and methods of using same |
Country Status (2)
Country | Link |
---|---|
US (2) | US11564833B2 (en) |
WO (1) | WO2017053885A1 (en) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7431710B2 (en) | 2002-04-08 | 2008-10-07 | Glaukos Corporation | Ocular implants with anchors and methods thereof |
US10206813B2 (en) | 2009-05-18 | 2019-02-19 | Dose Medical Corporation | Implants with controlled drug delivery features and methods of using same |
US10245178B1 (en) | 2011-06-07 | 2019-04-02 | Glaukos Corporation | Anterior chamber drug-eluting ocular implant |
JP6465490B2 (en) | 2012-03-26 | 2019-02-06 | グローコス コーポレーション | Implant delivery device |
US10517759B2 (en) | 2013-03-15 | 2019-12-31 | Glaukos Corporation | Glaucoma stent and methods thereof for glaucoma treatment |
US9592151B2 (en) | 2013-03-15 | 2017-03-14 | Glaukos Corporation | Systems and methods for delivering an ocular implant to the suprachoroidal space within an eye |
AU2015266850B2 (en) | 2014-05-29 | 2019-12-05 | Glaukos Corporation | Implants with controlled drug delivery features and methods of using same |
WO2016154066A2 (en) | 2015-03-20 | 2016-09-29 | Glaukos Corporation | Gonioscopic devices |
US11925578B2 (en) | 2015-09-02 | 2024-03-12 | Glaukos Corporation | Drug delivery implants with bi-directional delivery capacity |
WO2017053885A1 (en) | 2015-09-25 | 2017-03-30 | Glaukos Corporation | Punctal implants with controlled drug delivery features and methods of using same |
AU2017252294B2 (en) | 2016-04-20 | 2021-12-02 | Dose Medical Corporation | Bioresorbable ocular drug delivery device |
US10674906B2 (en) | 2017-02-24 | 2020-06-09 | Glaukos Corporation | Gonioscopes |
US11116625B2 (en) | 2017-09-28 | 2021-09-14 | Glaukos Corporation | Apparatus and method for controlling placement of intraocular implants |
CN113893085A (en) | 2017-10-06 | 2022-01-07 | 格劳科斯公司 | Systems and methods for delivering multiple ocular implants |
USD846738S1 (en) | 2017-10-27 | 2019-04-23 | Glaukos Corporation | Implant delivery apparatus |
CN110711075A (en) * | 2018-07-11 | 2020-01-21 | 吴坚 | Lacrimal duct embolism |
US11207267B2 (en) | 2019-10-02 | 2021-12-28 | Segal Innovations LLC | Bio-adhesive dissolving compounds and device |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5334137A (en) * | 1992-02-21 | 1994-08-02 | Eagle Vision, Inc. | Lacrimal fluid control device |
US20090104248A1 (en) * | 2007-09-07 | 2009-04-23 | Qlt Plug Delivery, Inc. -Qpdi | Lacrimal implants and related methods |
US20090306608A1 (en) * | 2008-05-07 | 2009-12-10 | Zhigang Li | Ophthalmic devices for the controlled release of active agents |
US20120059338A1 (en) * | 2010-09-08 | 2012-03-08 | Beeley Nathan R F | Punctal plug containing drug formulation |
US20120078362A1 (en) * | 2009-05-18 | 2012-03-29 | Dose Medical Corporation | Drug eluting ocular implant |
Family Cites Families (596)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US663670A (en) | 1900-07-30 | 1900-12-11 | Marion W Wiswall | Apparel dusting-cap. |
US3416530A (en) | 1966-03-02 | 1968-12-17 | Richard A. Ness | Eyeball medication dispensing tablet |
US3710795A (en) | 1970-09-29 | 1973-01-16 | Alza Corp | Drug-delivery device with stretched, rate-controlling membrane |
US4034756A (en) | 1971-01-13 | 1977-07-12 | Alza Corporation | Osmotically driven fluid dispenser |
US4450150A (en) | 1973-05-17 | 1984-05-22 | Arthur D. Little, Inc. | Biodegradable, implantable drug delivery depots, and method for preparing and using the same |
JPS5323011B2 (en) | 1973-09-12 | 1978-07-12 | ||
US3961628A (en) | 1974-04-10 | 1976-06-08 | Alza Corporation | Ocular drug dispensing system |
US3949750A (en) | 1974-10-07 | 1976-04-13 | Freeman Jerre M | Punctum plug and method for treating keratoconjunctivitis sicca (dry eye) and other ophthalmic aliments using same |
US4096238A (en) | 1974-12-23 | 1978-06-20 | Alza Corporation | Method for administering drug to the gastrointestinal tract |
US4207890A (en) | 1977-01-04 | 1980-06-17 | Mcneilab, Inc. | Drug-dispensing device and method |
US4113088A (en) | 1977-06-06 | 1978-09-12 | Binkhorst Richard D | Sterile package |
US4328803B1 (en) | 1980-10-20 | 1994-01-11 | Opthalmic Systems, Inc. | Opthalmological procedures |
DK90883A (en) | 1982-03-18 | 1983-09-19 | Merck & Co Inc | CONTAINER FOR OSMOTIC RELEASE OF A SUBSTANCE OR MIXTURE |
US4521210A (en) | 1982-12-27 | 1985-06-04 | Wong Vernon G | Eye implant for relieving glaucoma, and device and method for use therewith |
US4955881A (en) | 1985-08-16 | 1990-09-11 | Alza Corporation | Ruminant dispensing device |
US4883864A (en) | 1985-09-06 | 1989-11-28 | Minnesota Mining And Manufacturing Company | Modified collagen compound and method of preparation |
GB8603099D0 (en) | 1986-02-07 | 1986-03-12 | Blass K G | Gastrointestinal module |
US4743248A (en) | 1986-08-11 | 1988-05-10 | Alza Corporation | Dosage form for delivering acid sensitive beneficial agent |
US4863457A (en) | 1986-11-24 | 1989-09-05 | Lee David A | Drug delivery device |
US4736836A (en) | 1987-02-02 | 1988-04-12 | Alongi Salvatore A | Intraocular lens package |
US4846793A (en) | 1987-03-18 | 1989-07-11 | Endocon, Inc. | Injector for implanting multiple pellet medicaments |
US4997652A (en) | 1987-12-22 | 1991-03-05 | Visionex | Biodegradable ocular implants |
US4853224A (en) | 1987-12-22 | 1989-08-01 | Visionex | Biodegradable ocular implants |
CA1334168C (en) | 1988-04-26 | 1995-01-31 | Louis M. De Santis | Antiglaucoma compositions containing combinations of .alpha.-2 agonists and .beta. blockers |
US5202128A (en) | 1989-01-06 | 1993-04-13 | F. H. Faulding & Co. Limited | Sustained release pharmaceutical composition |
FR2644058B1 (en) | 1989-03-10 | 1994-06-03 | France Chirurgie Instr | MEATIC PLUG FOR LACRYMAL PATHOLOGY |
US5098443A (en) | 1989-03-23 | 1992-03-24 | University Of Miami | Method of implanting intraocular and intraorbital implantable devices for the controlled release of pharmacological agents |
US5164188A (en) | 1989-11-22 | 1992-11-17 | Visionex, Inc. | Biodegradable ocular implants |
US5324280A (en) | 1990-04-02 | 1994-06-28 | Alza Corporation | Osmotic dosage system for delivering a formulation comprising liquid carrier and drug |
US5017381A (en) * | 1990-05-02 | 1991-05-21 | Alza Corporation | Multi-unit pulsatile delivery system |
US5128145A (en) | 1990-06-13 | 1992-07-07 | Alza Corporation | Dosage form for Parkinson's disease, spasticity and muscle spasms |
US5378475A (en) | 1991-02-21 | 1995-01-03 | University Of Kentucky Research Foundation | Sustained release drug delivery devices |
US6007511A (en) | 1991-05-08 | 1999-12-28 | Prywes; Arnold S. | Shunt valve and therapeutic delivery system for treatment of glaucoma and methods and apparatus for its installation |
CA2071137A1 (en) | 1991-07-10 | 1993-01-11 | Clarence C. Lee | Composition and method for revitalizing scar tissue |
DK0601055T3 (en) | 1991-08-16 | 2000-10-02 | Joseph C Salamone | Drug coated refractory ocular anterior chamber implant |
US5464450A (en) | 1991-10-04 | 1995-11-07 | Scimed Lifesystems Inc. | Biodegradable drug delivery vascular stent |
US5318780A (en) | 1991-10-30 | 1994-06-07 | Mediventures Inc. | Medical uses of in situ formed gels |
IL100112A (en) | 1991-11-21 | 1996-01-31 | Yeda Res & Dev | Microdelivery device for enhanced drug administration to the eye |
US5384333A (en) | 1992-03-17 | 1995-01-24 | University Of Miami | Biodegradable injectable drug delivery polymer |
AU4282793A (en) | 1992-04-10 | 1993-11-18 | State Of Oregon Acting By And Through The Oregon State Board Of Higher Education On Behalf Of The Oregon Health Sciences University | A microneedle for injection of ocular blood vessels |
US5428123A (en) | 1992-04-24 | 1995-06-27 | The Polymer Technology Group | Copolymers and non-porous, semi-permeable membrane thereof and its use for permeating molecules of predetermined molecular weight range |
WO1993024121A1 (en) | 1992-05-22 | 1993-12-09 | Senju Pharmaceutical Co., Ltd. | Remedy for glaucoma |
US5629008A (en) | 1992-06-02 | 1997-05-13 | C.R. Bard, Inc. | Method and device for long-term delivery of drugs |
US5767079A (en) | 1992-07-08 | 1998-06-16 | Celtrix Pharmaceuticals, Inc. | Method of treating ophthalmic disorders using TGF -β |
WO1994002081A1 (en) | 1992-07-16 | 1994-02-03 | Wong Vernon G | Eye implant suitable for relief of glaucoma |
US5709854A (en) | 1993-04-30 | 1998-01-20 | Massachusetts Institute Of Technology | Tissue formation by injecting a cell-polymeric solution that gels in vivo |
DK0797988T3 (en) | 1993-07-19 | 2009-05-11 | Univ British Columbia | Anti-angiogenic compositions and methods for their use |
US20030203976A1 (en) | 1993-07-19 | 2003-10-30 | William L. Hunter | Anti-angiogenic compositions and methods of use |
US5731294A (en) | 1993-07-27 | 1998-03-24 | Hybridon, Inc. | Inhibition of neovasularization using VEGF-specific oligonucleotides |
US5443505A (en) | 1993-11-15 | 1995-08-22 | Oculex Pharmaceuticals, Inc. | Biocompatible ocular implants |
US5500465A (en) | 1994-03-10 | 1996-03-19 | Board Of Trustees Operating Michigan State University | Biodegradable multi-component polymeric materials based on unmodified starch-like polysaccharides |
US5516522A (en) | 1994-03-14 | 1996-05-14 | Board Of Supervisors Of Louisiana State University | Biodegradable porous device for long-term drug delivery with constant rate release and method of making the same |
US6551618B2 (en) | 1994-03-15 | 2003-04-22 | University Of Birmingham | Compositions and methods for delivery of agents for neuronal regeneration and survival |
GB9405304D0 (en) | 1994-03-16 | 1994-04-27 | Scherer Ltd R P | Delivery systems for hydrophobic drugs |
JPH09511507A (en) | 1994-04-04 | 1997-11-18 | フリーマン,ウイリアム・アール | Use of phosphonyl methoxyalkyl nucleosides to treat elevated intraocular pressure |
US5466233A (en) | 1994-04-25 | 1995-11-14 | Escalon Ophthalmics, Inc. | Tack for intraocular drug delivery and method for inserting and removing same |
AU2467395A (en) | 1994-05-04 | 1995-11-29 | Board Of Trustees Of The University Of Arkansas, The | Novel ophthalmologic uses of protein c |
US5599534A (en) | 1994-08-09 | 1997-02-04 | University Of Nebraska | Reversible gel-forming composition for sustained delivery of bio-affecting substances, and method of use |
US5665114A (en) | 1994-08-12 | 1997-09-09 | Meadox Medicals, Inc. | Tubular expanded polytetrafluoroethylene implantable prostheses |
SE9402816D0 (en) | 1994-08-24 | 1994-08-24 | Pharmacia Ab | Method and meams for drug administration |
GB9417399D0 (en) | 1994-08-30 | 1994-10-19 | Scherer Corp R P | Ocular treatment device |
CA2179304C (en) | 1994-10-17 | 2008-02-05 | Keiji Igaki | Stent for liberating drug |
US6063116A (en) | 1994-10-26 | 2000-05-16 | Medarex, Inc. | Modulation of cell proliferation and wound healing |
US6063396A (en) | 1994-10-26 | 2000-05-16 | Houston Biotechnology Incorporated | Methods and compositions for the modulation of cell proliferation and wound healing |
US5602143A (en) | 1994-12-08 | 1997-02-11 | Allergan | Method for reducing intraocular pressure in the mammalian eye by administration of guanylate cyclase inhibitors |
US6228873B1 (en) | 1994-12-09 | 2001-05-08 | The Regents Of The University Of California | Method for enhancing outflow of aqueous humor in treatment of glaucoma |
US5725493A (en) | 1994-12-12 | 1998-03-10 | Avery; Robert Logan | Intravitreal medicine delivery |
US5891084A (en) | 1994-12-27 | 1999-04-06 | Lee; Vincent W. | Multiple chamber catheter delivery system |
WO1996020742A1 (en) | 1995-01-06 | 1996-07-11 | Wong Vernon G | Improve eye implant for relief of glaucoma |
AU723047B2 (en) | 1995-02-10 | 2000-08-17 | University Of Toronto Innovations Foundation, The | Deprenyl compounds for treatment of glaucoma |
US6231600B1 (en) | 1995-02-22 | 2001-05-15 | Scimed Life Systems, Inc. | Stents with hybrid coating for medical devices |
US5869079A (en) | 1995-06-02 | 1999-02-09 | Oculex Pharmaceuticals, Inc. | Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents |
US6369116B1 (en) | 1995-06-02 | 2002-04-09 | Oculex Pharmaceuticals, Inc. | Composition and method for treating glaucoma |
US6129761A (en) | 1995-06-07 | 2000-10-10 | Reprogenesis, Inc. | Injectable hydrogel compositions |
US5773019A (en) | 1995-09-27 | 1998-06-30 | The University Of Kentucky Research Foundation | Implantable controlled release device to deliver drugs directly to an internal portion of the body |
US5547993A (en) | 1995-10-24 | 1996-08-20 | Mitsubishi Chemical Corporation | Therapeutic agent for glaucoma |
AU1201297A (en) | 1995-12-21 | 1997-07-17 | Pharmacia & Upjohn Ab | Ophthalmic treatment |
US5798380A (en) | 1996-02-21 | 1998-08-25 | Wisconsin Alumni Research Foundation | Cytoskeletal active agents for glaucoma therapy |
US6299895B1 (en) | 1997-03-24 | 2001-10-09 | Neurotech S.A. | Device and method for treating ophthalmic diseases |
US5670161A (en) | 1996-05-28 | 1997-09-23 | Healy; Kevin E. | Biodegradable stent |
US6120460A (en) | 1996-09-04 | 2000-09-19 | Abreu; Marcio Marc | Method and apparatus for signal acquisition, processing and transmission for evaluation of bodily functions |
US6544193B2 (en) | 1996-09-04 | 2003-04-08 | Marcio Marc Abreu | Noninvasive measurement of chemical substances |
AUPO251096A0 (en) | 1996-09-23 | 1996-10-17 | Cardiac Crc Nominees Pty Limited | Polysiloxane-containing polyurethane elastomeric compositions |
US5925342A (en) | 1996-11-13 | 1999-07-20 | Allergan | Method for reducing intraocular pressure in the mammalian eye by administration of potassium channel blockers |
US20020111603A1 (en) | 1996-12-02 | 2002-08-15 | Societe De Conseils De Recherches Et D'application | Device for local administration of solid or semi-solid formulations and delayed-release formulations for proposal parental administration and preparation process |
GB9700390D0 (en) | 1997-01-10 | 1997-02-26 | Biocompatibles Ltd | Device for use in the eye |
FR2759577B1 (en) | 1997-02-17 | 1999-08-06 | Corneal Ind | DEEP SCLERECTOMY IMPLANT |
US5893837A (en) | 1997-02-28 | 1999-04-13 | Staar Surgical Company, Inc. | Glaucoma drain implanting device and method |
US6059812A (en) | 1997-03-21 | 2000-05-09 | Schneider (Usa) Inc. | Self-expanding medical device for centering radioactive treatment sources in body vessels |
US5980928A (en) | 1997-07-29 | 1999-11-09 | Terry; Paul B. | Implant for preventing conjunctivitis in cattle |
US6306426B1 (en) | 1997-08-11 | 2001-10-23 | Allergan Sales, Inc. | Implant device with a retinoid for improved biocompatibility |
US5902598A (en) | 1997-08-28 | 1999-05-11 | Control Delivery Systems, Inc. | Sustained release drug delivery devices |
US6004302A (en) | 1997-08-28 | 1999-12-21 | Brierley; Lawrence A. | Cannula |
US6274138B1 (en) | 1997-09-03 | 2001-08-14 | Incyte Genomics, Inc. | Human mitochondrial malate dehydrogenase |
US7985415B2 (en) | 1997-09-10 | 2011-07-26 | Rutgers, The State University Of New Jersey | Medical devices employing novel polymers |
US20020164374A1 (en) | 1997-10-29 | 2002-11-07 | John Jackson | Polymeric systems for drug delivery and uses thereof |
US6159458A (en) | 1997-11-04 | 2000-12-12 | Insite Vision | Sustained release ophthalmic compositions containing water soluble medicaments |
US6203513B1 (en) | 1997-11-20 | 2001-03-20 | Optonol Ltd. | Flow regulating implant, method of manufacture, and delivery device |
US8313454B2 (en) | 1997-11-20 | 2012-11-20 | Optonol Ltd. | Fluid drainage device, delivery device, and associated methods of use and manufacture |
US6682500B2 (en) | 1998-01-29 | 2004-01-27 | David Soltanpour | Synthetic muscle based diaphragm pump apparatuses |
US6589198B1 (en) | 1998-01-29 | 2003-07-08 | David Soltanpour | Implantable micro-pump assembly |
US7780623B2 (en) | 1998-01-29 | 2010-08-24 | Soltanpour David P | Implantable pump apparatuses |
US6290684B1 (en) * | 1998-03-02 | 2001-09-18 | Herrick Family Limited Partnership | Punctum plug having a collapsible expanded section and distal tip extending substantially perpendicular thereto and method of inserting same |
US6196993B1 (en) * | 1998-04-20 | 2001-03-06 | Eyelab Group, Llc | Ophthalmic insert and method for sustained release of medication to the eye |
WO1999055321A1 (en) | 1998-04-24 | 1999-11-04 | Mitokor | Compounds and methods for treating mitochondria-associated diseases |
US5997498A (en) | 1998-05-07 | 1999-12-07 | Johns Hopkins University | Inline air humidifier, a system for humidifying air and methods related thereto |
TW586944B (en) | 1998-05-29 | 2004-05-11 | Sumitomo Pharma | Controlled release agent having a multi-layer structure |
US6231853B1 (en) | 1998-06-01 | 2001-05-15 | Incyte Pharmaceuticals, Inc. | Human glutathione peroxidase-6 |
US6503231B1 (en) | 1998-06-10 | 2003-01-07 | Georgia Tech Research Corporation | Microneedle device for transport of molecules across tissue |
US6378526B1 (en) | 1998-08-03 | 2002-04-30 | Insite Vision, Incorporated | Methods of ophthalmic administration |
KR100274842B1 (en) | 1998-10-01 | 2001-03-02 | 김효근 | Sustained-release Drug Release System of Retinoic Acid Using Microspheres |
US6454787B1 (en) | 1998-12-11 | 2002-09-24 | C. R. Bard, Inc. | Collagen hemostatic foam |
US6348042B1 (en) | 1999-02-02 | 2002-02-19 | W. Lee Warren, Jr. | Bioactive shunt |
US6248363B1 (en) | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
US6477410B1 (en) | 2000-05-31 | 2002-11-05 | Biophoretic Therapeutic Systems, Llc | Electrokinetic delivery of medicaments |
US6217895B1 (en) | 1999-03-22 | 2001-04-17 | Control Delivery Systems | Method for treating and/or preventing retinal diseases with sustained release corticosteroids |
AU767526B2 (en) | 1999-04-26 | 2003-11-13 | Gmp Vision Solutions, Inc. | Trabeculotomy device and method for treating glaucoma |
US20050119601A9 (en) | 1999-04-26 | 2005-06-02 | Lynch Mary G. | Shunt device and method for treating glaucoma |
US6558342B1 (en) | 1999-06-02 | 2003-05-06 | Optonol Ltd. | Flow control device, introducer and method of implanting |
US6306120B1 (en) | 1999-06-07 | 2001-10-23 | Ben Gee Tan | Applicator and method for delivery of mitomycin to eye tissues during glaucoma filtering surgery |
US20080277007A1 (en) | 1999-06-28 | 2008-11-13 | California Institute Of Technology | Microfabricated elastomeric valve and pump systems |
US8550119B2 (en) | 1999-06-28 | 2013-10-08 | California Institute Of Technology | Microfabricated elastomeric valve and pump systems |
US7601270B1 (en) | 1999-06-28 | 2009-10-13 | California Institute Of Technology | Microfabricated elastomeric valve and pump systems |
US6899137B2 (en) | 1999-06-28 | 2005-05-31 | California Institute Of Technology | Microfabricated elastomeric valve and pump systems |
AU6517900A (en) | 1999-08-03 | 2001-02-19 | Smith & Nephew, Inc. | Controlled release implantable devices |
EP1206254A1 (en) | 1999-08-06 | 2002-05-22 | The Board Of Regents, The University Of Texas System | Drug releasing biodegradable fiber implant |
US7033603B2 (en) | 1999-08-06 | 2006-04-25 | Board Of Regents The University Of Texas | Drug releasing biodegradable fiber for delivery of therapeutics |
ATE283013T1 (en) | 1999-10-21 | 2004-12-15 | Alcon Inc | MEDICATION DELIVERY DEVICE |
CA2383572C (en) | 1999-10-21 | 2007-12-11 | Alcon Universal Ltd. | Sub-tenon drug delivery |
US7943162B2 (en) | 1999-10-21 | 2011-05-17 | Alcon, Inc. | Drug delivery device |
US6416777B1 (en) | 1999-10-21 | 2002-07-09 | Alcon Universal Ltd. | Ophthalmic drug delivery device |
US6331313B1 (en) | 1999-10-22 | 2001-12-18 | Oculex Pharmaceticals, Inc. | Controlled-release biocompatible ocular drug delivery implant devices and methods |
US6436091B1 (en) | 1999-11-16 | 2002-08-20 | Microsolutions, Inc. | Methods and implantable devices and systems for long term delivery of a pharmaceutical agent |
ATE303757T1 (en) | 1999-12-10 | 2005-09-15 | Iscience Corp | TREATMENT OF EYE DISEASES |
NZ519632A (en) | 1999-12-16 | 2004-03-26 | Alza Corp | Dosage forms that include a barrier layer containing a material that allows the layer to remain intact during laser formation of the orifice(s) |
RU2262331C2 (en) | 2000-01-12 | 2005-10-20 | Бектон, Дикинсон Энд Компани | Shunt, implant, system and method for reducing intraocular pressure and method for producing corneal implants |
US20050119737A1 (en) | 2000-01-12 | 2005-06-02 | Bene Eric A. | Ocular implant and methods for making and using same |
US6660870B1 (en) | 2000-03-17 | 2003-12-09 | Alcon, Inc. | 2-acylaminobenzimidazole derivatives for treating glaucoma |
US20070031473A1 (en) | 2005-08-05 | 2007-02-08 | Peyman Gholam A | Drug delivery system and method |
US6998137B2 (en) | 2000-04-07 | 2006-02-14 | Macromed, Inc. | Proteins deposited onto sparingly soluble biocompatible particles for controlled protein release into a biological environment from a polymer matrix |
US7708711B2 (en) | 2000-04-14 | 2010-05-04 | Glaukos Corporation | Ocular implant with therapeutic agents and methods thereof |
US20040111050A1 (en) | 2000-04-14 | 2004-06-10 | Gregory Smedley | Implantable ocular pump to reduce intraocular pressure |
US20050277864A1 (en) | 2000-04-14 | 2005-12-15 | David Haffner | Injectable gel implant for glaucoma treatment |
US20050049578A1 (en) | 2000-04-14 | 2005-03-03 | Hosheng Tu | Implantable ocular pump to reduce intraocular pressure |
US20020143284A1 (en) | 2001-04-03 | 2002-10-03 | Hosheng Tu | Drug-releasing trabecular implant for glaucoma treatment |
US20030060752A1 (en) | 2000-04-14 | 2003-03-27 | Olav Bergheim | Glaucoma device and methods thereof |
US7867186B2 (en) | 2002-04-08 | 2011-01-11 | Glaukos Corporation | Devices and methods for treatment of ocular disorders |
US6638239B1 (en) | 2000-04-14 | 2003-10-28 | Glaukos Corporation | Apparatus and method for treating glaucoma |
US20040175410A1 (en) | 2000-04-26 | 2004-09-09 | Control Delivery Systems, Inc. | Sustained release device and method for ocular delivery of carbonic anhydrase inhibitors |
US20040115268A1 (en) | 2000-04-26 | 2004-06-17 | Control Delivery Systems, Inc. | Systemic delivery of antiviral agents |
US6375972B1 (en) | 2000-04-26 | 2002-04-23 | Control Delivery Systems, Inc. | Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof |
US20040208910A1 (en) | 2000-04-26 | 2004-10-21 | Control Delivery Systems, Inc. | Sustained release device and method for ocular delivery of adrenergic agents |
CA2408323C (en) | 2000-05-08 | 2012-06-12 | The University Of British Columbia | Drug delivery systems for photodynamic therapy |
AU2001263324A1 (en) | 2000-05-19 | 2001-12-03 | Michael S. Berlin | Laser delivery system and method of use for the eye |
WO2001097727A1 (en) | 2000-06-19 | 2001-12-27 | Glaukos Corporation | Stented trabecular shunt and methods thereof |
KR100355563B1 (en) | 2000-06-23 | 2002-10-11 | 주식회사 바이오메드랩 | Biodegradable porous polymer scaffolds by using effervescent mixture for tissue engineering and their preparation methods |
US6692759B1 (en) | 2000-06-28 | 2004-02-17 | The Regents Of The University Of California | Methods for preparing and using implantable substance delivery devices |
US6726918B1 (en) | 2000-07-05 | 2004-04-27 | Oculex Pharmaceuticals, Inc. | Methods for treating inflammation-mediated conditions of the eye |
EP3167872B1 (en) | 2000-07-05 | 2020-10-14 | Allergan, Inc. | Methods for treating inflammation-mediated conditions of the eye |
US6629992B2 (en) | 2000-08-04 | 2003-10-07 | Advanced Cardiovascular Systems, Inc. | Sheath for self-expanding stent |
AU2001281304B2 (en) | 2000-08-15 | 2006-05-25 | Surmodics, Inc. | Medicament incorporation matrix |
US6730056B1 (en) | 2000-09-21 | 2004-05-04 | Motorola, Inc. | Eye implant for treating glaucoma and method for manufacturing same |
AU2001261262A1 (en) | 2000-11-01 | 2002-05-15 | Glaukos Corporation | Glaucoma treatment device |
ES2250504T3 (en) | 2000-11-29 | 2006-04-16 | Allergan Inc. | PREVENTION OF REJECTION OF GRAFT IN THE EYE. |
EP1621219A3 (en) | 2000-11-29 | 2006-03-22 | Allergan, Inc. | Intraocular implants for preventing transplant rejection in the eye |
US7077859B2 (en) | 2000-12-22 | 2006-07-18 | Avantec Vascular Corporation | Apparatus and methods for variably controlled substance delivery from implanted prostheses |
WO2002056863A2 (en) | 2000-12-29 | 2002-07-25 | Bausch & Lomb Incorporated | Sustained release drug delivery devices |
WO2002053129A1 (en) | 2001-01-03 | 2002-07-11 | Bausch & Lomb Incorporated | Sustained release drug delivery devices with prefabricated permeable plugs |
DE60130928T2 (en) | 2001-01-03 | 2008-07-17 | Bausch & Lomb Inc. | DEVICE FOR DELAYED ACTIVE INGREDIENT RELIEF WITH COATED MEDICATION CORE |
US6756058B2 (en) | 2001-01-03 | 2004-06-29 | Bausch & Lomb Incorporated | Sustained release drug delivery devices with multiple agents |
JP4657577B2 (en) | 2001-01-09 | 2011-03-23 | マイクロチップス・インコーポレーテッド | Flexible microchip device for ocular and other applications |
JP2004520900A (en) | 2001-01-26 | 2004-07-15 | ボシュ・アンド・ロム・インコーポレイテッド | Improved manufacturing method of sustained release drug delivery device |
US6758837B2 (en) | 2001-02-08 | 2004-07-06 | Pharmacia Ab | Liquid delivery device and method of use thereof |
US6571125B2 (en) | 2001-02-12 | 2003-05-27 | Medtronic, Inc. | Drug delivery device |
US8060211B2 (en) | 2001-02-13 | 2011-11-15 | Second Sight Medical Products, Inc. | Method of reducing retinal stress caused by an implantable retinal electrode array |
US7181287B2 (en) | 2001-02-13 | 2007-02-20 | Second Sight Medical Products, Inc. | Implantable drug delivery device |
US6989007B2 (en) | 2001-02-21 | 2006-01-24 | Solx, Inc. | Devices and techniques for treating glaucoma |
US20040018238A1 (en) | 2001-02-26 | 2004-01-29 | Shukla Atul J | Biodegradable vehicles and delivery systems of biolgically active substances |
US20050278014A9 (en) | 2001-03-07 | 2005-12-15 | Wolfgang Daum | Stent and method for drug delivery from stents |
US6713081B2 (en) | 2001-03-15 | 2004-03-30 | The United States Of America As Represented By The Department Of Health And Human Services | Ocular therapeutic agent delivery devices and methods for making and using such devices |
US20020133168A1 (en) | 2001-03-16 | 2002-09-19 | Smedley Gregory T. | Applicator and methods for placing a trabecular shunt for glaucoma treatment |
US7431710B2 (en) | 2002-04-08 | 2008-10-07 | Glaukos Corporation | Ocular implants with anchors and methods thereof |
US7488303B1 (en) | 2002-09-21 | 2009-02-10 | Glaukos Corporation | Ocular implant with anchor and multiple openings |
US6666841B2 (en) | 2001-05-02 | 2003-12-23 | Glaukos Corporation | Bifurcatable trabecular shunt for glaucoma treatment |
EP1418868B1 (en) | 2001-04-07 | 2008-03-26 | Glaukos Corporation | Glaucoma stent for glaucoma treatment |
US6981958B1 (en) | 2001-05-02 | 2006-01-03 | Glaukos Corporation | Implant with pressure sensor for glaucoma treatment |
US20040022853A1 (en) | 2001-04-26 | 2004-02-05 | Control Delivery Systems, Inc. | Polymer-based, sustained release drug delivery system |
US7678065B2 (en) | 2001-05-02 | 2010-03-16 | Glaukos Corporation | Implant with intraocular pressure sensor for glaucoma treatment |
US6533769B2 (en) | 2001-05-03 | 2003-03-18 | Holmen Joergen | Method for use in cataract surgery |
AU2002305400A1 (en) | 2001-05-03 | 2002-11-18 | Glaukos Corporation | Medical device and methods of use for glaucoma treatment |
JP2004536631A (en) | 2001-05-03 | 2004-12-09 | マサチューセッツ・アイ・アンド・イア・インファーマリー | Implantable drug delivery device and use thereof |
US20020176844A1 (en) | 2001-05-11 | 2002-11-28 | Ng Steven Y. | Bioerodible polyorthoesters containing hydrogen bonding groups |
EP1404297B1 (en) | 2001-06-12 | 2011-04-27 | The Johns Hopkins University School Of Medicine | Reservoir device for intraocular drug delivery |
US20030010638A1 (en) | 2001-06-15 | 2003-01-16 | Hansford Derek J. | Nanopump devices and methods |
US7592016B2 (en) | 2001-06-28 | 2009-09-22 | Regents Of The University Of California | Methods for preparing and using implantable substance delivery devices |
AU2002319606B2 (en) | 2001-07-23 | 2006-09-14 | Alcon, Inc. | Ophthalmic drug delivery device |
EP1409065B1 (en) | 2001-07-23 | 2007-01-17 | Alcon, Inc. | Ophthalmic drug delivery device |
US7331984B2 (en) | 2001-08-28 | 2008-02-19 | Glaukos Corporation | Glaucoma stent for treating glaucoma and methods of use |
US7749528B2 (en) | 2001-08-29 | 2010-07-06 | Ricardo Azevedo Pontes De Carvalho | Implantable and sealable medical device for unidirectional delivery of therapeutic agents to tissues |
RU2311892C2 (en) | 2001-08-29 | 2007-12-10 | КАРВАЛХО Рикардо А. П. ДЕ | Implantable sealable system for one-way delivery of therapeutic preparations to tissues |
IN2014DN10834A (en) | 2001-09-17 | 2015-09-04 | Psivida Inc | |
US20030060873A1 (en) | 2001-09-19 | 2003-03-27 | Nanomedical Technologies, Inc. | Metallic structures incorporating bioactive materials and methods for creating the same |
WO2003026733A2 (en) | 2001-09-28 | 2003-04-03 | Biovalve Technologies, Inc. | Microneedle with membrane |
FR2830766B1 (en) | 2001-10-12 | 2004-03-12 | Optis France Sa | DEVICE OF ISSUE OF DRUGS THROUGH IONTOPHORESIS TRANSPALPEBRALE |
US20030097151A1 (en) | 2001-10-25 | 2003-05-22 | Smedley Gregory T. | Apparatus and mitochondrial treatment for glaucoma |
US8425892B2 (en) | 2001-10-29 | 2013-04-23 | Columbia Laboratories, Inc. | Extended, controlled-release pharmaceutical compositions using charged polymers |
US20030119000A1 (en) | 2001-11-05 | 2003-06-26 | Jon Polansky | Methods to screen and treat individuals with glaucoma or the propensity to develop glaucoma |
US20080039769A1 (en) | 2001-11-07 | 2008-02-14 | Minu Llc | Method of medical treatment using controlled heat delivery |
US7163543B2 (en) | 2001-11-08 | 2007-01-16 | Glaukos Corporation | Combined treatment for cataract and glaucoma treatment |
US6802829B2 (en) | 2001-11-16 | 2004-10-12 | Infinite Vision, Llc | Spray device |
JP4217624B2 (en) | 2001-11-22 | 2009-02-04 | アントン ヘフリガー,エーデュアルト | Apparatus and method for performing ophthalmic surgery |
US7348055B2 (en) | 2001-12-21 | 2008-03-25 | Surmodics, Inc. | Reagent and method for providing coatings on surfaces |
US20060034929A1 (en) | 2001-12-27 | 2006-02-16 | Brubaker Michael J | Sustained release drug delivery devices with prefabricated permeable plugs |
CA2473355C (en) | 2002-01-18 | 2012-01-03 | Michael E. Snyder | Sustained release ophthalmological device and method of making and using the same |
JP2003210513A (en) | 2002-01-23 | 2003-07-29 | Nidek Co Ltd | Ophthalmic treatment equipment |
US6939298B2 (en) | 2002-02-28 | 2005-09-06 | Gmp Vision Solutions, Inc | Device and method for monitoring aqueous flow within the eye |
WO2003074735A1 (en) | 2002-03-01 | 2003-09-12 | Flammer, Josef | Diagnostic method for glaucoma |
US20060200113A1 (en) | 2002-03-07 | 2006-09-07 | David Haffner | Liquid jet for glaucoma treatment |
US7186232B1 (en) | 2002-03-07 | 2007-03-06 | Glaukoa Corporation | Fluid infusion methods for glaucoma treatment |
US20060100408A1 (en) | 2002-03-11 | 2006-05-11 | Powell P M | Method for forming contact lenses comprising therapeutic agents |
MXPA04008903A (en) | 2002-03-11 | 2004-11-26 | Alcon Inc | Implantable drug delivery system. |
TW200304385A (en) | 2002-03-13 | 2003-10-01 | Novartis Ag | Materials containing multiple layers of vesicles |
US7951155B2 (en) | 2002-03-15 | 2011-05-31 | Glaukos Corporation | Combined treatment for cataract and glaucoma treatment |
US20030229303A1 (en) | 2002-03-22 | 2003-12-11 | Haffner David S. | Expandable glaucoma implant and methods of use |
JP4026745B2 (en) | 2002-03-26 | 2007-12-26 | 財団法人大阪産業振興機構 | Medical system and manufacturing method thereof |
US9301875B2 (en) | 2002-04-08 | 2016-04-05 | Glaukos Corporation | Ocular disorder treatment implants with multiple opening |
US20040147870A1 (en) | 2002-04-08 | 2004-07-29 | Burns Thomas W. | Glaucoma treatment kit |
US20030195438A1 (en) | 2002-04-12 | 2003-10-16 | Petillo Phillip J. | Method and apparatus to treat glaucoma |
US20040024345A1 (en) | 2002-04-19 | 2004-02-05 | Morteza Gharib | Glaucoma implant with valveless flow bias |
AU2003217531A1 (en) | 2002-05-02 | 2003-11-17 | Massachusetts Eye And Ear Infirmary | Ocular drug delivery systems and use thereof |
US8871241B2 (en) | 2002-05-07 | 2014-10-28 | Psivida Us, Inc. | Injectable sustained release delivery devices |
WO2003103549A1 (en) | 2002-06-05 | 2003-12-18 | University Of Florida | Ophthalmic drug delivery system |
US8273366B2 (en) | 2002-06-05 | 2012-09-25 | University Of Florida Research Foundation, Incorporated | Ophthalmic drug delivery system |
US6945952B2 (en) | 2002-06-25 | 2005-09-20 | Theraject, Inc. | Solid solution perforator for drug delivery and other applications |
CN100355455C (en) | 2002-07-15 | 2007-12-19 | 爱尔康公司 | Non-polymeric lipophilic pharmaceutical implant compositions for intraocular use |
US20040013702A1 (en) | 2002-07-16 | 2004-01-22 | Glover Eugene G. | Implantable devices for the controlled release of cytotoxic agents |
CN100591372C (en) | 2002-07-19 | 2010-02-24 | 耶鲁大学 | Uveoscleral drainage device |
ATE419027T1 (en) | 2002-08-08 | 2009-01-15 | Glaukos Corp | IMPLANTABLE EYE PUMP TO REDUCE INTRA EYE PRESSURE |
US7192412B1 (en) | 2002-09-14 | 2007-03-20 | Glaukos Corporation | Targeted stent placement and multi-stent therapy |
EP1539066B1 (en) | 2002-09-17 | 2012-11-07 | Iscience Surgical Corporation | Apparatus surgical bypass of aqueous humor |
US20050261641A1 (en) | 2002-09-26 | 2005-11-24 | Warchol Mark P | Method for ophthalmic administration of medicament |
US7615010B1 (en) | 2002-10-03 | 2009-11-10 | Integrated Sensing Systems, Inc. | System for monitoring the physiologic parameters of patients with congestive heart failure |
US20040154946A1 (en) | 2002-11-06 | 2004-08-12 | Kenneth Solovay | Storage apparatus for surgical implant device |
WO2004043435A2 (en) | 2002-11-13 | 2004-05-27 | Control Delivery Systems, Inc. | Systemic delivery of antiviral agents |
CN101336887A (en) | 2002-12-04 | 2009-01-07 | 参天制药株式会社 | Drug delivery system using subconjunctival depot |
US7531191B2 (en) | 2002-12-17 | 2009-05-12 | Massachusetts Institute Of Technology | Stimuli-responsive systems for controlled drug delivery |
US20050048099A1 (en) | 2003-01-09 | 2005-03-03 | Allergan, Inc. | Ocular implant made by a double extrusion process |
US20040137059A1 (en) | 2003-01-09 | 2004-07-15 | Thierry Nivaggioli | Biodegradable ocular implant |
US20040216749A1 (en) | 2003-01-23 | 2004-11-04 | Hosheng Tu | Vasomodulation during glaucoma surgery |
ES2338420T3 (en) | 2003-01-24 | 2010-05-07 | Psivida Us Inc. | DEVICE AND PROCEDURE FOR SUSTAINED RELEASE FOR THE OCULAR ADMINISTRATION OF INHIBITORS OF CARBONIC ANHYDRATION. |
US7794437B2 (en) | 2003-01-24 | 2010-09-14 | Doheny Retina Institute | Reservoirs with subretinal cannula for subretinal drug delivery |
US6969514B2 (en) | 2003-02-05 | 2005-11-29 | Soll David B | Method for treating elevated intraocular pressure, including glaucoma |
US8012115B2 (en) | 2003-02-18 | 2011-09-06 | S.K. Pharmaceuticals, Inc. | Optic nerve implants |
WO2004073551A2 (en) | 2003-02-18 | 2004-09-02 | Massachusetts Eye And Ear Infirmary | Transscleral drug delivery device and related methods |
MXPA05008675A (en) | 2003-02-18 | 2006-03-02 | Hampar Karageozian | Methods and devices for draining fluids and lowering intraocular pressure. |
US20040163652A1 (en) | 2003-02-25 | 2004-08-26 | Colin Watson | Condom with restriction band |
USD490152S1 (en) | 2003-02-28 | 2004-05-18 | Glaukos Corporation | Surgical handpiece |
WO2005105197A2 (en) | 2003-02-28 | 2005-11-10 | Gmp Vision Solutions, Inc. | Indwelling shunt device and methods for treating glaucoma |
US7483750B2 (en) | 2003-03-21 | 2009-01-27 | Second Sight Medical Products, Inc. | Transretinal implant and method of implantation |
US9216106B2 (en) | 2003-04-09 | 2015-12-22 | Directcontact Llc | Device and method for the delivery of drugs for the treatment of posterior segment disease |
US20050208102A1 (en) | 2003-04-09 | 2005-09-22 | Schultz Clyde L | Hydrogels used to deliver medicaments to the eye for the treatment of posterior segment diseases |
US8404269B2 (en) | 2003-04-11 | 2013-03-26 | Michael Snyder | Sustained release implantable eye device |
CA2524271C (en) | 2003-05-02 | 2012-09-04 | Surmodics, Inc. | Controlled release bioactive agent delivery device |
US8545463B2 (en) | 2003-05-20 | 2013-10-01 | Optimyst Systems Inc. | Ophthalmic fluid reservoir assembly for use with an ophthalmic fluid delivery device |
ZA200508654B (en) | 2003-07-10 | 2007-01-31 | Alcon Inc | Ophthalmic drug delivery device |
US7083802B2 (en) | 2003-07-31 | 2006-08-01 | Advanced Ocular Systems Limited | Treatment of ocular disease |
JP4869930B2 (en) | 2003-08-26 | 2012-02-08 | ヴィスタ サイエンティフィック エルエルシー | Ophthalmic drug supply device |
ES2388138T3 (en) | 2003-08-27 | 2012-10-09 | Ophthotech Corporation | Combination therapy for the treatment of ocular neovascular disorders |
US20050055075A1 (en) | 2003-09-08 | 2005-03-10 | Leonard Pinchuk | Methods for the manufacture of porous prostheses |
AU2004274026A1 (en) | 2003-09-18 | 2005-03-31 | Macusight, Inc. | Transscleral delivery |
US20050181018A1 (en) | 2003-09-19 | 2005-08-18 | Peyman Gholam A. | Ocular drug delivery |
WO2005044236A1 (en) | 2003-10-27 | 2005-05-19 | Control Delivery Systems, Inc. | Suspension delivery system for the sustained and controlled local release of pharmaceuticals |
WO2005048875A2 (en) | 2003-11-14 | 2005-06-02 | Medical Instill Technologies, Inc. | Delivery device and method of delivery |
CA2536188A1 (en) | 2003-11-20 | 2005-06-09 | Angiotech International Ag | Electrical devices and anti-scarring agents |
US20110112352A1 (en) | 2003-12-05 | 2011-05-12 | Pilla Arthur A | Apparatus and method for electromagnetic treatment |
US20050137538A1 (en) | 2003-12-22 | 2005-06-23 | Bausch & Lomb Incorporated | Drug delivery device |
US7976520B2 (en) | 2004-01-12 | 2011-07-12 | Nulens Ltd. | Eye wall anchored fixtures |
KR20060130648A (en) | 2004-01-12 | 2006-12-19 | 아이싸이언스 인터벤셔날 코포레이션 | Injector for viscous materials |
US9933079B2 (en) | 2004-01-29 | 2018-04-03 | Angiodynamics, Inc. | Stacked membrane for pressure actuated valve |
US20050250788A1 (en) | 2004-01-30 | 2005-11-10 | Hosheng Tu | Aqueous outflow enhancement with vasodilated aqueous cavity |
US20060004422A1 (en) | 2004-03-11 | 2006-01-05 | Dirk De Ridder | Electrical stimulation system and method for stimulating tissue in the brain to treat a neurological condition |
US7513893B2 (en) | 2004-03-12 | 2009-04-07 | Abraham Ebbie Soroudi | Device and method for treatment of eyelid diseases |
WO2005092260A1 (en) | 2004-03-26 | 2005-10-06 | Molteno Ophthalmic Ltd | Ophthalmic implant for treating glaucoma |
US7654985B2 (en) | 2004-03-30 | 2010-02-02 | Given Imaging Ltd. | Controlled detachment of intra-luminal medical device |
US20060083772A1 (en) | 2004-04-06 | 2006-04-20 | Dewitt David M | Coating compositions for bioactive agents |
US20050232972A1 (en) | 2004-04-15 | 2005-10-20 | Steven Odrich | Drug delivery via punctal plug |
US20100173866A1 (en) | 2004-04-29 | 2010-07-08 | Iscience Interventional Corporation | Apparatus and method for ocular treatment |
US20080058704A1 (en) | 2004-04-29 | 2008-03-06 | Michael Hee | Apparatus and Method for Ocular Treatment |
CA2564806A1 (en) | 2004-04-29 | 2005-11-17 | Iscience Surgical Corporation | Apparatus and method for surgical enhancement of aqueous humor drainage |
US8722097B2 (en) | 2004-04-30 | 2014-05-13 | Allergan, Inc. | Oil-in-water method for making polymeric implants containing a hypotensive lipid |
AU2005240078A1 (en) | 2004-04-30 | 2005-11-17 | Allergan, Inc. | Retinoid-containing sustained release intraocular drug delivery systems and related methods of manufacturing |
US8685435B2 (en) | 2004-04-30 | 2014-04-01 | Allergan, Inc. | Extended release biodegradable ocular implants |
US20050244472A1 (en) | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Intraocular drug delivery systems containing excipients with reduced toxicity and related methods |
US8147865B2 (en) | 2004-04-30 | 2012-04-03 | Allergan, Inc. | Steroid-containing sustained release intraocular implants and related methods |
US8455656B2 (en) | 2004-04-30 | 2013-06-04 | Allergan, Inc. | Kinase inhibitors |
US8425929B2 (en) | 2004-04-30 | 2013-04-23 | Allergan, Inc. | Sustained release intraocular implants and methods for preventing retinal dysfunction |
US7799336B2 (en) | 2004-04-30 | 2010-09-21 | Allergan, Inc. | Hypotensive lipid-containing biodegradable intraocular implants and related methods |
US20070059336A1 (en) | 2004-04-30 | 2007-03-15 | Allergan, Inc. | Anti-angiogenic sustained release intraocular implants and related methods |
US20050244500A1 (en) | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Intravitreal implants in conjuction with photodynamic therapy to improve vision |
US20050244458A1 (en) | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Sustained release intraocular implants and methods for treating ocular neuropathies |
US8673341B2 (en) | 2004-04-30 | 2014-03-18 | Allergan, Inc. | Intraocular pressure reduction with intracameral bimatoprost implants |
US20050244465A1 (en) | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Drug delivery systems and methods for treatment of an eye |
US8119154B2 (en) | 2004-04-30 | 2012-02-21 | Allergan, Inc. | Sustained release intraocular implants and related methods |
BRPI0510485A (en) | 2004-04-30 | 2007-11-13 | Allergan Inc | biodegradable intravitreal tyrosine kinase inhibitor implants |
US20070212395A1 (en) | 2006-03-08 | 2007-09-13 | Allergan, Inc. | Ocular therapy using sirtuin-activating agents |
KR20080018980A (en) | 2004-04-30 | 2008-02-29 | 아이게이트 파르마 에스아에스 | Irritation-reducing ocular ionthophoretic device |
US20050244461A1 (en) | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Controlled release drug delivery systems and methods for treatment of an eye |
US20050244469A1 (en) | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Extended therapeutic effect ocular implant treatments |
US7771742B2 (en) | 2004-04-30 | 2010-08-10 | Allergan, Inc. | Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods |
US8128954B2 (en) | 2004-06-07 | 2012-03-06 | California Institute Of Technology | Biodegradable drug-polymer delivery system |
EP1604697A1 (en) | 2004-06-09 | 2005-12-14 | J.A.C.C. GmbH | Implantable device |
US20060024350A1 (en) | 2004-06-24 | 2006-02-02 | Varner Signe E | Biodegradable ocular devices, methods and systems |
US20060110428A1 (en) | 2004-07-02 | 2006-05-25 | Eugene Dejuan | Methods and devices for the treatment of ocular conditions |
AU2005269988B2 (en) | 2004-07-02 | 2012-02-02 | Mati Therapeutics Inc. | Treatment medium delivery device and methods for delivery |
JP2008505978A (en) | 2004-07-12 | 2008-02-28 | アラーガン、インコーポレイテッド | Ophthalmic composition and eye disease treatment method |
US7117870B2 (en) * | 2004-07-26 | 2006-10-10 | Clarity Corporation | Lacrimal insert having reservoir with controlled release of medication and method of manufacturing the same |
US20060020253A1 (en) * | 2004-07-26 | 2006-01-26 | Prescott Anthony D | Implantable device having reservoir with controlled release of medication and method of manufacturing the same |
US20060021623A1 (en) | 2004-07-30 | 2006-02-02 | Miller Joan W | Methods and compositions for treating ocular glaucoma |
US20060032507A1 (en) | 2004-08-11 | 2006-02-16 | Hosheng Tu | Contrast-enhanced ocular imaging |
US7402156B2 (en) | 2004-09-01 | 2008-07-22 | Alcon, Inc. | Counter pressure device for ophthalmic drug delivery |
US20060084952A1 (en) | 2004-09-03 | 2006-04-20 | Pallikaris Ioannis G | Device for the irradiation of the ciliary body of the eye |
WO2006031532A2 (en) | 2004-09-10 | 2006-03-23 | Surmodics, Inc. | Methods, devices, and coatings for controlled active agent release |
US20080020018A1 (en) | 2004-09-27 | 2008-01-24 | Joey Moodley | Combination Products |
US20060067978A1 (en) | 2004-09-29 | 2006-03-30 | Bausch & Lomb Incorporated | Process for preparing poly(vinyl alcohol) drug delivery devices |
US20080038316A1 (en) | 2004-10-01 | 2008-02-14 | Wong Vernon G | Conveniently implantable sustained release drug compositions |
CA2582374A1 (en) | 2004-10-04 | 2006-04-20 | Qlt Usa, Inc. | Ocular delivery of polymeric delivery formulations |
GB0422525D0 (en) | 2004-10-11 | 2004-11-10 | Luebcke Peter | Dermatological compositions and methods |
US7226435B2 (en) | 2004-10-14 | 2007-06-05 | Alcon, Inc. | Drug delivery device |
US8246949B2 (en) | 2004-10-27 | 2012-08-21 | Aciont, Inc. | Methods and devices for sustained in-vivo release of an active agent |
US7958840B2 (en) | 2004-10-27 | 2011-06-14 | Surmodics, Inc. | Method and apparatus for coating of substrates |
US20080095822A1 (en) | 2004-11-16 | 2008-04-24 | Universite De Liege | Active Substance Delivery System Comprising A Hydrogel Atrix And Microcarriers |
US20060173397A1 (en) | 2004-11-23 | 2006-08-03 | Hosheng Tu | Ophthalmology implants and methods of manufacture |
CN100553588C (en) | 2004-11-23 | 2009-10-28 | 小爱德华·K·王 | Control eye and the medical treatment device that encloses tissue temperature near the eyes and treat ophthalmic |
WO2006057859A1 (en) | 2004-11-24 | 2006-06-01 | Therakine Corporation | An implant for intraocular drug delivery |
US7837644B2 (en) | 2004-12-03 | 2010-11-23 | Innfocus, Llc | Glaucoma implant device |
US20070118065A1 (en) | 2004-12-03 | 2007-05-24 | Leonard Pinchuk | Glaucoma Implant Device |
WO2006068898A1 (en) | 2004-12-22 | 2006-06-29 | Bausch & Lomb Incorporated | Reusable drug delivery device |
KR20070101865A (en) | 2004-12-22 | 2007-10-17 | 알콘, 인코퍼레이티드 | Device for ophthalmic drug delivery |
JP2008529606A (en) | 2005-02-04 | 2008-08-07 | オーバーン ユニバーシティ | Contact drug delivery system |
US8663639B2 (en) | 2005-02-09 | 2014-03-04 | Santen Pharmaceutical Co., Ltd. | Formulations for treating ocular diseases and conditions |
KR101387456B1 (en) | 2005-02-09 | 2014-04-21 | 산텐 세이야꾸 가부시키가이샤 | Liquid formulations for treatment of diseases or conditions |
KR20070121754A (en) | 2005-03-21 | 2007-12-27 | 마커사이트, 인코포레이티드 | Drug delivery systems for treatment of diseases or conditions |
WO2006110487A1 (en) | 2005-04-08 | 2006-10-19 | Surmodics, Inc. | Sustained release implants for subretinal delivery |
US8039445B2 (en) | 2005-04-18 | 2011-10-18 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods and devices for delivering a therapeutic product to the ocular sphere of a subject |
US7931909B2 (en) | 2005-05-10 | 2011-04-26 | Allergan, Inc. | Ocular therapy using alpha-2 adrenergic receptor compounds having enhanced anterior clearance rates |
US20060258994A1 (en) | 2005-05-12 | 2006-11-16 | Avery Robert L | Implantable delivery device for administering pharmacological agents to an internal portion of a body |
US20060276738A1 (en) * | 2005-06-06 | 2006-12-07 | Becker Bruce B | Lacrimal drainage bypass device and method |
US20060292222A1 (en) | 2005-06-21 | 2006-12-28 | Matthew Jonasse | Drug delivery device having zero or near zero-order release kinetics |
US20070021653A1 (en) | 2005-06-27 | 2007-01-25 | Lars-Olof Hattenbach | Device for the injection of drugs into microvessels |
AU2006270221B2 (en) | 2005-07-15 | 2012-01-19 | Micell Technologies, Inc. | Polymer coatings containing drug powder of controlled morphology |
US20100068141A1 (en) | 2005-07-27 | 2010-03-18 | University Of Florida | Use of heat shock to treat ocular disease |
US8663673B2 (en) | 2005-07-29 | 2014-03-04 | Surmodics, Inc. | Devices, articles, coatings, and methods for controlled active agent release or hemocompatibility |
US20070038174A1 (en) | 2005-08-09 | 2007-02-15 | Hopkins Mark A | Ophthalmic injector system |
US7261529B2 (en) | 2005-09-07 | 2007-08-28 | Southwest Research Institute | Apparatus for preparing biodegradable microparticle formulations containing pharmaceutically active agents |
US20070212397A1 (en) | 2005-09-15 | 2007-09-13 | Roth Daniel B | Pharmaceutical delivery device and method for providing ocular treatment |
DE602006005826D1 (en) | 2005-09-21 | 2009-04-30 | Univ Aston | CHRONOTHERAPEUTIC OKULAR DELIVERY SYSTEM FROM A COMBINATION OF PROSTAGELINES AND A BETABOLE LOCK FOR THE TREATMENT OF PRIMARY GLAUCOMA |
CN101309709A (en) | 2005-09-21 | 2008-11-19 | 苏尔莫迪克斯公司 | Coatings and articles including natural biodegradable polysaccharides |
US20080167600A1 (en) | 2005-09-26 | 2008-07-10 | Peyman Gholam A | Device for delivery of an agent to the eye and other sites |
US20070197957A1 (en) | 2005-10-03 | 2007-08-23 | Hunter William L | Implantable sensors, implantable pumps and anti-scarring drug combinations |
US8168584B2 (en) | 2005-10-08 | 2012-05-01 | Potentia Pharmaceuticals, Inc. | Methods of treating age-related macular degeneration by compstatin and analogs thereof |
KR101430760B1 (en) | 2005-10-18 | 2014-08-19 | 알러간, 인코포레이티드 | Ocular therapy using glucocorticoid derivatives selectively penetrating posterior segment tissues |
US20090082321A1 (en) | 2007-09-21 | 2009-03-26 | Allergan, Inc. | Steroid containing drug delivery systems |
TW200733993A (en) | 2005-11-03 | 2007-09-16 | Reseal Internat Ltd Partnership | Continuously sealing one way valve assembly and fluid delivery system and formulations for use therein |
US8099162B2 (en) | 2005-11-29 | 2012-01-17 | Eyegate Pharma, S.A.S. | Ocular iontophoresis device |
US20080177220A1 (en) | 2006-01-06 | 2008-07-24 | The Curators Of The University Of Missouri | Ultrasound-Mediated Transcleral Drug Delivery |
AU2007204617A1 (en) | 2006-01-12 | 2007-07-19 | Massachusetts Institute Of Technology | Biodegradable elastomers |
EP3632385A1 (en) | 2006-01-17 | 2020-04-08 | Novartis AG | Glaucoma treatment device |
US9084662B2 (en) | 2006-01-17 | 2015-07-21 | Transcend Medical, Inc. | Drug delivery treatment device |
US20070202186A1 (en) | 2006-02-22 | 2007-08-30 | Iscience Interventional Corporation | Apparatus and formulations for suprachoroidal drug delivery |
EP1998829B1 (en) | 2006-03-14 | 2011-02-09 | University Of Southern California | Mems device for delivery of therapeutic agents |
KR20110038144A (en) | 2006-03-31 | 2011-04-13 | 큐엘티 플러그 딜리버리, 인코포레이티드 | Drug delivery methods, structures, and compositions for nasolacrimal system |
WO2007127305A2 (en) | 2006-04-26 | 2007-11-08 | Eastern Virginia Medical School | Systems and methods for monitoring and controlling internal pressure of an eye or body part |
US20070293807A1 (en) | 2006-05-01 | 2007-12-20 | Lynch Mary G | Dual drainage pathway shunt device and method for treating glaucoma |
US8197435B2 (en) | 2006-05-02 | 2012-06-12 | Emory University | Methods and devices for drug delivery to ocular tissue using microneedle |
JP4829345B2 (en) | 2006-05-04 | 2011-12-07 | カフマン、ハーバート | Methods, devices, and systems for administering therapeutic agents to the eye |
US20070260203A1 (en) | 2006-05-04 | 2007-11-08 | Allergan, Inc. | Vasoactive agent intraocular implant |
US20070270750A1 (en) | 2006-05-17 | 2007-11-22 | Alcon, Inc. | Drug delivery device |
US20070270768A1 (en) | 2006-05-17 | 2007-11-22 | Bruno Dacquay | Mechanical Linkage Mechanism For Ophthalmic Injection Device |
US7674243B2 (en) | 2006-05-17 | 2010-03-09 | Alcon Inc. | Ophthalmic injection device using piezoelectric array |
US7815603B2 (en) | 2006-05-17 | 2010-10-19 | Alcon Research, Ltd. | Ophthalmic injection method |
US7811252B2 (en) | 2006-05-17 | 2010-10-12 | Alcon Research, Ltd. | Dosage control device |
US20070268340A1 (en) | 2006-05-17 | 2007-11-22 | Bruno Dacquay | Ophthalmic Injection System and Method Using Piezoelectric Array |
US7887521B2 (en) | 2006-05-17 | 2011-02-15 | Alcon Research, Ltd. | Ophthalmic injection system |
US7862540B2 (en) | 2006-05-17 | 2011-01-04 | Alcon Research, Ltd. | Ophthalmic injection device using shape memory alloy |
WO2007146342A2 (en) | 2006-06-12 | 2007-12-21 | Ivivi Technologies, Inc. | Electromagnetism for prophylaxis and opthalmic tissue repair |
US20070293873A1 (en) | 2006-06-19 | 2007-12-20 | Allergan, Inc. | Apparatus and methods for implanting particulate ocular implants |
US7458953B2 (en) | 2006-06-20 | 2008-12-02 | Gholam A. Peyman | Ocular drainage device |
US20080045911A1 (en) | 2006-06-21 | 2008-02-21 | Borgia Maureen J | Punctal plugs for the delivery of active agents |
US9474645B2 (en) | 2006-06-21 | 2016-10-25 | Johnson & Johnson Vision Care, Inc. | Punctal plugs for the delivery of active agents |
US20070298073A1 (en) | 2006-06-23 | 2007-12-27 | Allergan, Inc. | Steroid-containing sustained release intraocular implants and related methods |
US8802128B2 (en) | 2006-06-23 | 2014-08-12 | Allergan, Inc. | Steroid-containing sustained release intraocular implants and related methods |
EP2043572B1 (en) | 2006-06-30 | 2014-12-31 | Aquesys Inc. | Apparatus for relieving pressure in an organ |
CA2657380A1 (en) | 2006-07-20 | 2008-01-24 | Neurosystec Corporation | Devices, systems and methods for ophthalmic drug delivery |
US9248121B2 (en) | 2006-08-21 | 2016-02-02 | Abbott Laboratories | Medical devices for controlled drug release |
US20080086101A1 (en) | 2006-08-25 | 2008-04-10 | David Freilich | Ophthalmic insert |
MX2009002235A (en) | 2006-08-30 | 2009-03-13 | Jagotec Ag | Controlled release solid oral dosage formulations comprising nisoldipine. |
EP2059282A4 (en) | 2006-09-06 | 2014-04-09 | Innfocus Inc | Apparatus, methods and devices for treatment of ocular disorders |
WO2008039749A2 (en) | 2006-09-25 | 2008-04-03 | Surmodics, Inc. | Multi-layered coatings and methods for controlling elution of active agents |
US20080097379A1 (en) | 2006-09-26 | 2008-04-24 | Alcon Manufacturing, Ltd. | Ophthalmic injection method |
US20080125712A1 (en) | 2006-09-26 | 2008-05-29 | Alcon Manufacturing, Ltd. | Ophthalmic injection system |
US20080097390A1 (en) | 2006-09-27 | 2008-04-24 | Alcon Manufacturing, Ltd. | Spring actuated delivery system |
WO2008060360A2 (en) | 2006-09-28 | 2008-05-22 | Surmodics, Inc. | Implantable medical device with apertures for delivery of bioactive agents |
US20080089923A1 (en) | 2006-09-29 | 2008-04-17 | Burkstrand Michael J | Biodegradable ocular implants and methods for treating ocular conditions |
CL2007002851A1 (en) | 2006-10-05 | 2008-01-18 | M S Panacea Biotec Ltd | Injectable composition comprising micro or nanodegradable bio-particles including an active agent, a biodegradable polymer, an agent for intensifying the pharmaceutically acceptable viscosity and excipient; and preparation procedures |
US20100069842A1 (en) | 2006-10-16 | 2010-03-18 | Alcon Research, Ltd. | Ceramic Chamber With Integrated Temperature Control Device For Ophthalmic Medical Device |
US7620147B2 (en) | 2006-12-13 | 2009-11-17 | Oraya Therapeutics, Inc. | Orthovoltage radiotherapy |
US20080281292A1 (en) | 2006-10-16 | 2008-11-13 | Hickingbotham Dyson W | Retractable Injection Port |
US9022970B2 (en) | 2006-10-16 | 2015-05-05 | Alcon Research, Ltd. | Ophthalmic injection device including dosage control device |
US7496174B2 (en) | 2006-10-16 | 2009-02-24 | Oraya Therapeutics, Inc. | Portable orthovoltage radiotherapy |
US8039010B2 (en) | 2006-11-03 | 2011-10-18 | Allergan, Inc. | Sustained release intraocular drug delivery systems comprising a water soluble therapeutic agent and a release modifier |
US7494487B2 (en) | 2006-11-03 | 2009-02-24 | Mobius Therapeutics, Llc | Apparatus and method for application of a pharmaceutical to the tympanic membrane for photodynamic laser myringotomy |
US20080114076A1 (en) | 2006-11-09 | 2008-05-15 | Alcon Manufacturing Ltd. | Punctal plug comprising a water-insoluble polymeric matrix |
US8506515B2 (en) | 2006-11-10 | 2013-08-13 | Glaukos Corporation | Uveoscleral shunt and methods for implanting same |
WO2008060575A2 (en) | 2006-11-13 | 2008-05-22 | Auburn University | Drug delivery system and method |
US8143410B2 (en) | 2006-11-16 | 2012-03-27 | Allergan, Inc. | Kinase inhibitors |
WO2008064111A2 (en) | 2006-11-17 | 2008-05-29 | Boston Scientific Limited | Radiopaque medical devices |
EP2091482A2 (en) | 2006-12-01 | 2009-08-26 | Allergan, Inc. | Method for determining optimum intraocular locations for drug delivery systems |
US8969415B2 (en) | 2006-12-01 | 2015-03-03 | Allergan, Inc. | Intraocular drug delivery systems |
US8617143B2 (en) | 2006-12-07 | 2013-12-31 | The Regents Of The University Of California | Therapeutic agent delivery systems and devices |
US20080140024A1 (en) | 2006-12-08 | 2008-06-12 | Yoseph Yaacobi | Drug delivery device |
US20080145405A1 (en) | 2006-12-15 | 2008-06-19 | Kunzler Jay F | Drug delivery devices |
US20080147021A1 (en) | 2006-12-15 | 2008-06-19 | Jani Dharmendra M | Drug delivery devices |
WO2008076544A2 (en) | 2006-12-18 | 2008-06-26 | Alcon Research, Ltd. | Devices and methods for ophthalmic drug delivery |
US20080181928A1 (en) | 2006-12-22 | 2008-07-31 | Miv Therapeutics, Inc. | Coatings for implantable medical devices for liposome delivery |
JP2010514517A (en) | 2006-12-26 | 2010-05-06 | キューエルティー プラグ デリバリー,インク. | Drug delivery implants for the suppression of visual defects |
DE102007004906A1 (en) | 2007-01-25 | 2008-07-31 | Universität Rostock | eye implant |
UY30883A1 (en) | 2007-01-31 | 2008-05-31 | Alcon Res | PUNCTURAL PLUGS AND METHODS OF RELEASE OF THERAPEUTIC AGENTS |
ES2438041T3 (en) | 2007-02-08 | 2014-01-15 | Arnaldo Goncalves | Device for intraocular administration of a substance, for example a medicine, in a human or animal eye by means of a hypodermic needle |
JP4799444B2 (en) | 2007-02-26 | 2011-10-26 | パナソニック株式会社 | Simulation system |
TW200840554A (en) | 2007-02-28 | 2008-10-16 | Alcon Inc | Coated medical implants and lenses |
US7561085B2 (en) | 2007-03-21 | 2009-07-14 | Honeywell International Inc. | Systems and methods for improving data converters |
WO2008124009A2 (en) | 2007-04-02 | 2008-10-16 | The Cleveland Clinic Foundation | Treating glaucoma |
US8071119B2 (en) | 2007-05-14 | 2011-12-06 | Sustained Nano Systems Llc | Controlled release implantable dispensing device and method |
US20090148498A1 (en) | 2007-05-14 | 2009-06-11 | Sustained Nano Systems Llc | Controlled release implantable dispensing device and method |
US20080286338A1 (en) | 2007-05-15 | 2008-11-20 | Boston Foundation For Sight | Drug delivery system with scleral lens |
US8231892B2 (en) | 2007-05-24 | 2012-07-31 | Allergan, Inc. | Biodegradable drug delivery system |
WO2008154502A1 (en) | 2007-06-07 | 2008-12-18 | Yale University | Uveoscleral drainage device |
US8492334B2 (en) | 2007-06-21 | 2013-07-23 | Yale University | Sustained intraocular delivery of drugs from biodegradable polymeric microparticles |
US9492278B2 (en) | 2007-07-10 | 2016-11-15 | Warsaw Orthopedic, Inc. | Delivery system |
WO2009012406A1 (en) | 2007-07-17 | 2009-01-22 | Transcend Medical, Inc. | Ocular implant with hydrogel expansion capabilities reference to priority document |
US20090036827A1 (en) | 2007-07-31 | 2009-02-05 | Karl Cazzini | Juxtascleral Drug Delivery and Ocular Implant System |
US8366652B2 (en) | 2007-08-17 | 2013-02-05 | The Invention Science Fund I, Llc | Systems, devices, and methods including infection-fighting and monitoring shunts |
WO2009029958A2 (en) | 2007-08-30 | 2009-03-05 | Sunstorm Research Corporation | Implantable delivery device |
US8075909B2 (en) | 2007-09-04 | 2011-12-13 | University Of Florida Research Foundation, Incorporated | Contact lens based bioactive agent delivery system |
CA2698580C (en) | 2007-09-07 | 2016-10-11 | Qlt Plug Delivery, Inc. | Lacrimal implant detection |
KR101996336B1 (en) * | 2007-09-07 | 2019-07-04 | 마티 테라퓨틱스 인코포레이티드 | Drug cores for sustained release of therapeutic agents |
US7740604B2 (en) | 2007-09-24 | 2010-06-22 | Ivantis, Inc. | Ocular implants for placement in schlemm's canal |
US8480638B2 (en) | 2007-10-04 | 2013-07-09 | Aciont, Inc. | Intraocular iontophoretic device and associated methods |
US8109920B2 (en) | 2007-10-31 | 2012-02-07 | The Invention Science Fund I, Llc | Medical or veterinary digestive tract utilization systems and methods |
GB0722484D0 (en) | 2007-11-15 | 2007-12-27 | Ucl Business Plc | Solid compositions |
US20090130017A1 (en) | 2007-11-19 | 2009-05-21 | Searete Llc | Targeted short-lived drug delivery |
US20090143752A1 (en) | 2007-12-03 | 2009-06-04 | Higuchi John W | Passive intraocular drug delivery devices and associated methods |
US20100310622A1 (en) | 2007-12-17 | 2010-12-09 | University Of Florida Research Foundation, Inc. | Dry eye treatment by puncta plugs |
EP2666510B1 (en) | 2007-12-20 | 2017-10-18 | University Of Southern California | Apparatus for controlled delivery of therapeutic agents |
US20090162417A1 (en) | 2007-12-21 | 2009-06-25 | Cook Incorporated | Drug eluting ocular conformer |
US20110207987A1 (en) | 2009-11-02 | 2011-08-25 | Salutaris Medical Devices, Inc. | Methods And Devices For Delivering Appropriate Minimally-Invasive Extraocular Radiation |
KR101634983B1 (en) | 2008-01-07 | 2016-07-01 | 살루타리스 메디컬 디바이스즈, 인코퍼레이티드 | Methods and devices for minimally-invasive extraocular delivery of radiation to the posterior portion of the eye |
US20090177182A1 (en) | 2008-01-09 | 2009-07-09 | Hickingbotham Dyson W | Glass Drug Chamber For Automated Ophthalmic Injection Device |
WO2009092067A2 (en) | 2008-01-18 | 2009-07-23 | Neurosystec Corporation | Valveless impedance pump drug delivery systems |
WO2009097468A2 (en) | 2008-01-29 | 2009-08-06 | Kliman Gilbert H | Drug delivery devices, kits and methods therefor |
CN102014816B (en) | 2008-02-18 | 2015-04-15 | 马缇医疗股份有限公司 | Lacrimal implants and related methods |
WO2009151678A1 (en) | 2008-03-11 | 2009-12-17 | Massachusetts Institute Of Technology | Stimuli-responsive surfaces |
TNSN08110A1 (en) | 2008-03-11 | 2009-07-14 | Rekik Raouf Dr | Drug delivery to the anterior and posterior segment of the eye from drops |
US8951545B2 (en) | 2008-03-28 | 2015-02-10 | Surmodics, Inc. | Insertable medical devices having microparticulate-associated elastic substrates and methods for drug delivery |
US8496954B2 (en) | 2008-04-18 | 2013-07-30 | Surmodics, Inc. | Coating systems for the controlled delivery of hydrophilic bioactive agents |
CN103394142B (en) | 2008-05-08 | 2015-08-19 | 迷你泵有限责任公司 | Implantable drug delivery devices with for filling equipment and the method for this device |
US8231609B2 (en) | 2008-05-08 | 2012-07-31 | Minipumps, Llc | Drug-delivery pumps and methods of manufacture |
CN104353150A (en) | 2008-05-08 | 2015-02-18 | 迷你泵有限责任公司 | Implantable pums and cannulas therefor |
CN105251007A (en) * | 2008-05-09 | 2016-01-20 | 马缇医疗股份有限公司 | Sustained release delivery of active agents to treat glaucoma and ocular hypertension |
US9095404B2 (en) | 2008-05-12 | 2015-08-04 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
US8702995B2 (en) | 2008-05-27 | 2014-04-22 | Dober Chemical Corp. | Controlled release of microbiocides |
US8894602B2 (en) * | 2010-09-17 | 2014-11-25 | Johnson & Johnson Vision Care, Inc. | Punctal plugs with directional release |
TW201006453A (en) | 2008-07-08 | 2010-02-16 | Qlt Plug Delivery Inc | Lacrimal implant body including comforting agent |
EP2344095A1 (en) | 2008-09-26 | 2011-07-20 | The Cleveland Clinic Foundation | Apparatus and method for delivering a therapeutic agent to ocular tissue |
US7678078B1 (en) | 2008-10-21 | 2010-03-16 | KMG Pharma LLC | Intravitreal injection device, system and method |
US8221353B2 (en) | 2008-10-21 | 2012-07-17 | KMG Pharma, Inc | Intravitreal injection device and system |
US20110125090A1 (en) | 2008-11-13 | 2011-05-26 | Peyman Gholam A | Ophthalmic drug delivery system and method |
US20100119519A1 (en) | 2008-11-13 | 2010-05-13 | Peyman Gholam A | Ophthalmic drug delivery system and method |
CN102271732B (en) | 2008-11-14 | 2014-12-31 | 得克萨斯大学体系董事会 | Nanochanneled device and related methods |
US9095506B2 (en) | 2008-11-17 | 2015-08-04 | Allergan, Inc. | Biodegradable alpha-2 agonist polymeric implants and therapeutic uses thereof |
WO2010062394A2 (en) | 2008-11-26 | 2010-06-03 | Surmodics, Inc. | Implantable ocular drug delivery device and methods |
AU2009322146B2 (en) | 2008-12-05 | 2015-05-28 | Alcon Inc. | Methods and apparatus for delivering ocular implants into the eye |
WO2010068281A2 (en) | 2008-12-11 | 2010-06-17 | Massachusetts Institute Of Technology | Contact lens drug delivery device |
US20100152676A1 (en) | 2008-12-16 | 2010-06-17 | Alcon Research, Ltd. | Drug Loading Through Plunger |
US8070290B2 (en) | 2008-12-17 | 2011-12-06 | Glaukos Corporation | Gonioscope for improved viewing |
US20120257167A1 (en) | 2008-12-17 | 2012-10-11 | Glaukos Corporation | Gonioscope for improved viewing |
US20100158980A1 (en) | 2008-12-18 | 2010-06-24 | Casey Kopczynski | Drug delivery devices for delivery of therapeutic agents |
US20100160870A1 (en) | 2008-12-18 | 2010-06-24 | Alcon Research, Ltd. | Two Piece Housing For Drug Loading |
WO2010071844A1 (en) | 2008-12-19 | 2010-06-24 | Qlt Plug Delivery, Inc | Substance delivering punctum implants and methods |
WO2010078428A1 (en) | 2008-12-30 | 2010-07-08 | Optimyst Systems, Inc. | Ophthalmic fluid delivery system |
US20100174272A1 (en) | 2009-01-02 | 2010-07-08 | Weiner Alan L | In-situ refillable ophthalmic implant |
JP5524983B2 (en) | 2009-01-28 | 2014-06-18 | トランセンド・メディカル・インコーポレイテッド | Implant system |
PL2391419T3 (en) | 2009-01-29 | 2019-12-31 | Forsight Vision4, Inc. | Posterior segment drug delivery |
US9282891B2 (en) | 2009-01-30 | 2016-03-15 | Sundaraja Sitaram Iyengar | Monitoring intra ocular pressure using pattern and color changes |
JP5969212B2 (en) | 2009-02-10 | 2016-08-17 | シヴィダ・ユーエス・インコーポレイテッドPsivida Us,Inc. | Ophthalmic trocar assembly |
US20100204325A1 (en) | 2009-02-11 | 2010-08-12 | Allergan, Inc. | Valproic acid drug delivery systems and intraocular therapeutic uses thereof |
US9101475B2 (en) | 2009-02-12 | 2015-08-11 | Warsaw Orthopedic, Inc. | Segmented delivery system |
WO2010093945A2 (en) | 2009-02-13 | 2010-08-19 | Glaukos Corporation | Uveoscleral drug delivery implant and methods for implanting the same |
WO2010096449A2 (en) | 2009-02-17 | 2010-08-26 | Pharmanova, Inc. | Implantable drug delivery devices |
CN105997339B (en) | 2009-02-23 | 2018-09-04 | 马缇医疗股份有限公司 | Lacrimal implants |
US20100225061A1 (en) | 2009-03-09 | 2010-09-09 | Bath David L | System and method for gaming with an engagable projectile |
WO2010105093A2 (en) | 2009-03-12 | 2010-09-16 | Delpor, Inc. | Implantable device for long-term delivery of drugs |
US20100233241A1 (en) | 2009-03-13 | 2010-09-16 | Vista Scientific Llc | Ophthalmic drug delivery system and applications |
WO2010111232A2 (en) | 2009-03-23 | 2010-09-30 | Micell Technologies, Inc. | Drug delivery medical device |
US20100247606A1 (en) | 2009-03-25 | 2010-09-30 | Allergan, Inc. | Intraocular sustained release drug delivery systems and methods for treating ocular conditions |
TWI495459B (en) | 2009-03-31 | 2015-08-11 | Johnson & Johnson Vision Care | Punctal plugs |
US8337393B2 (en) | 2009-04-03 | 2012-12-25 | Transcend Medical, Inc. | Ocular implant delivery systems and methods |
US10206813B2 (en) | 2009-05-18 | 2019-02-19 | Dose Medical Corporation | Implants with controlled drug delivery features and methods of using same |
ES2921527T3 (en) | 2009-06-03 | 2022-08-29 | Forsight Vision5 Inc | Anterior segment drug delivery |
CA2765541A1 (en) | 2009-06-19 | 2010-12-23 | Sun Pharma Advanced Research Company Ltd. | Nanodispersion of a drug and process for its preparation |
EP2456509A1 (en) | 2009-07-22 | 2012-05-30 | Advanced Ophthalmic Pharma Ltd. | Device for applying an ophthalmic medicament mist |
CN102573813B (en) | 2009-08-18 | 2013-11-06 | 国立大学法人东北大学 | Sustained drug delivery system |
US8808257B2 (en) * | 2009-08-31 | 2014-08-19 | Johnson & Johnson Vision Care, Inc. | Methods and apparatus for pulsatile release of medicaments from a punctal plug |
MX2012002596A (en) | 2009-09-03 | 2012-07-03 | Allergan Inc | Compounds as tyrosine kinase modulators. |
US9174065B2 (en) | 2009-10-12 | 2015-11-03 | Kona Medical, Inc. | Energetic modulation of nerves |
EP2490617A1 (en) | 2009-10-22 | 2012-08-29 | On Demand Therapeutics, Inc. | Visual indication of rupture of drug reservoir |
ES2603057T3 (en) | 2009-10-30 | 2017-02-23 | Aton Pharma, Inc. | Ocular drug delivery devices |
DE102009052552A1 (en) | 2009-11-10 | 2011-05-26 | Fluoron Gmbh | syringe |
JP2013512045A (en) | 2009-11-27 | 2013-04-11 | キュー エル ティー インク. | Lacrimal implant including split and insertable drug core |
WO2011075481A1 (en) | 2009-12-16 | 2011-06-23 | Allergan, Inc. | Intracameral devices for sustained delivery |
USD645489S1 (en) | 2009-12-16 | 2011-09-20 | Glaukos Corporation | Gonioscopic system including an optical element attachment |
USD645490S1 (en) | 2009-12-16 | 2011-09-20 | Glaukos Corporation | Gonioscopic system including an optical element attachment |
US8177747B2 (en) | 2009-12-22 | 2012-05-15 | Alcon Research, Ltd. | Method and apparatus for drug delivery |
US20110238036A1 (en) | 2009-12-23 | 2011-09-29 | Psivida Us, Inc. | Sustained release delivery devices |
US8529492B2 (en) | 2009-12-23 | 2013-09-10 | Trascend Medical, Inc. | Drug delivery devices and methods |
KR102126007B1 (en) | 2010-01-22 | 2020-06-24 | 알러간, 인코포레이티드 | Intracameral sustained release therapeutic agent implants |
US10166142B2 (en) | 2010-01-29 | 2019-01-01 | Forsight Vision4, Inc. | Small molecule delivery with implantable therapeutic device |
EP2533737B1 (en) | 2010-02-08 | 2014-01-08 | On Demand Therapeutics, Inc. | Low-permeability, laser-activated drug delivery device |
US8889193B2 (en) | 2010-02-25 | 2014-11-18 | The Johns Hopkins University | Sustained delivery of therapeutic agents to an eye compartment |
US20130071349A1 (en) | 2010-03-02 | 2013-03-21 | Allergan, Inc. | Biodegradable polymers for lowering intraocular pressure |
GB201003731D0 (en) | 2010-03-05 | 2010-04-21 | Univ Strathclyde | Immediate/delayed drug delivery |
US9320647B2 (en) | 2010-03-31 | 2016-04-26 | Ocuject, Llc | Device and method for intraocular drug delivery |
US9408746B2 (en) | 2010-03-31 | 2016-08-09 | Ocuject, Llc | Device and method for intraocular drug delivery |
WO2011123180A1 (en) | 2010-04-03 | 2011-10-06 | Praful Doshi | Medical devices including medicaments and methods of making and using same |
JP2013523821A (en) | 2010-04-06 | 2013-06-17 | アラーガン、インコーポレイテッド | Sustained release reservoir implant for intra-anterior drug delivery |
US20110251568A1 (en) * | 2010-04-08 | 2011-10-13 | Beeley Nathan R F | Punctal plugs for controlled release of therapeutic agents |
WO2011146483A1 (en) | 2010-05-17 | 2011-11-24 | Aerie Pharmaceuticals, Inc. | Drug delivery devices for delivery of ocular therapeutic agents |
US8444589B2 (en) | 2010-06-09 | 2013-05-21 | Transcend Medical, Inc. | Ocular implant with fluid outflow pathways having microporous membranes |
KR101180032B1 (en) | 2010-07-12 | 2012-09-05 | 인싸이토(주) | Method for manufacturing Hollow Microneedle with Controlled External Appearance Characteristics |
WO2012012017A1 (en) | 2010-07-20 | 2012-01-26 | Alcon Research, Ltd. | Closed loop glaucoma drug delivery system |
EP3861969A1 (en) | 2010-08-05 | 2021-08-11 | ForSight Vision4, Inc. | Injector apparatus for drug delivery |
US8235053B2 (en) | 2010-09-08 | 2012-08-07 | Alcon Research, Ltd. | Implantable punctal plug |
US8864703B2 (en) | 2010-10-05 | 2014-10-21 | Alcon Research, Ltd. | Drug introduction and placement system |
US9022967B2 (en) | 2010-10-08 | 2015-05-05 | Sinopsys Surgical, Inc. | Implant device, tool, and methods relating to treatment of paranasal sinuses |
US9370444B2 (en) | 2010-10-12 | 2016-06-21 | Emmett T. Cunningham, JR. | Subconjunctival conformer device and uses thereof |
US8915877B2 (en) | 2010-10-12 | 2014-12-23 | Emmett T. Cunningham, JR. | Glaucoma drainage device and uses thereof |
US20120100187A1 (en) | 2010-10-26 | 2012-04-26 | Surmodics, Inc. | Coatings and methods for controlled elution of hydrophilic active agents |
US9668915B2 (en) | 2010-11-24 | 2017-06-06 | Dose Medical Corporation | Drug eluting ocular implant |
EP2651957B1 (en) | 2010-12-16 | 2015-02-18 | Allergan, Inc. | Phosphorous derivatives as chemokine receptor modulators |
WO2012088306A2 (en) | 2010-12-22 | 2012-06-28 | Psivida Us, Inc. | Two-piece injectable drug delivery device with heat-cured seal |
WO2012103124A2 (en) | 2011-01-24 | 2012-08-02 | Emd Millipore Corporation | Accelerated mixed gas integrity testing of porous materials |
JP2012198134A (en) | 2011-03-22 | 2012-10-18 | Chugoku Electric Power Co Inc:The | Fault point locating device and program |
US10245178B1 (en) | 2011-06-07 | 2019-04-02 | Glaukos Corporation | Anterior chamber drug-eluting ocular implant |
US20130004651A1 (en) | 2011-07-01 | 2013-01-03 | Patty Fu-Giles | Sustained drug release from body implants using nanoparticle-embedded polymeric coating materials |
US20130018360A1 (en) | 2011-07-13 | 2013-01-17 | Marissa Dockendorf | Method for delivering ophthalmic drugs |
US8486031B2 (en) | 2011-07-29 | 2013-07-16 | Allan J. Bogdan | Eye treatment apparatus |
CA2846384C (en) * | 2011-08-29 | 2020-12-15 | Qlt Inc. | Sustained release delivery of active agents to treat glaucoma and ocular hypertension |
WO2013040238A2 (en) | 2011-09-13 | 2013-03-21 | Vista Scientific Llc | Sustained release ocular drug delivery devices and methods of manufacture |
EP3659495B1 (en) | 2011-09-13 | 2022-12-14 | Dose Medical Corporation | Intraocular physiological sensor |
RU2740680C2 (en) | 2011-09-14 | 2021-01-19 | Форсайт Вижн5, Инк. | Eye inserter device and methods |
US10226417B2 (en) | 2011-09-16 | 2019-03-12 | Peter Jarrett | Drug delivery systems and applications |
US8771220B2 (en) | 2011-12-07 | 2014-07-08 | Alcon Research, Ltd. | Glaucoma active pressure regulation shunt |
US8852136B2 (en) | 2011-12-08 | 2014-10-07 | Aquesys, Inc. | Methods for placing a shunt into the intra-scleral space |
US8579848B2 (en) | 2011-12-09 | 2013-11-12 | Alcon Research, Ltd. | Active drainage systems with pressure-driven valves and electronically-driven pump |
US8945214B2 (en) | 2011-12-19 | 2015-02-03 | Allergan, Inc. | Intravitreal applicator |
US9241829B2 (en) | 2011-12-20 | 2016-01-26 | Abbott Medical Optics Inc. | Implantable intraocular drug delivery apparatus, system and method |
US8808256B2 (en) | 2012-01-16 | 2014-08-19 | Johnson & Johnson Vision Care, Inc. | Eye drug delivery system |
EP2811952A1 (en) | 2012-02-07 | 2014-12-17 | On Demand Therapeutics, Inc. | Drug delivery devices and methods of use thereof |
JP6465490B2 (en) | 2012-03-26 | 2019-02-06 | グローコス コーポレーション | Implant delivery device |
US9504603B2 (en) | 2012-04-02 | 2016-11-29 | Ocuject, Llc | Intraocular delivery devices and methods therefor |
CN109602691A (en) | 2013-02-15 | 2019-04-12 | 阿勒根公司 | Sustained drug delivery implantation material |
US9730638B2 (en) | 2013-03-13 | 2017-08-15 | Glaukos Corporation | Intraocular physiological sensor |
US10517759B2 (en) | 2013-03-15 | 2019-12-31 | Glaukos Corporation | Glaucoma stent and methods thereof for glaucoma treatment |
US9592151B2 (en) | 2013-03-15 | 2017-03-14 | Glaukos Corporation | Systems and methods for delivering an ocular implant to the suprachoroidal space within an eye |
CN105188666A (en) | 2013-04-01 | 2015-12-23 | 阿勒根公司 | Microsphere drug delivery system for sustained intraocular release |
CA2830555A1 (en) | 2013-10-18 | 2015-04-18 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
DK3062775T3 (en) | 2013-10-31 | 2018-03-12 | Allergan Inc | PROSTAMID-CONTAINING INTRAOCULAR IMPLANTS AND PROCEDURES FOR USE THEREOF |
EP3068371A1 (en) | 2013-11-15 | 2016-09-21 | Glaukos Corporation | Ocular implants configured to store and release stable drug formulations |
AU2015266850B2 (en) | 2014-05-29 | 2019-12-05 | Glaukos Corporation | Implants with controlled drug delivery features and methods of using same |
WO2016042163A2 (en) | 2014-09-19 | 2016-03-24 | Medterials, Inc. | Ophthalmic drug compositions |
WO2016154066A2 (en) | 2015-03-20 | 2016-09-29 | Glaukos Corporation | Gonioscopic devices |
US20180280194A1 (en) | 2015-05-20 | 2018-10-04 | Glaukos Corporation | Therapeutic drug compositions and implants for delivery of same |
NZ737997A (en) | 2015-06-03 | 2019-03-29 | Aquesys Inc | Ab externo intraocular shunt placement |
EP3324905A1 (en) | 2015-07-22 | 2018-05-30 | Glaukos Corporation | Ocular implants for reduction of intraocular pressure |
WO2017040855A1 (en) | 2015-09-02 | 2017-03-09 | Dose Medical Corporation | Drug delivery implants as intraocular drug depots and methods of using same |
US11925578B2 (en) | 2015-09-02 | 2024-03-12 | Glaukos Corporation | Drug delivery implants with bi-directional delivery capacity |
WO2017053885A1 (en) | 2015-09-25 | 2017-03-30 | Glaukos Corporation | Punctal implants with controlled drug delivery features and methods of using same |
KR20170058811A (en) | 2015-11-19 | 2017-05-29 | 글라우코스 코포레이션 | Delivery device systems and implants for treating glaucoma |
AU2017252294B2 (en) | 2016-04-20 | 2021-12-02 | Dose Medical Corporation | Bioresorbable ocular drug delivery device |
US10674906B2 (en) | 2017-02-24 | 2020-06-09 | Glaukos Corporation | Gonioscopes |
USD833008S1 (en) | 2017-02-27 | 2018-11-06 | Glaukos Corporation | Gonioscope |
US11116625B2 (en) | 2017-09-28 | 2021-09-14 | Glaukos Corporation | Apparatus and method for controlling placement of intraocular implants |
WO2019068026A1 (en) | 2017-09-29 | 2019-04-04 | Glaukos Corporation | Intraocular physiological sensor |
CN113893085A (en) | 2017-10-06 | 2022-01-07 | 格劳科斯公司 | Systems and methods for delivering multiple ocular implants |
USD846738S1 (en) | 2017-10-27 | 2019-04-23 | Glaukos Corporation | Implant delivery apparatus |
US20220119350A1 (en) | 2019-02-22 | 2022-04-21 | Glaukos Corporation | Compounds for the treatment of ocular disease |
-
2016
- 2016-09-23 WO PCT/US2016/053570 patent/WO2017053885A1/en active Application Filing
- 2016-09-23 US US15/762,969 patent/US11564833B2/en active Active
-
2023
- 2023-01-24 US US18/158,705 patent/US20230293344A1/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5334137A (en) * | 1992-02-21 | 1994-08-02 | Eagle Vision, Inc. | Lacrimal fluid control device |
US20090104248A1 (en) * | 2007-09-07 | 2009-04-23 | Qlt Plug Delivery, Inc. -Qpdi | Lacrimal implants and related methods |
US20090306608A1 (en) * | 2008-05-07 | 2009-12-10 | Zhigang Li | Ophthalmic devices for the controlled release of active agents |
US20120078362A1 (en) * | 2009-05-18 | 2012-03-29 | Dose Medical Corporation | Drug eluting ocular implant |
US20120059338A1 (en) * | 2010-09-08 | 2012-03-08 | Beeley Nathan R F | Punctal plug containing drug formulation |
Also Published As
Publication number | Publication date |
---|---|
US11564833B2 (en) | 2023-01-31 |
US20190083307A1 (en) | 2019-03-21 |
WO2017053885A1 (en) | 2017-03-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20230293344A1 (en) | Punctal implants with controlled drug delivery features and methods of using same | |
US20230157868A1 (en) | Implants with controlled drug delivery features and methods of using same | |
US20210298948A1 (en) | Drug eluting ocular implant with internal plug | |
US20210015662A1 (en) | Drug eluting ocular implant | |
AU2022201392A1 (en) | Bioresorbable ocular drug delivery device | |
AU2020201236A1 (en) | Implants with controlled drug delivery features and methods of using same | |
US11925578B2 (en) | Drug delivery implants with bi-directional delivery capacity | |
US20180280194A1 (en) | Therapeutic drug compositions and implants for delivery of same | |
US20240074897A1 (en) | Punctal implants, insertion systems and methods of using the same |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: FINAL REJECTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |