WO2010049900A1 - Nanoparticules de statine - Google Patents
Nanoparticules de statine Download PDFInfo
- Publication number
- WO2010049900A1 WO2010049900A1 PCT/IB2009/054781 IB2009054781W WO2010049900A1 WO 2010049900 A1 WO2010049900 A1 WO 2010049900A1 IB 2009054781 W IB2009054781 W IB 2009054781W WO 2010049900 A1 WO2010049900 A1 WO 2010049900A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- complex
- nanoparticles
- statin
- formula
- alkyl
- Prior art date
Links
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 78
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 title claims abstract description 60
- 239000004215 Carbon black (E152) Substances 0.000 claims abstract description 24
- 229930195733 hydrocarbon Natural products 0.000 claims abstract description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 13
- 230000002265 prevention Effects 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 208000035150 Hypercholesterolemia Diseases 0.000 claims abstract description 5
- 201000005577 familial hyperlipidemia Diseases 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 26
- 230000015572 biosynthetic process Effects 0.000 claims description 18
- 150000002430 hydrocarbons Chemical class 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 229960002965 pravastatin Drugs 0.000 claims description 8
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 6
- 239000012736 aqueous medium Substances 0.000 claims description 6
- 239000008346 aqueous phase Substances 0.000 claims description 6
- 239000006185 dispersion Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
- 239000010452 phosphate Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 claims description 5
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims description 5
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 claims description 5
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 229960003765 fluvastatin Drugs 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 229960004844 lovastatin Drugs 0.000 claims description 5
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 claims description 5
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 claims description 5
- 229960002855 simvastatin Drugs 0.000 claims description 5
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims description 5
- 150000003568 thioethers Chemical class 0.000 claims description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 4
- 229960000672 rosuvastatin Drugs 0.000 claims description 4
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 3
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 3
- 208000008589 Obesity Diseases 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 235000020824 obesity Nutrition 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- NJGFHHXZSDLYQJ-UHFFFAOYSA-N 4-hydroxy-2,3-dihydropyran-6-one Chemical compound OC1=CC(=O)OCC1 NJGFHHXZSDLYQJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000004108 freeze drying Methods 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical group CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 abstract description 4
- -1 hydrocarbon radical Chemical class 0.000 description 28
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol 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)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 22
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 21
- 230000006870 function Effects 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 18
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 18
- 229940031439 squalene Drugs 0.000 description 18
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 18
- 229920001223 polyethylene glycol Polymers 0.000 description 16
- 150000003254 radicals Chemical class 0.000 description 16
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 15
- 239000002202 Polyethylene glycol Substances 0.000 description 14
- 239000004480 active ingredient Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 235000012000 cholesterol Nutrition 0.000 description 9
- 239000004094 surface-active agent Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000009472 formulation Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 108010028554 LDL Cholesterol Proteins 0.000 description 5
- 238000008214 LDL Cholesterol Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 4
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 4
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229960005370 atorvastatin Drugs 0.000 description 4
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 description 4
- 125000005647 linker group Chemical group 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 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 3
- 230000007211 cardiovascular event Effects 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 208000010125 myocardial infarction Diseases 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- YYGNTYWPHWGJRM-AAJYLUCBSA-N squalene group Chemical group CC(C)=CCC\C(\C)=C\CC\C(\C)=C\CC\C=C(/C)\CC\C=C(/C)\CCC=C(C)C YYGNTYWPHWGJRM-AAJYLUCBSA-N 0.000 description 3
- 150000003421 squalenes Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 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
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 2
- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 2
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000001435 Thromboembolism Diseases 0.000 description 2
- 108010062497 VLDL Lipoproteins Proteins 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 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 2
- 229960000528 amlodipine Drugs 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 239000002934 diuretic Substances 0.000 description 2
- 229940030606 diuretics Drugs 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 210000003238 esophagus Anatomy 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000004130 lipolysis Effects 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 235000020660 omega-3 fatty acid Nutrition 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 2
- 238000001556 precipitation Methods 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
- 210000002307 prostate Anatomy 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000000935 solvent evaporation Methods 0.000 description 2
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- 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
- CEMAWMOMDPGJMB-UHFFFAOYSA-N (+-)-Oxprenolol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1OCC=C CEMAWMOMDPGJMB-UHFFFAOYSA-N 0.000 description 1
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 description 1
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 1
- BJHPHCBHTOHNEI-KDSGDVRDSA-N (4e,8e,12e,16e)-4,8,13,17,21-pentamethyldocosa-4,8,12,16,20-pentaenoic acid Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C=C(/C)CC\C=C(/C)CCC(O)=O BJHPHCBHTOHNEI-KDSGDVRDSA-N 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 1
- KJTLQQUUPVSXIM-ZCFIWIBFSA-N (R)-mevalonic acid Chemical compound OCC[C@](O)(C)CC(O)=O KJTLQQUUPVSXIM-ZCFIWIBFSA-N 0.000 description 1
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 description 1
- 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
- KOHIRBRYDXPAMZ-YHBROIRLSA-N (S,R,R,R)-nebivolol Chemical compound C1CC2=CC(F)=CC=C2O[C@H]1[C@H](O)CNC[C@@H](O)[C@H]1OC2=CC=C(F)C=C2CC1 KOHIRBRYDXPAMZ-YHBROIRLSA-N 0.000 description 1
- ZEPAXLPHESYSJU-UHFFFAOYSA-N 2,3,4,5,6,7,8-heptahydroxyoctanal Chemical compound OCC(O)C(O)C(O)C(O)C(O)C(O)C=O ZEPAXLPHESYSJU-UHFFFAOYSA-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
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-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
- 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
- 229960000549 4-dimethylaminophenol Drugs 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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 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 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 200000000007 Arterial disease Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 239000002080 C09CA02 - Eprosartan Substances 0.000 description 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 1
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 1
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 1
- 239000002051 C09CA08 - Olmesartan medoxomil Substances 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 102000005600 Cathepsins Human genes 0.000 description 1
- 108010084457 Cathepsins Proteins 0.000 description 1
- 229920001268 Cholestyramine Polymers 0.000 description 1
- 229920002911 Colestipol Polymers 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000002330 Congenital Heart Defects Diseases 0.000 description 1
- YTBSYETUWUMLBZ-UHFFFAOYSA-N D-Erythrose Natural products OCC(O)C(O)C=O YTBSYETUWUMLBZ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-CBPJZXOFSA-N D-Gulose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O WQZGKKKJIJFFOK-CBPJZXOFSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- WQZGKKKJIJFFOK-WHZQZERISA-N D-aldose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-WHZQZERISA-N 0.000 description 1
- WQZGKKKJIJFFOK-IVMDWMLBSA-N D-allopyranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@H](O)[C@@H]1O WQZGKKKJIJFFOK-IVMDWMLBSA-N 0.000 description 1
- LKDRXBCSQODPBY-JDJSBBGDSA-N D-allulose Chemical compound OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O LKDRXBCSQODPBY-JDJSBBGDSA-N 0.000 description 1
- YTBSYETUWUMLBZ-IUYQGCFVSA-N D-erythrose Chemical compound OC[C@@H](O)[C@@H](O)C=O YTBSYETUWUMLBZ-IUYQGCFVSA-N 0.000 description 1
- MNQZXJOMYWMBOU-VKHMYHEASA-N D-glyceraldehyde Chemical compound OC[C@@H](O)C=O MNQZXJOMYWMBOU-VKHMYHEASA-N 0.000 description 1
- HSNZZMHEPUFJNZ-QMTIVRBISA-N D-keto-manno-heptulose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)CO HSNZZMHEPUFJNZ-QMTIVRBISA-N 0.000 description 1
- HAIWUXASLYEWLM-UHFFFAOYSA-N D-manno-Heptulose Natural products OCC1OC(O)(CO)C(O)C(O)C1O HAIWUXASLYEWLM-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- ZAQJHHRNXZUBTE-NQXXGFSBSA-N D-ribulose Chemical compound OC[C@@H](O)[C@@H](O)C(=O)CO ZAQJHHRNXZUBTE-NQXXGFSBSA-N 0.000 description 1
- ZAQJHHRNXZUBTE-UHFFFAOYSA-N D-threo-2-Pentulose Natural products OCC(O)C(O)C(=O)CO ZAQJHHRNXZUBTE-UHFFFAOYSA-N 0.000 description 1
- YTBSYETUWUMLBZ-QWWZWVQMSA-N D-threose Chemical compound OC[C@@H](O)[C@H](O)C=O YTBSYETUWUMLBZ-QWWZWVQMSA-N 0.000 description 1
- ZAQJHHRNXZUBTE-WUJLRWPWSA-N D-xylulose Chemical compound OC[C@@H](O)[C@H](O)C(=O)CO ZAQJHHRNXZUBTE-WUJLRWPWSA-N 0.000 description 1
- KJTLQQUUPVSXIM-UHFFFAOYSA-N DL-mevalonic acid Natural products OCCC(O)(C)CC(O)=O KJTLQQUUPVSXIM-UHFFFAOYSA-N 0.000 description 1
- 208000002251 Dissecting Aneurysm Diseases 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 206010056474 Erythrosis Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 229930091371 Fructose Natural products 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
- 239000005715 Fructose Substances 0.000 description 1
- XQLWNAFCTODIRK-UHFFFAOYSA-N Gallopamil Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC(OC)=C(OC)C(OC)=C1 XQLWNAFCTODIRK-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- LKDRXBCSQODPBY-AMVSKUEXSA-N L-(-)-Sorbose Chemical compound OCC1(O)OC[C@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-AMVSKUEXSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VSOAQEOCSA-N L-altropyranose Chemical compound OC[C@@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-VSOAQEOCSA-N 0.000 description 1
- HSNZZMHEPUFJNZ-UHFFFAOYSA-N L-galacto-2-Heptulose Natural products OCC(O)C(O)C(O)C(O)C(=O)CO HSNZZMHEPUFJNZ-UHFFFAOYSA-N 0.000 description 1
- 108010007622 LDL Lipoproteins Proteins 0.000 description 1
- 102000007330 LDL Lipoproteins Human genes 0.000 description 1
- 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 1
- 108010007859 Lisinopril Proteins 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- UWWDHYUMIORJTA-HSQYWUDLSA-N Moexipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC(OC)=C(OC)C=C2C1)C(O)=O)CC1=CC=CC=C1 UWWDHYUMIORJTA-HSQYWUDLSA-N 0.000 description 1
- 208000021642 Muscular disease Diseases 0.000 description 1
- 201000009623 Myopathy Diseases 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
- 239000005480 Olmesartan Substances 0.000 description 1
- UQGKUQLKSCSZGY-UHFFFAOYSA-N Olmesartan medoxomil Chemical compound C=1C=C(C=2C(=CC=CC=2)C2=NNN=N2)C=CC=1CN1C(CCC)=NC(C(C)(C)O)=C1C(=O)OCC=1OC(=O)OC=1C UQGKUQLKSCSZGY-UHFFFAOYSA-N 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- HAIWUXASLYEWLM-AZEWMMITSA-N Sedoheptulose Natural products OC[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@](O)(CO)O1 HAIWUXASLYEWLM-AZEWMMITSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- DRHKJLXJIQTDTD-OAHLLOKOSA-N Tamsulosine Chemical compound CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-OAHLLOKOSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- VXFJYXUZANRPDJ-WTNASJBWSA-N Trandopril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@H]2CCCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 VXFJYXUZANRPDJ-WTNASJBWSA-N 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- KNDHRUPPBXRELB-UHFFFAOYSA-M [4-[3-(4-ethylphenyl)butyl]phenyl]-trimethylazanium;chloride Chemical compound [Cl-].C1=CC(CC)=CC=C1C(C)CCC1=CC=C([N+](C)(C)C)C=C1 KNDHRUPPBXRELB-UHFFFAOYSA-M 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960002122 acebutolol Drugs 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
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- WNMJYKCGWZFFKR-UHFFFAOYSA-N alfuzosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(C)CCCNC(=O)C1CCCO1 WNMJYKCGWZFFKR-UHFFFAOYSA-N 0.000 description 1
- 229960004607 alfuzosin Drugs 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 239000002160 alpha blocker Substances 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- SRBFZHDQGSBBOR-STGXQOJASA-N alpha-D-lyxopyranose Chemical compound O[C@@H]1CO[C@H](O)[C@@H](O)[C@H]1O SRBFZHDQGSBBOR-STGXQOJASA-N 0.000 description 1
- 229940124308 alpha-adrenoreceptor antagonist Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 206010002895 aortic dissection Diseases 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 208000037849 arterial hypertension Diseases 0.000 description 1
- 206010003230 arteritis Diseases 0.000 description 1
- 229960002274 atenolol Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960002992 barnidipine Drugs 0.000 description 1
- VXMOONUMYLCFJD-DHLKQENFSA-N barnidipine Chemical compound C1([C@@H]2C(=C(C)NC(C)=C2C(=O)OC)C(=O)O[C@@H]2CN(CC=3C=CC=CC=3)CC2)=CC=CC([N+]([O-])=O)=C1 VXMOONUMYLCFJD-DHLKQENFSA-N 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 229960004530 benazepril Drugs 0.000 description 1
- 229960001264 benfluorex Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- CJAVTWRYCDNHSM-UHFFFAOYSA-N benzoic acid 2-[1-[3-(trifluoromethyl)phenyl]propan-2-ylamino]ethyl ester Chemical compound C=1C=CC=CC=1C(=O)OCCNC(C)CC1=CC=CC(C(F)(F)F)=C1 CJAVTWRYCDNHSM-UHFFFAOYSA-N 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 229960004324 betaxolol Drugs 0.000 description 1
- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 description 1
- 229960000516 bezafibrate Drugs 0.000 description 1
- IIBYAHWJQTYFKB-UHFFFAOYSA-N bezafibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1CCNC(=O)C1=CC=C(Cl)C=C1 IIBYAHWJQTYFKB-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 229940093761 bile salts Drugs 0.000 description 1
- 229960002781 bisoprolol 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
- 229920001400 block copolymer Polymers 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 229960000932 candesartan Drugs 0.000 description 1
- 229960004349 candesartan cilexetil Drugs 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 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
- 229960004195 carvedilol Drugs 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960005025 cilazapril Drugs 0.000 description 1
- HHHKFGXWKKUNCY-FHWLQOOXSA-N cilazapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N2[C@@H](CCCN2CCC1)C(O)=O)=O)CC1=CC=CC=C1 HHHKFGXWKKUNCY-FHWLQOOXSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- GMRWGQCZJGVHKL-UHFFFAOYSA-N colestipol Chemical compound ClCC1CO1.NCCNCCNCCNCCN GMRWGQCZJGVHKL-UHFFFAOYSA-N 0.000 description 1
- 229960002604 colestipol Drugs 0.000 description 1
- 229960001678 colestyramine Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 208000028831 congenital heart disease Diseases 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000019621 digestibility Nutrition 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 229940120503 dihydroxyacetone Drugs 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229960001389 doxazosin Drugs 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
- 239000008298 dragée Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 229960004563 eprosartan Drugs 0.000 description 1
- OROAFUQRIXKEMV-LDADJPATSA-N eprosartan Chemical compound C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 OROAFUQRIXKEMV-LDADJPATSA-N 0.000 description 1
- UQPHVQVXLPRNCX-UHFFFAOYSA-N erythrulose Chemical compound OCC(O)C(=O)CO UQPHVQVXLPRNCX-UHFFFAOYSA-N 0.000 description 1
- 229960003745 esmolol Drugs 0.000 description 1
- AQNDDEOPVVGCPG-UHFFFAOYSA-N esmolol Chemical compound COC(=O)CCC1=CC=C(OCC(O)CNC(C)C)C=C1 AQNDDEOPVVGCPG-UHFFFAOYSA-N 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000003916 ethylene diamine group Chemical group 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 1
- 229960000815 ezetimibe Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229960003580 felodipine Drugs 0.000 description 1
- 229960002297 fenofibrate Drugs 0.000 description 1
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229960002490 fosinopril Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 229960000457 gallopamil Drugs 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
- 230000002496 gastric effect Effects 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
- 229960003627 gemfibrozil Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 210000003547 hepatic macrophage Anatomy 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 150000002386 heptoses Chemical class 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 150000002402 hexoses Chemical class 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 150000002454 idoses Chemical class 0.000 description 1
- 229960001195 imidapril Drugs 0.000 description 1
- KLZWOWYOHUKJIG-BPUTZDHNSA-N imidapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1C(N(C)C[C@H]1C(O)=O)=O)CC1=CC=CC=C1 KLZWOWYOHUKJIG-BPUTZDHNSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229960002198 irbesartan Drugs 0.000 description 1
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229960004427 isradipine Drugs 0.000 description 1
- BJHIKXHVCXFQLS-PQLUHFTBSA-N keto-D-tagatose Chemical compound OC[C@@H](O)[C@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-PQLUHFTBSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 229960001632 labetalol Drugs 0.000 description 1
- 229960004340 lacidipine Drugs 0.000 description 1
- GKQPCPXONLDCMU-CCEZHUSRSA-N lacidipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1C1=CC=CC=C1\C=C\C(=O)OC(C)(C)C GKQPCPXONLDCMU-CCEZHUSRSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960004294 lercanidipine Drugs 0.000 description 1
- ZDXUKAKRHYTAKV-UHFFFAOYSA-N lercanidipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)(C)CN(C)CCC(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZDXUKAKRHYTAKV-UHFFFAOYSA-N 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
- 229960000831 levobunolol Drugs 0.000 description 1
- 229960002394 lisinopril Drugs 0.000 description 1
- CZRQXSDBMCMPNJ-ZUIPZQNBSA-N lisinopril dihydrate Chemical compound O.O.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 CZRQXSDBMCMPNJ-ZUIPZQNBSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960002237 metoprolol Drugs 0.000 description 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229960005170 moexipril Drugs 0.000 description 1
- 125000002950 monocyclic group Chemical group 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
- 229960000619 nebivolol 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
- 229960000715 nimodipine Drugs 0.000 description 1
- 229960000227 nisoldipine Drugs 0.000 description 1
- 229960005425 nitrendipine Drugs 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 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
- 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
- 229960001199 olmesartan medoxomil Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229960004570 oxprenolol Drugs 0.000 description 1
- 229910052760 oxygen Chemical group 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 229960002582 perindopril Drugs 0.000 description 1
- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 125000005542 phthalazyl group Chemical group 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
- 229920001987 poloxamine Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000223 polyglycerol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229960001289 prazosin 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
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229960001455 quinapril Drugs 0.000 description 1
- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 229960003401 ramipril Drugs 0.000 description 1
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- HSNZZMHEPUFJNZ-SHUUEZRQSA-N sedoheptulose Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO HSNZZMHEPUFJNZ-SHUUEZRQSA-N 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 238000010099 solid forming Methods 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 229960002370 sotalol Drugs 0.000 description 1
- ZBMZVLHSJCTVON-UHFFFAOYSA-N sotalol Chemical compound CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 ZBMZVLHSJCTVON-UHFFFAOYSA-N 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 229960002909 spirapril Drugs 0.000 description 1
- HRWCVUIFMSZDJS-SZMVWBNQSA-N spirapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2(C1)SCCS2)C(O)=O)CC1=CC=CC=C1 HRWCVUIFMSZDJS-SZMVWBNQSA-N 0.000 description 1
- 108700035424 spirapril Proteins 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
- 239000008223 sterile water Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960002613 tamsulosin Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- 229960001693 terazosin Drugs 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
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 150000003538 tetroses Chemical class 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- WRCITXQNXAIKLR-UHFFFAOYSA-N tiadenol Chemical compound OCCSCCCCCCCCCCSCCO WRCITXQNXAIKLR-UHFFFAOYSA-N 0.000 description 1
- 229960000822 tiadenol Drugs 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229960002051 trandolapril Drugs 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 229920000428 triblock copolymer Polymers 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 150000003641 trioses Chemical class 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229960001722 verapamil Drugs 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
- 239000000080 wetting agent Substances 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
- C07C2602/28—Hydrogenated naphthalenes
Definitions
- the present invention aims at providing novel statin derivatives, in particular in a water-dispersible nanoparticulate form, compositions containing them and their therapeutic uses.
- Statins belong to the therapeutic class of cholesterol-lowering drugs.
- they lower LDL-cholesterol (for "Low Density Lipoprotein Cholesterol") and are particularly useful for treating or preventing certain cardiovascular diseases (Journal of the American Medical Association, 251, No.3, 351-374). (1984)).
- LDL-cholesterol for "Low Density Lipoprotein Cholesterol”
- LDL-cholesterol represents the type of lipids most responsible for the formation of atheroma plaques.
- statins decrease the biosynthesis of cholesterol in the liver by inhibiting the enzyme HMG-CoA reductase which controls the limiting step in mevalonic cholesterol synthesis by transforming 3-hydroxy-3-methylglutaryl-coenzyme A in mevalonic acid, a precursor of sterols.
- HMG-CoA reductase which controls the limiting step in mevalonic cholesterol synthesis by transforming 3-hydroxy-3-methylglutaryl-coenzyme A in mevalonic acid, a precursor of sterols.
- statins is prescribed if LDL-cholesterol levels exceed 2.4 mmol / l in coronary patients.
- statins can lower by 20 to 50%, the total cholesterol concentration, by 25 to 60%, the concentration of LDL cholesterol and by 15 to 30%, the concentration of triglycerides.
- statins are often heavy and may for example manifest as hypersensitivity to one of the constituents of the drug, myopathy, which can sometimes lead to severe renal failure, progressive liver disease and / or or a prolonged elevation of transaminases (Armitage J., Lancet 2007; 370: 1781-1790). These effects are notably due to inadequate tissue and / or cell distribution. It is therefore necessary to adjust at best the dose and the mode of administration of the statins.
- improving the bioavailability of active ingredients, intended to be administered orally is a major concern for galenists.
- statins molecules
- lipophilic poses real problems, due mainly to their low solubility in aqueous liquid pharmaceutical excipients, their propensity to precipitate or recrystallize in aqueous solution and their low solubility in liquids. gastrointestinal tract from which they must be absorbed.
- bioavailability of an active ingredient is furthermore a function of its concentration in the gastrointestinal fluid, which itself depends on the release of the active ingredient.
- concentration in the gastrointestinal fluid which itself depends on the release of the active ingredient.
- the more lipophilic an active ingredient the less it tends to migrate into the digestive fluids.
- the digestion of the oily ingredients of this type of formulation often has the advantage of solubilizing the active ingredient in mixed micelles consisting of bile salts and triglyceride lipolysis products of the digestible oil used.
- the presence of surfactants can inhibit lipolysis, which requires the prior in vitro evaluation of the digestibility of the oils of a given formulation.
- the present invention aims precisely to overcome the aforementioned drawbacks and to provide formulations adapted to statins.
- the present invention relates to a complex formed of at least one statin molecule or derivative, covalently coupled to at least one hydrocarbon radical comprising at least 18 carbon atoms and containing at least one unit represented by the following formula:
- the invention provides a complex as defined above, in which the hydrocarbon compound comprises from 18 to 40 carbon atoms, preferably from 18 to 32 carbon atoms.
- the two entities forming the complex defined above are coupled by a covalent bond of the ester, ether, thioether, disulfide, phosphate or amide type and preferably ester.
- Another object of the present invention is nanoparticles of a complex as described above.
- the formulation of the therapeutic active agents considered according to the present invention in the form of nanoparticles according to the present invention constitutes an advantageous alternative with regard to already existing formulations, for several reasons.
- the nanoparticulate state of the statins advantageously makes it possible to improve the tissue and / or cell distribution, making it possible in particular to overcome the side effects of statins and thus to adapt the modes and doses of administration as well as possible.
- the average size of these nanoparticles varies from 30 to
- 500 nm in particular 50 to 250 nm, or even 100 to 400 nm.
- the present invention also relates to a process for the preparation of said nanoparticles comprising at least the dispersion of the complex according to the present invention, in at least one organic solvent, at a concentration which is sufficient, when the resulting mixture is added, to stir, to an aqueous phase, the instantaneous formation of nanoparticles of said complex in suspension in said aqueous phase, and, where appropriate, the isolation of said nanoparticles.
- said method may further comprise a lyophilization step, particularly suitable for accessing solid forming.
- a lyophilization step particularly suitable for accessing solid forming.
- the present invention further relates to a lyophilizate comprising at least one complex and / or at least nanoparticles as described above.
- the present invention aims at a complex and / or nanoparticles as defined above, optionally in the form of a lyophilizate as defined above, for the preparation of a pharmaceutical composition intended for the treatment and / or the prevention of hyperlipemia, hypercholesterolemia, and in particular for the treatment and / or prevention of cardiovascular diseases, obesity, dyslipidemia and / or the prevention of a cardio vascular accident e.
- the subject of the present invention is a complex and / or nanoparticles, optionally in the form of a lyophilizate, as defined according to the present invention, for the treatment and / or prevention of hyperlipemia, hypercholesterolemia, and in particular for the treatment and / or prevention of cardiovascular disease, obesity, dyslipidemia and / or the prevention of a cardiovascular event.
- cardiovascular diseases atherosclerosis (atheroma plaques), cerebral or stroke attacks or cardiac (infarction), arteritis of the lower limbs, coronary diseases such as angina (or angina of chest) or heart attacks such as myocardial infarction, ischemia, thromboses and thromboembolic diseases, diseases of the vessels, such as aneurysms, arteriopathy obliterans of the lower limbs, acute aortic dissection, pulmonary arterial hypertension, thromboembolic diseases, heart attacks, congenital heart disease.
- Hypercholesterolemia usually results from disruption of cholesterol biosynthesis and / or is due to abnormal circulating cholesterol levels.
- statins are also useful as adjuvants of current cancer therapies.
- the subject of the present invention is also the complexes and / or nanoparticles according to the invention, optionally in the form of a lyophilisate, for the treatment and / or prevention of cancers, in particular of the lung, prostate, breast, pancreas , esophagus or colon or as adjuncts to current cancer therapies.
- the present invention also extends to a pharmaceutical composition, in particular a medicament, comprising at least one complex and / or nanoparticles, said complexes and / or nanoparticles being optionally in the form of a lyophilizate, as described above, in association with at least one pharmaceutically acceptable carrier.
- the present invention also relates to said composition for use as a medicament for the treatment and / or prevention of the aforementioned diseases and / or disorders.
- a composition may be particularly useful as a medicament for the treatment and / or prevention of the aforementioned diseases and disorders in so-called "at risk" patients, that is to say in patients having a high blood pressure and with other cardiovascular risk factors such as smoking, overweight, a family history of heart disease or diabetes, including type II diabetes In fact, the presence of such risk factors in a patient increases his risk of occurrence cardiovascular events.
- a compound or radical with a squalene or squalenoyl structure is a compound or radical comprising at least one 2-methyl-buta-2-ene unit, as defined above.
- a compound or hydrocarbon radical with squalene or squalenoyl structure comprises at least 18 carbon atoms and containing at least one 2-methyl-buta-2-ene unit, like a squalene radical.
- the term “compound” or “radical” with a squalene or squalenoyl structure is used as the case may be.
- the term “compound” is more specifically intended to define a compound with a squalene or squalenoyl structure, which, when reacted with an active molecule, forms a complex, whereas the term “radical” defines more precisely the squalene or squalenoyl of the complex formed.
- a hydrocarbon radical with a squalene structure may be represented by the following formula (I):
- - mi 1, 2, 3, 4, 5 or 6;
- n 2 0, 1, 2, 3, 4, 5 or 6; and represents the binding to the statin molecule or derivative, it being understood that when m 2 is 0, then mi is at least 2.
- this compound or one of its derivatives can be represented by the compound of formula (Ibis):
- Y represents a hydrogen atom or a group -L 2 -X 'in which X' represents a function of alcohol, carboxylic acid, thiol, phosphate, amine, carboxamide or ketone type and L 2 represents a single covalent bond or a group C 1 -C 4 alkylene; and mi and m 2 are as defined for the radical of formula (I).
- the hydrocarbon radical comprises at least 18 carbon atoms, in particular from 18 to 40 carbon atoms and preferably from 18 to 32 carbon atoms.
- a compound useful for the formation of a complex according to the present invention is squalene (also called spiracene or sirprene), which is an essential intermediate of cholesterol biosynthesis. Chemically, it is also called (E) 2, 6, 10, 15, 19, 23-Hexamethyl-2, 6, 10, 14, 18, 22-tetracosahexene) of the following formula:
- mi 2, 3, 4, 5 or 6.
- hydrocarbon compounds capable of forming a complex according to the present invention mention may be made more particularly of squalene acid and its derivatives such as 1, 1 ', 2-tris-norsqualenic acid, 1, 1', 2-tris-norsqualenamine, 1,1 ', 2-tris-norsqualenol, 1,1', 2-tris-norsqualethiol, squalenacetic acid, squalenylethanol, squalenylethanethiol, squalenylethylamine
- a complex according to the present invention comprises at least one hydrocarbon radical represented by a radical of formula (I) as defined above.
- a complex according to the present invention may contain at least one radical derived from a molecule of 1, Y, 2-tris-norsqualenic acid.
- a complex according to the present invention comprises at least two hydrocarbon radicals as defined according to the present invention and in particular, represented by the compound of formula (I) above.
- a hydrocarbon compound as defined above spontaneously shows, when it is placed in the presence of a polar medium and more particularly water, a compacted conformation.
- statin molecule can indeed be only partially or totally in the compacted state in the nanoparticles formed.
- At least one hydrocarbon radical mentioned above is covalently bound to a statin molecule.
- the number of hydrocarbon derivative molecules capable of interacting with said molecule may be greater than 1.
- statins or derivatives have in common a 4-hydroxy-6-oxo-2H-pyran system, which can also be in dihydroxy acid form which interacts with the active site of the HMG-CoA reductase enzyme involved in the synthesis of cholesterol and a lipophilic moiety presenting itself in particular as a polysubstituted hexahydronaphthalenic system but may also be replaced by a polysubstituted heteroaromatic system as in atorvastatin or fluvastatin.
- statins are: simvastatin, lovastatin, pravastatin, atorvastatin, fluvastatin and rosuvastatin.
- statins are generally of a lipophilic nature (WO 02/053131).
- the lipophilicity of an active principle can be determined according to its partition coefficient (P) between octanol and water, which corresponds to the ratio of concentration of the active ingredient in octanol (C oct ) / concentration of the active principle in water (CEau).
- statin or derivative is understood to mean a compound represented by the formula (IIa), (Hb) or (IIc) which follows:
- Ra represents an aryl group, heteroaryl, optionally substituted with one or more group (s) R;
- - R independently represents a hydroxyl group, a Ci-C 6 alkyl
- Ci-C 6 an -0-C (O) Ci-C 6 alkyl, phenyl, -NRiR 2 group, a -C (O) NRiR 2, -C (O) OR3, said alkyl and phenyl groups being optionally substituted with one or more halogen atoms or with one or more hydroxyl groups;
- R 1 and R 2 represent, independently of one another, a hydrogen atom, a C 1 -C 6 alkyl group, -SO 2 -C 1 -C 6 alkyl, a phenyl, said groups C 1 -C 6 alkyl and phenyl being optionally substituted with one or more halogen atoms or with one or more hydroxyl groups;
- R3 represents a hydrogen atom, a Ci-C 6 alkyl optionally substituted by one or more halogen atoms or by one or more hydroxyl groups.
- halogen atom a fluorine atom, a chlorine atom, a bromine atom or an iodine atom
- a hydroxyl group an -OH group
- an alkyl a saturated, linear or branched aliphatic group.
- alkoxy an -O-alkyl radical where the alkyl group is as defined previously, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert -butoxy;
- an aryl group an aromatic group which may be partially unsaturated monocyclic or bicyclic comprising from 6 to 10 carbon atoms.
- a unicycle mention may be made of phenyl.
- naphthyl By way of example of a bicycle, there may be mentioned naphthyl, said naphthyl may be partially unsaturated, such as 1,2,6,7,8,8a-hexahydronaphthyl;
- a heteroaryl group a said aryl group further comprising at least one heteroatom selected from nitrogen, sulfur or oxygen.
- a monocycle mention may be made of furanyl, thiophenyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyridinyl, pyrimidyl and pyrazinyl.
- the compounds of general formula (IIa), (Hb) or (IIc) may comprise one or more asymmetric carbons. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention.
- the compounds of the aforementioned formulas may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.
- salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the separation of the compounds of the abovementioned formulas also form part of the invention.
- the compounds of general formula (IIa), (Hb) or (IIc) may, in addition, be in the form of hydrates or solvates, namely in the form of associations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates are also part of the invention.
- statins of formula (IIa) that are suitable for the present invention, mention may be made, for example, of pravastatin and atorvastatin.
- statins of formula (Hb) that are suitable for the present invention, mention may be made, for example, of simvastatin and lovastatin.
- statins of formula (IIc) that are suitable for the present invention, mention may be made, for example, of fluvastatin and rosuvastatin.
- a statin particularly suitable for the implementation of the present invention is represented by a compound of formula (IIa).
- simvastatin simvastatin, lovastatin, pravastatin, atorvastatin, fluvastatin or rosuvastatin, and most particularly pravastatin.
- the conjugation of a molecule of statin with a hydrocarbon derivative according to the invention, and more particularly with 1,1 ', 2-tris-norsqualenol, confers on the molecule of statin physico-chemical characteristics which are sufficient to confer on it ability to form particles by nanoprecipitation, particles whose size is compatible with any mode of administration, in particular intravenous and oral.
- such conjugation leads to the formation of a complex or conjugate statin / hydrocarbon radical according to the present invention, that is to say an entity comprising a radical derived from a molecule of statin, bound covalently, to a hydrocarbon radical as defined above.
- a complex or conjugate statin / hydrocarbon radical that is to say an entity comprising a radical derived from a molecule of statin, bound covalently, to a hydrocarbon radical as defined above.
- the terms “complex” or “conjugate” will thus be used indifferently to designate such an entity.
- the present invention relates to a complex characterized in that it has the ability to spontaneously organize in the state of nanoparticles when in the presence of an aqueous medium.
- statin / hydrocarbon radical complex requires that the two entities of the complex carry functions capable of forming a covalent bond and / or a linker, as defined below. These functions may or may not be present on the two starting entities. In the negative, the 171st entity (s) of departure will have to undergo a modification, prior to the coupling reaction.
- the hydrocarbon compound according to the invention is generally carrying a function capable of reacting with a function present on the molecule of said statin, so as to establish a covalent bond between the two entities, for example ester, ether , thioether, disulfide, phosphate or amide, thereby forming a covalent complex.
- the terpene-containing hydrocarbon compound is 1,1 ', 2-tris-norsqualenol or a derivative thereof and in particular 1,1', 2-tris-norsqualenol bromoacetate.
- the covalent link existing between the two types of molecules can be represented by a spacer or linker.
- Such an arm may in particular be useful for increasing the strength of the statin / hydrocarbon radical interaction according to the invention or to facilitate the activation of the conjugate after its administration by the enzymes of the organism (esterases, cathepsins, for example ) and thus allow the controlled release of the statin molecule.
- Such an arm makes it possible precisely to introduce, via each of the two ends of its skeleton, the appropriate functions, that is to say respectively possessing the expected reaction affinity, one for the function present on the derivative with hydrocarbon structure according to US Pat. invention and the other for the function present on the relevant statin molecule.
- this linker also has at its skeleton a labile function, which is favorable later to the separation of the compound from hydrocarbon structure of the statin molecule considered. It may for example be a peptide motif recognizable by an enzyme.
- linkage type patterns are well known to those skilled in the art and their implementation clearly falls within its competence.
- the following terms mean:
- saccharide unit a radical comprising at least one radical chosen from trioses (glyceraldehyde, dihydroxyacetone), tetroses (erythrose, threose, erythrulose), pentoses (arabinose, lyxose, ribose, deoxyribose, xylose, ribulose, xylulose), hexoses (allose, altrose, galactose, glucose, gulose, idose, mannose, talose, fructose, psicose, sorbose, tagatose, heptoses (mannoheptulose, sedoheptulose), octose (octolose, 2-keto-3-deoxy-manno-octonate), isonoses (sialose), and - "(poly) amino acid motif", a unit having at least one unit:
- n is greater than or equal to 1
- R ' represents a hydrogen atom, a C 1-6 alkyl group, optionally substituted by one or more hydroxyls, a C 1-6 alkoxy group.
- a "covalent bond” preferably represents a covalent bond especially as specified above, but also covers a covalent bond represented by a linker as defined above.
- the covalent complex according to the present invention can be represented by the compound of formula (III) which follows:
- X represents a single covalent bond or a function of ester, ether, thioether, disulfide, phosphate or amide type
- Li and L 2 represent, independently of each other, a single covalent bond or a C 1 -C 4 alkylene group
- Ra is as defined for the compound of formula (IIa) (Hb) or (IIc); and mi and m 2 are as defined above for the compound of formula (I); and
- Ci-C 4 alkylene group a divalent alkyl group may include 1 to 4 carbon atoms.
- the present invention relates more particularly to a complex, represented by the compound of formula (HIa) or (HIb) which follows:
- mi and m 2 are as defined for the compound of formula (I) and L 2 is as defined for the compound of formula (III).
- An object of the present invention is therefore a complex according to the invention, which can be represented by formulas (III), (HIa) or (HIb), as defined above.
- reaction necessary for the establishment of at least one covalent bond between at least one molecule of said statin and at least one hydrocarbon-based radical according to the present invention can be carried out according to standard conditions and its realization therefore clearly falls within the knowledge of the skilled person.
- the bond between the statin and the hydrocarbon radical is produced by nucleophilic substitution with 1,1 ', 2-tris-nor-squalenyl bromoacetate.
- This reaction is generally carried out in solution in a polar solvent in the presence and in excess of at least one hydrocarbon compound considered according to the present invention with respect to the statin molecule implemented according to the invention, for example at the rate of two equivalents. , according to the standard conditions required to make the two specific functions carried by each of the two entities interact.
- each of the groups to be reacted carries functions capable of reacting with each other such that by for example a carboxyl function with a hydroxyl function to form an ester bond or an amino function with a carboxyl function to form an amide bond.
- the statin molecule on the one hand, and the hydrocarbon compound on the other hand are modified prior to the coupling reaction in order to provide them with the appropriate function to give them the reactivity necessary for the formation of a covalent bond between them.
- each of the two molecules is modified in order to establish an amide or ester bond between them.
- a hydrocarbon compound starting for the synthesis of a complex according to the invention is a squalene derivative, such as, for example, 1, 1 ', 2-tris-norsqualenol, as illustrated in step 1.1 of Example 1 Nanoparticles according to the invention
- the covalent coupling of at least one molecule of statin considered according to the invention with at least one hydrocarbon compound according to the invention is such as to confer on the molecule of statin thus complexed, an ability to organize under a compacted form in a polar solvent medium, thus leading to the formation of nanoparticles.
- the nanoparticles thus obtained have an average size ranging from 30 to 500 nm, and in particular from 50 to 250 nm, or even from 100 to 400 nm, measured by light scattering using the Coulter ® nanosizer. N4MD, Coulter Electronics, Hialeah, USA.
- An object of the invention is nanoparticles according to the invention, the mean size of which varies from 30 to 500 nm, in particular from 50 to 250 nm, or even from 100 to 400 nm.
- Another object of the present invention relates to 4- (N) - squalenoylpravastatin nanoparticles. Obtaining such nanoparticles is illustrated in Example 2.
- the nanoparticles according to the present invention are particularly advantageous for administration intended for the oral route.
- nanoparticles from the complex described above can be carried out according to conventional techniques insofar as they involve bringing into the presence of a complex with an aqueous medium under conditions conducive to its agglomeration in the state of nanoparticles. It may in particular be methods known as nanoprecipitation or emulsion / solvent evaporation.
- the nanoparticles according to the present invention can preferably be obtained in the following manner.
- a statin / hydrocarbon compound complex is formed, by coupling at least one hydrocarbon compound according to the invention to at least one statin molecule according to the invention, as described above.
- Said complex obtained is then dispersed in at least one organic solvent (for example an alcohol such as ethanol or acetone) at a concentration of sufficient to obtain, during the addition of the resulting mixture, with stirring, and generally at drip, with an aqueous phase, the instantaneous formation of nanoparticles according to the invention in suspension in said aqueous phase. If necessary, the nanoparticles are isolated according to the techniques well known to those skilled in the art.
- organic solvent for example an alcohol such as ethanol or acetone
- the reaction can generally be carried out at room temperature. Whatever it is, the reaction temperature must not affect the activity of the statin molecule under consideration.
- the process for preparing the nanoparticles according to the invention is particularly advantageous insofar as it does not necessarily require the presence of surfactants, but may nevertheless be necessary in the case, for example, where the use of pravastatin.
- surfactants generally advantageously devoid of any toxicity
- This type of surfactant can also provide access to even smaller sizes during the formation of nanoparticles.
- polyoxyethylene-polyoxypropylene copolymers, phospholipid derivatives and lipophilic derivatives of polyethylene glycol may be mentioned.
- polyethylene glycol As the lipophilic derivative of polyethylene glycol, mention may be made, for example, of polyethylene glycol cholesterol and polyethylene glycol squalene.
- polyoxyethylene-polyoxypropylene block copolymers there may be mentioned polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymers, also called poloxamers ® , pluronics ® or synperonics and which are sold in particular by the company BASF.
- poloxamines which consist of hydrophobic segments (based on polyoxypropylene), hydrophilic segments (based on polyoxyethylene) and a central portion derived from the ethylene diamine unit can also be used.
- the nanoparticles according to the invention are of course capable of carrying on the surface a multitude of reactive functions, such as hydroxyl functions or amine for example. It is therefore conceivable to fix these functions all kinds of molecules, including covalent bonds.
- marker-type molecules compounds capable of providing a targeting function, as well as any compound capable of conferring on them characteristics. specific pharmacokinetics.
- lipophilic derivatives of polyethylene glycol such as, for example, the polyethylene glycol / cholesterol conjugate, polyethylene glycol-phosphatidylethanolamine or better still polyethylene glycol / squalene.
- the polyethylene glycol / squalene conjugate is associated, in this case, with the nanoparticles according to the invention, and thus leads to the formation of coated nanoparticles. on the surface of polyethylene glycol.
- the polyethylene glycol / squalene conjugate advantageously acts during the process of forming the nanoparticles according to the invention as a surfactant because of its amphiphilic behavior and thus stabilizes the colloidal solution, thus reducing the size of the nanoparticles formed. .
- a surface coating based on such compounds and in particular polyethylene glycol or the polyethylene glycol / cholesterol conjugate or the polyethylene glycol / squalene conjugate is in fact advantageous for conferring increased vascular remanence because of a significant reduction in the capture of nanoparticles by hepatic macrophages.
- the nanoparticles according to the invention are formulated in the form of an aqueous dispersion.
- this aqueous dispersion contains less than 5% by weight, or even less than 2% by weight and more particularly is devoid of surfactant or the like such as, for example, polyethylene glycols, polyglycerol and their derivatives, such as esters for example.
- surfactant or the like such as, for example, polyethylene glycols, polyglycerol and their derivatives, such as esters for example.
- this aqueous dispersion contains less than 5% by weight, or even less than 2% by weight of C 2 to C 4 alcohol such as, for example, ethanol.
- the formulation in an aqueous medium of the statin in question using squalenic acid in the form of water-dispersible nanoparticles makes it possible advantageously to to obtain a suspension of nanoparticles with no other additive than the 5% dextrose necessary to obtain the isotonicity of the injectable suspension.
- the nanoparticles according to the invention are in the form of lyophilisate.
- the present invention also relates to the use of at least one nanoparticle according to the invention in pharmaceutical compositions.
- Another aspect of the invention therefore relates to a pharmaceutical composition
- a pharmaceutical composition comprising at least, as an active ingredient, a complex according to the present invention, in particular in the form of nanoparticles.
- the complexes according to the present invention can be associated with at least one pharmaceutically acceptable vehicle.
- the complexes and / or nanoparticles When used in dispersion in an aqueous solution, they can be combined with sequestering or chelating agent excipients, antioxidant, pH modifying agents and / or buffering agents.
- the pharmaceutical compositions according to the invention may contain preserving agents, wetting agents, solubilizing agents and coloring agents.
- statins may contain other assets that may benefit from therapeutic benefit, in addition to the effect of statins.
- active substances that can be combined with the complexes and / or nanoparticles according to the present invention, mention may be made in particular of active agents intended to reduce arterial hypertension, such as antihypertensives or hypotensives or other compounds with lipid-lowering activity.
- diuretics such as thiazides, diuretics of Henle's loop such as furozemide, anti-aldosterones, or ⁇ -blockers such as acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol, nebivolol, nadolol, oxprenolol, propranolol, pindolol, sotalol, carvedilol, labetalol, levobunolol, timolol, angiotensin converting enzyme inhibitors ( IECA, IEC) such as benazepril, captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril,
- the complexes and / or nanoparticles according to the present invention can be administered by any conventional route. However, as previously stated, given the small size of their particles, they can be administered in the form of an aqueous suspension intravenously and therefore compatible with vascular microcirculation. For obvious reasons, the quantities of the complex and / or nanoparticle according to the invention that may be used may vary significantly depending on the mode of use and the route chosen for their administration.
- Infrared spectra are obtained by measurement on a solid or a pure liquid using a Fourier spectrometer (Transform Bruker Vector ® 22). Only significant absorptions are noted. Optical rotations were measured using a Perkin-Elmer ® 241, at a wavelength of 589 nm.
- the 1 H and 13 C NMR spectra were recorded using a Bruker ARX ® 400 spectrometer (at 400 MHz and 100 MHz, respectively for 1 H and 13 C) or Bruker Avance ® 300 (at 300 MHz and 75 MHz, respectively for 1 H and 13 C). Mass spectra were recorded using a Bruker Esquire-LC ® instrument.
- Step 1.1 (4 J E, 8 J E, 12 J E, 16 J E) -4,8,13,17,21-Pentamethyldocosa-4,8,12,16,20-pentaen-1-ol:
- Squalene aldehyde is reduced to squalenol.
- 1.15 g (3 mmol) of squalene aldehyde dissolved in 6 mL of ethanol are added, at 0 ° C., in small portions to 106 mg (0.9 equiv., 2.7 mmol) of sodium borohydride.
- the mixture is stirred under nitrogen at room temperature for 15 min, then the reaction mixture is neutralized with a solution of 2N HCl. Then, the solvent is distilled under reduced pressure.
- Step 1.2 Bromoacetate (4 J , 8 J E, 12 J E, 16 J E) -4,8,13,17,21-pentamethyldocosa-4,8,12,16,20-pentaen-1-yl. 500 mg (1.3 mmol) of squalenol dissolved in 6 ml of anhydrous CH 2 Cl 2 are added, 216 mg (1.55 equiv., 2.01 mmol) of bromoacetic acid and a few mg of DMAP. The mixture is cooled to 0 ° C., then 317 mg (1.5 equiv, 1.95 mmol) of DCC dissolved in 2 ml of CH 2 Cl 2 are added in small portions.
- Step 1.3 2-Oxo-2 - ⁇ [(4E, 8E, 12E, 16E) -4,8,13,17,21-pentamethyldocosa-
- the nanoparticles are obtained by the precipitation / solvent evaporation method, by analogy with the method described in Fessi H. et al, Int. J. Pharm., 55; 1989, R1-R4.
- SQpravastatin 4 mg are dissolved in 0.5 mL of ethanol in a pillbox.
- 2 mg of SQ-PEG is dissolved in 0.2 ml of acetone and 0.1 ml of ethanol, in the order mentioned.
- the two solutions are then mixed and the solution obtained is added dropwise, with stirring (500 rpm) to 1 ml of a 5% aqueous dextrose solution.
- the precipitation of the nanoparticles is immediate.
- the vial containing the SQpravastatin solution is rinsed and the rinse solution added to the nanoparticle suspension.
- the suspension of nanoparticles is transferred to a calibrated flask and concentrated under reduced pressure in a rotary evaporator (50-100 mbar at 20 ° C. for 10 min and then at 37 ° C. for approximately 3-5 minutes) to a weight of from 0.8 to 0.degree. 9 g.
- the solution is then supplemented to 1 g using either a 5% dextrose solution or sterile water.
- the size of the nanoparticles obtained, measured with a Malvern nanosizer (Zetasizer) is 146 nm.
- the nanoparticles have an average size, compatible with any mode of administration, as well as a good stability in aqueous solution.
- the polydispersity index was determined according to the methods well known to those skilled in the art (for example, by analogy with the method described in Couvreur et al., Nanoletters, Vol 6, No. 1, pages 2544-2548). , 2006).
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Child & Adolescent Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2742181A CA2742181A1 (fr) | 2008-10-29 | 2009-10-28 | Nanoparticules de statine |
US13/126,752 US8748414B2 (en) | 2008-10-29 | 2009-10-28 | Statin nanoparticles |
JP2011533903A JP2012507503A (ja) | 2008-10-29 | 2009-10-28 | スタチンナノ粒子 |
EP09759783A EP2355801A1 (fr) | 2008-10-29 | 2009-10-28 | Nanoparticules de statine |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0857356A FR2937537A1 (fr) | 2008-10-29 | 2008-10-29 | Nanoparticules de statine |
FR0857356 | 2008-10-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2010049900A1 true WO2010049900A1 (fr) | 2010-05-06 |
Family
ID=40616616
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2009/054781 WO2010049900A1 (fr) | 2008-10-29 | 2009-10-28 | Nanoparticules de statine |
Country Status (6)
Country | Link |
---|---|
US (1) | US8748414B2 (fr) |
EP (1) | EP2355801A1 (fr) |
JP (1) | JP2012507503A (fr) |
CA (1) | CA2742181A1 (fr) |
FR (1) | FR2937537A1 (fr) |
WO (1) | WO2010049900A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013136294A1 (fr) | 2012-03-16 | 2013-09-19 | Centre National De La Recherche Scientifique | Complexes de vitamine c |
FR3110427A1 (fr) | 2020-05-20 | 2021-11-26 | Laboratoires Eriger | Conjugué terpenique de couplage |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2931152B1 (fr) * | 2008-05-16 | 2010-07-30 | Centre Nat Rech Scient | Nouveau systeme de transfert d'acide nucleique |
FR2937549B1 (fr) * | 2008-10-29 | 2011-04-01 | Centre Nat Rech Scient | Nanoparticules de derives beta-lactamine |
AU2013256362A1 (en) * | 2012-05-01 | 2014-11-13 | Catabasis Pharmaceuticals, Inc. | Fatty acid conjugates of statin and FXR agonists: compositions and methods of use |
EP2742955A1 (fr) | 2012-12-12 | 2014-06-18 | Centre National De La Recherche Scientifique | Nanoparticules à base de bioconjugué de GAG |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2073193A (en) * | 1980-03-31 | 1981-10-14 | Sankyo Co | Inhibitors of Cholesterol Biosynthesis, their Preparation and Use |
WO1997020835A1 (fr) * | 1995-12-05 | 1997-06-12 | Harbor Branch Oceanographic Institution, Inc. | Composes de discodermolide et compositions pharmaceutiques contenant ces composes, a utiliser dans la therapie du cancer |
WO2003103640A1 (fr) * | 2002-06-10 | 2003-12-18 | Elan Pharma International, Ltd | Formulations nanoparticulaires comprenant des derives d'un inhibiteur de la hmg coa-reductase (≤statines≥), nouvelles combinaisons associees et production de ces compositions pharmaceutiques |
US20060013882A1 (en) * | 2002-05-15 | 2006-01-19 | Rutgers, The State University | Tri-block copolymers for nanosphere-based drug delivery |
WO2006090029A1 (fr) * | 2004-06-30 | 2006-08-31 | Centre National De La Recherche Scientifique | Nanoparticules de derives de la gemcitabine |
US20070237827A1 (en) * | 2005-01-04 | 2007-10-11 | Hsing-Wen Sung | Nanoparticles for drug delivery |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9405304D0 (en) | 1994-03-16 | 1994-04-27 | Scherer Ltd R P | Delivery systems for hydrophobic drugs |
US6726911B1 (en) | 1999-03-09 | 2004-04-27 | Ganomycin | Biologically active compounds of Ganoderma pfeifferi DSM 13239 |
FR2818905A1 (fr) | 2000-12-28 | 2002-07-05 | Cll Pharma | Compositions pharmaceutiques colloidales micellaires renfermant un principe actif lipophile |
US7026472B2 (en) | 2002-05-06 | 2006-04-11 | University Of South Florida | Methods for preventing and treating cancer using N-thiolated β-lactam compounds and analogs thereof |
US20090004277A1 (en) | 2004-05-18 | 2009-01-01 | Franchini Miriam K | Nanoparticle dispersion containing lactam compound |
US7846920B2 (en) | 2006-09-13 | 2010-12-07 | University Of South Florida | Heterosubstituted N-thiolated beta-lactam compounds and methods of use |
FR2924024B1 (fr) | 2007-11-27 | 2012-08-17 | Centre Nat Rech Scient | Nanoparticules d'actifs therapeutiques de faible solubilite aqueuse |
FR2931152B1 (fr) | 2008-05-16 | 2010-07-30 | Centre Nat Rech Scient | Nouveau systeme de transfert d'acide nucleique |
FR2937549B1 (fr) | 2008-10-29 | 2011-04-01 | Centre Nat Rech Scient | Nanoparticules de derives beta-lactamine |
-
2008
- 2008-10-29 FR FR0857356A patent/FR2937537A1/fr not_active Withdrawn
-
2009
- 2009-10-28 EP EP09759783A patent/EP2355801A1/fr not_active Withdrawn
- 2009-10-28 CA CA2742181A patent/CA2742181A1/fr not_active Abandoned
- 2009-10-28 WO PCT/IB2009/054781 patent/WO2010049900A1/fr active Application Filing
- 2009-10-28 JP JP2011533903A patent/JP2012507503A/ja active Pending
- 2009-10-28 US US13/126,752 patent/US8748414B2/en not_active Expired - Fee Related
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2073193A (en) * | 1980-03-31 | 1981-10-14 | Sankyo Co | Inhibitors of Cholesterol Biosynthesis, their Preparation and Use |
WO1997020835A1 (fr) * | 1995-12-05 | 1997-06-12 | Harbor Branch Oceanographic Institution, Inc. | Composes de discodermolide et compositions pharmaceutiques contenant ces composes, a utiliser dans la therapie du cancer |
US20060013882A1 (en) * | 2002-05-15 | 2006-01-19 | Rutgers, The State University | Tri-block copolymers for nanosphere-based drug delivery |
WO2003103640A1 (fr) * | 2002-06-10 | 2003-12-18 | Elan Pharma International, Ltd | Formulations nanoparticulaires comprenant des derives d'un inhibiteur de la hmg coa-reductase (≤statines≥), nouvelles combinaisons associees et production de ces compositions pharmaceutiques |
WO2006090029A1 (fr) * | 2004-06-30 | 2006-08-31 | Centre National De La Recherche Scientifique | Nanoparticules de derives de la gemcitabine |
US20070237827A1 (en) * | 2005-01-04 | 2007-10-11 | Hsing-Wen Sung | Nanoparticles for drug delivery |
Non-Patent Citations (7)
Title |
---|
BHATT A ET AL: "Accumulation of an E,E,E-Triene by the Monensin-Producing Polyketide Synthase when Oxidative Cyclization is Blocked", ANGEWANDTE CHEMIE, vol. 117, no. 43, 4 November 2005 (2005-11-04), pages 7237 - 7240, XP002528559, ISSN: 0044-8249 * |
COUVREUR PATRICK ET AL: "Squalenoyl nanomedicines as potential therapeutics", NANO LETTERS, vol. 6, no. 11, 1 November 2006 (2006-11-01), pages 2544 - 2548, XP002489419, ISSN: 1530-6984 * |
DATE ET AL: "Design and evaluation of self-nanoemulsifying drug delivery systems (SNEDDS) for cefpodoxime proxetil", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 329, no. 1-2, 20 December 2006 (2006-12-20), pages 166 - 172, XP005809188, ISSN: 0378-5173 * |
DIXIT R P ET AL: "Formulation and in vivo evaluation of self-nanoemulsifying granules for oral delivery of a combination of ezetimibe and simvastatin", DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, vol. 34, no. 12, 1 January 2008 (2008-01-01), pages 1285 - 1296, XP009117110, ISSN: 0363-9045 * |
GUNASEKERA S P ET AL: "Five new discodermolide analogues from the marine sponge discodermia species", JOURNAL OF NATURAL PRODUCTS, vol. 65, 1 January 2002 (2002-01-01), pages 1643 - 1648, XP003007586, ISSN: 0163-3864 * |
KANG BOK KI ET AL: "Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs.", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 274, no. 1-2, 15 April 2004 (2004-04-15), pages 65 - 73, XP009117164, ISSN: 0378-5173 * |
SURESH G ET AL: "Preparation, characterization, and in vitro and in vivo evaluation of lovastatin solid lipid nanoparticles", AAPS PHARMSCITECH, vol. 8, no. 1, 23 March 2007 (2007-03-23), pages E162 - E170, XP009117188, ISSN: 1530-9932 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013136294A1 (fr) | 2012-03-16 | 2013-09-19 | Centre National De La Recherche Scientifique | Complexes de vitamine c |
JP2015516944A (ja) * | 2012-03-16 | 2015-06-18 | セントレ・ナショナル・デ・ラ・レシェルシェ・サイエンティフィーク | ビタミンc複合体 |
US9295630B2 (en) | 2012-03-16 | 2016-03-29 | Centre National De La Recherche Scientifique | Vitamin C complexes |
FR3110427A1 (fr) | 2020-05-20 | 2021-11-26 | Laboratoires Eriger | Conjugué terpenique de couplage |
WO2021240099A1 (fr) | 2020-05-20 | 2021-12-02 | Laboratoires Eriger | Conjugue terpenique de couplage |
Also Published As
Publication number | Publication date |
---|---|
EP2355801A1 (fr) | 2011-08-17 |
CA2742181A1 (fr) | 2010-05-06 |
JP2012507503A (ja) | 2012-03-29 |
FR2937537A1 (fr) | 2010-04-30 |
US20110269830A1 (en) | 2011-11-03 |
US8748414B2 (en) | 2014-06-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2055711B1 (fr) | Utilisation de l'acide squalénique pour la formulation d'un principe actif à l'état de nanoparticules | |
CN106715456B (zh) | 定向淋巴的前药 | |
FI119474B (fi) | Ei-steroidisten tulehduksenvastaisten karboksyylihappojen estereitä ja amideja, joita voidaan käyttää antioksidantteina, 5-lipoksigenaasi-inhibiittoreina ja ei-steroidisina tulehduksenvastaisina tuotteina | |
WO2010049900A1 (fr) | Nanoparticules de statine | |
TWI355934B (en) | Pharmaceutical composition for treatment or prophy | |
EP2355800A1 (fr) | Nanoparticules de derives beta-lactamine | |
EP0087378A2 (fr) | Ethers-oximes d'alcoylaminoalcools comme médicaments, produits nouveaux et procédés pour leur préparation | |
EP1212313B1 (fr) | Derives de 7-carboxy-flavones, procede de preparation et application en therapeutique | |
JP3974397B2 (ja) | デクルシノール(Decursinol)またはその誘導体からなる鎮痛剤 | |
EP1664012A1 (fr) | Derives de tocopherol a longue chaine hydroxylee utiles comme neurotrophiques | |
WO2001036437A1 (fr) | DERIVES DE β-D-5-THIOXYLOSE, PROCEDE DE PREPARATION ET UTILISATION EN THERAPEUTIQUE | |
EP2825531B1 (fr) | Conjugués de vitamine c | |
FR3122827A1 (fr) | Prodrogue nucléolipidique antioxydante, composition pharmaceutique pour son administration et leurs utilisations thérapeutiques | |
WO2012093227A1 (fr) | Promédicaments pour une délivrance au niveau du foie d'une statine | |
FR3104946A1 (fr) | Formulation d’un dendrimère anti-inflammatoire pour le traitement de psoriasis | |
FR3124946A1 (fr) | Nouveaux composés dérivés des schweinfurthines G, E, F | |
TW201930261A (zh) | 光學活性之反式蝦紅素衍生物或其鹽、及含有該等化合物之組合物 | |
ES2359435T3 (es) | Ácido 2,3,4,5-tetrahidroxi-6-sulfooxihexanoico y sus sales metálicas para uso médico. | |
EP3157903A1 (fr) | Utilisation d'un nouveau compose 3-aryl-4-catechol-pyrrole-n-propanol et ses derives pour le traitement du cancer et des pathologies associees a une angiogenese excessive | |
JP2005306829A (ja) | 低比重リポタンパクの酸化変性防止剤および抗アテローム性動脈硬化剤 | |
CA2780627A1 (fr) | Nouveaux derives de mannopyranoside ayant une activite anticancereuse | |
WO2003002586A1 (fr) | Derives de [4-(4-cyanobenzoyl)phenyl]glycofuranoside, utilisation en tant que medicament, procede d'obtention et compositions pharmaceutiques les contenant | |
WO2003002585A1 (fr) | Derives de [4-(4-cyanobenzoyl)phenyl]glycopyranoside, utilisation en tant que medicament, procede d'obtention et compositions | |
FR2920991A1 (fr) | Composition a base de diacerheine pour le traitement de l'arthrose |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09759783 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2742181 Country of ref document: CA Ref document number: 2011533903 Country of ref document: JP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REEP | Request for entry into the european phase |
Ref document number: 2009759783 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009759783 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13126752 Country of ref document: US |