CN113143888A - 用于治疗心血管疾病的口服制剂 - Google Patents
用于治疗心血管疾病的口服制剂 Download PDFInfo
- Publication number
- CN113143888A CN113143888A CN202110259129.4A CN202110259129A CN113143888A CN 113143888 A CN113143888 A CN 113143888A CN 202110259129 A CN202110259129 A CN 202110259129A CN 113143888 A CN113143888 A CN 113143888A
- Authority
- CN
- China
- Prior art keywords
- acetylsalicylic acid
- coating
- dosage form
- dosage unit
- pharmaceutical dosage
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000024172 Cardiovascular disease Diseases 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title description 7
- 229960001138 acetylsalicylic acid Drugs 0.000 claims abstract description 91
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims abstract description 88
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims abstract description 40
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims abstract description 29
- 238000011282 treatment Methods 0.000 claims abstract description 10
- 230000002265 prevention Effects 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 44
- 238000000576 coating method Methods 0.000 claims description 39
- 239000011248 coating agent Substances 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 30
- 239000002552 dosage form Substances 0.000 claims description 28
- 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 claims description 26
- 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 claims description 26
- 229960005370 atorvastatin Drugs 0.000 claims description 26
- 229920000642 polymer Polymers 0.000 claims description 23
- 239000002775 capsule Substances 0.000 claims description 22
- 239000013543 active substance Substances 0.000 claims description 19
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 15
- -1 polyethylene Polymers 0.000 claims description 15
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 15
- 229920003169 water-soluble polymer Polymers 0.000 claims description 15
- 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 13
- 229960000672 rosuvastatin Drugs 0.000 claims description 13
- 229920003176 water-insoluble polymer Polymers 0.000 claims description 8
- 239000008351 acetate buffer Substances 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 239000004698 Polyethylene Substances 0.000 claims description 3
- 239000008199 coating composition Substances 0.000 claims description 3
- 229920000573 polyethylene Polymers 0.000 claims description 3
- 230000003993 interaction Effects 0.000 abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 5
- 239000003826 tablet Substances 0.000 description 45
- 235000002639 sodium chloride Nutrition 0.000 description 33
- 238000004090 dissolution Methods 0.000 description 30
- 238000009472 formulation Methods 0.000 description 22
- 239000007941 film coated tablet Substances 0.000 description 18
- 230000000694 effects Effects 0.000 description 16
- 239000002253 acid Substances 0.000 description 15
- 229960003401 ramipril Drugs 0.000 description 13
- 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 13
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 9
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 9
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 9
- 239000008187 granular material Substances 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 9
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 8
- 239000005541 ACE inhibitor Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 8
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 8
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 8
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 7
- 125000005273 2-acetoxybenzoic acid group Chemical group 0.000 description 6
- 108010010803 Gelatin Proteins 0.000 description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 6
- 108090000783 Renin Proteins 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 6
- 229940125364 angiotensin receptor blocker Drugs 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 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 6
- 239000011247 coating layer Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 229920000159 gelatin Polymers 0.000 description 6
- 235000019322 gelatine Nutrition 0.000 description 6
- 235000011852 gelatine desserts Nutrition 0.000 description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000006187 pill Substances 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 101800000733 Angiotensin-2 Proteins 0.000 description 5
- 102400000345 Angiotensin-2 Human genes 0.000 description 5
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 5
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 5
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 5
- 102100028255 Renin Human genes 0.000 description 5
- 229950006323 angiotensin ii Drugs 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 230000002526 effect on cardiovascular system Effects 0.000 description 5
- 238000009505 enteric coating Methods 0.000 description 5
- 239000002702 enteric coating Substances 0.000 description 5
- 239000007888 film coating Substances 0.000 description 5
- 238000009501 film coating Methods 0.000 description 5
- 239000008273 gelatin Substances 0.000 description 5
- 229940014259 gelatin Drugs 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 150000002596 lactones Chemical group 0.000 description 5
- 239000011859 microparticle Substances 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 239000002461 renin inhibitor Substances 0.000 description 5
- 229940086526 renin-inhibitors Drugs 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000000454 talc Substances 0.000 description 5
- 235000012222 talc Nutrition 0.000 description 5
- 229910052623 talc Inorganic materials 0.000 description 5
- 229940033134 talc Drugs 0.000 description 5
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 4
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 4
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 4
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 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 4
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 229960002478 aldosterone Drugs 0.000 description 4
- 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 4
- 239000011230 binding agent Substances 0.000 description 4
- 230000036772 blood pressure Effects 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 229960005069 calcium Drugs 0.000 description 4
- 235000001465 calcium Nutrition 0.000 description 4
- 125000002091 cationic group Chemical group 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000007884 disintegrant Substances 0.000 description 4
- 238000007922 dissolution test Methods 0.000 description 4
- 229960001375 lactose Drugs 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 208000010125 myocardial infarction Diseases 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 235000021317 phosphate Nutrition 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 235000010413 sodium alginate Nutrition 0.000 description 4
- 239000000661 sodium alginate Substances 0.000 description 4
- 229940005550 sodium alginate Drugs 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 3
- 239000001856 Ethyl cellulose Substances 0.000 description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 3
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 3
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 230000004888 barrier function Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 230000007211 cardiovascular event Effects 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002301 cellulose acetate Polymers 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 239000012738 dissolution medium Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 235000019325 ethyl cellulose Nutrition 0.000 description 3
- 229920001249 ethyl cellulose Polymers 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 239000004014 plasticizer Substances 0.000 description 3
- 229920002689 polyvinyl acetate Polymers 0.000 description 3
- 239000011118 polyvinyl acetate Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- 229940032147 starch Drugs 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 229960000281 trometamol Drugs 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- SERLAGPUMNYUCK-DCUALPFSSA-N 1-O-alpha-D-glucopyranosyl-D-mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-DCUALPFSSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 2
- 101800000734 Angiotensin-1 Proteins 0.000 description 2
- 102400000344 Angiotensin-1 Human genes 0.000 description 2
- 102000004881 Angiotensinogen Human genes 0.000 description 2
- 108090001067 Angiotensinogen Proteins 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 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 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 206010013710 Drug interaction Diseases 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- 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 2
- 102000015779 HDL Lipoproteins Human genes 0.000 description 2
- 108010010234 HDL Lipoproteins Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 229920002774 Maltodextrin Polymers 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- 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 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- DLRVVLDZNNYCBX-UHFFFAOYSA-N Polydextrose Polymers OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(O)O1 DLRVVLDZNNYCBX-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 210000004404 adrenal cortex Anatomy 0.000 description 2
- 210000001943 adrenal medulla Anatomy 0.000 description 2
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 2
- 230000000702 anti-platelet effect Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 229960004829 atorvastatin calcium trihydrate Drugs 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical class [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- 229920003086 cellulose ether Polymers 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 229960000913 crospovidone Drugs 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- PPQREHKVAOVYBT-UHFFFAOYSA-H dialuminum;tricarbonate Chemical compound [Al+3].[Al+3].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O PPQREHKVAOVYBT-UHFFFAOYSA-H 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 229940043237 diethanolamine Drugs 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 2
- 229960001123 epoprostenol Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- 229920001600 hydrophobic polymer Polymers 0.000 description 2
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 2
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000000905 isomalt Substances 0.000 description 2
- 235000010439 isomalt Nutrition 0.000 description 2
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 description 2
- 229960001021 lactose monohydrate Drugs 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 2
- 239000000347 magnesium hydroxide Substances 0.000 description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 2
- 235000012254 magnesium hydroxide Nutrition 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 229960001855 mannitol Drugs 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 229960003194 meglumine Drugs 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 239000008185 minitablet Substances 0.000 description 2
- 229960005170 moexipril Drugs 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 235000019371 penicillin G benzathine Nutrition 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 2
- 229920000915 polyvinyl chloride Polymers 0.000 description 2
- 239000004800 polyvinyl chloride Substances 0.000 description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 229960002231 ramiprilat Drugs 0.000 description 2
- KEDYTOTWMPBSLG-HILJTLORSA-N ramiprilat Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)C(O)=O)CC1=CC=CC=C1 KEDYTOTWMPBSLG-HILJTLORSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000036454 renin-angiotensin system Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 229920003109 sodium starch glycolate Polymers 0.000 description 2
- 239000008109 sodium starch glycolate Substances 0.000 description 2
- 229940079832 sodium starch glycolate Drugs 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 229960002920 sorbitol Drugs 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 238000003786 synthesis reaction 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
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 239000005526 vasoconstrictor agent Substances 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
- 235000010447 xylitol Nutrition 0.000 description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- 229960002675 xylitol Drugs 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- OJRHUICOVVSGSY-RXMQYKEDSA-N (2s)-2-chloro-3-methylbutan-1-ol Chemical compound CC(C)[C@H](Cl)CO OJRHUICOVVSGSY-RXMQYKEDSA-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
- TUZYXOIXSAXUGO-JFBQIPGGSA-N (3r,5r)-7-[(2s,6s,8s,8ar)-6-hydroxy-2-methyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C1=C[C@H](C)C(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-JFBQIPGGSA-N 0.000 description 1
- XUKUURHRXDUEBC-SVBPBHIXSA-N (3s,5s)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid 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-SVBPBHIXSA-N 0.000 description 1
- PUXOYQIZZIWCHH-NSLUPJTDSA-N 1-(4-methoxybutyl)-n-(2-methylpropyl)-n-[(3s,5r)-5-(morpholine-4-carbonyl)piperidin-3-yl]benzimidazole-2-carboxamide;hydrochloride Chemical compound Cl.O=C([C@H]1CNC[C@H](C1)N(CC(C)C)C(=O)C=1N(C2=CC=CC=C2N=1)CCCCOC)N1CCOCC1 PUXOYQIZZIWCHH-NSLUPJTDSA-N 0.000 description 1
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- FHHHOYXPRDYHEZ-COXVUDFISA-N Alacepril Chemical compound CC(=O)SC[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 FHHHOYXPRDYHEZ-COXVUDFISA-N 0.000 description 1
- UXOWGYHJODZGMF-QORCZRPOSA-N Aliskiren Chemical compound COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC UXOWGYHJODZGMF-QORCZRPOSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 239000005485 Azilsartan Substances 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
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 208000014644 Brain disease Diseases 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
- 239000002081 C09CA05 - Tasosartan Substances 0.000 description 1
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 1
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 1
- 239000001736 Calcium glycerylphosphate Substances 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 229920008347 Cellulose acetate propionate Polymers 0.000 description 1
- DQEFEBPAPFSJLV-UHFFFAOYSA-N Cellulose propionate Chemical compound CCC(=O)OCC1OC(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C1OC1C(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C(COC(=O)CC)O1 DQEFEBPAPFSJLV-UHFFFAOYSA-N 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 0.000 description 1
- IFYLTXNCFVRALQ-OALUTQOASA-N Ceronapril Chemical compound O([C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)P(O)(=O)CCCCC1=CC=CC=C1 IFYLTXNCFVRALQ-OALUTQOASA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 102000004860 Dipeptidases Human genes 0.000 description 1
- 108090001081 Dipeptidases Proteins 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010014476 Elevated cholesterol Diseases 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 108010066671 Enalaprilat Proteins 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 208000012895 Gastric disease Diseases 0.000 description 1
- 206010071602 Genetic polymorphism Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 108010007859 Lisinopril Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 208000001089 Multiple system atrophy Diseases 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- HDVDLQFPDLTOSI-UHFFFAOYSA-L O[AlH]O Chemical compound O[AlH]O HDVDLQFPDLTOSI-UHFFFAOYSA-L 0.000 description 1
- 239000005480 Olmesartan Substances 0.000 description 1
- 206010031127 Orthostatic hypotension Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 229920001100 Polydextrose Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 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 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 208000001871 Tachycardia 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
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- 102000010913 Type 1 Angiotensin Receptor Human genes 0.000 description 1
- 108010062481 Type 1 Angiotensin Receptor Proteins 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229940023476 agar Drugs 0.000 description 1
- 230000004931 aggregating effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229950007884 alacepril Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229960004601 aliskiren Drugs 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 229920013820 alkyl cellulose Polymers 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- BWZOPYPOZJBVLQ-UHFFFAOYSA-K aluminium glycinate Chemical compound O[Al+]O.NCC([O-])=O BWZOPYPOZJBVLQ-UHFFFAOYSA-K 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 159000000013 aluminium salts Chemical class 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940118662 aluminum carbonate Drugs 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000002280 amphoteric surfactant Substances 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003529 anticholesteremic agent Substances 0.000 description 1
- 229940127226 anticholesterol agent Drugs 0.000 description 1
- 229940124572 antihypotensive agent Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229940049950 atorvastatin 10 mg Drugs 0.000 description 1
- 229940049949 atorvastatin 20 mg Drugs 0.000 description 1
- 229960001770 atorvastatin calcium Drugs 0.000 description 1
- KGSXMPPBFPAXLY-UHFFFAOYSA-N azilsartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NOC(=O)N1 KGSXMPPBFPAXLY-UHFFFAOYSA-N 0.000 description 1
- 229960002731 azilsartan Drugs 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 229960004530 benazepril Drugs 0.000 description 1
- 229960004067 benazeprilat Drugs 0.000 description 1
- MADRIHWFJGRSBP-ROUUACIJSA-N benazeprilat Chemical compound C([C@H](N[C@H]1CCC2=CC=CC=C2N(C1=O)CC(=O)O)C(O)=O)CC1=CC=CC=C1 MADRIHWFJGRSBP-ROUUACIJSA-N 0.000 description 1
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical compound C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 1
- YXKTVDFXDRQTKV-HNNXBMFYSA-N benzphetamine Chemical compound C([C@H](C)N(C)CC=1C=CC=CC=1)C1=CC=CC=C1 YXKTVDFXDRQTKV-HNNXBMFYSA-N 0.000 description 1
- 229960002837 benzphetamine Drugs 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000004227 calcium gluconate Substances 0.000 description 1
- 235000013927 calcium gluconate Nutrition 0.000 description 1
- 229960004494 calcium gluconate Drugs 0.000 description 1
- UHHRFSOMMCWGSO-UHFFFAOYSA-L calcium glycerophosphate Chemical compound [Ca+2].OCC(CO)OP([O-])([O-])=O UHHRFSOMMCWGSO-UHFFFAOYSA-L 0.000 description 1
- 229940095618 calcium glycerophosphate Drugs 0.000 description 1
- 235000019299 calcium glycerylphosphate Nutrition 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 1
- 229960000932 candesartan Drugs 0.000 description 1
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 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
- 229960001631 carbomer Drugs 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229920006217 cellulose acetate butyrate Polymers 0.000 description 1
- 229920006218 cellulose propionate Polymers 0.000 description 1
- 229950005749 ceronapril Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000001684 chronic effect Effects 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
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 239000013066 combination product Substances 0.000 description 1
- 229940127555 combination product Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229960005227 delapril Drugs 0.000 description 1
- WOUOLAUOZXOLJQ-MBSDFSHPSA-N delapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N(CC(O)=O)C1CC2=CC=CC=C2C1)CC1=CC=CC=C1 WOUOLAUOZXOLJQ-MBSDFSHPSA-N 0.000 description 1
- 238000012938 design process Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229940015826 dihydroxyaluminum aminoacetate Drugs 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 208000022602 disease susceptibility Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229960000878 docusate sodium Drugs 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical class CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent 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
- 229960002680 enalaprilat Drugs 0.000 description 1
- MZYVOFLIPYDBGD-MLZQUWKJSA-N enalaprilat dihydrate Chemical compound O.O.C([C@H](N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 MZYVOFLIPYDBGD-MLZQUWKJSA-N 0.000 description 1
- 230000002255 enzymatic effect Effects 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
- 238000005886 esterification reaction Methods 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- SLFUXNFVAANERW-UHFFFAOYSA-N ethyl hexanoate;potassium Chemical compound [K].CCCCCC(=O)OCC SLFUXNFVAANERW-UHFFFAOYSA-N 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229960002490 fosinopril Drugs 0.000 description 1
- 229960002737 fructose Drugs 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 1
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 229920006158 high molecular weight polymer Polymers 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 229920013821 hydroxy alkyl cellulose Polymers 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 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
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 229920000831 ionic polymer Polymers 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
- 230000000302 ischemic effect Effects 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 229960003451 lactitol 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
- 230000003908 liver function Effects 0.000 description 1
- 238000012153 long-term therapy Methods 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
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 229960002160 maltose Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- GXHMMDRXHUIUMN-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O.CS(O)(=O)=O GXHMMDRXHUIUMN-UHFFFAOYSA-N 0.000 description 1
- AXLHVTKGDPVANO-UHFFFAOYSA-N methyl 2-amino-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound COC(=O)C(N)CNC(=O)OC(C)(C)C AXLHVTKGDPVANO-UHFFFAOYSA-N 0.000 description 1
- NXWASIVXQMMPLM-ZXMXYHOLSA-N methyl n-[2-[(r)-(3-chlorophenyl)-[(3r)-1-[[(2s)-2-(methylamino)-3-[(3r)-oxan-3-yl]propyl]carbamoyl]piperidin-3-yl]methoxy]ethyl]carbamate Chemical compound C1([C@H](OCCNC(=O)OC)[C@@H]2CCCN(C2)C(=O)NC[C@@H](NC)C[C@@H]2COCCC2)=CC=CC(Cl)=C1 NXWASIVXQMMPLM-ZXMXYHOLSA-N 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 description 1
- 229910052901 montmorillonite Inorganic materials 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 210000001640 nerve ending Anatomy 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 229960005117 olmesartan Drugs 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
- 230000002746 orthostatic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229960000292 pectin Drugs 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 125000001151 peptidyl group Chemical group 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
- 238000011338 personalized therapy Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229960005141 piperazine Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 235000013856 polydextrose Nutrition 0.000 description 1
- 239000001259 polydextrose Substances 0.000 description 1
- 229940035035 polydextrose Drugs 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- 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 description 1
- 229960001495 pravastatin sodium Drugs 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000008213 purified water Substances 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
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 239000006254 rheological additive Substances 0.000 description 1
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].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.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 LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 description 1
- 229960004796 rosuvastatin calcium Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229940001593 sodium carbonate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 241000894007 species Species 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
- 239000007921 spray Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 210000002820 sympathetic nervous system Anatomy 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 229960000651 tasosartan Drugs 0.000 description 1
- ADXGNEYLLLSOAR-UHFFFAOYSA-N tasosartan Chemical compound C12=NC(C)=NC(C)=C2CCC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 ADXGNEYLLLSOAR-UHFFFAOYSA-N 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- 229960004084 temocapril Drugs 0.000 description 1
- FIQOFIRCTOWDOW-BJLQDIEVSA-N temocapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C[C@H](SC1)C=1SC=CC=1)=O)CC1=CC=CC=C1 FIQOFIRCTOWDOW-BJLQDIEVSA-N 0.000 description 1
- UZQBKCWYZBHBOW-YIPNQBBMSA-N terlakiren Chemical compound C([C@@H](C(=O)N[C@@H](CSC)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)C(=O)OC(C)C)NC(=O)N1CCOCC1)C1=CC=CC=C1 UZQBKCWYZBHBOW-YIPNQBBMSA-N 0.000 description 1
- 108010069247 terlakiren Proteins 0.000 description 1
- 229950003204 terlakiren Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229960005196 titanium dioxide Drugs 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 229960002051 trandolapril Drugs 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 150000005691 triesters Chemical class 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 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
- 230000002792 vascular Effects 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
- 229960002769 zofenopril Drugs 0.000 description 1
- IAIDUHCBNLFXEF-MNEFBYGVSA-N zofenopril Chemical compound C([C@@H](C)C(=O)N1[C@@H](C[C@@H](C1)SC=1C=CC=CC=1)C(O)=O)SC(=O)C1=CC=CC=C1 IAIDUHCBNLFXEF-MNEFBYGVSA-N 0.000 description 1
- 229950004433 zolasartan Drugs 0.000 description 1
- FIKYECRHLXONOX-UHFFFAOYSA-N zolasartan Chemical compound CCCCC1=NC(Cl)=C(C(O)=O)N1CC1=CC=C(OC(=C2Br)C=3C(=CC=CC=3)C3=NNN=N3)C2=C1 FIKYECRHLXONOX-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- 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
-
- 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
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及一种以使得乙酰水杨酸与他汀的相互作用最小化的方式包括HMG‑CoA还原酶抑制剂、特别是他汀和乙酰水杨酸的药物组合物,其用于预防或治疗心血管疾病。
Description
本申请是申请号为201410249657.1、申请日为2014年6月6日、发明名称为“用于治疗心血管疾病的口服制剂”的中国专利申请的分案申请。
技术领域
本发明涉及一种以使得乙酰水杨酸与他汀的相互作用最小化的方式包括HMG-CoA还原酶抑制剂(特别是他汀)和乙酰水杨酸的药物组合物,其用于预防或治疗心血管疾病。
背景技术
心血管疾病是世界上的主要死亡原因之一并且这些疾病的最显著性因素之一在于总/高密度脂蛋白(HDL)胆固醇水平。然而,近期的研发已经表明仅考虑使胆固醇水平处于控制之下不足以用于心血管治疗。与这一需求一致,研究人员已经发现一些活性剂的组合应用提供了更有效的治疗方法。
已经充分记录了乙酰水杨酸在降低心肌梗死风险中的应用和他汀在降低胆固醇和预防或治疗心血管疾病和脑血管疾病中的应用。实际上,具有升高胆固醇水平的处于心肌梗死高风险中的患者既服用他汀,又服用乙酰水杨酸,这并不罕见。然而,他汀和乙酰水杨酸的应用可能需要专门的护理以确保将药物的相互作用、包括物理和化学不相容性和副作用保持最低,同时从这些药物中获得最大的有益性。
HMG-CoA还原酶抑制剂可以被分成两种类型:那些作为前体药物给予的类型,即内酯形式;和那些以活性成分形式给予的类型,即酸形式或酸形式的盐(例如普伐他汀钠、阿托伐他汀钙和瑞舒伐他汀钙)。这些化合物不稳定,因为它们对热、湿度、低pH环境和光敏感。阿托伐他汀和瑞舒伐他汀及其盐(包括钙和镁盐)与其他他汀类药物相比特别不稳定。特别地,作为分子内酯化反应的结果,阿托伐他汀被转化成内酯。作为他汀类药物崩解结果产生的主要降解产物(3R,5S)是内酯类和氧化产物。这一事实降解了阿托伐他汀的稳定性且由此缩短了其贮存期限。
现有技术中已知HMG-CoA还原酶抑制剂在贮存过程中在乙酰水杨酸的存在下降解。
文献WO9738694公开了包含阿司匹林和他汀的药物组合物。然而。他汀-阿司匹林相互作用的问题未得到解决。文献EP1071403解决了所述相互作用的问题并且描述了双层片形式的制剂。颗粒形式的阿司匹林存在于第一层中,而他汀存在于第二层中。然而,在双层剂型中制备的组合产品可能无法防止活性剂彼此之间的相互作用。在这种情况中,该产品在其贮存期限过程中可能降解。这可能对患者产生严重的并发症和摄取剂量不足。
文献EP 1581194涉及包含普伐他汀和阿司匹林作为活性剂的多层片剂型。包含活性剂的层被屏障层隔离以防止其相互作用。然而,生产这种类型的片剂十分不便,并且尚不能肯定地了解在贮存期限过程中屏障层是否可能影响其效果。
文献WO2011096665描述了通过用包含疏水性添加剂的屏障层给阿司匹林包衣防止HMG-CoA还原酶的稳定性降低。根据该文献,当用常规的包衣材料给阿司匹林包衣时,HMG-CoA还原酶抑制剂降解。当将疏水性添加剂加入到包衣层中时,HMG-CoA还原酶抑制剂的降解减少。
鉴于上述描述,可以观察到在需要服用这两种药物的患者中存在这样的需求,其需要他汀-乙酰水杨酸制剂,这种制剂提供预防和治疗心血管疾病中的最大效果,而没有不期望的副作用以及通常与这种组合应用相关的药物相互作用。
根据本发明,提供了药物组合物,其包括选自阿托伐他汀和瑞舒伐他汀及其盐的HMG-CoA还原酶抑制剂以及乙酰水杨酸,该药物组合物提供了对患者的最大有益性,而物理和化学不相容性最低,并且减少了通常与这种药物的应用相关的副作用。
发明内容
本发明的作者已经发现,当以口服制剂提供乙酰水杨酸且乙酰水杨酸单元包衣的量高于6mg/cm2且所述包衣包含水溶性聚合物时,阿托伐他汀和瑞舒伐他汀的稳定性降低可以令人意外地得以防止。
因此,本发明涉及可口服给药的用于预防和/或治疗心血管疾病的药物剂型,其包含:
(a)作为第一种活性剂的乙酰水杨酸;和
(b)作为第二种活性剂的HMG-CoA还原酶抑制剂,
其中所述HMG-CoA还原酶抑制剂选自阿托伐他汀和瑞舒伐他汀及其盐,且其中
(a)为两个或多个单独分开的包衣剂量单元,其在所述包衣中包含一种或多种水溶性聚合物,且所述包衣基本上不含水不溶性聚合物或肠溶聚合物;且其中包衣的量高于6mg/cm2;且显示非改性释放特性;且
(b)为一个或多个单独分开的包衣剂量单元;且
所述剂量单元选自片剂、微粒、颗粒、丸剂和胶囊。
附图说明
图1表示100mg和50mg ASA浓度制剂(4.3mg/cm2包衣)的溶出特性。
图2显示包含不同量膜包衣剂/cm2(2.17、4.3和8.7)的乙酰水杨酸100mg片剂的溶出特性。
图3显示包含4.3和8.7mg/cm2膜包衣剂的50mg与100mg ASA片剂的溶出特性。
图4显示包含具有8.7mg/cm2的ASA 50mg x2片膜-包衣片的AAR胶囊在pH 4.5下的溶出特性。
图5显示包含具有8.7mg/cm2的ASA 50mg x2片膜-包衣片的AAR胶囊在pH 6.8下的溶出特性。
发明详述
本发明的药物剂型显示HMG-CoA还原酶抑制剂阿托伐他汀和瑞舒伐他汀(及其盐)在乙酰水杨酸的存在下贮存稳定性改善,由此提供了用于预防和治疗心血管疾病的有用的组合。
本发明的作者研发了新制剂。这种新制剂由包含每种药物物质的分开的包衣剂量单元组成,所述单元是片剂、微粒、颗粒或丸剂且乙酰水杨酸单元的包衣的量高于标准水平。实际上,本发明的作者已经发现,当乙酰水杨酸单元的包衣的量高于6mg/cm2且所述包衣包含水溶性聚合物时,阿托伐他汀或瑞舒伐他汀的稳定性降低可以令人意外地得以防止。正如在下文实施例中所示的,作为阿托伐他汀主要降解产物的内酯H的产生在本发明的制剂中明显降低,与包含标准包衣的制剂相比。
因此,在第一个方面中,本发明涉及可口服给药的用于预防和/或治疗心血管疾病的药物剂型,其包含:
(a)作为第一种活性剂的乙酰水杨酸;和
(b)作为第二种活性剂的HMG-CoA还原酶抑制剂,
其中所述HMG-CoA还原酶抑制剂选自阿托伐他汀和瑞舒伐他汀及其盐,且其中
(a)为两个或多个单独分开的包衣剂量单元,其在所述包衣层中包含一种或多种水溶性聚合物,且所述包衣基本上不含水不溶性聚合物或肠溶聚合物;且其中包衣的量高于6mg/cm2;且显示非改性释放特性;且
(b)为一个或多个单独分开的包衣剂量单元;且
所述剂量单元选自片剂、微粒、颗粒、丸剂和胶囊。
本文所用的术语“剂量单元”是指在每个单元中包含药物物质的单剂量或部分剂量的剂型。根据本发明,所述剂量单元可以是片剂、微粒、颗粒、丸剂或胶囊的形式。
可以通过在口服制剂中合并一个或多个剂量单元制备本发明的多剂型。这些剂量单元可以是片剂、颗粒、丸剂、胶囊或微粒或其组合。正如制药工业中普通技术人员可以理解的。术语“制粒”是指这样的行为或过程,其中使主要的粉末微粒粘合成较大的称作颗粒的多微粒本体。因此,它是通过在微粒之间产生结合而聚集微粒的过程。通过压制或通过使用粘合剂形成结合。制粒广泛地应用于制备片剂和丸剂(或球形体)。
本文所用的术语“片剂”包括片、小片或微小片。类似地,术语“胶囊”也可以指微囊。适合的胶囊可以是硬胶囊或软胶囊且一般由明胶、淀粉或纤维质材料制成,优选明胶胶囊。优选用明胶带等密封两件式硬胶囊。在一个优选的实施方案中,本发明所述可口服给药的药物剂型是胶囊形式。在另一个优选的实施方案中,其中(a)和/或(b)剂量单元是片剂形式。
本文所用的术语"心血管疾病"是指这样的疾病,例如高胆固醇血症、动脉粥样硬化、冠状动脉疾病和脑病,例如心肌梗死、继发性心肌梗死、心肌缺血、心绞痛、充血性心力衰竭、脑梗死、脑血栓形成、脑缺血症和暂时性局部缺血发作。
本发明的组合物可以用作急性心血管事件的治疗手段和用于预防心血管事件发生或降低其发生风险的长期疗法。
本文所用的术语动名词"治疗"和名词"治疗"是指严重性和/或症状频率减轻、症状和/或潜在原因消除、预防症状和/或其潜在原因发生和损害改善或修复。因此,例如,"治疗"患者包括预防易感个体中特定疾病或不良生理情况和治疗临床有症状的个体。
本文所用的术语“阿司匹林”或“乙酰水杨酸(ASA)”可以互换使用。
本发明使用作为HMG CoA还原酶抑制剂的有效降胆固醇药。可以将HMG-CoA还原酶抑制剂分成两类:作为前体药物给予的那些,即内酯形式;和以活性成分形式给予的那些,即酸形式(例如阿托伐他汀和瑞舒伐他汀)。
可以通过使用本领域众所周知的测定法容易地鉴定具有对HMG-CoA还原酶抑制活性的化合物。例如,参见美国专利US4,231,938第6栏和WO 84/02131第30-33页中所述或引用的那些测定法。
用于本发明制剂的HMG-CoA还原酶抑制剂选自阿托伐他汀和瑞舒伐他汀及其盐,特别是钙和镁盐。
术语“HMG-CoA还原酶抑制剂”预以包括根据本发明具有HMG-CoA还原酶抑制活性的化合物的所有药学可接受的盐或酯且由此这种盐或酯类的应用包括在本发明范围内。
表述"药学可接受的盐"包括药学可接受的酸加成的盐和药学可接受的阳离子盐。表述"药学可接受的阳离子盐"预以定义、但不限于这样的盐,例如碱金属盐(例如钠和钾)、碱土金属(例如钙和镁)、铝盐、铵盐;和与有机胺类的盐,例如苄星青霉素(N,N'-二苄基乙二胺)、胆碱、二乙醇胺、乙二胺、葡甲胺(N-甲基葡糖胺)、苯乙苄胺(N-苄基苯乙胺)、二乙胺、哌嗪、氨丁三醇(2-氨基-2-羟基甲基-1,3-丙二醇)和普鲁卡因。表述"药学可接受的酸的加成盐"预以定义、但不限于这样的盐,例如盐酸盐、氢溴酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、磷酸二氢盐、乙酸盐、琥珀酸盐、柠檬酸盐、甲基磺酸盐(methanesulfonate)(甲磺酸盐,mesylate)和对甲苯磺酸盐(tosylate,甲苯磺酸盐)。还认为能够给予他汀类药物的无定形形式。
易于通过使他汀的游离酸形式与适合的碱(通常为1当量的碱)在共溶剂中反应制备包含游离羧酸的药学可接受的阳离子盐。典型的碱为氢氧化钠、甲醇钠、乙醇钠、氢化钠、甲醇钾、氢氧化镁、氢氧化钙、苄星青霉素、胆碱、二乙醇胺、哌嗪和氨丁三醇。通过浓缩至干或通过添加非溶剂分离盐。在许多情况中,优选通过混合酸溶液与不同阳离子盐(乙基己酸钠或乙基己酸钾、油酸镁)的溶液、使用期望的阳离子盐从其中沉淀出来的溶剂制备盐,或者,另外可以通过浓缩和/或添加非溶剂分离盐。
易于通过使他汀的游离碱形式与适合的酸反应制备包含游离胺基的药学可接受的酸加成的盐。当盐具有一元酸(例如盐酸盐、氢溴酸盐、对甲苯磺酸盐、乙酸盐)、二元酸的氢形式(例如硫酸氢盐、琥珀酸盐)或三元酸的二氢形式(例如磷酸二氢盐、柠檬酸盐)时,使用至少一摩尔当量且通常是摩尔过量的酸。然而,当期望这种盐为硫酸盐、半琥珀酸盐、磷酸氢盐或磷酸盐时,一般使用适合的和确切化学当量的酸。通常将游离碱和酸合并在使期望的盐从其中沉淀出来的共溶剂中,或者,另外可以通过浓缩和/或添加非溶剂分离期望的盐。
许多机制可能影响乙酰水杨酸的心血管保护活性,但其抗血栓形成、抗血小板聚集活性在这方面可能高度显著。乙酰水杨酸不可逆地使环加氧酶乙酰化,从而使得其非功能化。环加氧酶对于合成如下化合物而言是必不可少的,***素(等化合物),其中许多是促炎的;血栓烷A2,其由血小板合成以促进血小板聚集和最终血栓形成(凝血);和前列环素,其具有抗血小板聚集特性。环加氧酶在内皮细胞中、而不是在血小板中合成。低剂量的乙酰水杨酸选择性地中和血小板中的环加氧酶,同时能够使得内皮细胞中的环加氧酶和前列环素持续合成。净效应在于减轻血管中的炎症和血小板聚集以及由此的血栓形成。
如上所述,当每个乙酰水杨酸剂量单元的包衣量高于6mg/cm2且所述包衣包含水溶性聚合物时,HMG-CoA还原酶抑制剂(特别是阿托伐他汀和瑞舒伐他汀)的稳定性的降低令人意外地得以减少。此外,正如在本发明附带的实施例中所示的,根据本发明包含两个剂量单元形式的乙酰水杨酸的剂型(其中所述乙酰水杨酸单元的包衣量高于6mg/cm2)具有减少产生的阿托伐他汀杂质的量的作用,同时维持乙酰水杨酸剂量单元的非改性释放特性。
本文所用的以mg/cm2表示的包衣的量是指活性成分芯表面的包衣量/cm2。在本发明的一个具体的实施方案中,乙酰水杨酸剂量单元的包衣的量是6-12mg/cm2,包含端值,更具体地,乙酰水杨酸剂量单元的包衣的量是7-11mg/cm2,包含端值。在一个优选的实施方案中,乙酰水杨酸剂量单元的包衣的量是8-10mg/cm2,包含端值。
根据本发明,乙酰水杨酸剂量单元(a)具有非改性的或常规的释放特性。根据另一个具体的实施方案,本发明制剂中的所有剂量单元均具有非改性的或常规的释放特性。
本文所用的术语"常规释放”或“非改性的释放"特性无差异地使用,且应将其理解为涉及显示不以因专门的制剂设计和/或制备方法而有意识地改变活性物质的释放的剂型。就固体剂型而言,活性物质的溶出特性主要取决于其内在特性。还应理解,非改性的或常规的释放主要是活性成分的速释。进一步应将其理解为传统或常规的释放特性,其中未掺入缓释、延迟释放或延长释放效应。优选是指在美国药典1型仪器中在0.05M乙酸盐缓冲液中在pH 4.5、100rpm下的900ml体积中显示在60分钟内、优选在30分钟内且更优选在15分钟内溶出的活性成分百分比等于或大于65%。更优选活性成分的溶出百分比大于75%,更优选大于80%。
本文所用的术语“水溶性聚合物”是指宽泛的高度可变类型的天然或合成来源的产品类型。这些聚合物通常用作增稠剂、稳定剂、成膜剂、流变调节剂、乳化剂和润滑助剂。基本上,水溶性聚合物由于存在氧和氮原子:羟基、羧酸、硫酸盐、磷酸盐、氨基、亚氨基等,是高度亲水性的。本发明适合的水溶性聚合物的实例包括,例如水溶性纤维素衍生物,例如羟丙基甲基纤维素、羟丙基纤维素、羟乙基纤维素、羟乙基甲基纤维素、羧甲基纤维素钙或钠、甲基纤维素或其组合;糖类,例如葡萄糖、果糖或聚葡萄糖;多元醇类,例如山梨醇、甘露糖醇、麦芽糖醇、木糖醇和异麦芽糖(isomalt)、麦芽糖糊精、聚氧化乙烯、聚维酮、交聚维酮、明胶、部分水解的聚乙烯醇、聚乙烯醇、泊洛沙姆或其组合。在本发明的一个具体的实施方案中,所述水溶性聚合物选自水溶性纤维素醚,其选自甲基纤维素、羟丙基纤维素和羟丙基甲基纤维素及其混合物;水溶性聚乙烯衍生物,其选自聚乙烯吡咯烷酮、部分水解的聚乙烯醇和聚乙烯醇及其混合物;烯烃氧化物聚合物,其选自聚乙二醇和聚丙二醇;及其混合物。
在一个优选的实施方案中,所述水溶性聚合物以占包衣总重40%以上重量的量存在。在另一个优选的实施方案中,所述水溶性聚合物选自羟丙基甲基纤维素、部分水解的聚乙烯醇和聚乙烯醇或其混合物。
根据本发明,乙酰水杨酸剂量单元包衣基本上不含水不溶性聚合物或肠溶聚合物。本文所用的术语“基本上不含”是指所涉及物质的存在,即水不溶性聚合物或肠溶聚合物,其量在0-5%b.w.,更优选用量占包衣组成重量的0-1%。在一个优选的实施方案中,所述包衣包含占不超过包衣组成重量约0.1%的水不溶性聚合物或肠溶聚合物。
水不溶性聚合物的实例包括蜡例如巴西棕榈蜡、单硬脂酸甘油酯、单油酸甘油酯和蜂蜡;和合成或半合成疏水性聚合物,例如乙基纤维素、甲基丙烯酸氨基烷基酯共聚物RS、丙烯酸乙酯-甲基丙烯酸甲酯共聚物、聚氯乙烯、聚醋酸乙烯酯和醋酸纤维素。
正如本领域已知的,乙酰水杨酸长期应用可以导致胃疾病。因此,根据本发明,乙酰水杨酸单元可以任选地包含肠溶包衣层。所述包衣层优选包括在乙酰水杨酸芯与水溶性聚合物包衣层之间。肠溶或抵抗胃液的包衣层预以抵抗胃液并且在肠液中释放活性物质。
可以用于所述剂型肠溶包衣层的包衣材料可以选自甲基丙烯酸共聚物例如甲基丙烯酸/甲基丙烯酸甲酯、甲基丙烯酸/丙烯酸乙酯共聚物、甲基丙烯酸/丙烯酸甲酯/甲基丙烯酸甲酯共聚物、虫胶、邻苯二甲酸羟丙基甲基纤维素、羟丙基甲基纤维素醋酸琥珀酸酯、偏苯三酸羟丙基甲基纤维素、醋酸邻苯二甲酸纤维素、邻苯二甲酸聚醋酸乙烯酯或其组合。可以使用常用的增塑剂作为适合于特定的肠溶聚合物。可以理解,任意聚合物与适合的增塑剂可以用于水性或非水***中,以便在乙酰水杨酸剂量单元上形成肠溶包衣层。包衣可以且通常包含增塑剂以防止能够允许胃液透入的孔和裂缝的形成。
可以使用标准肠溶包衣过程和设备制备肠溶剂型。例如,可以使用包衣锅、无空气喷雾技术、流化床包衣设备等涂布肠溶包衣。
除活性剂外,为口服给药制备的本发明制剂剂量单元将一般包含其他药学可接受的赋形剂,例如粘合剂、稀释剂、润滑剂、崩解剂、填充剂、稳定剂、表面活性剂、着色剂等。术语“药学可接受的赋形剂”、“药学相容性赋形剂”和“赋形剂”在本说明书中可以互换使用。它们指用于配制药物产品的非-API物质,例如粘合剂、稀释剂、润滑剂、崩解剂、填充剂、稳定剂、表面活性剂、着色剂等。根据建立的政府标准,它们对人体给药而言一般是安全的。
粘合剂用于赋予剂型粘着特性。适合的粘合剂材料包括、但不限于淀粉(包括玉米淀粉和预胶化淀粉)、明胶、糖类(包括蔗糖、葡萄糖、右旋糖和乳糖)、聚乙二醇、蜡和天然和合成树胶(例如***胶、藻酸钠)、聚乙烯吡咯烷酮、纤维质聚合物(包括羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、乙基纤维素、羟乙基纤维素等)和水洗蒙脱石粘土,例如
稀释剂典型地用于增加容量,从而最终得到实际大小的剂量单元,例如片剂。适合的稀释剂包括碱金属碳酸盐、纤维素衍生物(微晶纤维素、醋酸纤维素等)、磷酸盐、麦芽糖糊精、糊精、果糖、右旋糖、棕榈酸硬脂酸甘油酯、拉克替醇、乳糖,包括直接压片的乳糖、麦芽糖、甘露糖醇、山梨醇、淀粉、滑石粉、木糖醇和/或其水合物和/或其衍生物。
适合的润滑剂的实例包括,例如硬脂酸金属盐(例如硬脂酸镁、硬脂酸钙、硬脂酸铝)、脂肪酸酯(例如硬脂酰醇富马酸钠)、脂肪酸(例如硬脂酸)、脂肪醇类、山嵛酸甘油酯、矿物油、石蜡、氢化植物油、亮氨酸、聚乙二醇类(PEG)、十二烷基硫酸金属盐(例如十二烷基硫酸钠、十二烷基硫酸镁)、氯化钠、苯甲酸钠、乙酸钠、滑石粉、硅化处理的滑石粉和/或其水合物。
用于本发明的崩解剂能够使剂型易于和快速地分散于水中。崩解剂可以选自具有高分散特性的聚合物,例如交联羟丙基纤维素、聚乙烯吡咯烷酮、高分子量聚合物、微晶纤维素、羟基乙酸淀粉钠、交联羧甲基纤维素钠、交聚维酮;已知在商标Kollidon(R)CL、Polyplasdone(R)下的产品或藻酸、藻酸钠、玉米淀粉。
本发明的碱性试剂是水溶性或水不溶性的且选自葡甲胺、氨丁三醇、碳酸氢钠、碳酸钠、柠檬酸钠、葡萄糖酸钙、磷酸氢二钠、磷酸氢二钾、磷酸三钾、酒石酸钠、乙酸钠、甘油磷酸钙、氧化镁、氢氧化镁、氢氧化铝、二羟基铝、碳酸钠、碳酸钙、碳酸铝、氨基乙酸二羟基铝、二乙醇胺、三乙醇胺、N-甲基-葡萄糖胺、葡糖胺(glucosamine)、乙二胺、三乙胺、异丙基胺、二异丙基胺或其组合。
稳定剂用于抑制或阻止药物分解反应,作为实例,包括氧化反应。
表面活性剂可以是阴离子型、阳离子型、两性或非离子型表面活性剂。可以任选地用于本发明的表面活性剂选自十二烷基硫酸钠、二辛基磺基丁二酸盐、明胶、酪蛋白、卵磷脂、葡聚糖、山梨坦酯类、聚氧乙烯烷基醚类、聚乙二醇类、聚乙烯硬脂酸酯类、胶体二氧化硅。
抗粘剂可以用于本发明以防止包含活性剂的混合物粘着在装置和机器表面上并且生成粗糙面。用于该目的的物质可以包含一种或多种选自滑石粉、胶体二氧化硅(Aerosil、Syloid、Cab-OSil)、硬脂酸镁和玉米淀粉的成分。
可以用于本发明制剂的决定释放速率的聚合物可以是pH-依赖性聚合物、非pH-依赖性聚合物、可溶胀聚合物、不可溶胀聚合物、亲水性聚合物、疏水性聚合物和/或一种或多种疏水性物质;离子聚合物,例如藻酸钠、卡波姆、羧甲基纤维素钙或羧甲基纤维素;非离子聚合物,例如羟丙基甲基纤维素;天然和/或合成多糖类,例如烷基纤维素、羟基烷基纤维素、纤维素醚类、硝化纤维素、糊精、琼脂、角叉菜胶、果胶、淀粉和淀粉衍生物或其混合物;纤维质聚合物;甲基丙烯酸聚合物、甲基丙烯酸共聚物、聚乙烯吡咯烷酮、聚乙烯吡咯烷酮-聚醋酸乙烯酯共聚物、乙基纤维素、醋酸纤维素、丙酸纤维素(高、中和低分子量)、醋酸丙酸纤维素、醋酸丁酸纤维素、醋酸邻苯二甲酸纤维素、三酯酸纤维素、聚醋酸乙烯酯、聚氯乙烯及其混合物。
如上所述,乙酰水杨酸剂量单元(a)显示非改性或常规的释放特性。然而,如上述段落中所举出的决定释放速率的聚合物也可以用于本发明剂型的其他剂量单元。因此,本发明的剂量单元可以显示改性的释放特性。本文所用的术语"改性释放"包括所有类型的改性释放特性,例如控释、缓释、延迟释放等。
本发明的膜包衣材料可以包含如下成分和/或其组合:乳糖、羟丙基甲基纤维素、羟丙基纤维素、三醋精、邻苯二甲酸羟丙基甲基纤维素、醋酸邻苯二甲酸羟丙基甲基纤维素、聚醋酸乙烯邻苯二甲酸酯、邻苯二甲酸二乙酯、糖衍生物、聚乙烯衍生物、蜡、脂肪和明胶、柠檬酸三乙酯、甘油酯、氧化钛、滑石粉、藻酸钠、硬脂酸、卵磷脂。
本文所用的术语"治疗有效量"预以指研究人员、兽医、医生或其他临床医师寻求的可以引起组织、***、动物或人的生物学或医学响应的药物或药物活性剂的量。采用HMG-CoA还原酶抑制剂与乙酰水杨酸相组合的剂量方案可以根据不同因素选择,包括患者的类型、种类、年龄、体重、性别和医学情况;所治疗疾病的严重性;给药途径;患者的肾和肝功能;和所用的具体化合物或其盐或酯。由于两种或多种不同的活性剂在联合疗法中一起使用,所以也必须考虑到每种活性剂的效力和将它们合并在一起获得的增强的效果。这些因素的考量充分属于普通临床医师的范围,目的在于确定预防、抵抗或阻止疾病发展所需的药物组合的治疗有效量。
在本发明的一个具体的实施方案中,制剂中乙酰水杨酸的量在10-400mg/剂量单元的范围。更优选乙酰水杨酸的量在30-100mg/剂量单元的范围。在一个更优选的实施方案中,乙酰水杨酸的量在40-85mg/剂量单元、更优选40-60mg/剂量单元的范围,甚至更优选50mg。
本发明的药物剂型包含HMG-CoA还原酶抑制剂,特别是选自阿托伐他汀和瑞舒伐他汀的他汀及其盐,其用量为常用于这种他汀的用量。因此,根据具体他汀的不同,可以使用的量在约0.1mg-2000mg/天,以单剂量或分次剂量,优选约0.2-约200mg/天。阿托伐他汀的临床剂量范围在10-80mg/天。因此,在本发明的一个具体的实施方案中,本发明剂型中HMG-CoA还原酶抑制剂的量可以为1-40mg/剂量单元,更优选5–40mg/剂量单元,甚至更优选5-20mg/剂量单元。在本发明的一个优选的实施方案中,HMG-CoA还原酶抑制剂在本发明剂型中为两个或更多个剂量单元的形式。
在本发明的一个具体的实施方案中,所述组合物还包含一个或多个单独分开的剂量单元,其包含肾素-血管紧张素***抑制剂作为第三种活性剂。
肾素醛固酮血管紧张素***(RAAS)在调节血压和容量自体稳定中起重要作用且在心血管、肾和代谢疾病的病理生理学中起关键作用。肾素由肾分泌作为对循环容量和血压降低的响应并且可将底物血管紧张素原裂解成无活性的十肽血管紧张素I(Ang I)。AngI通过血管紧张素转化酶(ACE)转化成活性的八肽血管紧张素II(Ang II)。Ang II与细胞受体、特别是ATI受体发生相互作用,从而诱导血管收缩以及从肾上腺髓质和结合前的神经末梢中释放儿茶酚胺类。它还促进醛固酮分泌和钠重吸收。此外,Ang II抑制肾素释放,由此提供对该***的负反馈。因此,Ang II以不同水平发挥其作用(例如脉管***、交感神经***、肾上腺皮质和髓质)以增加血管阻力和血压。
RAAS可以在不同水平上被阻断。肾素抑制剂、ACE抑制剂(ACEi)和血管紧张素受体阻滞剂(ARB)代表了阻断RAAS的主要药物类型。每种药物类型各自具有不同的作用模式且由此以不同水平阻断RAAS:肾素通过竞争性抑制酶肾素阻断RAAS级联的第一个限速步骤,由此防止由血管紧张素原形成Ang I。ACEi通过竞争性抑制酶ACE阻断RAAS级联的第二个步骤,由此防止形成Ang II。最终,ARB通过结合并且占据ATI受体但不活化它们而阻断RAAS级联的第三个和最终的步骤。因此,ARBs通过Ang II防止了结合和活化所述ATI受体。已经公开了在心血管***上反映出的一些基因多态现象用作预测疾病易感性或进展的生物标记,或作为个体化治疗(包括药物疗法)的指导。
本发明应用的肾素抑制剂是具有体内肾素抑制活性的任意那些肾素抑制剂。本文所用的肾素抑制剂包括、但不限于EP 678.503、WO 00/64887、WO 00/064873、WO 2005/051895、WO 2006/095020、US 2009/0076062、WO 2011/056126、Yokokawa等人(ExpertOpin.Ther.Patents 18(6):581-602,2008)和Maibaum等人(Expert Opin.Ther.Patents13(5):589-603,2003)中公开的那些。此外,适合的肾素抑制剂包括具有不同结构特征的化合物。在一个实施方案中,肾素抑制剂优选自阿利吉仑、地替吉仑、特拉吉仑、占吉仑、RO66-1132、RO 66-1168、VTP27999、ACT-280778和TAK-272及其药学可接受的盐、前体药物、衍生物和异构体。
根据本发明的ARB是可以特异性地拮抗或阻断血管紧张素II 1型受体(ATI受体)的任意分子。适用于本文的ARB包括、但不限于氯沙坦、缬沙坦、厄贝沙坦、坎地沙坦、替米沙坦、依普罗沙坦、他索沙坦、佐拉沙坦(zolarsartan)、阿齐沙坦、奥美沙坦、沙普立沙坦、福拉沙坦、E-4177和ZD-8731及其药学可接受的盐、前体药物、衍生物和异构体。
在一个优选的实施方案中,肾素-血管紧张素***抑制剂是血管紧张素转化酶(ACE)抑制剂。本发明的ACEi是可以特异性地抑制血管紧张素转化酶的酶活性的任意分子。适用于本文的ACEi包括、但不限于贝那普利、贝那普利拉、卡托普利、佐芬普利、依那普利、依那普利拉(enaprilat)、福辛普利、西罗普利、赖诺普利、莫昔普利、培哚普利、喹那普利、雷米普利、群多普利、阿拉普利、西拉普利、地拉普利、咪达普利、伦唑普利、螺普利、替莫普利和莫维普利及其药学可接受的盐、前体药物、衍生物和异构体。在一个实施方案中,优选的ACEi是雷米普利及其药学可接受的盐。
雷米普利是前体药物,起在吸收后快速地水解成活性代谢物雷米普利拉。雷米普利和雷米普利拉抑制血管紧张素转化酶(ACE)。ACE是催化血管紧张素I转化成血管收缩物质血管紧张素II的肽基二肽酶。血管紧张素II还通过肾上腺皮质刺激醛固酮分泌。抑制ACE导致血浆血管紧张素II减少,其导致血管加压活性降低和醛固酮分泌减少。后者的减少可以导致血浆钾少量增加。雷米普利对高血压的作用显示至少部分导致组织和循环ACE活性抑制,由此减少了组织和血浆中血管紧张素II形成。对具有轻度至中度高血压的患者给予雷米普利导致仰卧和直立性血压降至与非代偿性心动过速大约相同的程度。症状性***性低血压是不常见的,不过,它出现在盐-和/或容量-耗尽的患者中。雷米普利显著地减少了年龄在>或=55岁的患者中MI、中风或因心血管原因导致的死亡的发生率,所述年龄段的患者处于发生局部缺血性心血管事件发生的增加的风险中。
在本发明的一个具体的实施方案中,ACE抑制剂剂量单元具有未改性的释放特性。在另一个具体的实施方案中,所述ACE抑制剂是一个或多个分开的单独剂量单元的形式,其选自片剂、微粒、颗粒、丸剂和胶囊。在一个优选的实施方案中,所述剂量单元是包衣的剂量单元。
平均而言,雷米普利在体重约为75kg的患者中的每日剂量至少为0.001mg/kg体重,优选0.01mg/kg-约20mg/kg体重,优选1mg/kg体重。在本发明的一个具体的实施方案中,所述制剂中雷米普利的量为1-100mg/剂量单元,更优选为2-50mg/剂量单元。
举出下列实施例是为了给本领域技术人员提供如何制备和使用本发明的完整的说明和描述,而不预以限制本发明的范围或表示下列实验是全部或仅进行的实验。努力确保所有数值的精确性(例如量、温度等),但可能存在一定的实验误差和偏差。
具体实施方式
制备包含乙酰水杨酸(ASA)、阿托伐他汀和雷米普利的膜-包衣片并且装胶囊(AAR胶囊)。
如上所述,可以根据本发明使用不同的成膜聚合物。本文所用的术语PVA是指部分水解的聚乙烯醇。
阿托伐他汀包衣片的制备
通过湿法制粒、使用高剪切混合器和流化床干燥器制备阿托伐他汀片剂。通过将聚山梨醇酯80和羟丙基纤维素分散于纯水制备制粒溶液。将粒内成分(参见表2)掺入制粒的掺合物。最终,加入粒外成分(参见表2),并且与得到的颗粒掺合。用旋转压片机压制每种掺合物。压片后,给得到的芯包薄膜衣。
ASA包衣片的制备
按照适当比例过筛乙酰水杨酸、羟基乙酸淀粉钠和微晶纤维素(参见表5)并且掺合。过筛滑石粉(润滑剂)并且与在先得到的掺合物掺合,且压制最终的掺合物。用成膜水溶液给得到的芯包衣。
如上所述制备阿托伐他汀(10mg或20mg)和ASA(40.5;50mg或100mg)膜包衣片并且与雷米普利(2.5、5或10mg)膜包衣片一起装胶囊。雷米普利膜包衣片是商购的。
制成的胶囊组成如下:
表1:AAR胶囊的组成
表2:阿托伐他汀10mg膜-包衣片的组成
(1)相当于10mg阿托伐他汀。阿托伐他汀钙三水合物纯度用一水合乳糖校正。
(2)在制备过程中除去
表3:阿托伐他汀20mg薄膜-包衣片的粒内组成
(1)相当于20mg阿托伐他汀。阿托伐他汀钙三水合物纯度用一水合乳糖校正。
(2)在制备过程中除去
表4:100mg、50mg和40.5mg ASA膜-包衣片的组成
在最终的产品中,将阿托伐他汀膜包衣片与雷米普利膜包衣片和乙酰水杨酸(ASA)膜包衣片一起放入胶囊内部。
为了改善制剂的稳定性,将部分水解的聚乙烯醇用作乙酰水杨酸(ASA)片剂的成膜剂。测试ASA片剂的不同量膜包衣:2.17mg/cm2、4.3mg/cm2和8.7mg/cm2。
表5:PVA包衣的组成
成分 | w/w% |
部分水解的聚乙烯醇 | 45.50 |
二氧化钛 | 30.00 |
滑石粉 | 22.00 |
大豆卵磷脂 | 2.00 |
黄原胶 | 0.50 |
总计 | 100.00 |
测试不同压力条件下(40℃、30℃和25℃)包含ASA膜-包衣片(1片100mg ASA或2x50mg)的胶囊中存在的阿托伐他汀杂质。
正如表6中所示,在所有情况中(40℃、30℃和25℃),具有8.7mg/cm2包衣的阿司匹林片剂产生了低于具有4.3mg/cm2包衣(标准水平)的片剂的内酯H水平。
表6:当ASA用不同厚度的PVA包衣(4.3mg/cm2和8.7mg/cm2)给包衣时的阿托伐他汀杂质:
实施例1AAR胶囊:
ASA片剂的溶出特性
制备50mg或40.5mg浓度配方的ASA片剂(参见表4),以检查溶出速率是否因制剂浓度下降而改善。
表7:100mg和50mg ASA浓度制剂的对比溶出速率
使用下列条件进行溶出试验:pH 4.5的0.05M乙酸盐缓冲液;50rpm美国药典1型仪器;500ml。
溶出数据显示(参见图1和表7)当制剂浓度降低时ASA片剂的溶出特性改善。2片50mg乙酰水杨酸的溶出速率快于1片100mg乙酰水杨酸的溶出速率。
下一步在于测试当使用膜-包衣片时是否得到相似的结果。测试50mg ASA膜-包衣片与100mg ASA片剂对比PVA包衣在溶出特性方面中的作用。测试不同量的膜包衣剂:2.17mg/cm2、4.3mg/cm2和8.7mg/cm2。
正如表8和图2中所示,通过将包衣的量增加到大于4.3mg/cm2,100mg ASA片剂的溶出特性受到影响。在15分钟时的溶出%平均值在包含2.17mg/cm2和4.3mg/cm2包衣的ASA片剂中为85%以上。然而,所述值在包含8.7mg/cm2包衣的片剂中低于75%。
溶出试验条件:
仪器:USP 1(篮)
搅拌速度:50rpm
溶出体积:500mL
溶出介质:pH 4.5乙酸盐缓冲液
表8:ASA 100mg膜-包衣片(PVA包衣)溶出结果
然而,正如表9中所示,包含8.7mg/cm2的包衣的50mg ASA片剂未显示任何对溶出特性的负面影响,因为在15分钟时溶出%的平均值超过85%。
表9:2x50mg ASA PVA包衣片溶出结果
溶出结果(参见图3;表11和12)显示在所有情况中(2.17mg/cm2、4.3mg/cm2和8.7mg/cm2)2片50mg ASA的溶出速率快于1片100mg ASA的溶出速率。此外,对比具有4.3mg/cm2和8.7mg/cm2包衣的50mg片剂和100mg片剂的溶出特性,可以观察到具有8.7mg/cm2包衣层的50mg(2x)片的溶出快于具有4.3mg/cm2包衣的100mg片剂。
还在不同条件下测试了包含具有8.7mg/cm2的ASA 50mg x2膜-包衣片的AAR胶囊的溶出特性:
溶出试验条件:
仪器:USP 1(篮)
搅拌速度:100rpm
溶出体积:900mL
溶出介质:pH 4.5乙酸盐缓冲液
结果(表10和图4)如下:
表10:在AAR胶囊中溶出的ASA%的溶出结果
溶出试验条件:
仪器:USP 1(篮)
搅拌速度:100rpm
溶出体积:900mL
溶出介质:pH 6.8磷酸盐缓冲液
结果(表11和图5)如下:
表11:在AAR胶囊中溶出的ASA%的溶出结果
正如表10和表11中所示,包含含有8.7mg/cm2片剂包衣的50mg ASA膜-包衣片x2的AAR胶囊显示在pH 4.5的情况下在15分钟时的平均值超过80%,而在pH 6.8时接近75%。
包含具有8.7mg/cm2包衣的ASA片剂的制剂提供了对乙酰水杨酸片的更多的保护和隔离,使得水杨酸升华并可以使得其他成分、特别是最终胶囊内部的阿托伐他汀或瑞舒伐他汀降解的可能性更难。
Claims (10)
1.用于预防和/或治疗心血管疾病的可口服给药的药物剂型,包含:
(a)作为第一种活性剂的乙酰水杨酸;和
(b)作为第二种活性剂的HMG-CoA还原酶抑制剂,其中所述HMG-CoA还原酶抑制剂选自阿托伐他汀和瑞舒伐他汀及其盐,且其中
(a)为两个或多个单独分开的包衣剂量单元,其在所述包衣中包含一种或多种水溶性聚合物,且所述包衣基本上不含水不溶性聚合物或肠溶聚合物,即所述包衣包含占包衣组成重量0-5%的水不溶性聚合物或肠溶聚合物;且其中包衣的量为8-12mg/cm2;且显示非改性释放特性;且
(b)为一个或多个单独分开的包衣剂量单元;
所述剂量单元为片剂形式;且
所述水溶性聚合物以占包衣总重大于40%重量的量存在,并且选自下组的水溶性聚乙烯衍生物:聚乙烯吡咯烷酮、部分水解的聚乙烯醇、聚乙烯醇及其混合物。
2.权利要求1的药物剂型,其中所述剂型为胶囊形式。
3.权利要求1的药物剂型,其中所述水溶性聚合物选自部分水解的聚乙烯醇、聚乙烯醇及其混合物。
4.权利要求1的药物剂型,其中乙酰水杨酸剂量单元(a)在美国药典1型仪器中在pH4.5的0.05M乙酸盐缓冲液中、100rpm下的900ml体积中显示在60分钟内溶出的乙酰水杨酸百分比等于或大于65%。
5.权利要求4的药物剂型,其中乙酰水杨酸剂量单元(a)在美国药典1型仪器中显示在60分钟内溶出的乙酰水杨酸百分比大于75%。
6.权利要求4的药物剂型,其中乙酰水杨酸剂量单元(a)在美国药典1型仪器中显示在60分钟内溶出的乙酰水杨酸百分比大于80%。
7.权利要求4的药物剂型,其中乙酰水杨酸剂量单元(a)在美国药典1型仪器中显示在60分钟内溶出的乙酰水杨酸百分比大于85%。
8.权利要求4的药物剂型,其中乙酰水杨酸剂量单元(a)在美国药典1型仪器中显示在30分钟内溶出的乙酰水杨酸百分比等于或大于65%。
9.权利要求4的药物剂型,其中乙酰水杨酸剂量单元(a)在美国药典1型仪器中显示在30分钟内溶出的乙酰水杨酸百分比大于75%。
10.权利要求4的药物剂型,其中乙酰水杨酸剂量单元(a)在美国药典1型仪器中显示在30分钟内溶出的乙酰水杨酸百分比大于80%。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP13170909.9 | 2013-06-06 | ||
EP13170909.9A EP2810644A1 (en) | 2013-06-06 | 2013-06-06 | Oral formulation for the treatment of cardiovascular diseases |
CN201410249657.1A CN104224804A (zh) | 2013-06-06 | 2014-06-06 | 用于治疗心血管疾病的口服制剂 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410249657.1A Division CN104224804A (zh) | 2013-06-06 | 2014-06-06 | 用于治疗心血管疾病的口服制剂 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113143888A true CN113143888A (zh) | 2021-07-23 |
Family
ID=48569993
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410249657.1A Pending CN104224804A (zh) | 2013-06-06 | 2014-06-06 | 用于治疗心血管疾病的口服制剂 |
CN202110259129.4A Pending CN113143888A (zh) | 2013-06-06 | 2014-06-06 | 用于治疗心血管疾病的口服制剂 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410249657.1A Pending CN104224804A (zh) | 2013-06-06 | 2014-06-06 | 用于治疗心血管疾病的口服制剂 |
Country Status (42)
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK3283058T3 (da) * | 2015-04-16 | 2023-02-13 | Novartis Ag | Ribociclib-tablet |
CN111135149B (zh) * | 2018-11-04 | 2021-05-11 | 张家港市中医医院 | 一种瑞舒伐他汀钙片及其制备方法 |
CN110693929A (zh) * | 2019-09-09 | 2020-01-17 | 安徽中医药大学 | 复方药物组份在治疗脑梗死恢复期中的应用 |
EP4299063B1 (en) | 2022-06-30 | 2024-05-01 | Ferrer Internacional, S.A. | Oral capsules comprising atorvastatin tablets showing suitable dissolution profile and bioavailability |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6235311B1 (en) * | 1998-03-18 | 2001-05-22 | Bristol-Myers Squibb Company | Pharmaceutical composition containing a combination of a statin and aspirin and method |
CN101176725A (zh) * | 2006-07-14 | 2008-05-14 | 兰贝克赛实验室有限公司 | 辛伐他汀和阿司匹林的稳定剂型 |
CN101642459A (zh) * | 2001-08-28 | 2010-02-10 | 布里格姆及妇女医院股份有限公司 | 含有降低胆固醇的药物、肾素-血管紧张素抑制剂和阿司匹林的联合剂型 |
CN101980701A (zh) * | 2008-03-28 | 2011-02-23 | 菲尔若国际公司 | 用于预防心血管疾病的胶囊 |
US20120301549A1 (en) * | 2010-02-02 | 2012-11-29 | Hanmi Science Co., Ltd. | Complex formulation comprising aspirin coated with barrier containing hydrophobic additive, and hmg-coa reductase inhibitor |
Family Cites Families (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4231938A (en) | 1979-06-15 | 1980-11-04 | Merck & Co., Inc. | Hypocholesteremic fermentation products and process of preparation |
AU570021B2 (en) | 1982-11-22 | 1988-03-03 | Novartis Ag | Analogs of mevalolactone |
MY119161A (en) | 1994-04-18 | 2005-04-30 | Novartis Ag | Delta-amino-gamma-hydroxy-omega-aryl-alkanoic acid amides with enzyme especially renin inhibiting activities |
EP0904082A4 (en) * | 1996-04-17 | 2001-09-26 | Merck & Co Inc | COMBINATION THERAPY TO REDUCE THE RISKS OF HEART CIRCULAR DISEASES |
US6376672B1 (en) | 1999-04-27 | 2002-04-23 | Hoffmann-La Roche Inc. | Naphthalenylmethoxypiperidines as renin inhibitors |
US6197959B1 (en) | 1999-04-27 | 2001-03-06 | Hoffmann-La Roche Inc. | Piperidine derivatives |
US6448323B1 (en) | 1999-07-09 | 2002-09-10 | Bpsi Holdings, Inc. | Film coatings and film coating compositions based on polyvinyl alcohol |
IL150850A0 (en) | 2000-02-10 | 2003-02-12 | Bpsi Holdings Inc | Enteric coating compositions containing acrylic resin |
US6576256B2 (en) * | 2001-08-28 | 2003-06-10 | The Brigham And Women's Hospital, Inc. | Treatment of patients at elevated cardiovascular risk with a combination of a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, and aspirin |
US20040115265A1 (en) * | 2002-12-11 | 2004-06-17 | Loutfy Benkerrour | Multilayered tablet containing pravastatin and aspirin and method |
WO2004080488A2 (de) | 2003-03-10 | 2004-09-23 | Bayer Healthcare Ag | Kombinationspräparate von acetylsalicylsäure mit einem hmg-coa-reduktase |
CN1822820A (zh) * | 2003-07-28 | 2006-08-23 | 雷迪实验室有限公司 | 心血管疾病的治疗和预防 |
ES2395724T3 (es) | 2003-08-20 | 2013-02-14 | Shionogi & Co., Ltd. | Nueva composición de recubrimiento |
BRPI0417017A (pt) | 2003-11-26 | 2007-02-21 | Novartis Ag | compostos orgánicos |
CA2571447A1 (en) * | 2004-06-28 | 2006-01-05 | Howard J Smith & Associates Pty Ltd | Composition and method for treatment and prevention of atherosclerosis |
JP2008532983A (ja) | 2005-03-11 | 2008-08-21 | シュペーデル・エクスペリメンタ・アーゲー | レニン阻害剤として有用な複素環置換アルカンアミド |
US20070009591A1 (en) | 2005-07-07 | 2007-01-11 | Trivedi Jay S | ACE inhibitor formulation |
US20070116756A1 (en) | 2005-11-23 | 2007-05-24 | Dr. Reddy's Laboratories Limited | Stable pharmaceutical compositions |
US7427414B2 (en) | 2006-01-18 | 2008-09-23 | Astron Research Limited | Modified release oral dosage form using co-polymer of polyvinyl acetate |
PL2120878T3 (pl) * | 2007-02-09 | 2015-01-30 | Alphapharm Pty Ltd | Postać dawkowania zawierająca dwa czynne składniki farmaceutyczne o różnych postaciach fizycznych |
US20120015032A1 (en) | 2007-08-13 | 2012-01-19 | Hanall Pharmaceutical Company, Ltd. | Combination preparation comprising inhibitor of hmg-coa reductase and aspirin and method for manufacturing the same |
US20090076062A1 (en) | 2007-09-13 | 2009-03-19 | Juergen Klaus Maibaum | Organic Compounds |
CN102480954B (zh) * | 2009-02-11 | 2015-03-18 | 卡帝拉药物有限公司 | 用于动脉粥样硬化的稳定的药物组合物 |
NZ596064A (en) * | 2009-04-30 | 2014-03-28 | Reddy’S Lab Ltd Dr | Fixed dose drug combination formulations |
KR20120130078A (ko) | 2009-11-09 | 2012-11-28 | 메디비르 아베 | 신규한 1,3-옥사졸리딘 화합물 및 이의 레닌 억제제로서의 용도 |
CN102049049A (zh) * | 2010-11-27 | 2011-05-11 | 王定豪 | 包含阿司匹林盐和他汀类药物的药物组合物 |
-
2013
- 2013-06-06 EP EP13170909.9A patent/EP2810644A1/en not_active Withdrawn
-
2014
- 2014-05-20 AR ARP140101992A patent/AR096350A1/es not_active Application Discontinuation
- 2014-06-04 TW TW103119340A patent/TWI630928B/zh active
- 2014-06-05 EA EA201600012A patent/EA028969B1/ru unknown
- 2014-06-05 AP AP2015008882A patent/AP2015008882A0/xx unknown
- 2014-06-05 MA MA38699A patent/MA38699B1/fr unknown
- 2014-06-05 KR KR1020157033956A patent/KR101839665B1/ko active IP Right Grant
- 2014-06-05 MY MYPI2015704409A patent/MY181272A/en unknown
- 2014-06-05 AU AU2014276883A patent/AU2014276883B2/en active Active
- 2014-06-05 PE PE2015002519A patent/PE20160051A1/es unknown
- 2014-06-05 EP EP14728940.9A patent/EP2986281B1/en active Active
- 2014-06-05 WO PCT/EP2014/061735 patent/WO2014195421A1/en active Application Filing
- 2014-06-05 CA CA2912350A patent/CA2912350C/en active Active
- 2014-06-05 PL PL14728940T patent/PL2986281T3/pl unknown
- 2014-06-05 JP JP2016517607A patent/JP6151854B2/ja active Active
- 2014-06-05 US US14/893,902 patent/US10617699B2/en active Active
- 2014-06-05 MX MX2015015753A patent/MX347801B/es active IP Right Grant
- 2014-06-05 PT PT147289409T patent/PT2986281T/pt unknown
- 2014-06-05 EP EP16204436.6A patent/EP3175849A1/en not_active Withdrawn
- 2014-06-05 MD MDA20160001A patent/MD4475C1/ro active IP Right Grant
- 2014-06-05 NZ NZ714707A patent/NZ714707A/en unknown
- 2014-06-05 GE GEAP201414027A patent/GEP201706743B/en unknown
- 2014-06-05 HU HUE14728940A patent/HUE033458T2/en unknown
- 2014-06-05 UA UAA201512002A patent/UA113806C2/uk unknown
- 2014-06-05 DK DK14728940.9T patent/DK2986281T3/en active
- 2014-06-05 ES ES14728940.9T patent/ES2620078T3/es active Active
- 2014-06-05 TN TN2015000501A patent/TN2015000501A1/en unknown
- 2014-06-05 BR BR112015030350-1A patent/BR112015030350B1/pt active IP Right Grant
- 2014-06-05 SI SI201430175A patent/SI2986281T1/sl unknown
- 2014-06-05 SG SG11201509353QA patent/SG11201509353QA/en unknown
- 2014-06-05 RS RS20170286A patent/RS55786B1/sr unknown
- 2014-06-05 CU CUP2015000173A patent/CU24326B1/es unknown
- 2014-06-06 CN CN201410249657.1A patent/CN104224804A/zh active Pending
- 2014-06-06 CN CN202110259129.4A patent/CN113143888A/zh active Pending
-
2015
- 2015-05-28 HK HK15105100.9A patent/HK1204562A1/zh unknown
- 2015-11-12 IL IL242569A patent/IL242569B/en active IP Right Grant
- 2015-11-16 ZA ZA2015/08452A patent/ZA201508452B/en unknown
- 2015-12-01 EC ECIEPI201550273A patent/ECSP15050273A/es unknown
- 2015-12-03 CR CR20150635A patent/CR20150635A/es unknown
- 2015-12-04 CL CL2015003561A patent/CL2015003561A1/es unknown
- 2015-12-04 PH PH12015502706A patent/PH12015502706B1/en unknown
- 2015-12-04 NI NI201500171A patent/NI201500171A/es unknown
- 2015-12-05 SA SA515370243A patent/SA515370243B1/ar unknown
- 2015-12-08 DO DO2015000296A patent/DOP2015000296A/es unknown
-
2017
- 2017-03-17 CY CY20171100340T patent/CY1118766T1/el unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6235311B1 (en) * | 1998-03-18 | 2001-05-22 | Bristol-Myers Squibb Company | Pharmaceutical composition containing a combination of a statin and aspirin and method |
CN101642459A (zh) * | 2001-08-28 | 2010-02-10 | 布里格姆及妇女医院股份有限公司 | 含有降低胆固醇的药物、肾素-血管紧张素抑制剂和阿司匹林的联合剂型 |
CN101176725A (zh) * | 2006-07-14 | 2008-05-14 | 兰贝克赛实验室有限公司 | 辛伐他汀和阿司匹林的稳定剂型 |
CN101980701A (zh) * | 2008-03-28 | 2011-02-23 | 菲尔若国际公司 | 用于预防心血管疾病的胶囊 |
US20120301549A1 (en) * | 2010-02-02 | 2012-11-29 | Hanmi Science Co., Ltd. | Complex formulation comprising aspirin coated with barrier containing hydrophobic additive, and hmg-coa reductase inhibitor |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20110117194A1 (en) | Pharmaceutical formulation containing angiotensin-ii receptor blocker | |
US20110111022A1 (en) | Pharmaceutical formulation | |
EP2356985A1 (en) | Novel pharmaceutical compositions comprising a combination of metformin and sitagliptin | |
WO2008068217A2 (en) | Pharmaceutical composition comprising a coated hmg-coa reductase inhibitor and an inhibitor of the renin-angiotensin system | |
US20100143460A1 (en) | Solid dosage forms comprising aliskiren and pharmaceutically acceptable salts thereof | |
WO2009010810A2 (en) | Cardiovascular combinations comprising ace and hmg-co-a inhibitors | |
CA2912350C (en) | Oral formulation for the treatment of cardiovascular diseases | |
US20030147957A1 (en) | Dual release formulation comprising levodopa ethyl ester and a decarboxylase inhibitor in immediate release layer with levodopa ethyl ester and a decarboxylase inhibitor in a controlled release core | |
WO2008010008A2 (en) | Cardiovascular combinations using rennin-angiotensin inhibitors | |
KR101171375B1 (ko) | 난용성 약물을 함유하는 경구 제형 | |
EP2890371A1 (en) | Pharmaceutical composite capsule formulation comprising irbesartan and hmg-coa reductase inhibitor | |
WO2011080706A1 (en) | Enhanced solubility of ziprasidone | |
OA17601A (en) | Oral formulation for the treatment of cardiovascular diseases. | |
KR101072600B1 (ko) | 플루바스타틴을 포함하는 안정한 약제학적 조성물 및 그의 제조방법 | |
US20090061000A1 (en) | Pharmaceutical formulation use 030 | |
KR20070058296A (ko) | Ace저해제와 스타틴류 약물의 복합제제 조성물 및 그의제조방법 | |
CA2654243A1 (en) | Oral pharmaceutical composition of a poorly water-soluble active substance |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210723 |
|
RJ01 | Rejection of invention patent application after publication |