CN101801348A - 含有阿扎那韦的压片组合物 - Google Patents
含有阿扎那韦的压片组合物 Download PDFInfo
- Publication number
- CN101801348A CN101801348A CN200880103525A CN200880103525A CN101801348A CN 101801348 A CN101801348 A CN 101801348A CN 200880103525 A CN200880103525 A CN 200880103525A CN 200880103525 A CN200880103525 A CN 200880103525A CN 101801348 A CN101801348 A CN 101801348A
- Authority
- CN
- China
- Prior art keywords
- compressed tablets
- granule
- tablet
- atazanavir
- sulphuric acid
- 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
- 108010019625 Atazanavir Sulfate Proteins 0.000 title claims abstract description 131
- 239000000203 mixture Substances 0.000 title claims abstract description 103
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 title claims description 126
- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 title claims description 124
- 229960003277 atazanavir Drugs 0.000 title claims description 124
- 239000008187 granular material Substances 0.000 claims abstract description 136
- 239000007891 compressed tablet Substances 0.000 claims abstract description 92
- 239000003826 tablet Substances 0.000 claims abstract description 53
- 239000000314 lubricant Substances 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 31
- -1 e.g. Substances 0.000 claims abstract description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 97
- 239000001117 sulphuric acid Substances 0.000 claims description 97
- 235000011149 sulphuric acid Nutrition 0.000 claims description 97
- 238000002156 mixing Methods 0.000 claims description 55
- 239000003513 alkali Substances 0.000 claims description 41
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 27
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 25
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 20
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 18
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 18
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 18
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 18
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 16
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 16
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 16
- 229920003110 Primojel Polymers 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- 235000021355 Stearic acid Nutrition 0.000 claims description 12
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 12
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 12
- 239000008117 stearic acid Substances 0.000 claims description 12
- 239000010410 layer Substances 0.000 claims description 10
- 235000019359 magnesium stearate Nutrition 0.000 claims description 10
- 229920002261 Corn starch Polymers 0.000 claims description 9
- 239000004605 External Lubricant Substances 0.000 claims description 9
- 239000008120 corn starch Substances 0.000 claims description 9
- 229920000881 Modified starch Polymers 0.000 claims description 8
- 229930006000 Sucrose Natural products 0.000 claims description 8
- 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 claims description 8
- 239000005720 sucrose Substances 0.000 claims description 8
- 238000005550 wet granulation Methods 0.000 claims description 8
- 229920002774 Maltodextrin Polymers 0.000 claims description 7
- 239000005913 Maltodextrin Substances 0.000 claims description 7
- 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 claims description 7
- 239000011230 binding agent Substances 0.000 claims description 7
- 239000001506 calcium phosphate Substances 0.000 claims description 7
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 7
- 239000000945 filler Substances 0.000 claims description 7
- 229940035034 maltodextrin Drugs 0.000 claims description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 7
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 7
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 7
- 239000004375 Dextrin Substances 0.000 claims description 6
- 229920001353 Dextrin Polymers 0.000 claims description 6
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 235000019425 dextrin Nutrition 0.000 claims description 6
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 6
- 229960000311 ritonavir Drugs 0.000 claims description 6
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 claims description 6
- 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 claims description 5
- 235000011010 calcium phosphates Nutrition 0.000 claims description 5
- 239000004203 carnauba wax Substances 0.000 claims description 5
- 229920000609 methyl cellulose Polymers 0.000 claims description 5
- 239000001923 methylcellulose Substances 0.000 claims description 5
- 235000010981 methylcellulose Nutrition 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 229920000193 polymethacrylate Polymers 0.000 claims description 5
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims 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 claims description 4
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims 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 claims description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 229920002907 Guar gum Polymers 0.000 claims 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 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- 235000010443 alginic acid Nutrition 0.000 claims description 4
- 229920000615 alginic acid Polymers 0.000 claims description 4
- 239000000783 alginic acid Substances 0.000 claims description 4
- 229960001126 alginic acid Drugs 0.000 claims description 4
- 150000004781 alginic acids Chemical class 0.000 claims description 4
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 claims description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 229940096516 dextrates Drugs 0.000 claims description 4
- 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 claims description 4
- 239000000665 guar gum Substances 0.000 claims description 4
- 235000010417 guar gum Nutrition 0.000 claims description 4
- 229960002154 guar gum Drugs 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 239000002356 single layer Substances 0.000 claims description 4
- 235000010413 sodium alginate Nutrition 0.000 claims description 4
- 239000000661 sodium alginate Substances 0.000 claims description 4
- 229940005550 sodium alginate Drugs 0.000 claims description 4
- 239000001856 Ethyl cellulose Substances 0.000 claims 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 claims description 3
- 108010010803 Gelatin Proteins 0.000 claims description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 3
- 229920002494 Zein Polymers 0.000 claims description 3
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 3
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 3
- 229920001249 ethyl cellulose Polymers 0.000 claims description 3
- 239000008273 gelatin Substances 0.000 claims description 3
- 229920000159 gelatin Polymers 0.000 claims description 3
- 235000019322 gelatine Nutrition 0.000 claims description 3
- 235000011852 gelatine desserts Nutrition 0.000 claims description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 3
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 3
- 239000004200 microcrystalline wax Substances 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 239000005019 zein Substances 0.000 claims description 3
- 229940093612 zein Drugs 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- 239000005995 Aluminium silicate Substances 0.000 claims 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 claims 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 claims 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 claims description 2
- 235000019739 Dicalciumphosphate Nutrition 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims 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 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 239000004698 Polyethylene Substances 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 235000010489 acacia gum Nutrition 0.000 claims description 2
- 239000001785 acacia senegal l. willd gum Substances 0.000 claims description 2
- 235000012211 aluminium silicate Nutrition 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 235000010216 calcium carbonate Nutrition 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 229960001631 carbomer Drugs 0.000 claims description 2
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 claims description 2
- 239000004359 castor oil Substances 0.000 claims description 2
- 235000019438 castor oil Nutrition 0.000 claims description 2
- 235000010980 cellulose Nutrition 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920002301 cellulose acetate Polymers 0.000 claims description 2
- 239000008121 dextrose Substances 0.000 claims description 2
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 claims description 2
- 229910000390 dicalcium phosphate Inorganic materials 0.000 claims description 2
- 229940038472 dicalcium phosphate Drugs 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 2
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 2
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 claims description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 2
- 239000001095 magnesium carbonate Substances 0.000 claims description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 2
- 235000014380 magnesium carbonate Nutrition 0.000 claims description 2
- 239000000395 magnesium oxide Substances 0.000 claims description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 2
- 235000012245 magnesium oxide Nutrition 0.000 claims description 2
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 239000002480 mineral oil Substances 0.000 claims description 2
- 235000010446 mineral oil Nutrition 0.000 claims description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 2
- 239000012188 paraffin wax Substances 0.000 claims description 2
- 229960000540 polacrilin potassium Drugs 0.000 claims description 2
- 229920000573 polyethylene Polymers 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 claims description 2
- 229920001592 potato starch Polymers 0.000 claims description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 2
- 239000004299 sodium benzoate Substances 0.000 claims description 2
- 235000010234 sodium benzoate Nutrition 0.000 claims description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 239000012177 spermaceti Substances 0.000 claims description 2
- 229940084106 spermaceti Drugs 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 2
- 238000004132 cross linking Methods 0.000 claims 1
- YSIBYEBNVMDAPN-CMDGGOBGSA-N (e)-4-oxo-4-(3-triethoxysilylpropylamino)but-2-enoic acid Chemical compound CCO[Si](OCC)(OCC)CCCNC(=O)\C=C\C(O)=O YSIBYEBNVMDAPN-CMDGGOBGSA-N 0.000 abstract description 5
- 229960003796 atazanavir sulfate Drugs 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 5
- 239000013543 active substance Substances 0.000 abstract 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 abstract 1
- 229940124411 anti-hiv antiviral agent Drugs 0.000 abstract 1
- 208000030507 AIDS Diseases 0.000 description 59
- 239000003814 drug Substances 0.000 description 56
- 241000725303 Human immunodeficiency virus Species 0.000 description 54
- 238000002360 preparation method Methods 0.000 description 47
- 229940079593 drug Drugs 0.000 description 42
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 32
- 238000000576 coating method Methods 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 239000011248 coating agent Substances 0.000 description 23
- 150000003839 salts Chemical class 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 239000013078 crystal Substances 0.000 description 17
- 239000003112 inhibitor Substances 0.000 description 16
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 15
- 229960002555 zidovudine Drugs 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 13
- 238000001035 drying Methods 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 238000004090 dissolution Methods 0.000 description 11
- 239000006260 foam Substances 0.000 description 11
- 239000000376 reactant Substances 0.000 description 11
- 239000007779 soft material Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 206010039491 Sarcoma Diseases 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 238000005469 granulation Methods 0.000 description 8
- 230000003179 granulation Effects 0.000 description 8
- 238000003801 milling Methods 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 8
- 238000009492 tablet coating Methods 0.000 description 8
- 239000002700 tablet coating Substances 0.000 description 8
- VERWQPYQDXWOGT-LVJNJWHOSA-N 4-amino-5-fluoro-1-[(2r,5s)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one;[[(2r)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-(propan-2-yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate;(e)-but-2-enedioic acid Chemical compound OC(=O)\C=C\C(O)=O.C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VERWQPYQDXWOGT-LVJNJWHOSA-N 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 208000035126 Facies Diseases 0.000 description 6
- 229940122440 HIV protease inhibitor Drugs 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229960004756 ethanol Drugs 0.000 description 6
- 239000004030 hiv protease inhibitor Substances 0.000 description 6
- 238000011081 inoculation Methods 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000002351 wastewater Substances 0.000 description 5
- 206010048843 Cytomegalovirus chorioretinitis Diseases 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 4
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical group C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 208000001763 cytomegalovirus retinitis Diseases 0.000 description 4
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical group CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 4
- 239000002777 nucleoside Substances 0.000 description 4
- 150000003833 nucleoside derivatives Chemical class 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 239000011593 sulfur Substances 0.000 description 4
- 229960004556 tenofovir Drugs 0.000 description 4
- 102000003390 tumor necrosis factor Human genes 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 3
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 3
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 3
- 108010002350 Interleukin-2 Proteins 0.000 description 3
- 102100020873 Interleukin-2 Human genes 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960004748 abacavir Drugs 0.000 description 3
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical group C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 230000001186 cumulative effect Effects 0.000 description 3
- 239000007888 film coating Substances 0.000 description 3
- 238000009501 film coating Methods 0.000 description 3
- 238000011010 flushing procedure Methods 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000005498 polishing Methods 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 229960000523 zalcitabine Drugs 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 2
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 description 2
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 2
- 208000006081 Cryptococcal meningitis Diseases 0.000 description 2
- 206010011831 Cytomegalovirus infection Diseases 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Natural products OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 229940126656 GS-4224 Drugs 0.000 description 2
- 208000031886 HIV Infections Diseases 0.000 description 2
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 description 2
- 208000037357 HIV infectious disease Diseases 0.000 description 2
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 2
- 101100005713 Homo sapiens CD4 gene Proteins 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- 101900297506 Human immunodeficiency virus type 1 group M subtype B Reverse transcriptase/ribonuclease H Proteins 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 102000008070 Interferon-gamma Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- 206010027209 Meningitis cryptococcal Diseases 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 240000002853 Nelumbo nucifera Species 0.000 description 2
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 2
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- WMHSRBZIJNQHKT-FFKFEZPRSA-N abacavir sulfate Chemical compound OS(O)(=O)=O.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 WMHSRBZIJNQHKT-FFKFEZPRSA-N 0.000 description 2
- XOYXESIZZFUVRD-UVSAJTFZSA-M acemannan Chemical compound CC(=O)O[C@@H]1[C@H](O)[C@@H](OC)O[C@H](CO)[C@H]1O[C@@H]1[C@@H](O)[C@@H](OC(C)=O)[C@H](O[C@@H]2[C@H]([C@@H](OC(C)=O)[C@H](O[C@@H]3[C@H]([C@@H](O)[C@H](O[C@@H]4[C@H]([C@@H](OC(C)=O)[C@H](O[C@@H]5[C@H]([C@@H](OC(C)=O)[C@H](O[C@@H]6[C@H]([C@@H](OC(C)=O)[C@H](O[C@@H]7[C@H]([C@@H](OC(C)=O)[C@H](OC)[C@@H](CO)O7)O)[C@@H](CO)O6)O)[C@H](O5)C([O-])=O)O)[C@@H](CO)O4)O)[C@@H](CO)O3)NC(C)=O)[C@@H](CO)O2)O)[C@@H](CO)O1 XOYXESIZZFUVRD-UVSAJTFZSA-M 0.000 description 2
- 229960005327 acemannan Drugs 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229960001830 amprenavir Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000011162 core material Substances 0.000 description 2
- 238000011262 co‐therapy Methods 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 229960005319 delavirdine Drugs 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- VFNGKCDDZUSWLR-UHFFFAOYSA-L disulfate(2-) Chemical compound [O-]S(=O)(=O)OS([O-])(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-L 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229960002759 eflornithine Drugs 0.000 description 2
- 229960000366 emtricitabine Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 229940044627 gamma-interferon Drugs 0.000 description 2
- 229960002963 ganciclovir Drugs 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000002835 hiv fusion inhibitor Substances 0.000 description 2
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 229960001627 lamivudine Drugs 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- ZAHQPTJLOCWVPG-UHFFFAOYSA-N mitoxantrone dihydrochloride Chemical compound Cl.Cl.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO ZAHQPTJLOCWVPG-UHFFFAOYSA-N 0.000 description 2
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 2
- 229960000689 nevirapine Drugs 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229960001624 pentamidine isethionate Drugs 0.000 description 2
- YBVNFKZSMZGRAD-UHFFFAOYSA-N pentamidine isethionate Chemical compound OCCS(O)(=O)=O.OCCS(O)(=O)=O.C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 YBVNFKZSMZGRAD-UHFFFAOYSA-N 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- ATEBXHFBFRCZMA-VXTBVIBXSA-N rifabutin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC(=C2N3)C(=O)C=4C(O)=C5C)C)OC)C5=C1C=4C2=NC13CCN(CC(C)C)CC1 ATEBXHFBFRCZMA-VXTBVIBXSA-N 0.000 description 2
- 229960001852 saquinavir Drugs 0.000 description 2
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 2
- 238000010900 secondary nucleation Methods 0.000 description 2
- 238000010008 shearing Methods 0.000 description 2
- 229960001203 stavudine Drugs 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 2
- BEUUJDAEPJZWHM-COROXYKFSA-N tert-butyl n-[(2s,3s,5r)-3-hydroxy-6-[[(2s)-1-(2-methoxyethylamino)-3-methyl-1-oxobutan-2-yl]amino]-6-oxo-1-phenyl-5-[(2,3,4-trimethoxyphenyl)methyl]hexan-2-yl]carbamate Chemical compound C([C@@H]([C@@H](O)C[C@H](C(=O)N[C@H](C(=O)NCCOC)C(C)C)CC=1C(=C(OC)C(OC)=CC=1)OC)NC(=O)OC(C)(C)C)C1=CC=CC=C1 BEUUJDAEPJZWHM-COROXYKFSA-N 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 2
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 2
- 229960001082 trimethoprim Drugs 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 229940023080 viracept Drugs 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- ASSJTMUEFHUKMJ-UHFFFAOYSA-N 1-acetyl-n-[3-[4-[(4-carbamoylphenyl)methyl]piperidin-1-yl]propyl]-n-(3-chloro-4-methylphenyl)piperidine-4-carboxamide Chemical compound C1CN(C(=O)C)CCC1C(=O)N(C=1C=C(Cl)C(C)=CC=1)CCCN1CCC(CC=2C=CC(=CC=2)C(N)=O)CC1 ASSJTMUEFHUKMJ-UHFFFAOYSA-N 0.000 description 1
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 description 1
- WVXRAFOPTSTNLL-NKWVEPMBSA-N 2',3'-dideoxyadenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1CC[C@@H](CO)O1 WVXRAFOPTSTNLL-NKWVEPMBSA-N 0.000 description 1
- ACTOXUHEUCPTEW-BWHGAVFKSA-N 2-[(4r,5s,6s,7r,9r,10r,11e,13e,16r)-6-[(2s,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[(2s,5s,6r)-5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-o Chemical compound O([C@H]1/C=C/C=C/C[C@@H](C)OC(=O)C[C@@H](O)[C@@H]([C@H]([C@@H](CC=O)C[C@H]1C)O[C@H]1[C@@H]([C@H]([C@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(O)C2)[C@@H](C)O1)N(C)C)O)OC)[C@@H]1CC[C@H](N(C)C)[C@@H](C)O1 ACTOXUHEUCPTEW-BWHGAVFKSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- PMZBHPUNQNKBOA-UHFFFAOYSA-N 5-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=CC(C(O)=O)=CC(C(O)=O)=C1 PMZBHPUNQNKBOA-UHFFFAOYSA-N 0.000 description 1
- VJXSSYDSOJBUAV-UHFFFAOYSA-N 6-(2,5-dimethoxy-benzyl)-5-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine Chemical compound COC1=CC=C(OC)C(CC=2C(=C3C(N)=NC(N)=NC3=NC=2)C)=C1 VJXSSYDSOJBUAV-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- 229940124321 AIDS medicine Drugs 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000427202 Adria Species 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- CIUUIPMOFZIWIZ-UHFFFAOYSA-N Bropirimine Chemical compound NC1=NC(O)=C(Br)C(C=2C=CC=CC=2)=N1 CIUUIPMOFZIWIZ-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- 241001227713 Chiron Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000008953 Cryptosporidiosis Diseases 0.000 description 1
- 206010011502 Cryptosporidiosis infection Diseases 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 229940099797 HIV integrase inhibitor Drugs 0.000 description 1
- 208000009889 Herpes Simplex Diseases 0.000 description 1
- 241000228404 Histoplasma capsulatum Species 0.000 description 1
- 101000987586 Homo sapiens Eosinophil peroxidase Proteins 0.000 description 1
- 101000920686 Homo sapiens Erythropoietin Proteins 0.000 description 1
- 102000002265 Human Growth Hormone Human genes 0.000 description 1
- 108010000521 Human Growth Hormone Proteins 0.000 description 1
- 239000000854 Human Growth Hormone Substances 0.000 description 1
- 241000701806 Human papillomavirus Species 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 108010054710 IMREG-1 Proteins 0.000 description 1
- 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 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- MCPUZZJBAHRIPO-UHFFFAOYSA-N Lersivirine Chemical compound CCC1=NN(CCO)C(CC)=C1OC1=CC(C#N)=CC(C#N)=C1 MCPUZZJBAHRIPO-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010025476 Malabsorption Diseases 0.000 description 1
- 208000004155 Malabsorption Syndromes Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- YFGBQHOOROIVKG-FKBYEOEOSA-N Met-enkephalin Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 YFGBQHOOROIVKG-FKBYEOEOSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 108010042237 Methionine Enkephalin Proteins 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 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 1
- POJYNXJIOJKXRG-UHFFFAOYSA-N NC(=S)S.[S] Chemical compound NC(=S)S.[S] POJYNXJIOJKXRG-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 208000007027 Oral Candidiasis Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 240000003296 Petasites japonicus Species 0.000 description 1
- 235000003823 Petasites japonicus Nutrition 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241001417524 Pomacanthidae Species 0.000 description 1
- 239000004187 Spiramycin Substances 0.000 description 1
- 229940123317 Sulfonamide antibiotic Drugs 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 101800001703 Thymopentin Proteins 0.000 description 1
- 102400000160 Thymopentin Human genes 0.000 description 1
- SUJUHGSWHZTSEU-UHFFFAOYSA-N Tipranavir Natural products C1C(O)=C(C(CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)C(=O)OC1(CCC)CCC1=CC=CC=C1 SUJUHGSWHZTSEU-UHFFFAOYSA-N 0.000 description 1
- HIINQLBHPIQYHN-JTQLQIEISA-N Tyr-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H](N)CC1=CC=C(O)C=C1 HIINQLBHPIQYHN-JTQLQIEISA-N 0.000 description 1
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229960000531 abacavir sulfate Drugs 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 229950010850 acistrate Drugs 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 108700025316 aldesleukin Proteins 0.000 description 1
- 229960005310 aldesleukin Drugs 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005037 alkyl phenyl group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- 150000001538 azepines Chemical class 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229950009494 bropirimine Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 201000003984 candidiasis Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 210000004970 cd4 cell Anatomy 0.000 description 1
- 230000007910 cell fusion Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000019365 chlortetracycline Nutrition 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 229960000724 cidofovir Drugs 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 229940002080 cytomegalovirus immune globulin Drugs 0.000 description 1
- 229940087451 cytovene Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 229960002656 didanosine Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000011363 dried mixture Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 229960003804 efavirenz Drugs 0.000 description 1
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 1
- 229940059826 emtricitabine 200 mg Drugs 0.000 description 1
- 229940019131 epzicom Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229960003142 fosamprenavir Drugs 0.000 description 1
- MLBVMOWEQCZNCC-OEMFJLHTSA-N fosamprenavir Chemical compound C([C@@H]([C@H](OP(O)(O)=O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 MLBVMOWEQCZNCC-OEMFJLHTSA-N 0.000 description 1
- 229960000848 foscarnet sodium Drugs 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 239000003084 hiv integrase inhibitor Substances 0.000 description 1
- 102000044890 human EPO Human genes 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 229960001438 immunostimulant agent Drugs 0.000 description 1
- 239000003022 immunostimulating agent Substances 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229960001936 indinavir Drugs 0.000 description 1
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000002850 integrase inhibitor Substances 0.000 description 1
- 229940124524 integrase inhibitor Drugs 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- BWHLPLXXIDYSNW-UHFFFAOYSA-N ketorolac tromethamine Chemical compound OCC(N)(CO)CO.OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 BWHLPLXXIDYSNW-UHFFFAOYSA-N 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229940029101 lamivudine 300 mg Drugs 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 229940121292 leronlimab Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229960004525 lopinavir Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960005225 mifamurtide Drugs 0.000 description 1
- JMUHBNWAORSSBD-WKYWBUFDSA-N mifamurtide Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCC)COP(O)(=O)OCCNC(=O)[C@H](C)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](C)O[C@H]1[C@H](O)[C@@H](CO)OC(O)[C@@H]1NC(C)=O JMUHBNWAORSSBD-WKYWBUFDSA-N 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 229960000988 nystatin Drugs 0.000 description 1
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229950001030 piritrexim Drugs 0.000 description 1
- 229960002169 plerixafor Drugs 0.000 description 1
- YIQPUIGJQJDJOS-UHFFFAOYSA-N plerixafor Chemical compound C=1C=C(CN2CCNCCCNCCNCCC2)C=CC=1CN1CCCNCCNCCCNCC1 YIQPUIGJQJDJOS-UHFFFAOYSA-N 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
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- INDBQLZJXZLFIT-UHFFFAOYSA-N primaquine Chemical compound N1=CC=CC2=CC(OC)=CC(NC(C)CCCN)=C21 INDBQLZJXZLFIT-UHFFFAOYSA-N 0.000 description 1
- 229960005179 primaquine Drugs 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000012207 quantitative assay Methods 0.000 description 1
- 108700018720 recombinant interferon alpha 2b-like Proteins 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229940064914 retrovir Drugs 0.000 description 1
- 229940107904 reyataz Drugs 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 229960000885 rifabutin Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229960004532 somatropin Drugs 0.000 description 1
- 235000019372 spiramycin Nutrition 0.000 description 1
- 229960001294 spiramycin Drugs 0.000 description 1
- 229930191512 spiramycin Natural products 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 229960004517 thymopentin Drugs 0.000 description 1
- PSWFFKRAVBDQEG-YGQNSOCVSA-N thymopentin Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 PSWFFKRAVBDQEG-YGQNSOCVSA-N 0.000 description 1
- 229960000838 tipranavir Drugs 0.000 description 1
- SUJUHGSWHZTSEU-FYBSXPHGSA-N tipranavir Chemical compound C([C@@]1(CCC)OC(=O)C([C@H](CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)=C(O)C1)CC1=CC=CC=C1 SUJUHGSWHZTSEU-FYBSXPHGSA-N 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- DFHAXXVZCFXGOQ-UHFFFAOYSA-K trisodium phosphonoformate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)P([O-])([O-])=O DFHAXXVZCFXGOQ-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229940008349 truvada Drugs 0.000 description 1
- 229940093257 valacyclovir Drugs 0.000 description 1
- 229940100050 virazole Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
-
- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
Abstract
公开了包含硫酸阿扎那韦,任选含有其它活性药物例如抗HIV药物的压制片剂;含硫酸阿扎那韦和可用于制备片剂的颗粒内润滑剂的颗粒;包含许多颗粒的组合物;制备所述颗粒和片剂的方法;和治疗HIV的方法。
Description
发明领域
本发明涉及药用组合物、方法和治疗方法。
发明背景
已确定人免疫缺陷病毒(HIV)为导致获得性免疫缺陷综合征(AIDS)的病原体,该获得性免疫缺陷综合征(AIDS)为特征在于免疫系统破坏和不能治好威胁生命的机会性感染的严重疾病。
其中
R1为低级烷氧基羰基,
R2为仲或叔低级烷基,或低级烷硫基-低级烷基,
R3为未被取代的苯基或被一个或多个低级烷氧基取代的苯基,或C4-C8环烷基,
R4为各自在4-位被不饱和杂环基取代的苯基或环己基,所述不饱和杂环基通过环碳原子连接,具有5-8个环原子,含有选自氮、氧、硫、亚磺酰基(-SO-)和磺酰基(-SO2-)的1-4个杂原子,且未被取代或被低级烷基或苯基-低级烷基取代,
R5独立于R2,具有所述R2含义之一,且
R6独立于R1,为低级烷氧基羰基或其盐,条件是存在至少一个成盐基团,包括其各种药学上可接受的酸加成盐。
Singh等的美国专利号6,087,383公开了称为阿扎那韦的氮杂肽HIV蛋白酶抑制剂的硫酸氢盐,其具有以下结构
(本文中称为“阿扎那韦硫酸氢盐”或“硫酸阿扎那韦”)。
2005年11月17日公布的美国专利公布号US20050256202A1公开了制备HIV蛋白酶抑制剂阿扎那韦硫酸氢盐及其新形式的方法。
阿扎那韦商业上可作为处方药从Bristol-Myers Squibb Company,New York得到,商品名为(硫酸阿扎那韦),用于治疗HIV。于2003年通过美国食品和药品管理局批准后,(硫酸阿扎那韦)目前可以100毫克(“mg”)、150mg、200mg和300mg胶囊形式得到。需要(硫酸阿扎那韦)的患者数量很大并在继续增加。
目前,硫酸阿扎那韦不能以片剂形式从商业上得到。尽管通常需要以胶囊形式释放药物,但按片剂形式释放可能最好。例如,片剂可提供:降低易于干预的倾向;便于吞咽;可容易分开的剂量;和将药物按固定剂量组合混合在单层或多层片例如双层片中的能力。
发明概述
本发明包括压制片,该压制片包含硫酸阿扎那韦,任选含有其他活性药物例如抗HIV药物。本发明也包括含硫酸阿扎那韦和可用于制备片剂的颗粒内润滑剂的颗粒;包含许多颗粒的组合物;制备所述颗粒和片剂的方法;和治疗HIV的方法。
通过本发明,现在可以提供压片形式的阿扎那韦片剂。按照本发明,在颗粒制备期间,将润滑剂与硫酸阿扎那韦混合。相当意外,由所述颗粒形成的片剂可具有期望的片剂溶出特性和在制备期间期望的加工特性。
发明详述
根据本发明,其中制备硫酸阿扎那韦的方法并不是关键的。通常,硫酸阿扎那韦以A型、E3型或C型存在,尤其优选为药学上可接受的形式。通常,阿扎那韦及其盐的晶型为基本上纯的形式。在2005年11月17日公布的美国专利公布号US20050256202A1中描述了这些形式。本文中使用的术语“药学上可接受的”是指在合理的医学判断范围内,适合与人类和动物的组织接触,而无过度毒性、刺激性、过敏反应或其它并发症问题,并具有合理的益处/风险比的那些化合物、材料、组合物和/或剂型。术语“基本上纯的”表示具有至少约90wt%,优选至少约95wt%,更优选至少约98wt%的化合物,且小于约10wt%,优选小于约5wt%,更优选小于约2wt%的其他化合物的化学纯度的化合物,所述其他化合物具有与所述化合物不同的化学结构。
在一种合适的方法中,为其游离碱形式的阿扎那韦可通过以下步骤制备:在约25℃-约50℃,优选约30℃-约40℃范围内的温度下,在有机溶剂例如二氯甲烷、四氢呋喃或甲醇的存在下,所述溶剂优选为二氯甲烷,用酸优选盐酸(其中使用Boc),或碱(其中使用三氟乙酰基)处理以下结构的保护的三胺盐溶液
(其中PG代表保护基团例如叔-丁氧基羰基(Boc)或三氟乙酰基,优选Boc),形成三胺酸式盐,优选以下结构的盐酸盐
不分离三胺酸式盐,使该三胺酸式盐与以下结构的酸的活性酯
优选以下结构的活性酯
在以下的条件下反应:在约25℃-约50℃,优选约30℃-约40℃范围内的温度下,在碱例如K2HPO4、二异丙基乙胺、N-甲基吗啉、碳酸钠或碳酸钾,优选K2HPO4的存在下,在有机溶剂例如二氯甲烷、乙酸乙酯和乙酸丁酯的混合物、乙腈或乙酸乙酯,优选二氯甲烷的存在下,形成阿扎那韦游离碱。
保护的三胺起始原料可通过以下方法制备:
在异丙醇或其它醇例如乙醇或丁醇的存在下,使环氧化物
其中PG优选为Boc例如N-(叔-丁氧基羰基)-2(S)-氨基-1-苯基-3(R)-3,4-环氧-丁烷,
与以下氨基甲酰肼(hydrazine carbamate)反应
其中PG优选为Boc。
用于制备阿扎那韦硫酸盐的A型晶体的一种合适的方法采用改进的立方结晶技术,其中将阿扎那韦游离碱溶于在其中阿扎那韦硫酸盐基本上不溶的有机溶剂中,所述有机溶剂包括丙酮、丙酮和N-甲基吡咯烷酮的混合物、乙醇、乙醇和丙酮的混合物等,得到溶液,按阿扎那韦游离碱计,所述溶液具有在约6.5-约9.7%重量,优选约6.9-约8.1%重量范围内的阿扎那韦游离碱的浓度
将阿扎那韦游离碱溶液在约35℃-约55℃,优选约40℃-约50℃范围内的温度下加热,并与一定量的浓硫酸(含约95-约100%H2SO4)反应,该一定量的浓硫酸与小于约15%,优选约5-小于约12%,更优选约8-约10%重量的总阿扎那韦游离碱反应。因此,阿扎那韦游离碱的起始溶液将先与小于约15%,优选约5-约12%重量的所采用的硫酸总量反应。在反应期间,将反应混合物维持在约35℃-约55℃,优选约40℃-约50℃范围内的温度下。
反应允许持续约12-约60分钟,优选约15-约30分钟的一段时间。
基于保留在反应混合物中的阿扎那韦游离碱的重量计,采用在约0.1-约80%重量,优选约3-约8%重量范围内的晶种量,将反应混合物用A型硫酸阿扎那韦的晶体接种,同时将反应混合物维持在约35℃-约55℃,优选约40℃-约50℃范围内的温度下。
反应允许继续进行直至结晶开始。然后,以按照2005年11月17日公布的美国专利公布号US20050256202A1中所述三次方程递增的速度,在多个阶段加入硫酸,形成硫酸阿扎那韦,干燥后,其得到A型晶体。
形成的阿扎那韦硫酸盐的晶体粒度和形态取决于硫酸的加入速度,该加入速度决定结晶速度。发现,与恒定的加入速度结晶相比,改进的“立方”结晶技术(酸以按照三次方程递增的速度加入)提供相对较大、更充分限定的硫酸阿扎那韦晶体以及较窄的粒度范围和较少的细粒。缓慢的初始酸流动速度显示相对于二次成核有利于晶体生长。因此,当表面积随粒度增加时,晶种床能够接受递增的酸流动速度,而不诱导二次成核。缓慢的初始加入速度允许时间使晶体长的较大,使平均尺寸增加。立方结晶提供较不易压缩的滤饼,其有助于滤饼有效的除去液体和洗涤,并给出比恒定加入速度结晶的产物更容易干燥的产物,其具有较少的硬快。
C型原料可通过例如将A型晶体暴露于水,然后干燥制备。C型原料也可通过以下方法形成:将A型晶体暴露于大于约95%RH,优选约95%-约100%RH(水蒸汽)的高相对湿度,保持至少24小时,优选约24-约48小时。C型原料也可通过以下方法制备:将硫酸阿扎那韦A型湿法制粒,得到硫酸阿扎那韦的颗粒,然后将该颗粒干燥。
E3型可通过例如以下方法制备:将阿扎那韦游离碱在乙醇中打浆,采用约1∶1-约1.1∶1的酸∶游离碱的摩尔比,用浓硫酸处理浆状物,将得到的溶液在约30℃-约40℃下加热,用硫酸阿扎那韦的乙醇湿E3晶体接种溶液,将混合物用庚烷(或其它溶剂例如己烷或甲苯)处理,过滤,干燥,得到硫酸阿扎那韦E3型(三乙醇溶剂合物)。接种步骤将采用一定量的晶种来实现E3晶体的形成,例如在约0.02∶1-约0.04∶1范围内的硫酸阿扎那韦E-3晶种:游离碱的摩尔比。
关于适用于根据本发明制备硫酸阿扎那韦的进一步细节,在2005年11月17日公布的美国专利公布号US20050256202A1中进行了描述。
本发明考虑使用任何药学上可接受的成分,例如润滑剂、崩解剂、粘合剂、填充剂(也称为“压缩助剂”)、表面活性剂、薄膜包衣剂和溶剂。某些这些成分的实例见以下所述,且在Handbook of PharmaceuticalExcipients,第二版,Ed.A.Wade and P.J.Weller,1994,ThePharmaceutical Press,London,England中进行了更详细的描述。根据本发明使用的此类成分的选择和量并不是关键的,且可通过本领域技术人员确定。
根据本发明适合使用的润滑剂的实例有但不限于硬脂酸镁、硬脂酸锌、硬脂酸钙、硬脂酸、棕榈酸、硬脂酰富马酸钠、苯甲酸钠、十二烷基硫酸钠、甘油单硬脂酸酯、甘油棕榈酸硬脂酸酯、氢化蓖麻油、氢化植物油、矿物油、巴西棕榈蜡和聚乙二醇。根据本发明,也称为“助流剂”的成分将包括在润滑剂的范围内。实例包括但不限于二氧化硅、硅酸钙、磷酸钙和滑石粉。
根据本发明适合使用的崩解剂的实例有但不限于羧甲基纤维素钠、交联聚维酮、马铃薯淀粉、预胶化淀粉、玉米淀粉、淀粉羟乙酸钠、微晶纤维素、粉末状纤维素、甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠、藻酸、胶体二氧化硅、瓜尔胶、硅酸镁铝、波拉克林钾(polyacrilin potassium)和藻酸钠。
根据本发明适合使用的粘合剂的实例有但不限于阿拉伯胶、卡波姆、糊精、明胶、瓜尔胶、氢化植物油、甲基纤维素、乙基纤维素、醋酸纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、葡萄糖、乳糖、硅酸镁铝、麦芽糖糊精、聚甲基丙烯酸酯、聚维酮、聚乙烯吡咯烷酮、玉米淀粉、预胶化淀粉、藻酸、藻酸钠、玉米蛋白、巴西棕榈蜡、石蜡、鲸蜡、聚乙烯和微晶蜡。
根据本发明适合使用的填充剂的实例有但不限于微晶纤维素、乳糖、蔗糖、淀粉、预胶化淀粉、右旋糖、葡萄糖结合剂、糊精、甘露醇、果糖、木糖醇、山梨醇、玉米淀粉、改性玉米淀粉;无机盐例如碳酸钙、碳酸镁、氧化镁、磷酸钙、磷酸二钙、三碱式磷酸钙、硫酸钙、糊精/葡萄糖结合剂、麦芽糖糊精、可压缩性糖、蔗糖和玉米淀粉磨制而成的药用辅料;甘油棕榈酸硬脂酸酯、氢化植物油、高岭土、麦芽糖糊精、聚甲基丙烯酸酯、氯化钾、氯化钠、蔗糖、糖球和滑石粉。
根据本发明,当成分在制粒前掺入时,它们称为“颗粒内”,即在颗粒内。当成分在制粒后掺入时,它们称为“颗粒外”。
本发明的一个方面提供含硫酸阿扎那韦和颗粒内润滑剂的颗粒,所述颗粒具有内部部分和外部表面,且其中至少一部分颗粒内润滑剂存在于颗粒的内部部分,即在颗粒内。颗粒的内部部分由在颗粒内具有一定体积的空间限定。通常,所述空间的体积为颗粒总体积的至少10%,更通常为颗粒总体积的至少50%,甚至更通常为颗粒总体积的至少80%。为了清楚的目的,颗粒内部部分占据的空间不能与空的空间相混淆。空的空间被硫酸阿扎那韦、颗粒内润滑剂和任选的其它成分占据。
通常,基于颗粒的总重量计,所述颗粒含约0.1-15%的颗粒内润滑剂,更通常约1-5%的颗粒内润滑剂。
通常,基于颗粒的总重量计,所述颗粒含约10-99.9%的硫酸阿扎那韦,更通常约30-90%的硫酸阿扎那韦。
基于颗粒的总重量计,所述颗粒还可含例如约1-20%的崩解剂。
基于颗粒的总重量计,所述颗粒可任选还含例如约0-20%的粘合剂。
基于颗粒的总重量计,所述颗粒可还含例如约1-20%的填充剂。
本发明还包括包含许多颗粒的组合物。这种组合物可存在于容器中,例如,当颗粒在一个制备位置制备,而在另一个位置压片时。
在本发明的一个方面,提供含颗粒的压制片,该颗粒含硫酸阿扎那韦和颗粒内润滑剂,所述颗粒具有内部部分和外部表面,且其中至少一部分颗粒内润滑剂存在于颗粒的内部部分。
通常,基于压制片的总重量计,所述压制片含约0.1-10%的颗粒内润滑剂,更通常约0.5-8%的颗粒内润滑剂。
通常,基于压制片的总重量计,所述压制片含约10-99.9%的硫酸阿扎那韦,更通常约30-90%的硫酸阿扎那韦。所述压制片含治疗有效量的以硫酸阿扎那韦提供的阿扎那韦。术语“治疗有效量”表示足以显示有意义的患者益处例如病毒荷量持续减少的各活性组分的总量。一般而言,治疗目的为抑制病毒荷量、恢复和维持免疫功能、提高生活质量,和减少HIV有关的发病率和死亡率。当应用到单一活性成分时,术语单独给予是指单独的该成分。当应用到联合药物时,该术语是指以组合、序贯或同时给药时产生疗效的活性成分的合并量。术语“患者”包括人和其它哺乳动物。给予患者例如约70千克(“kg”)体重的人的阿扎那韦的典型剂量为约3毫克(“mg”)-约1.5克(“g”),优选约10mg-约1.25g,例如约50mg-约600mg/人/日,优选分为1-4个单剂量,这些单剂量可例如大小相同。通常,儿童接受成人剂量的一半。本发明也包括在患者中治疗HIV感染,其包括给予患者治疗有效量的本发明压制片。
通常,基于压制片的总重量计,所述压制片含约1-20%,更通常约2-12%的崩解剂。
通常,基于压制片的总重量计,所述压制片含约0-10%,更通常约0.2-6%的粘合剂。
通常,基于压制片的总重量计,所述压制片含约5-90%,更通常约15-40%的填充剂。
通常,基于压制片的总重量计,所述压制片含约0.1-3%,更通常约0.2-1.5%的颗粒外润滑剂。
在本发明的一个方面,提供一种压制片,基于压制片的总重量计,所述压制片含:
(a)约10-98.9%的硫酸阿扎那韦;
(b)约0.1-10%的颗粒内润滑剂;和
(c)约1-20%的崩解剂。
在本发明的另一方面,提供一种压制片,该压制片含:硫酸阿扎那韦、颗粒内润滑剂和颗粒外润滑剂,其中所述片剂通过湿法制粒制备,其中将硫酸阿扎那韦和颗粒内润滑剂在颗粒内掺混,并在颗粒外加入颗粒外润滑剂。基于压制片的总重量计,在该方面典型的压制片含:
(a)约10-98.9%的硫酸阿扎那韦;
(b)约0.1-10%的颗粒内润滑剂;
(c)约0.1-3.0%的颗粒外润滑剂,和
(d)约1-20%的崩解剂。
在该方面,颗粒内润滑剂的实例选自硬脂酸、二氧化硅及其混合物。颗粒外润滑剂的实例为硬脂酸镁。
本发明压制片组合物的实例包括以下组合物,所述百分率基于压制片的总重量计:
也可将本发明压制片薄膜包衣。薄膜衣料浓度可变化最高达约10%以补充药物量,优选约2.5%-约3.5%。典型的薄膜衣料悬浮液包括以下组分中一种、二种或三种的组合:羧甲基纤维素钠、巴西棕榈蜡、醋酞纤维素、鲸蜡醇、蔗糖和玉米淀粉磨制而成的药用辅料、乙基纤维素、明胶、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、液体葡萄糖、麦芽糖糊精、甲基纤维素、微晶蜡、欧巴代和欧巴代II、聚甲基丙烯酸酯、聚乙烯醇、虫胶、蔗糖、滑石粉、二氧化钛和玉米蛋白。
在本发明的另一方面,将具有抗HIV活性的一种或多种其他药物包括在压制片中。本文中使用的术语“抗HIV活性”表示具有抗HIV病毒效力的药物。其它药物可选自例如核苷类HIV逆转录酶抑制剂、非核苷类HIV逆转录酶抑制剂、HIV蛋白酶抑制剂、HIV融合抑制剂、HIV附着抑制剂、CCR5抑制剂、CXCR4抑制剂、HIV出芽或成熟抑制剂和HIV整合酶抑制剂。
本发明的另一方面是压制片,其中所述其它药物为核苷HIV逆转录酶抑制剂,所述抑制剂选自阿巴卡韦、去羟肌苷、恩曲他滨、拉米夫定、司他夫定、替诺福韦、扎西他宾和齐多夫定或其药学上可接受的盐。与阿扎那韦组合的优选联合药物为其中所述其它药物为富马酸替诺福韦酯和恩曲他滨的联合药物。药物TruvadaTM(恩曲他滨-富马酸替诺福韦酯)的典型剂量为恩曲他滨200mg+替诺福韦300mg/片,每日一次。药物EpzicomTM(阿巴卡韦-拉米夫定)的典型剂量为硫酸阿巴卡韦600mg和拉米夫定300mg。与阿扎那韦联合的联合疗法的合适的剂量可由本领域技术人员确定。
本发明的另一方面为压制片,其中所述其它药物为非核苷HIV逆转录酶抑制剂,所述抑制剂选自地位韦啶、依法韦仑、奈韦拉平和UK 453061或其药学上可接受的盐。
本发明的另一方面是压制片,其中所述其它药物为HIV蛋白酶抑制剂,所述抑制剂选自氨普奈韦、茚地那韦、洛匹那韦、奈非那韦、利托那韦、沙奎那韦和福沙那韦或其药学上可接受的盐。利托那韦为作为具有抗HIV活性的另一种药物,与硫酸阿扎那韦联合使用的优选药物。但是,利托那韦更通常用作另一种药物例如阿扎那韦的激发剂。当作为蛋白酶抑制剂的激发剂给予时,给予剂量通常为100-400mg,每日两次,或如果用作每日一次方案的一部分,则给予剂量为100-200mg,每日一次。
本发明的另一方面为压制片,其中所述其它药物为HIV融合抑制剂,该抑制剂选自恩夫韦地或T-1249或其药学上可接受的盐。
本发明的另一方面为压制片,其中所述其它药物为CCR5抑制剂,该抑制剂选自马拉维诺、Sch-C、Sch-D、TAK-220、PRO-140、PF-232798和UK-427,857或其药学上可接受的盐。
本发明的另一方面为压制片,其中所述其它药物为CXCR4抑制剂AMD-3100或其药学上可接受的盐。
本发明的另一方面为压制片,其中所述其它药物为出芽或成熟抑制剂PA-457或其药学上可接受的盐。
本发明的另一方面为压制片,其中所述其它药物为整合酶抑制剂雷特格韦或其药学上可接受的盐。钾盐的化学名称为N-[(4-氟苯基)甲基]-1,6-二氢-5-羟基-1-甲基-2-[1-甲基-1-[[(5-甲基-1,3,4-噁二唑-2-基)羰基]氨基]乙基]-6-氧代-4-嘧啶甲酰胺单钾盐。在例如2003年5月1日公布的WO 2003/035077和Drugs of the Future 2007,32(2):118-122,Y Wang.等中描述了雷特格韦。单一疗法中雷特格韦的典型剂量为100、200、400和600mg,每日给药两次。与阿扎那韦联合的联合疗法的合适剂量可由本领域技术人员确定。
表1包括可用于治疗AIDS和HIV感染的一些药物,根据本发明,它们可适合用作具有抗HIV活性的其它药物以及可共给药的其它药物。
表1.抗病毒药物
药物名称 | 生产商 | 适应症 |
097(非核苷逆转录酶抑制剂) | Hoechst/Bayer | HIV感染,AIDS,ARC |
氨普奈韦141 W94GW 141(蛋白酶抑制剂) | Glaxo Wellcome | HIV感染,AIDS,ARC |
阿巴卡韦(1592U89)GW 1592(RT抑制剂) | Glaxo Wellcome | HIV感染,AIDS,ARC |
醋孟南 | Carrington Labs(Irving,TX) | ARC |
阿昔洛韦 | Burroughs Wellcome | HIV感染,AIDS,ARC,与AZT联合 |
AD-439 | Tanox Biosystems | HIV感染,AIDS,ARC |
AD-519 | Tanox Biosystems | HIV感染,AIDS,ARC |
阿得福韦二匹伏酯AL-721 | Gilead SciencesEthigen(Los Angeles,CA) | HIV感染,ARC,PGLHIV阳性,AIDS |
药物名称 | 生产商 | 适应症 |
α-干扰素HIV与立妥韦联合 | Glaxo Wellcome | 卡泊西肉瘤 |
药物名称 | 生产商 | 适应症 |
安莎霉素LM 427 | Adria Laboratories(Dublin,OH)Erbamont(Stamford,CT) | ARC |
中和pH不稳定性α-异常干扰素的抗体 | Advanced BiotherapyConcepts(Rockville,MD) | AIDS,ARC |
AR177 | Aronex Pharm | HIV感染,AIDS,ARC |
β-氟-ddA | Nat′l Cancer Institute | AIDS相关性疾病 |
BMS-232623(CGP-73547)(蛋白酶抑制剂) | Bristol-Myers Squibb/Novartis | HIV感染,AIDS,ARC |
BMS-234475(CGP-61755)(蛋白酶抑制剂) | Bristol-Myers Squibb/Novartis | HIV感染,AIDS,ARC |
CI-1012 | Warner-Lambert | HIV-1感染 |
西多福韦 | Gilead Science | CMV视网膜炎、疱疹、乳头瘤病毒 |
硫酸热凝多糖 | AJI Pharma USA | HIV感染 |
巨细胞病毒免疫球蛋白 | MedImmune | CMV视网膜炎 |
药物名称 | 生产商 | 适应症 |
更昔洛韦(Cytovene) | Syntex | 威胁视力的疾病 |
更昔洛韦 | CMV外周疾病、CMV视网膜炎 | |
地位韦啶(RT抑制剂) | Pharmacia-Upjohn | HIV感染,AIDS,ARC |
硫酸右旋糖酐 | Ueno Fine Chem.Ind.Ltd.(Osaka,Japan) | AIDS,ARC,HIV阳性无症状 |
ddC二脱氧胞苷 | Hoffman-La Roche | HIV感染,AIDS,ARC |
ddI二脱氧腺苷 | Bristol-Myers Squibb | HIV感染,AIDS,ARC;与AZT/d4T联合 |
药物名称 | 生产商 | 适应症 |
奈非那韦(蛋白酶抑制剂) | AgouronPharmaceuticals | HIV感染,AIDS,ARC |
奈韦拉平(RT抑制剂) | BoeheringerIngleheim | HIV感染,AIDS,ARC |
Novapren | Novaferon Labs,Inc.(Akron,OH) | HIV抑制剂 |
T肽八肽序列 | Peninsula Labs(Belmont,CA) | AIDS |
膦甲酸钠 | Astra Pharm.Products,Inc. | CMV视网膜炎、HIV感染、其它CMV感染 |
PNU-140690(蛋白酶抑制剂) | Pharmacia Upjohn | HIV感染,AIDS,ARC |
丙丁酚 | Vyrex | HIV感染,AIDS |
RBC-CD4 | Sheffield Med.Tech(Houston,TX) | HIV感染,AIDS,ARC |
利托那韦(蛋白酶抑制剂) | Abbott | HIV感染,AIDS,ARC |
沙奎那韦(蛋白酶抑制剂) | Hoffmann-LaRoche | HIV感染,AIDS,ARC |
司他夫定;d4T二脱氢脱氧-胸苷 | Bristol-Myers Squibb | HIV感染,AIDS,ARC |
伐昔洛韦 | Glaxo Wellcome | 生殖器HSV和CMV感染 |
药物名称 | 生产商 | 适应症 |
病毒唑利巴韦林 | Viratek/ICN(Costa Mesa,CA) | 无症状HIV阳性,LAS,ARC |
VX-478 | Vertex | HIV感染,AIDS,ARC |
扎西他宾 | Hoffmann-LaRoche | HIV感染,AIDS,ARC,与AZT联合 |
齐多夫定;AZT | Glaxo Wellcome | HIV感染,AIDS,ARC,卡泊西肉瘤,与其它疗法联合 |
免疫调节剂
药物名称 | 生产商 | 适应症 |
AS-101 | Wyeth-Ayerst | AIDS |
溴匹立明 | Pharmacia Upjohn | 晚期AIDS |
药物名称 | 生产商 | 适应症 |
醋孟南 | Carrington Labs,Inc.(Irving,TX) | AIDS,ARC |
CL246,738 | American CyanamidLederle Labs | AIDS,卡泊西肉瘤 |
EL10 | Elan Corp,PLC(Gainesville,GA) | HIV感染 |
FP-21399 | Fuki ImmunoPharm | 阻断HIV与CD4+细胞融合 |
γ-干扰素 | Genentech | ARC,与TNF(肿瘤坏死因子)联合 |
粒细胞巨噬细胞集落刺激因子 | Genetics InstituteSandoz | AIDS |
粒细胞巨噬细胞集落刺激因子 | Hoechst-RousselImmunex | AIDS |
药物名称 | 生产商 | 适应症 |
粒细胞巨噬细胞集落刺激因子 | Schering-Plough | AIDS,与AZT联合 |
HIV核心颗粒免疫刺激剂 | Rorer | 血清阳性HIV |
药物名称 | 生产商 | 适应症 |
IL-2白介素-2 | Cetus | AIDS,与AZT联合 |
IL-2白介素-2 | Hoffman-LaRocheImmunex | AIDS,ARC,HIV,与AZT联合 |
IL-2白介素-2(阿地白介素) | Chiron | AIDS,增加CD4细胞计数 |
免疫球蛋白静脉内(人) | Cutter Biological(Berkeley,CA) | 儿科AIDS,与AZT联合 |
IMREG-1 | Imreg(New Orleans,LA) | AIDS,卡泊西肉瘤,ARC,PGL |
IMREG-2 | Imreg(New Orleans,LA) | AIDS,卡泊西肉瘤,ARC,PGL |
依木硫二硫代氨基甲酸二乙酯 | Merieux Institute | AIDS,ARC |
α-2干扰素 | Schering Plough | 卡泊西肉瘤w/AZT,AIDS |
蛋氨酸-脑啡肽 | TNI Pharmaceutical(Chicago,IL) | AIDS,ARC |
药物名称 | 生产商 | 适应症 |
MTP-PE胞壁酰三肽粒细胞集落刺激因子 | Ciba-Geigy Corp.Amgen | 卡泊西肉瘤、AIDS,与AZT联合 |
Remune | Immune Response Corp. | 免疫疗法 |
rCD4重组可溶性人CD4 | Genentech | AIDS,ARC |
药物名称 | 生产商 | 适应症 |
rCD4-IgG杂种 | AIDS,ARC | |
重组可溶性人CD4 | Biogen | AIDS,ARC |
干扰素α2a | Hoffman-La Roche与AZT联合 | 卡泊西肉瘤,AIDS,ARC |
SK&F106528可溶性T4 | Smith Kline | HIV感染 |
胸腺喷丁 | ImmunobiologyResearch Institute(Annandale,NJ) | HIV感染 |
肿瘤坏死因子;TNF | Genentech | ARC,与γ-干扰素联合 |
抗感染药物
药物名称 | 生产商 | 适应症 |
克林霉素加伯氨奎 | Pharmacia Upjohn | PCP |
氟康唑 | Pfizer | 隐球菌性脑膜炎、念珠菌病 |
锭剂制菌霉素锭剂 | Squibb Corp. | 预防口腔念珠菌病 |
Ornidyl依氟鸟氨酸 | Merrell Dow | PCP |
依西酸喷他脒(IM &IV) | LyphoMed(Rosemont,IL) | PCP治疗 |
甲氧苄啶 | 抗菌 | |
甲氧苄啶/磺胺药物 | 抗菌 | |
吡曲克辛 | Burroughs Wellcome | PCP治疗 |
吸入用依西酸喷他脒 | Fisons Corporation | PCP预防 |
螺旋霉素 | Rhone-Poulenc腹泻 | 隐孢子虫病 |
药物名称 | 生产商 | 适应症 |
伊曲康唑-R51211 | Janssen-Pharm. | 组织胞浆菌瘤;隐球菌性脑膜炎 |
三甲曲沙 | Warner-Lambert | PCP |
柔红霉素 | NeXstar,Sequus | 卡泊西肉瘤 |
药物名称 | 生产商 | 适应症 |
重组人红细胞生成素 | Ortho Pharm.Corp. | 与AZT疗法有关的严重贫血 |
重组人生长激素 | Serono | AIDS有关的消瘦、恶病质 |
醋酸甲地孕酮 | Bristol-Myers Squibb | 治疗与AIDS有关的厌食症 |
睾酮 | Alza,Smith Kline | AIDS有关的消瘦 |
全肠道内营养 | Norwich EatonPharmaceuticals | 腹泻和与AIDS有关的吸收障碍 |
当将具有抗HIV活性的另一种药物包括在压制片中时,其可包括在与硫酸阿扎那韦或其制剂相同的相中,即为单层(monolithic)片;或其可包括在另一个相内,即为多层片。当包括在单层片中时,其它药物可与硫酸阿扎那韦或其制剂一起颗粒内掺混,或颗粒外加入。当包括在多层片中时,硫酸阿扎那韦在一层,而其它药物(或多种)在另一层例如双层。或者,当大于一种具有抗HIV活性的其它药物例如利托那韦、恩曲他滨和替诺福韦与硫酸阿扎那韦组合在多层片时,可能需要通过将它们掺入单独的层来使某些药物分开。
按照本发明,提供制备颗粒的方法,该方法包括:
(a)将硫酸阿扎那韦和颗粒内润滑剂掺混,形成第一掺混物;
(b)在流体(例如羟丙基纤维素的水、乙醇溶液、羟丙基纤维素的泡沫、聚维酮溶液)的存在下,将第一掺混物制粒(例如通过湿法制粒),形成湿颗粒;
(c)将至少一部分液体从湿颗粒中除去,形成干颗粒。通常,该方法还包括将干颗粒整粒(例如碾磨),形成整粒的颗粒,将整粒的颗粒压缩形成压制片,并将压制片用薄膜衣料包衣,形成包衣压制片。
可例如用制粒机混合机例如Fielder 10 L高剪切制粒机混合机;低剪切、转鼓或盘式制粒机和流化床制粒机进行湿法制粒。制粒也可用辊压方法,通过进行干法制粒(无流体)来实现。根据本发明,进行制粒步骤的一种优选的技术是采用例如2006年3月14日颁布的美国专利号7,011,702中所述含水空气泡沫。可例如用Glatt WSG-15流化床干燥器或盘式干燥机进行干燥步骤。可例如用研磨机例如Comil或Fitz研磨机进行整粒(例如碾磨)步骤。掺混步骤可在V形混合机或带状混合机中进行。形成片剂的压缩步骤可例如用各种压机包括β-压机、单站F-压机或6-站Korsh进行。薄膜包衣可在例如Glatt Column包衣机或较小的Hi包衣机(9″、12″锅)中进行。
以下实施例代表本发明的优选实施方案。
实施例1
1-[4-(吡啶-2-基)苯基]-5(S)-2,5-二{[N-(甲氧基羰基)-L-叔-亮氨酰基]氨基}-4-(S)-羟基-6-苯基-2-氮杂己烷,硫酸盐(A型)(硫酸阿扎那韦-A型)
A.
(1-[4-(吡啶-2-基)苯基]-5(S)-2,5-二[叔-丁氧基羰基)氨基]-4(S)-羟基-6-苯基-2-氮杂己烷·3HCl(三胺·3HCl盐))
向安装机械搅拌器、氮气入口和温度探头的1000mL3颈圆底烧瓶中加入保护的三胺1-[4-(吡啶-2-基)苯基]-5(S)-2,5-二[叔-丁氧基羰基)氨基]-4(S)-羟基-6-苯基-2-氮杂己烷
(100g,0.178mol)和CH2Cl2(500mL;5mL/g保护的三胺进料)(按Z.Xu等,HIV蛋白酶抑制剂BMS-232,632有效合成的工艺研究和开发,Organic Process Research and Development,6,323-328(2002)中所述制备),将得到的浆状物搅拌,同时将温度保持在约5-约22℃。
按使反应混合物的温度保持在5-30℃之间的速度,将浓盐酸(68mL,0.82摩尔,4.6当量)加入反应混合物中。将反应混合物加热至30-40℃,并搅拌,直至通过HPLC测定判断反应完成。
将水(70-210mL,0.7-2.1mL/g保护的三胺进料)加入反应混合物中,将反应混合物搅拌15分钟,允许各相分离。将上层富集产物(三胺·3HCl盐)的含水油层转移至加料漏斗中。
B.
(N-甲氧基羰基-L-叔-亮氨酸()的活性酯)
向安装机械搅拌器、加料漏斗、氮气入口和温度探头的3000mL3颈圆底烧瓶中加入N-甲氧基羰基-L-叔-亮氨酸(77.2g,0.408mol,2.30当量)、1-羟基苯并三唑(HOBT)(60.8g,0.450mol,2.53当量)和N-乙基N′-二甲氨基丙基碳二亚胺(EDAC)(82.0g,0.430mol,2.42当量),然后加入CH2Cl2(880mL;8.8mL/g保护的三胺进料),将混合物在环境温度(18-25℃)下搅拌,直至通过HPLC判断活性酯的形成完成。
C.1-[4-(吡啶-2-基)苯基]-5(S)-2,5-二{[N-(甲氧基羰基)-L-叔-亮氨酰基]氨基}-4(S)-羟基-6-苯基-2-氮杂己烷(阿扎那韦游离碱)
将无水磷酸氢二钾(K2HPO4;226g,1.30mol,7.30当量wrt保护的三胺)溶于1130mL水(11.3mL/g保护的胺;5mL/g K2HPO4)。
将K2HPO4溶液加入在部分B中制备的活性酯溶液中。搅拌下,在1.5-2.0h的时间内,向活性酯/K2HPO4水溶液混合物中缓慢加入部分A盐酸盐水溶液,同时保持搅拌,并将釜温度保持在5-20℃之间。
部分A盐酸盐溶液加入结束后,将反应混合物(偶联反应)加热至30-40℃,搅拌,直至通过HPLC测定判断偶联反应完成。
将偶合混合物冷却至15-20℃,将富集产物的下层有机相与上层废水相分离。
将富集产物的有机相用1M NaH2PO4(880mL;pH=1.5;8.8mL/g保护的三胺进料;5摩尔当量wrt保护的三胺)洗涤,允许各相分离,将废水相除去。
将洗涤后的富集产物的有机相和0.5N NaOH(800mL;8mL/g保护的三胺进料)一起搅拌,直至富集有机相的HPLC测定显示活性酯各自在0.3I.I.以下。允许各相分离,将废水相除去。
将富集有机相用5%NaH2PO4(450mL,4.5mL/g保护的三胺进料;pH=4.3)洗涤,允许各相分离,将废水相除去。
将富集有机相用10w/v%NaCl(475mL,4.75mL/g保护的三胺进料)洗涤,将废水相除去。
在溶液中标题游离碱的浓度为120-150mg/mL,并且计算的过程中收率为95-100mol%。
D.从CH2Cl2至丙酮/N-甲基吡咯烷酮的溶剂交换
向在安装机械搅拌器、温度探头和蒸馏冷凝器的3000mL 3颈圆底烧瓶中的富集部分C游离碱溶液中加入N-甲基吡咯烷酮(148mL;1.25mL/g部分C游离碱,基于过程中定量测定计)。采用70℃或以下的夹套温度,将溶液浓缩至约360mL(2.5-3.5mL/g部分C游离碱);将500mL丙酮(4-5mL/g部分C游离碱)加入浓缩溶液中,将混合物蒸馏至约400mL或以下的体积。
丙酮加入和蒸馏重复进行,直至过程中测定表明CH2Cl2水平达到目标终点。在结晶体积下,在富集有机溶液中的CH2Cl2含量为0.77v/v%。将丙酮加入浓缩的游离碱溶液中,以达到游离碱为16mL/g的总溶液。将浴温保持在40-50℃,防止游离碱结晶。通过10微米或更细的滤器将溶液抛光过滤,同时将温度保持在40-50℃。将抛光的滤器用丙酮(125mL,1.0mL/g游离碱)冲洗,将冲洗液加入富集游离碱的丙酮/N-甲基吡咯烷酮溶液中,该溶液用于下一步骤。
E.1-[4-(吡啶-2-基)苯基]-5(S)-2,5-二{[N-(甲氧基羰基)-L-叔-亮氨酰基]氨基}-4(S)-羟基-6-苯基-2-氮杂己烷硫酸盐
通过液面下加入,将浓硫酸总装料(19g,1.10当量)的约10%(2g)加入部分D的游离碱丙酮/N-甲基吡咯烷酮溶液中,同时将温度保持在40-50℃。
将反应混合物用5.0wt%(wrt计算的溶液中的游离碱)的硫酸盐接种。将接种的混合物在40-50℃下搅拌至少30分钟,在该时间期间硫酸盐开始结晶,这通过在该时间期间混合物浑浊度增加来证明。
在约5h的时间内,分5个阶段,按由三次方程定义的以下方案加入剩余的硫酸(17.8g),同时将温度保持在40-50℃。
各加入阶段的速度按2005年11月17日公布的美国专利公布号US20050256202A1中所述三次方程确定。
H2SO4加入完成后,搅拌下,将浆状物冷却至20-25℃,保持至少1h。将浆状物在20-25℃下搅拌至少1h。将硫酸盐过滤,根据需要母液循环使用,以实现完全转移。将滤饼用丙酮(5-10mL/g游离碱;1200mL丙酮)洗涤。将硫酸盐在NMT 55℃下真空干燥,直至LOD<1%,得到结晶物质。
关于该化合物的制备和表征的进一步细节见2005年11月17日公布的美国专利公布号US20050256202A1中所公开的。
实施例2
硫酸阿扎那韦-C型原料
方法A:
将硫酸阿扎那韦的A型晶体(按实施例1中所述制备)(25.33g)悬浮于200mL水中,将混合物机械搅拌,以得到稠的凝胶,将该凝胶干燥。
将干燥的混合物用刮刀研磨,得到C型原料。
关于该化合物的制备和表征的进一步细节见2005年11月17日公布的美国专利公布号US20050256202A1中所公开。
方法B:
在合适的混合机-制粒机中,将硫酸阿扎那韦的A型晶体用足量的水(约40%w/w)湿法制粒。将软材(wet mass)在烘箱中干燥。将产物用合适的筛整粒。
关于该化合物的制备和表征的进一步细节见2005年11月17日公布的美国专利公布号US20050256202A1中所公开。
实施例3
硫酸阿扎那韦-E3型(三乙醇溶剂合物)
在安装机械搅拌器、温度探头和恒压滴液漏斗的100mL 3颈圆底烧瓶中,将阿扎那韦游离碱(按实施例1,部分C中所述制备)(3.0g,4.26mmol)在200标准浓度(proof)无水乙醇(20.25mL,6.75mL/g游离碱)中打浆。
将浓H2SO4(0.25mL,0.46g,4.69mmol,1.1当量)加入阿扎那韦游离碱的浆状物中,将该浆状物保持在20-25℃。将得到的溶液(0.2-1.0%水的KF)抛光过滤(Whatman #1纸),将滤器用2.25mL无水乙醇冲洗,将冲洗液加入滤液中。将溶液加热至37℃,用由E3型晶体衍生的10mg无定形硫酸阿扎那韦(通过将E3型晶体暴露于环境温度)接种,将混合物搅拌15分钟。在1小时内,加入庚烷(380mL,8.25mL/g游离碱)。将得到的结晶混合物在15-25℃下搅拌8h。在布氏漏斗上将结晶的硫酸阿扎那韦过滤。将产物滤饼用184mL(4mL/g游离碱)1∶1的乙醇∶庚烷洗涤。将产物滤饼用46mL(1mL/g游离碱)庚烷洗涤。将得到的产物在40-50℃下真空干燥,直至其具有LOD=0.97%。
关于该化合物的制备和表征的进一步细节见2005年11月17日公布的美国专利公布号US20050256202A1中所公开。
实施例4
硫酸阿扎那韦片
为在其余实施例中使用,硫酸阿扎那韦按与实施例1-3中所述基本上相同的方法制备。
制备具有300mg剂量(游离碱)的压制片,该压制片具有以下组成。
包衣料:欧巴代II,按3%包衣
通过在转鼓型混合机例如V形混合机中将颗粒内成分掺混,开始按3步法制备硫酸阿扎那韦片。第一步,将一部分硫酸阿扎那韦(占硫酸阿扎那韦总重12%)和硬脂酸掺混125转。第二步,加入剩余的硫酸阿扎那韦,再掺混250转。第三步,加入微晶纤维素、淀粉羟乙酸钠和交联聚维酮,将混合物进一步掺混250转。
将颗粒内掺混物转移到高剪切混合机例如65L Diosna或Glatt-Fuji中。制备羟丙基纤维素(“HPC”)溶液,并转移至泡沫发生器(Dow Chemical Company),制备HPC泡沫。泡沫特征值(表示为:(空气体积-HPC溶液体积)/(空气体积)×100)大于70%。HPC重量占颗粒内掺混物干重0.5-3%w/w,加入水,使HPC溶液占颗粒内掺混物干重30-38%w/w。按以下混合速度,进行颗粒内粉末和HPC泡沫的制粒:90-200 RPM叶轮转速(取决于批量大小和高-剪切混合机类型),1300-1770 RPM切碎机(chopper)速度。计算量的HPC溶液作为泡沫加入完成后,在不停止高剪切混合机的情况下进行软材制备(wetmassing)。软材制备的时间为0.5-2分钟。
将湿颗粒转移到流化床干燥器,并干燥至干燥失重不大于4.5%w/w的水平。
使干燥的颗粒通过1毫米(“mm”)筛整粒。
将碾磨的颗粒与计算的颗粒外微晶纤维素、淀粉羟乙酸钠和交联聚维酮在转鼓型混合机中掺混250转。然后将硬脂酸镁加入掺混物中,并掺混75转。
然后,将得到的最终掺混物压片,得到期望的片重和硬度(通常按照USP通则:<1216>片剂脆碎度测定)。也可用最终掺混物制备任何其它的口服剂型例如胶囊剂、颗粒散剂或丸剂。
制备欧巴代II包衣料悬浮液(18%w/w固体),将片剂包衣。在包衣过程期间连续搅拌该悬浮液。用包衣机(Glatt,Thomas Engineering或Vector)将片剂包衣,至片重增加2-3.5%w/w,该包衣量足够。
如此形成的硫酸阿扎那韦薄膜衣片具有优异的释放特性,按照USP通则:<1092>溶出度方法:开发和验证测定,在45分钟后释放约95%,这与Reyataz(硫酸阿扎那韦)胶囊剂相似,即释产品的体外溶出度曲线通常显示在约30-45分钟,逐渐增加达到85%-100%。
制备片剂的备选方法包括例如:
A)将颗粒内成分掺混的操作:
1.在转鼓型混合机中进行2步混合处理。第一步,将一部分硫酸阿扎那韦(占硫酸阿扎那韦总重50%)和硬脂酸掺混5-15分钟。第二步,将所有剩余的硫酸阿扎那韦、微晶纤维素、淀粉羟乙酸钠和交联聚维酮加入硫酸阿扎那韦/硬脂酸混合物中,掺混10分钟。
2.高剪切混合处理。第一步,在合适大小的高剪切混合机(50-350RPM叶轮转速)中,将一部分硫酸阿扎那韦与硬脂酸掺混。然后,将所有剩余的硫酸阿扎那韦、微晶纤维素、淀粉羟乙酸钠和交联聚维酮加入硫酸阿扎那韦/硬脂酸混合物中,掺混。或者,在1个步骤中,将所有成分加入并在高剪切混合机中掺混。
B)掺入HPC
1.HPC以干粉末加入,并与其他成分混入颗粒内掺混物中。在制粒期间,水代替HPC泡沫加入。
2.将HPC溶于水,且在制粒期间加入HPC溶液。
C)颗粒也用托盘烘箱干燥。
实施例5
硫酸阿扎那韦片
制备具有300mg剂量(游离碱)的压制片,该压制片具有以下组成。
包衣料:欧巴代II,按3%包衣
通过在转鼓型混合机例如V形混合机中,将颗粒内成分掺混,按3步法,开始制备阿扎那韦片。第一步,将一部分硫酸阿扎那韦(占硫酸阿扎那韦总重12%)和硬脂酸掺混125转。第二步,加入剩余的硫酸阿扎那韦,再掺混250转。第三步,加入微晶纤维素、淀粉羟乙酸钠、交联聚维酮和聚维酮,将混合物进一步掺混250转。
将颗粒内掺混物转移到高剪切混合机例如65L Diosna或Glatt-Fuji。按以下混合速度将颗粒内粉末和水进行制粒:90-200 RPM叶轮转速(取决于批量大小和高-剪切混合机类型),1300-1770 RPM切碎机速度。计算量的水加入完成后,在不停止高剪切混合机的情况下进行软材制备。软材制备的时间为0.5-2分钟。
将湿颗粒转移到流化床干燥器中,并干燥至干燥失重不大于4.5%w/w的水平。
使干燥的颗粒通过1mm整粒的筛整粒。
将碾磨的颗粒与计算的颗粒外微晶纤维素和交联聚维酮在转鼓型混合机中掺混250转。然后将硬脂酸镁加入掺混物中,并掺混75转。
然后将得到的最终掺混物压片,得到期望的片重和硬度(通常按照USP通则:<1216>片剂脆碎度测定)。
制备欧巴代II包衣料悬浮液(18%w/w固体),将片剂包衣。该悬浮液在包衣过程期间连续搅拌。用包衣机(Glatt,Thomas Engineering或Vector)将片剂包衣,至片重增加2-3.5%w/w,该包衣量足够。
实施例6
硫酸阿扎那韦片
制备具有300mg剂量(游离碱)的压制片,该压制片具有以下组成。
包衣料:欧巴代II,按3%包衣
通过将颗粒内成分在转鼓型混合机例如V形混合机中掺混,按3步法,开始制备阿扎那韦片。第一步,将一部分硫酸阿扎那韦(占硫酸阿扎那韦总重的12%)和硬脂酸掺混125转。第二步,加入剩余的硫酸阿扎那韦,再掺混250转。第三步,加入微晶纤维素、淀粉羟乙酸钠和交联聚维酮,将混合物进一步掺混250转。
将颗粒内掺混物转移到高剪切混合机例如65L Diosna或Glatt-Fuji。制备HPC溶液,转移至泡沫发生器(Dow ChemicalCompany),制备HPC泡沫。泡沫特征值(表示为:(空气体积-HPC溶液体积)/(空气体积)×100)大于70%。HPC重量占颗粒内掺混物干重0.5-3%w/w,加入水,使HPC溶液占颗粒内掺混物干重30-38%w/w。按以下混合速度,进行颗粒内粉末和HPC泡沫的制粒:90-200 RPM叶轮转速(取决于批量大小和高-剪切混合机类型),1300-1770 RPM切碎机速度。计算量的HPC溶液作为泡沫加入完成后,在不停止高剪切混合机的情况下进行软材制备。软材制备的时间为0.5-2分钟。
将湿颗粒转移到流化床干燥器,并干燥至干燥失重不大于4.5%w/w的水平。
使干燥的颗粒通过1毫米筛整粒。
将碾磨的颗粒与计算的颗粒外微晶纤维素、淀粉羟乙酸钠和交联聚维酮在转鼓型混合机中掺混250转。然后将硬脂酸镁加入掺混物中,并掺混75转。
然后将得到的最终掺混物压片,得到期望的片重和硬度(通常按照USP通则:<1216>片剂脆碎度测定)。
制备欧巴代II包衣料悬浮液(12-18%w/w固体),将片剂包衣。该悬浮液在包衣过程期间连续搅拌。用合适的包衣机将片剂包衣,至片重增加2-3.5%w/w,该包衣量足够。
实施例7
硫酸阿扎那韦片
制备具有300mg剂量(游离碱)的压制片,该压制片具有以下组成。
包衣料:欧巴代II,按3%包衣
通过将颗粒内成分在转鼓型混合机例如V形混合机中掺混,按3步法,开始制备阿扎那韦片。第一步,将一部分硫酸阿扎那韦(占硫酸阿扎那韦总重12%)和硬脂酸掺混125转。第二步,加入剩余的硫酸阿扎那韦,再掺混250转。第三步,加入微晶纤维素、淀粉羟乙酸钠、交联聚维酮和聚维酮,将混合物进一步掺混250转。
将颗粒内掺混物转移到高剪切混合机例如65L Diosona或Glatt-Fuji。按以下混合速度,进行颗粒内粉末和水的制粒:90-200RPM叶轮转速(取决于批量大小和高-剪切混合机类型),1300-1770RPM切碎机速度。计算量的水加入完成后,在不停止高剪切混合机的情况下进行软材制备。软材制备的时间为0.5-2分钟。
将湿颗粒转移到流化床干燥器,并干燥至干燥失重不大于4.5%w/w的水平。
使干燥的颗粒通过1mm的筛整粒。
将碾磨的颗粒与计算的颗粒外微晶纤维素和交联聚维酮在转鼓型混合机例如V形混合机中掺混250转。然后将硬脂酸镁加入掺混物中,并掺混75转。
然后将得到的最终掺混物压片,得到期望的片重和硬度(通常按照USP通则:<1216>片剂脆碎度测定)。
制备欧巴代II包衣料悬浮液(18%w/w固体),将片剂包衣。该悬浮液在包衣过程期间连续搅拌。用合适的包衣机将片剂包衣,至片重增加2-3.5%w/w,该包衣量足够。
实施例8
硫酸阿扎那韦片
制备具有300mg剂量(游离碱)的压制片,该压制片具有以下组成。
通过将颗粒内成分掺混,开始制备阿扎那韦片。第一步,将一部分硫酸阿扎那韦(占硫酸阿扎那韦总重34%)和二氧化硅在转鼓型混合机例如V形混合机中掺混2分钟。将混合物转移到高剪切混合机例如65L Diosona或Glatt-Fuji,加入剩余量的API,掺混1分钟(叶轮片转速600 RPM,切碎机速度1300 RPM)。加入微晶纤维素、淀粉羟乙酸钠、交联聚维酮和HPC,再掺混2分钟(叶轮片转速600 RPM,切碎机速度1300 RPM)。
按以下混合速度,进行颗粒内粉末和水的制粒:400 RPM叶轮转速,1300 RPM切碎机速度。水加入完成后,在不停止高剪切混合机的情况下进行2.5分钟的软材制备。
将湿颗粒干燥至干燥失重不大于3%w/w的水平。
使干燥的颗粒通过1mm筛整粒。
将碾磨的颗粒与计算的颗粒外微晶纤维素、淀粉羟乙酸钠和交联聚维酮在转鼓型混合机中掺混420转。然后将硬脂酸镁加入掺混物中,掺混126转。
然后将得到的最终掺混物压片,得到期望的片重和硬度(通常按照USP通则:<1216>片剂脆碎度测定)。
比较实施例9
硫酸阿扎那韦片
制备具有300mg剂量(游离碱)的压制片,该压制片具有以下组成。
通过将颗粒内成分掺混,开始制备阿扎那韦片。将颗粒内成分按照表中的顺序加入到高剪切混合机例如65L Diosona或Glatt-Fuji,并混合2分钟(叶轮片转速600 RPM,切碎机速度1200 RPM)。
按以下混合速度,进行颗粒内粉末和水的制粒:300 RPM叶轮转速,1200 RPM切碎机速度。水加入完成后,在不停止高剪切混合机的情况下进行0.5分钟的软材制备。
将湿颗粒干燥至干燥失重不大于3%w/w的水平。
使干燥的颗粒通过1mm的筛整粒。
将碾磨的颗粒与计算的颗粒外微晶纤维素、淀粉羟乙酸钠和交联聚维酮在转鼓型混合机例如V形混合机中掺混420转。然后将硬脂酸镁加入掺混物中,掺混126转。
然后将得到的最终掺混物压片,得到期望的片重和硬度(通常按照USP通则:<1216>片剂脆碎度测定)。
实施例10
溶出度特性
测试实施例4和9的压制片的溶出度特性。溶出介质为50毫摩尔浓度(“mM”)的柠檬酸盐缓冲液,pH 2.8,1000ml;溶出条件为50RPM桨速度,37℃。
溶出度以标示要求溶出的百分比表示,其为本领域中常用的术语,用于定义在给定的时间例如60分钟内溶解的剂量例如300mg的百分比。
时间,min | 比较实施例9标示要求溶出的百分比 | 实施例1标示要求溶出的百分比 |
0 | 0 | 0 |
5 | 64 | 59 |
10 | 78 | 76 |
15 | 84 | 83 |
时间,min | 比较实施例9标示要求溶出的百分比 | 实施例1标示要求溶出的百分比 |
20 | 87 | 88 |
30 | 90 | 93 |
45 | 91 | 96 |
60 | 91 | 97 |
相当意外,发现通过颗粒内掺入润滑剂,观察到溶出度特性随溶出时间增加而提高。例如,在最高达约20分钟的溶出时间,溶出速率基本上相等,而在较长溶出时间例如45和60分钟,本发明压制片的溶出速率明显较高,例如在60分钟时高6.6%。另外,发现当包括颗粒内润滑剂时,根据本发明的颗粒制剂明显更有效。观察到显著较少的材料粘附至剪切设备上。
实施例11
硫酸阿扎那韦联合药物片剂
制备具有以下组成的压制双层片,该压制双层片在一层中具有阿扎那韦(硫酸阿扎那韦)300mg(游离碱)的剂量,在另一层中具有恩曲他滨/替诺福韦DF(200mg/300mg)。
成分 | 占阿扎那韦层的%(w/w) | 占最终组合物的%(w/w) |
阿扎那韦(盐) | 56.9 | 27.3 |
硬脂酸 | 2.8 | 1.3 |
微晶纤维素 | 31.05 | 14.9 |
淀粉羟乙酸钠 | 4.4 | 2.1 |
交联聚维酮 | 3.4 | 1.6 |
HPC | 0.7 | 0.3 |
硬脂酸镁 | 0.75 | 0.4 |
恩曲他滨/替诺福韦DF制剂 | - | 52.1 |
按照基本上与实施例4中所述相同的方法制备该片剂。将硫酸阿扎那韦制剂作为双层片中的一层压片,并且恩曲他滨/替诺福韦DF在另一层中,得到期望的片重和硬度(通常按照USP通则:<1216>片剂脆碎度测定)。
制备具有以上组成的压制单层片,该压制单层片具有阿扎那韦(硫酸阿扎那韦)300mg(游离碱)的剂量和恩曲他滨/替诺福韦DF(200mg/300mg)。按照基本上与实施例4中所述相同的方法制备该片剂,其中在初始掺混步骤中将恩曲他滨/替诺福韦DF与阿扎那韦混合。
将硫酸阿扎那韦/恩曲他滨/替诺福韦DF制剂作为单层片压片,得到期望的片重和硬度(通常按照USP通则:<1216>片剂脆碎度测定)。
本发明不限于前述或示例性实施例,且其可以其它特定的形式实施而不背离其必要特征,这对本领域技术人员而言将是显而易见的。因此,期望说明书和实施例在所有方面被视为对权利要求的举例说明和非限制性参考,落入权利要求的等同权利要求含义和范围内的所有变化因此将包括在其中。
例如,尽管本发明关于硫酸阿扎那韦进行了描述,但本发明适用于可用于治疗HIV或其它疾病的其它药物的盐。更具体地说,通过在颗粒形成之前,使润滑剂与药物盐混合,可将其它药物的盐制备成压片形式。通常,药学上可接受的盐是其中反荷离子对化合物的生理活性或毒性无显著贡献并起与药理学等同物相同的此类功能的那些。这些盐可按照普通有机技术,采用商业上可得到的试剂制备。某些阴离子盐形式包括乙酸盐、醋硬脂酸盐、苯磺酸盐、溴化物、氯化物、柠檬酸盐、富马酸盐、葡糖醛酸盐、氢溴酸盐、盐酸盐、氢碘酸盐、碘化物、乳酸盐、马来酸盐、甲磺酸盐、硝酸盐、扑酸盐、磷酸盐、琥珀酸盐、硫酸盐、酒石酸盐、甲苯磺酸盐和xinofoate。某些阳离子盐形式包括铵、铝、苯乍生(benzathine)、铋、钙、胆碱、二乙胺、二乙醇胺、锂、镁、葡甲胺、4-苯基环己胺、哌嗪、钾、钠、氨丁三醇和锌。
另外,尽管在压制片的上下文中描述了本发明的颗粒,但其它释放形式是可能的。经口给药的药用组合物可通过以下方法得到:使活性成分例如硫酸阿扎那韦与固体载体混合,将得到的混合物制粒,如果期望或需要,在合适的赋形剂加入后,将混合物加工成为口服用的片剂、糖锭剂芯、胶囊剂或散剂。
并且,尽管具体公开了具有抗HIV活性的某些其它药物,但可将除具体公开的那些以外的药物包括在本发明的组合物中。也可将大于一种具有抗HIV活性的其它药物包括在本发明的组合物中。
在本说明书中引用的所有专利、专利申请和参考文献均通过引用而整体结合到本文中。在出现不一致的情况,以本发明的公开内容包括定义为准。
Claims (24)
1.一种压制片剂,所述片剂包含雷特格韦和颗粒,所述颗粒含有硫酸阿扎那韦和颗粒内润滑剂,所述颗粒具有内部部分和外部表面,且其中至少一部分颗粒内润滑剂存在于所述颗粒的内部部分。
2.权利要求1的压制片剂,基于所述压制片剂的总重量计,所述片剂包含约0.1-10%的颗粒内润滑剂。
3.权利要求1的压制片剂,基于所述压制片剂的总重量计,所述片剂包含约0.5-8%的颗粒内润滑剂。
4.权利要求1的压制片剂,基于所述压制片剂的总重量计,所述片剂包含约10-99.9%的硫酸阿扎那韦。
5.权利要求1的压制片剂,基于所述压制片剂的总重量计,所述片剂包含约30-90%的硫酸阿扎那韦。
6.权利要求1的压制片剂,其中所述颗粒内润滑剂选自硬脂酸镁、硬脂酸锌、硬脂酸钙、硬脂酸、棕榈酸、硬脂酰富马酸钠、苯甲酸钠、十二烷基硫酸钠、甘油单硬脂酸酯、甘油棕榈酸硬脂酸酯、氢化蓖麻油、氢化植物油、矿物油、巴西棕榈蜡、聚乙二醇及其混合物。
7.权利要求1的压制片剂,基于所述压制片剂的总重量计,所述片剂还包含约1-20%的崩解剂。
8.权利要求1的压制片剂,基于所述压制片剂的总重量计,所述片剂还包含约2-12%的崩解剂。
9.权利要求7的压制片剂,其中所述崩解剂选自交联羧甲基纤维素钠、交联聚维酮、马铃薯淀粉、预胶化淀粉、玉米淀粉、淀粉羟乙酸钠、微晶纤维素、粉末状纤维素、甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠、藻酸、胶体二氧化硅、瓜尔胶、硅酸镁铝、波拉克林钾、藻酸钠及其混合物。
10.权利要求1的压制片剂,基于所述压制片剂的总重量计,所述片剂还包含约0.1-10%的粘合剂。
11.权利要求1的压制片剂,基于所述压制片剂的总重量计,所述片剂还包含约0.2-6%的粘合剂。
12.权利要求10的压制片剂,其中所述粘合剂选自阿拉伯胶、卡波姆、糊精、明胶、瓜尔胶、氢化植物油、甲基纤维素、乙基纤维素、醋酸纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、葡萄糖、乳糖、硅酸镁铝、麦芽糖糊精、聚甲基丙烯酸酯、聚维酮、聚乙烯吡咯烷酮、玉米淀粉、预胶化淀粉、藻酸、藻酸钠、玉米蛋白、巴西棕榈蜡、石蜡、鲸蜡、聚乙烯、微晶蜡及其混合物。
13.权利要求1的压制片剂,基于所述压制片剂的总重量计,所述片剂还包含约5-90%的填充剂。
14.权利要求1的压制片剂,基于所述压制片剂的总重量计,所述片剂还包含约15-40%的填充剂。
15.权利要求17的压制片剂,其中所述填充剂选自微晶纤维素、乳糖、蔗糖、淀粉、预胶化淀粉、右旋糖、葡萄糖结合剂、糊精、甘露醇、果糖、木糖醇、山梨醇、玉米淀粉、改性玉米淀粉、无机盐例如碳酸钙、碳酸镁、氧化镁、磷酸钙、磷酸二钙、三碱式磷酸钙、硫酸钙;糊精/葡萄糖结合剂、麦芽糖糊精、可压缩性糖、蔗糖和玉米淀粉磨制而成的药用辅料、甘油棕榈酸硬脂酸酯、氢化植物油、高岭土、麦芽糖糊精、聚甲基丙烯酸酯、氯化钾、氯化钠、蔗糖、糖球、滑石粉及其混合物。
16.权利要求1的压制片剂,基于所述压制片剂的总重量计,所述片剂还包含约0.1-3%的颗粒外润滑剂。
17.权利要求1的压制片剂,基于所述压制片剂的总重量计,所述片剂还包含约0.2-1.5%的颗粒外润滑剂。
18.权利要求1的压制片剂,所述片剂还包含利托那韦。
19.一种压制片剂,所述片剂包含雷特格韦、硫酸阿扎那韦、颗粒内润滑剂和颗粒外润滑剂,其中所述片剂通过湿法制粒制备,其中将硫酸阿扎那韦和颗粒内润滑剂颗粒内掺混,并在颗粒外加入颗粒外润滑剂。
20.权利要求1的压制片剂,所述片剂为多层片形式,其中硫酸阿扎那韦在一层,而所述雷特格韦在另一层。
21.权利要求1的压制片剂,所述片剂为单层片形式,其中硫酸阿扎那韦和雷特格韦在同一层。
22.权利要求1的压制片剂,其中所述片剂通过湿法制粒制备,其中将雷特格韦、硫酸阿扎那韦和颗粒内润滑剂颗粒内掺混。
23.权利要求1的压制片剂,其中所述片剂通过湿法制粒制备,其中将硫酸阿扎那韦和所述颗粒内润滑剂颗粒内掺混,并在颗粒外加入雷特格韦。
24.一种在患者中治疗HIV感染的方法,所述方法包括给予所述患者治疗有效量的权利要求1的压制片剂。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US94570607P | 2007-06-22 | 2007-06-22 | |
US60/945706 | 2007-06-22 | ||
PCT/US2008/067624 WO2009002823A2 (en) | 2007-06-22 | 2008-06-20 | Tableted compositions containing atazanavir |
Publications (1)
Publication Number | Publication Date |
---|---|
CN101801348A true CN101801348A (zh) | 2010-08-11 |
Family
ID=39645408
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200880103525A Pending CN101801348A (zh) | 2007-06-22 | 2008-06-20 | 含有阿扎那韦的压片组合物 |
Country Status (11)
Country | Link |
---|---|
US (1) | US20100178339A1 (zh) |
EP (1) | EP2178511B1 (zh) |
JP (1) | JP2010530889A (zh) |
KR (1) | KR20100033378A (zh) |
CN (1) | CN101801348A (zh) |
AT (1) | ATE499927T1 (zh) |
AU (1) | AU2008268627A1 (zh) |
DE (1) | DE602008005316D1 (zh) |
ES (1) | ES2360336T3 (zh) |
MX (1) | MX2009013462A (zh) |
WO (1) | WO2009002823A2 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106029058A (zh) * | 2013-10-07 | 2016-10-12 | 百时美-施贵宝爱尔兰控股公司 | 阿扎那韦和考比泰特的hiv治疗制剂 |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20100033379A (ko) * | 2007-06-22 | 2010-03-29 | 브리스톨-마이어스 스큅 컴퍼니 | 아타자나비르를 함유하는 정제 조성물 |
LT2493312T (lt) | 2009-10-26 | 2022-01-10 | Merck Sharp & Dohme Corp. | Kieta farmacinė kompozicija, kurios sudėtyje yra integrazės inhibitorius |
WO2011127244A2 (en) * | 2010-04-09 | 2011-10-13 | Bristol-Myers Squibb Company | ATAZANAVIR SULFATE FORMULATIONS WITH IMPROVED pH EFFECT |
WO2012041488A1 (en) | 2010-09-28 | 2012-04-05 | Ratiopharm Gmbh | Dry processing of atazanavir |
EP2677868B1 (en) * | 2011-02-21 | 2020-01-15 | Hetero Research Foundation | Pharmaceutical compositions of maraviroc and process for the preparation thereof |
CA2833006A1 (en) * | 2011-04-22 | 2012-10-26 | Merck Sharp & Dohme Corp. | Taste-masked formulations of raltegravir |
US20140038992A1 (en) * | 2011-04-25 | 2014-02-06 | Hetero Research Foundation | Methods of administering raltegravir and raltegravir compositions |
US9968607B2 (en) * | 2011-04-25 | 2018-05-15 | Hetero Research Foundation | Pharmaceutical compositions of raltegravir, methods of preparation and methods of use therof |
WO2014064711A2 (en) * | 2012-10-22 | 2014-05-01 | Hetero Research Foundation | Methods of administering raltegravir and raltegravir compositions |
KR101497508B1 (ko) * | 2013-12-20 | 2015-03-03 | 한국유나이티드제약 주식회사 | 펠라고니움 시도이데스 추출물 및 규산 화합물을 포함하는 고형 제제 및 이의 제조 방법 |
CN105237526B (zh) * | 2014-06-20 | 2018-01-23 | 朱靖华 | 一种抗艾滋病毒药物及其制备方法 |
CA2937365C (en) | 2016-03-29 | 2018-09-18 | F. Hoffmann-La Roche Ag | Granulate formulation of 5-methyl-1-phenyl-2-(1h)-pyridone and method of making the same |
Family Cites Families (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2940998A (en) * | 1953-10-15 | 1960-06-14 | Ajinomoto Kk | Process for resolution of racemic glutamic acid and salts thereof |
GB919491A (en) * | 1958-12-23 | 1963-02-27 | Ici Ltd | Pharmaceutical compositions |
US4022776A (en) * | 1974-01-31 | 1977-05-10 | Otsuka Pharmaceutical Company Limited | 5-[1-Hydroxy-2-(substituted-amino)]ethyl-8-hydroxycarbostyril derivatives |
US3980637A (en) * | 1975-03-17 | 1976-09-14 | Bristol-Myers Company | Production of amoxicillin |
US4556654A (en) * | 1983-06-28 | 1985-12-03 | Warner-Lambert Company | Antimicrobial substituted anthra[1,9-cd]pyrazol-6(2H)-ones |
DE3403329A1 (de) * | 1984-02-01 | 1985-08-01 | Horst Dr. 4019 Monheim Zerbe | Pharmazeutisches produkt in form von pellets mit kontinuierlicher, verzoegerter wirkstoffabgabe |
FR2623810B2 (fr) * | 1987-02-17 | 1992-01-24 | Sanofi Sa | Sels de l'alpha-(tetrahydro-4,5,6,7 thieno(3,2-c) pyridyl-5) (chloro-2 phenyl) -acetate de methyle dextrogyre et compositions pharmaceutiques en contenant |
US5158777A (en) * | 1990-02-16 | 1992-10-27 | E. R. Squibb & Sons, Inc. | Captopril formulation providing increased duration of activity |
CA2068402C (en) * | 1991-06-14 | 1998-09-22 | Michael R. Hoy | Taste mask coatings for preparation of chewable pharmaceutical tablets |
US5753652A (en) * | 1991-07-03 | 1998-05-19 | Novartis Corporation | Antiretroviral hydrazine derivatives |
CA2103932A1 (en) * | 1992-11-05 | 1994-05-06 | Ramesh N. Patel | Stereoselective reduction of ketones |
US5461067A (en) * | 1993-02-25 | 1995-10-24 | Abbott Laboratories | Retroviral protease inhibiting compounds |
US5428048A (en) * | 1993-11-08 | 1995-06-27 | American Home Products Corporation | Aryl-N-hydroxyureas as inhibitors of 5-lipoxygenase and anto-arteriosclerotic agents |
GB9407386D0 (en) * | 1994-04-14 | 1994-06-08 | Smithkline Beecham Plc | Pharmaceutical formulation |
UA49803C2 (uk) * | 1994-06-03 | 2002-10-15 | Дж.Д. Сьорль Енд Ко | Спосіб лікування ретровірусних інфекцій |
TW483763B (en) * | 1994-09-02 | 2002-04-21 | Astra Ab | Pharmaceutical composition comprising of ramipril and dihydropyridine compound |
JP3529904B2 (ja) * | 1995-06-19 | 2004-05-24 | 鐘淵化学工業株式会社 | 光学活性1−ハロ−3−アミノ−4−フェニル−2−ブタノール誘導体の製造法 |
US6037157A (en) * | 1995-06-29 | 2000-03-14 | Abbott Laboratories | Method for improving pharmacokinetics |
US5750493A (en) * | 1995-08-30 | 1998-05-12 | Raymond F. Schinazi | Method to improve the biological and antiviral activity of protease inhibitors |
EP1097919A3 (en) * | 1995-11-17 | 2003-08-06 | Ajinomoto Co., Inc. | Process for producing 4-amino-3-oxo-butanoic acid ester |
US5849911A (en) * | 1996-04-22 | 1998-12-15 | Novartis Finance Corporation | Antivirally active heterocyclic azahexane derivatives |
US6087383A (en) * | 1998-01-20 | 2000-07-11 | Bristol-Myers Squibb Company | Bisulfate salt of HIV protease inhibitor |
JP4927258B2 (ja) * | 1999-01-21 | 2012-05-09 | 株式会社カネカ | (2s,3s)−又は(2r,3s)−ハロヒドリン誘導体の精製、単離方法 |
ATE334121T1 (de) * | 1999-01-29 | 2006-08-15 | Kaneka Corp | Verfahren zur herstellung von threo-1,2-epoxy-3- amino-4-phenylbutan-derivaten |
WO2000056719A1 (en) * | 1999-03-22 | 2000-09-28 | Bristol-Myers Squibb Company | FUSED PYRIDOPYRIDAZINE INHIBITORS OF cGMP PHOSPHODIESTERASE |
US6605732B1 (en) * | 1999-05-03 | 2003-08-12 | Aerojet Fine Chemicals Llc | Clean, high-yield preparation of S,S and R,S amino acid isosteres |
KR100708221B1 (ko) * | 1999-08-31 | 2007-04-17 | 아지노모토 가부시키가이샤 | 에폭사이드 결정의 제조방법 |
US6399393B1 (en) * | 1999-09-21 | 2002-06-04 | The United States Of America As Represented By The Department Of Energy | Cryogenic homogenization and sampling of heterogeneous multi-phase feedstock |
US6414002B1 (en) * | 1999-09-22 | 2002-07-02 | Bristol-Myers Squibb Company | Substituted acid derivatives useful as antidiabetic and antiobesity agents and method |
US6254888B1 (en) * | 2000-01-28 | 2001-07-03 | Boehringer Ingelheim Pharmaceuticals, Inc. | Method for coating pharmaceutical dosage forms |
US6395767B2 (en) * | 2000-03-10 | 2002-05-28 | Bristol-Myers Squibb Company | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
CZ20011726A3 (cs) * | 2000-05-26 | 2002-02-13 | Pfizer Products Inc. | Způsob reakční krystalizace, který umoľňuje řídit velikost částic |
US20020042124A1 (en) * | 2000-08-16 | 2002-04-11 | Patel Ramesh N. | Stereoselective reduction of substituted oxo-butanes |
IL145106A0 (en) * | 2000-08-30 | 2002-06-30 | Pfizer Prod Inc | Intermittent administration of a geowth hormone secretagogue |
US6670344B2 (en) * | 2000-09-14 | 2003-12-30 | Bristol-Myers Squibb Company | Combretastatin A-4 phosphate prodrug mono- and di-organic amine salts, mono- and di- amino acid salts, and mono- and di-amino acid ester salts |
US6764545B2 (en) * | 2000-12-12 | 2004-07-20 | Ajinomoto Co., Inc. | Production method of epoxide crystal |
DE60215189T2 (de) * | 2001-08-31 | 2007-10-25 | Bristol-Myers Squibb Co. | Verwendung von atazanavir in der hiv-therapie |
KR100933625B1 (ko) * | 2001-09-04 | 2009-12-24 | 다우 글로벌 테크놀로지스 인크. | 수성 에어 포움, 이를 사용한 고체 입자의 응집방법 및 피복방법 |
CN1700918B (zh) * | 2001-10-26 | 2011-06-08 | P·安杰莱蒂分子生物学研究所 | 关于hiv整合酶的n-取代的羟基嘧啶酮甲酰胺抑制剂 |
US7384734B2 (en) * | 2002-02-15 | 2008-06-10 | Monogram Biosciences, Inc. | Compositions and methods for determining the susceptibility of a pathogenic virus to protease inhibitors |
KR100456833B1 (ko) * | 2002-08-01 | 2004-11-10 | 주식회사 대웅 | 아목시실린 및 클라불라네이트를 함유하는 유핵정 |
US20050148523A1 (en) * | 2003-12-15 | 2005-07-07 | Colonno Richard J. | Method of treating HIV infection in atazanavir-resistant patients using a combination of atazanavir and another protease inhibitor |
TW200534879A (en) * | 2004-03-25 | 2005-11-01 | Bristol Myers Squibb Co | Coated tablet formulation and method |
US20050256314A1 (en) * | 2004-05-04 | 2005-11-17 | Soojin Kim | Process employing controlled crystallization in forming crystals of a pharmaceutical |
US7829720B2 (en) * | 2004-05-04 | 2010-11-09 | Bristol-Myers Squibb Company | Process for preparing atazanavir bisulfate and novel forms |
US20050288343A1 (en) * | 2004-05-19 | 2005-12-29 | Andrew Rusowicz | Process of preparing substituted carbamates and intermediates thereof |
TWI415635B (zh) * | 2004-05-28 | 2013-11-21 | 必治妥施貴寶公司 | 加衣錠片調製物及製備彼之方法 |
US7582468B2 (en) * | 2005-05-25 | 2009-09-01 | Bristol-Myers Squibb Company | Process for preparing (2R,3S)-1,2-epoxy-3-(protected)amino-4-substituted butane and intermediates thereof |
WO2007013047A2 (en) * | 2005-07-29 | 2007-02-01 | Ranbaxy Laboratories Limited | Water-dispersible anti-retroviral pharmaceutical compositions |
-
2008
- 2008-06-20 EP EP08780880A patent/EP2178511B1/en not_active Not-in-force
- 2008-06-20 MX MX2009013462A patent/MX2009013462A/es active IP Right Grant
- 2008-06-20 KR KR1020097026605A patent/KR20100033378A/ko not_active Application Discontinuation
- 2008-06-20 JP JP2010513433A patent/JP2010530889A/ja not_active Withdrawn
- 2008-06-20 WO PCT/US2008/067624 patent/WO2009002823A2/en active Application Filing
- 2008-06-20 CN CN200880103525A patent/CN101801348A/zh active Pending
- 2008-06-20 AU AU2008268627A patent/AU2008268627A1/en not_active Abandoned
- 2008-06-20 DE DE602008005316T patent/DE602008005316D1/de active Active
- 2008-06-20 ES ES08780880T patent/ES2360336T3/es active Active
- 2008-06-20 US US12/664,793 patent/US20100178339A1/en not_active Abandoned
- 2008-06-20 AT AT08780880T patent/ATE499927T1/de not_active IP Right Cessation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106029058A (zh) * | 2013-10-07 | 2016-10-12 | 百时美-施贵宝爱尔兰控股公司 | 阿扎那韦和考比泰特的hiv治疗制剂 |
Also Published As
Publication number | Publication date |
---|---|
US20100178339A1 (en) | 2010-07-15 |
KR20100033378A (ko) | 2010-03-29 |
WO2009002823A3 (en) | 2009-11-05 |
DE602008005316D1 (de) | 2011-04-14 |
JP2010530889A (ja) | 2010-09-16 |
EP2178511B1 (en) | 2011-03-02 |
ATE499927T1 (de) | 2011-03-15 |
MX2009013462A (es) | 2010-01-15 |
WO2009002823A2 (en) | 2008-12-31 |
AU2008268627A1 (en) | 2008-12-31 |
EP2178511A2 (en) | 2010-04-28 |
ES2360336T3 (es) | 2011-06-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101801348A (zh) | 含有阿扎那韦的压片组合物 | |
CN101795674A (zh) | 含有阿扎那韦的压片组合物 | |
CN101778624A (zh) | 含有阿扎那韦的压片组合物 | |
ES2286226T3 (es) | Metodo para fabricar una composicion farmaceutica de baja dosis. | |
KR101285008B1 (ko) | 저용량 엔테카비어의 경구투여 제제의 제조방법 | |
CN108779114A (zh) | 作为整联蛋白拮抗剂的萘啶化合物 | |
CN101778625A (zh) | 含有阿扎那韦的压片组合物 | |
CN104650091A (zh) | 替格瑞洛的微粉化及其晶型,以及制备方法和药物应用 | |
US20190125875A1 (en) | ATAZANAVIR SULFATE FORMULATIONS WITH IMPROVED Ph EFFECT | |
CN1903869A (zh) | 替比夫定的衍生物盐及其制备方法和药物应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20100811 |