CN1067580A - 乙酸孕甾酮配方 - Google Patents
乙酸孕甾酮配方 Download PDFInfo
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- CN1067580A CN1067580A CN92104762A CN92104762A CN1067580A CN 1067580 A CN1067580 A CN 1067580A CN 92104762 A CN92104762 A CN 92104762A CN 92104762 A CN92104762 A CN 92104762A CN 1067580 A CN1067580 A CN 1067580A
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- megestrol acetate
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- 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 title claims abstract description 56
- 229960004296 megestrol acetate Drugs 0.000 title claims abstract description 55
- 239000000203 mixture Substances 0.000 title claims abstract description 24
- 238000009472 formulation Methods 0.000 title claims abstract description 7
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 14
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 13
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 13
- 238000010298 pulverizing process Methods 0.000 claims abstract description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000000796 flavoring agent Substances 0.000 claims abstract description 7
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 7
- 239000003292 glue Substances 0.000 claims description 12
- 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 6
- 229930006000 Sucrose Natural products 0.000 claims description 6
- 239000005720 sucrose Substances 0.000 claims description 6
- 239000005060 rubber Substances 0.000 claims description 4
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 4
- 239000004299 sodium benzoate Substances 0.000 claims description 4
- 235000010234 sodium benzoate Nutrition 0.000 claims description 4
- 239000008213 purified water Substances 0.000 claims description 3
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 3
- 239000001509 sodium citrate Substances 0.000 claims description 3
- 239000008177 pharmaceutical agent Substances 0.000 claims 2
- 241000207199 Citrus Species 0.000 claims 1
- 240000004307 Citrus medica Species 0.000 claims 1
- 235000020971 citrus fruits Nutrition 0.000 claims 1
- 230000002421 anti-septic effect Effects 0.000 abstract description 2
- 239000008203 oral pharmaceutical composition Substances 0.000 abstract 1
- 239000004793 Polystyrene Substances 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000004094 surface-active agent Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 229920002534 Polyethylene Glycol 1450 Polymers 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
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- 150000001875 compounds Chemical class 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 229940100474 polyethylene glycol 1450 Drugs 0.000 description 4
- 230000003637 steroidlike Effects 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229940126701 oral medication Drugs 0.000 description 3
- 244000248349 Citrus limon Species 0.000 description 2
- 235000005979 Citrus limon Nutrition 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 230000002280 anti-androgenic effect Effects 0.000 description 2
- 239000000051 antiandrogen Substances 0.000 description 2
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- 239000004568 cement Substances 0.000 description 2
- 239000000084 colloidal system Substances 0.000 description 2
- ZGMKDHIDEAYLPG-UHFFFAOYSA-L disodium 2-hydroxypropane-1,2,3-tricarboxylic acid dibenzoate Chemical compound C(C1=CC=CC=C1)(=O)[O-].[Na+].[Na+].C(CC(O)(C(=O)O)CC(=O)O)(=O)O.C(CC(O)(C(=O)O)CC(=O)O)(=O)O.C(C1=CC=CC=C1)(=O)[O-] ZGMKDHIDEAYLPG-UHFFFAOYSA-L 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000003311 flocculating effect Effects 0.000 description 2
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- 239000008384 inner phase Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
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- 239000002245 particle Substances 0.000 description 2
- 239000011236 particulate material Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- BKWJSCFKITXBBM-NTNOATJHSA-N (8s,9s,10r,13s,14s,17s)-17-acetyl-10,13-dimethyl-6-methylidene-2,7,8,9,11,12,14,15,16,17-decahydro-1h-cyclopenta[a]phenanthren-3-one Chemical compound C1C(=C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 BKWJSCFKITXBBM-NTNOATJHSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- ITRJWOMZKQRYTA-RFZYENFJSA-N Cortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2=O ITRJWOMZKQRYTA-RFZYENFJSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- HUMXXHTVHHLNRO-KAJVQRHHSA-N Prednisolone tebutate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)CC(C)(C)C)(O)[C@@]1(C)C[C@@H]2O HUMXXHTVHHLNRO-KAJVQRHHSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- XGMPVBXKDAHORN-RBWIMXSLSA-N Triamcinolone diacetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](OC(C)=O)[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O XGMPVBXKDAHORN-RBWIMXSLSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 description 1
- 229960003290 cortisone acetate Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940063223 depo-provera Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- ZDGGJQMSELMHLK-UHFFFAOYSA-N m-Trifluoromethylhippuric acid Chemical compound OC(=O)CNC(=O)C1=CC=CC(C(F)(F)F)=C1 ZDGGJQMSELMHLK-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 229940090004 megace Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229940100691 oral capsule Drugs 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000007971 pharmaceutical suspension Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229940050929 polyethylene glycol 3350 Drugs 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- -1 subsequently Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009974 thixotropic effect Effects 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- 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
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Abstract
本发明涉及浓度为15—150mg/ml粉碎的乙酸
孕甾酮的新型口服药物组合物，其含有浓度为
0.005％—0.1 5％(重量/体积)的多乙氧基醚和浓度
为5—30％(重量/体积)的聚乙二醇。该组合物在
水中可形成稳定的絮状混悬剂。本发明还包括加有
防腐剂，缓冲剂，甜味剂和香味剂的上述的粉碎的乙
酸孕甾酮配方。
Description
本申请书为07/839，016的级联改进计划（CIP），是已放弃的0/717，155的继续申请。
本发明涉及到含有乙酸孕甾酮的药物组合物。乙酸孕甾酮是17-α-乙酰氧基-6-甲基孕甾-4，6二烯-3，20-二酮的属名。是由Bristol-Myers Squibb Corpora-tion（公司）以专利名Megace提供的抗肿瘤药物。
Kirk等人在美国专利3，356，573中介绍了含有乳糖，硬脂酸镁和淀粉的乙酸孕甾酮片剂。Kirk等人还提出，乙酸孕甾酮的液体组合物可形成溶液剂，乳剂，悬浮剂，糖浆和酏剂，但并未提供这些剂型的具体组成。
Petrow等人在美国专利4，396，615中介绍了用6-亚甲基黄体酮衍生物与乙酸孕甾酮治疗与雄性激素有关的综合症的方法，但未说明乙酸孕甾酮配方的组成。
Greaney等人在美国专利4，370，321中介绍了使用乙酸孕甾酮做乳腺癌治疗的辅助治疗。但未详述乙酸孕甾酮配方的类型或组成。
Labrie在美国专利4，666，885中介绍了用促黄体激素与抗雄性激素如乙酸孕甾酮合并治疗妇女乳腺癌。具体地，在该
项专利中（4，666，885）第8栏，第58-61行，介绍了将雄性激素和常规药用赋形剂（如，喷雾干燥的乳糖和硬脂酸镁）制成口服片剂或胶囊剂。
Labrie在美国专利4，760，053中介绍了使用乙酸孕甾酮联合治疗性甾体化合物依赖性癌症，但未介绍治疗中所用的药剂配方的类型或组成。
Labrie在美国专利4，775，661中介绍了用乙酸孕甾酮做为适宜的甾体抗雄性激素联合治疗妇女乳腺癌。同时，介绍了用乙酸孕甾酮做活性物质，与粘合剂，如聚乙二醇混合，且可含有矫味物质制成片剂或糖锭剂芯。
J.H.Von Roenn等人在Annals of Internal Medicine，109，840-841（1988）中，介绍了用乙酸孕甾酮治疗人类免疫缺损病毒（HIV）感染所致的恶病。报导了乙酸孕甾酮的剂量，但未报导配方的类型或组成。
目前，乙酸孕甾酮可以片剂形式用于治疗。上述的有关工艺均未述及除片剂或胶囊以外的其它药物组合物。
鉴于乙酸孕甾酮在临床医学中的广泛应用，应该有液体剂型，以方便那些不能吞咽片剂或胶囊的病人，或是当剂量较高时，以免要病人消化较大量的片剂。
因此，本发明目的之一，是提供乙酸孕甾酮的口服液体剂型。
本发明的目的之一是提供混悬剂型的乙酸孕甾酮口服液体药物组合物。
本发明的目的之一是提供絮状混悬剂型的乙酸孕甾酮口服液体药物组合物。
本发明的目的之一，是提供在产品贮存期限内不消絮凝的，絮状混悬剂型的乙酸孕甾酮药物组合物。
本发明的目的之一，是提供在水中分散的乙酸孕甾酮口服液体剂型，其在最少为两年的贮存期限内保持易于分散，以确保乙酸孕甾酮剂量一致。
根据本发明，乙酸孕甾酮的口服药物组合物包括粉碎的乙酸孕甾酮，并与多乙氧基醚、聚乙二醇，及缓冲剂混合，还可加甜味剂和香味剂改善口味。
本发明的其它内容及优点可通过下列叙述及所附的权利要求显而易见。
本发明的一项优选内容是制备一个含有浓度为15-150mg/ml的粉碎的乙酸孕甾酮、浓度为0.005%-0.015%（重量/体积）的多乙氧基醚及浓度超过5%（重量/体积）的聚乙二醇的口服药物组合物，该组合物在水中可形成稳定的絮状混悬剂。本发明的优选内容还包括，含有浓度为15-150mg/ml，优选20-120mg/ml，最优选40mg/ml的粉碎的乙酸孕甾酮的口服药物组合物。
混悬剂是一类特殊的分散体，由颗粒状物质形成的内相（被分散相），在由混悬介质或赋形剂所形成的外相中完全不溶，但可均匀分散。本发明最优选的配方中，内相包括质中直径为3-10
μm的粉碎的乙酸孕甾酮，外相包括纯化水，多乙氧基醚80，聚乙二醇1450，苍耳烷胶，苯甲酸钠，橡胶酸，枸椽酸钠，蔗糖和香味剂。
絮状混悬剂的颗粒状物质具有松散聚集（絮状物），其中分散的颗粒围聚形成网络样结构。称作“稳定絮状物”的絮状物，在网络样结构中常含有含量变化的残存液体介质或赋形剂，该絮状物通过弱的聚集作用可形成簇状物。絮状混悬剂放置时不结块，振摇易分散。絮状混悬剂的配方通常需要加表面活性剂、润湿剂，保护胶体/混悬剂，以便得到可防止消絮凝或聚集结块的稳定絮状物。也可使用防腐剂，缓冲剂，甜味剂和香味剂。因为很微小的变化都可以影响稳定的絮状混悬剂，所以赋形剂的选择是很关键的。
疏水性固体乙酸孕甾酮不易被水润湿，而且具有较高的表面张力，吸附于颗粒表面的空气增强了其表面张力。因此需要表面活性剂和润湿剂使其混悬并维持物理稳定性。
本发明的乙酸孕甾酮絮状混悬剂要求乙酸孕甾酮被粉碎，使占重量90%的颗粒小于20微米，而且质中直径为3.0-10微米，粉碎的颗粒被分散于含有表面活性剂或润湿剂，如多乙氧基醚80和聚乙二醇1450的水中，表面活性剂或润湿剂用于降低颗粒，残留空气和水之间的表面张力。在制备稳定絮状物时，表面活性剂或润湿剂的量特别关键。根据R.A.Nash在Chap.5，page 181，Pharmaceutical Suspensions，Pharmaceutical Dosage Forms，Marcel
Decker，New York中所述，表面活性剂的浓度在0.05-0.5%（重量/体积）内变化，并取决于要混悬的固体含量。这些混悬剂的实例列于表1中，表中列出一些目前销售的甾体混悬剂（1989 Physicians Desk Reference，43rd Edition）和多乙氧基醚80表面活性剂浓度。
表1
Physician′s Desk Reference，43rd Edition中甾体化合物混悬剂中所用的多乙氧基醚80的百分浓度
甾体化合物 甾体化合物浓度 多乙氧基醚
mg/ml 百分浓度W/V
Aristocort Forte 40 0.2
Artistospan 20 0.4
5 0.2
Cortone Acetate 25to50 0.4
Decadron-LA 8 0.075
Depo-Provera 100 0.184
Hydeltra-T.B.A. 20 0.1
Hydrocortone Acetate 25to50 0.4
Kenalog-40 40 0.04
按上述多乙氧基醚浓度制备的乙酸孕甾酮混悬剂，由于发生消絮凝和结块而不稳定。为得到稳定的絮状乙酸孕甾酮混悬剂，多乙氧基醚浓度必须在大约或低于0.02%（重量/体积），优选0.005%-0.015%（W/V），最优选0.01%（W/V）。当多乙氧基醚80浓度低达0.025%（W/V）时，将发生明显的消絮凝和结块。当多乙氧基醚浓度在或低于0.005-0.01%（W/V）时，可得到物理性质稳定的产品，但在这么低的浓度下，难于润湿粉碎的乙酸孕甾酮。还可使用与多乙氧基醚80性质类似的表面活性剂。因此，多乙氧基醚85也具有适宜的润湿性。其它适用的表面活性剂还有多乙氧基醚20，40，60和65。
使用亲水性聚合物可增加粉碎的乙酸孕甾酮的润湿性和混悬性。因此，本发明的乙酸孕甾酮混悬剂优选的亲水性聚合物为聚乙二醇（PEG）1450，其浓度为5-30%（重量/体积），优选12-24%（W/V），最优选20%（W/V）。浓度为30%（重量/体积）的PEG1450使混悬剂粘度增高，造成操作间题，但可得到物理性质优良的混悬剂。用浓度低于8%的PEG1450制备的混悬剂需要额外的帮助以使药物润湿，由于其使少量药物仍处于干燥状态，且含有残留空气，而漂洗在液体表面，因此不可取。在制备完全润湿的混悬剂时，聚乙二醇3350浓度为3%（重量/体积）时，不如PEG1450有效。还可使用优选浓度的其它级别的PEG，包括那些平均分子量约为400
-4000的。特别优选PEG1450，因为高分子量可提高粘度，而低分子量影响口味。
苍耳烷胶优选用做助悬剂，浓度约为0.2%（重量/体积）使用助悬剂可以使乙酸孕甾酮颗粒，在给药期内较长的一段时间里保持均匀混悬，而保持剂量均一。苍耳烷胶是具有触变性的、中等粘度的高分子量多糖。因此，浓度为0.1-0.3%（重量/体积）的苍耳烷胶提供了最有效和最好的剂型，因此较为优选，浓度为0.2%（重量/体积）最为优选。
可使用常规防腐剂，缓冲剂，甜味剂和香味剂，因此，优选下列物质：
防腐剂-0.2%（重量/体积）的苯甲酸钠，
缓冲剂-分别为0.244和0.015%（重量/体积）的枸椽酸和枸椽酸钠，
甜味剂-5%（重量/体积）的蔗糖
香味剂-0.91%（重量/体积）的矫味柠檬
实施例1
乙酸孕甾酮口服悬浮剂
每毫升含有40mg乙酸孕甾酮的柠檬加香口服混悬剂具有下列组分。
实施例2
乙酸孕甾酮组合物
每毫升含有120mg乙酸孕甾酮的柠檬加香口服混悬剂具有下列组分。
表2 乙酸孕淄酮组合物
| 成份 | 每ml含量 | %重量／体积 |
| 粉碎的乙酸孕淄酮聚乙二醇 1450多乙氧基醚 80苍耳烷胶， TF TF苯甲酸钠构椽酸构椽酸钠蔗糖N＆A柠檬加香剂＃400639纯化水 | 40mg200mg0.1mg2.0mg2.0mg2.44mg0.15mg50.0mg0.91mgq.s.1.0ml | 4200.010.20.20.2440.0155.00.091 |
表3 乙酸孕淄酮组合物
| 成份 | 每ml含量 | %重量／体积 |
| 粉碎的乙酸孕淄酮聚乙二醇 1450多乙氧基醚 80苍耳烷胶， TF苯甲酸钠构椽酸构椽酸钠蔗糖N＆A柠檬加香剂＃400639纯化剂 | 120mg200mg0.1mg2.0mg2.0mg2.44mg0.15mg50.0mg0.91mgq.s.1.0ml | 12200.010.20.20.2440.0155.00.091 |
按下列方法，用比例量的各种成分，制备乙酸孕甾酮混悬剂。约90%的PEG被融化（加热），与等量的水和多乙氧基醚80混合，制备溶液。将溶液冷至室温，加粉碎的乙酸孕甾酮，用装有高速切片（如Jiffy Cowles或Hockmeyer）的Lightin混合器使其分散。苍耳烷胶分次分散于约10%的溶化的PEG中该胶浆加入水中，使其均匀水合，该方法使胶迅速水合，且在水中均匀分散。往胶分散系中加枸椽酸盐，蔗糖，苯甲酸钠和香味剂，使胶浆过筛，随后，将胶分散系与乙酸孕甾酮分散系合并，混匀得到均匀的口服混悬剂。将全部混悬剂通过胶体磨，或均化器，得到含有40mg/ml乙酸孕甾酮的口服混悬剂。按同样的方法，制备含有75-200mg/ml乙酸孕甾酮的混悬剂。
实施例3
悬浮剂稳定性
考虑混悬剂适用性的一个主要方面，是混悬剂发生絮凝的程度，通常，絮凝程度越高，重分散性越好。评价该点的常用方法是测定沉降物高度。这是测定乙酸孕甾酮混悬系物理特性的一个方便而实用的方法。一般，该方法是用量筒测定絮状混悬剂的沉降速率，定期测定沉降高度，而不需破坏混悬系。
以起始混悬剂总高度的百分比表示的沉降高度列于表4中，表中按实施例1的配方中所用的多乙氧基醚80的浓度不同。
表4
沉降高度占起始高度的百分比
多乙氧基醚80百分 时间 (星期)
浓度W/V
0 4 15
0.005 100 91 68
0.01 100 90 70
0.02 100 94 25
0.03 100 91 29
显然，多乙氧基醚80浓度为0.005W/V和0.01W/V时，乙酸孕甾酮混悬剂的相对絮凝程度高于多乙氧基醚80浓度为0.02W/V或更高者。
实施例4
PEG1450的混悬剂稳定性
实施例1的配方中，PEG1450的浓度范围为5-20%（W/V）。于不同时间间隔测定沉降高度，并列于表5中。
显然，实施例1配方中，PEG1450含量范围的最低限为10-15%（W/V）。
实施例5
多乙氧基80的混悬剂稳定性
按实施例1的配方，不加助悬剂苍耳烷胶，多乙氧基醚80的浓度在0.005-0.025%范围内变化，于不同的时间间隔测沉降高度，列于表6中。
该例肯定了实施例3的长期结果，即在用各种试验浓度的多乙氧基醚80时，观察絮凝情况，浓度为0.005-0.015%（W/V）时，得到高稳定性的絮状混悬剂。
Claims (10)
1、含有浓度为15-150mg/ml的粉碎的乙酸孕甾酮，和浓度为0.005%-0.015%重量/体积的多乙氧基醚，及浓度高于5%(重量/体积)的聚乙二醇的口服药剂配方，其可在水中形成稳定的絮状混悬剂。
2、权利要求1的配方，其中粉碎的乙酸孕甾酮的浓度为20-120mg/ml。
3、权利要求1的配方，其中粉碎的乙酸孕甾酮的浓度为40mg/ml。
4、权利要求1的配方，其中应用了多乙氧基醚80。
5、权利要求1的配方，其中聚乙二醇的浓度为5%-30%（重量/体积）。
6、权利要求1的配方，其中聚乙二醇的浓度为12-24%（重量/体积）。
7、权利要求1的配方，其中聚乙二醇的浓度为20%（重量/体积）。
8、权利要求1的配方，其中多乙氧基醚浓度为0.01%（重量/体积）。
9、权利要求1的配方，其含有缓冲剂，甜味剂和香味剂。
10、按重量/体积百分含量，含有乙酸孕甾酮4%，聚乙二醇14.50 20%，多乙氧基醚80 0.01%，苍耳烷胶0.2%，苯甲酸钠0.2%，橡枸椽0.244%，枸椽酸钠0.15%，蔗糖5%，柠檬香味剂0.091%及用于形成稳定的絮状混悬剂的足量纯化水的口服药剂配方。
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| US6656505B2 (en) * | 2000-07-21 | 2003-12-02 | Alpharma Uspd Inc. | Method for forming an aqueous flocculated suspension |
| US20030198679A1 (en) * | 2000-11-08 | 2003-10-23 | Kundu Subhas C. | Flocculated pharmaceutical suspensions and methods for actives |
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| DE10224086A1 (de) * | 2002-05-31 | 2003-12-11 | Bayer Ag | Pharmazeutische Zubereitungen zur oralen Anwendung enthaltend wirkstoffbeladene Ionentauscherharze sowie strukturviskose Gelbildner als Verdicker |
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| US20080275030A1 (en) | 2007-01-19 | 2008-11-06 | Sveinbjorn Gizurarson | Methods and Compositions for the Delivery of a Therapeutic Agent |
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| KR101279568B1 (ko) * | 2010-12-10 | 2013-07-15 | 재단법인 유타 인하 디디에스 및 신의료기술개발 공동연구소 | 메게스트롤 아세테이트를 포함하는 경구용 약학 조성물 |
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