TWI454265B - 含有羅蘇伐他汀鈣（ｒｏｓｕｖａｓｔａｔｉｎ ｃａｌｃｉｕｍ）之藥學組成物 - Google Patents
含有羅蘇伐他汀鈣（ｒｏｓｕｖａｓｔａｔｉｎ ｃａｌｃｉｕｍ）之藥學組成物 Download PDFInfo
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 28
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 title claims description 11
- 229960004796 rosuvastatin calcium Drugs 0.000 title claims description 9
- 239000000203 mixture Substances 0.000 claims description 20
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 17
- 239000004480 active ingredient Substances 0.000 claims description 14
- 239000000654 additive Substances 0.000 claims description 13
- 230000000087 stabilizing effect Effects 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 10
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 9
- 239000000347 magnesium hydroxide Substances 0.000 claims description 9
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 9
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims description 8
- 239000001639 calcium acetate Substances 0.000 claims description 8
- 229960005147 calcium acetate Drugs 0.000 claims description 8
- 235000011092 calcium acetate Nutrition 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 7
- 230000000996 additive effect Effects 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 239000000314 lubricant Substances 0.000 claims description 7
- 239000011230 binding agent Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 229940069328 povidone Drugs 0.000 claims description 5
- 239000001736 Calcium glycerylphosphate Substances 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
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- UHHRFSOMMCWGSO-UHFFFAOYSA-L calcium glycerophosphate Chemical compound [Ca+2].OCC(CO)OP([O-])([O-])=O UHHRFSOMMCWGSO-UHFFFAOYSA-L 0.000 claims description 4
- 229940095618 calcium glycerophosphate Drugs 0.000 claims description 4
- 235000019299 calcium glycerylphosphate Nutrition 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000007884 disintegrant Substances 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 4
- 238000012216 screening Methods 0.000 claims description 4
- 239000007888 film coating Substances 0.000 claims description 3
- 238000009501 film coating Methods 0.000 claims description 3
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 239000008384 inner phase Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 239000003826 tablet Substances 0.000 description 8
- 235000012254 magnesium hydroxide Nutrition 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000004227 calcium gluconate Substances 0.000 description 4
- 235000013927 calcium gluconate Nutrition 0.000 description 4
- 229960004494 calcium gluconate Drugs 0.000 description 4
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 3
- 229940024545 aluminum hydroxide Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 229960000672 rosuvastatin Drugs 0.000 description 3
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 3
- 235000019731 tricalcium phosphate Nutrition 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- -1 alkaline earth metal salts Chemical class 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229960005069 calcium Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229940066901 crestor Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 150000002337 glycosamines Chemical class 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 1
- 239000011654 magnesium acetate Substances 0.000 description 1
- 235000011285 magnesium acetate Nutrition 0.000 description 1
- 229940069446 magnesium acetate Drugs 0.000 description 1
- 229960000816 magnesium hydroxide Drugs 0.000 description 1
- GVALZJMUIHGIMD-UHFFFAOYSA-H magnesium phosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GVALZJMUIHGIMD-UHFFFAOYSA-H 0.000 description 1
- 239000004137 magnesium phosphate Substances 0.000 description 1
- 229910000157 magnesium phosphate Inorganic materials 0.000 description 1
- 229960002261 magnesium phosphate Drugs 0.000 description 1
- 235000010994 magnesium phosphates Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000006864 oxidative decomposition reaction Methods 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Animal Behavior & Ethology (AREA)
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- General Health & Medical Sciences (AREA)
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- Epidemiology (AREA)
- Molecular Biology (AREA)
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- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Emergency Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Diabetes (AREA)
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本發明係關於一種新穎藥學組成物，其包含羅蘇伐他汀鈣(rosuvastatin calcium)作為活性成分，和氫氧化鎂及/或醋酸鈣或葡萄糖酸鈣或甘油磷酸鈣或氫氧化鋁作為穩定化劑，以及其製造方法。
羅蘇伐他汀鈣{(E)－7－〔4－(4－氟苯基)－6－異丙基－2－〔甲基(甲基磺醯基)胺基〕嘧啶－5－基〕(3R,5S)3,5－二羥基庚－6－烯酸鈣鹽}作為活性成分及其合成方法，係已知首次描述於專利EP 521,471中。
同樣已知的是，已售藥學組成物(商品名稱“冠脂妥(Crestor)”)也特別於WO 01/54668，WO 01/54669或美國專利第6,316,460號專利說明書中有述及。根據此等說明，含有羅蘇伐他汀的穩定，固體藥學組成物的製造，不能只藉由使用pH佐劑化合物來完成，其也需要多價金屬無機鹽的存在來防止內酯和氧化分解產品的形成。在該藥學組成物中，係使用多價金屬(Ca、Mg、Zn、Al、Fe和彼等的組合)之無機鹽作為穩定化添加劑，諸如鋁，偏矽酸鎂，三鹼基磷酸鈣，三鹼基磷酸鎂及三鹼基磷酸鋁。已上市銷售的藥學組成物(商品名稱“冠脂妥”)含有三鹼基磷酸鈣來作為穩定化劑。
一般說來，有數個專利申請及說明書係關於HMG－CoA還原酶抑制劑，即施德丁(statin)，的調配問題。從文獻可知，來自HMG－CoA還原酶抑制劑，脂質降低性藥物者，數種化合物對於組成物的微環境之性質具有敏感性，事實上是針對光，熱和濕度。下面的專利說明書描述包含施德丁，特別者羅蘇伐他汀的藥學組成物。
WO 02/089788述及含施德丁的藥學組成物，其穩定性是藉由添加胺基醣(例如N－甲基－葡萄糖胺)來提供。根據該說明，胺基醣相對於無機鹼土金屬鹽的優點在於彼等不會刺激腸內黏膜。
WO 00/53173述及含有施德丁作為活性成分的延遲釋放性藥學組成物，其中該活性成分在胃中的釋放及在酸性條件下內酯的形成，係經由特殊凝膠構造及腸衣劑型予以防止。
WO 01/62230述及一種以甘露醇為基的粒狀物，其中活性成分施德丁係溶解於NaOH溶液中，且也與造粒溶液一起添加到藥學劑型內。
根據上述技藝狀態，有需要製造容易調配的含施德丁－在我們的情況中為羅蘇伐他汀－之穩定藥學組成物。
本發明的目的為開發一種含有羅蘇伐他汀鈣的穩定藥學組成物，其製造是簡易的且其精製組成物使得活性成分的劑比例性劑量(dose－proportional dosage)成為可能。
在我們的實驗中，出人意料地發現，穩定的藥學組成物可藉由使用氫氧化鎂及/或醋酸鈣或葡萄糖酸鈣或甘油磷酸鈣或氫氧化鋁作為藥學賦形劑來製成。除此之外，此等藥學劑型的可能組成係以適合產品族的劑比例性調配之方式所界定。
本發明係有關一種新穎藥學組成物，其含有非晶態羅蘇伐他汀鈣，和氫氧化鎂及/或醋酸鈣或葡萄糖酸鈣或甘油磷酸鈣或氫氧化鋁作為安定劑，以及一或多種藥學上可接受的賦形劑。
根據本發明，該藥學組成物較佳地含有氫氧化鎂及/或醋酸鈣作為穩定化添加劑。
根據本發明，該藥學組成物含有稀釋劑及/或黏合劑及/或崩解劑及/或潤滑劑及/或膜塗覆材料作為藥學上可接受的賦形劑，及在所給個例中作為另外的賦形劑。
該藥學組成物含有乳糖及/或微晶纖維素作為稀釋劑，普維酮(povidone)作為黏合劑，交聯普維酮(crospovidone)作為崩解劑及硬脂酸鎂作為潤滑劑。
此新藥學組成物係經膜塗覆者。
本發明也關於本發明藥學組成物的製造方法，其包括下列步驟：篩選活性成分及賦形劑，摻合活性成分、穩定化添加劑、稀釋劑、黏合劑、崩解劑，添加潤滑劑於內相中，摻合此混合物，在所給個例中添加另外的賦形劑至混合物中，然後壓縮成藥片，最後塗覆該藥片。
本發明要用下面諸實施例予以進一步闡述。
實施例1－8為了證實本發明藥學組成物之穩定性，乃檢驗實施例1－8含羅蘇伐他汀鈣的劑型之穩定性，其係採用等量但不同的穩定化添加劑，以相同的程序製成。
在應力－穩定性研究中，係將此等藥學組成物置於75℃下7天。
上面諸組成物(實施例1－8)都是以下述方式製成：篩選活性成分及賦形劑，將活性成分、上述穩定化添加劑之一者、稀釋劑和崩解劑摻合。然後添加潤滑劑到內相中，再摻合混合物且壓縮成藥片。
表2概括出應力－穩定性研究之結果。
根據組成物1－8應力－穩定性研究的結果，我們可以敘述，於受檢驗的諸實施例中，含穩定化添加劑，諸如氫氧化鎂、醋酸鈣、葡萄糖酸鈣、甘油磷酸鈣及氫氧化鋁的樣品之降解量變曲線係類似於市售含磷酸三鈣作為穩定化添加劑的產品(冠脂妥(Crestor))。因此，此等組成物適合用來製造含非晶態羅蘇伐他汀鈣之穩定藥學劑型。
根據此結果，以等量使用的醋酸鎂和胺基丁三醇不適合用來穩定化含非晶態羅蘇伐他汀鈣之藥學劑型。
下面諸實施例係說明劑比例性產品族(5毫克、10毫克、20毫克及40毫克活性)之主體組成及製造：實施例9
實施例10
實施例11
實施例12
實施例13本發明藥片的製造方法實施例9－12藥片的製造係由下列步驟組成：1.篩選賦形劑。
2.用兩種不同的方法將諸成分勻化：2a.在容器摻合器中摻合：將活性成分及內相的賦形劑(乳糖、微晶纖維素、氫氧化鎂及/或醋酸鈣，交聯普維酮，及有需要時的普維酮)於勻化設備中以20 rpm(轉/分)攪拌速度摻合5分鐘。然後將外相的賦形劑(硬脂酸鎂)添加至粉末混合物中，且在容器摻合器內以20 rpm的攪拌速度摻合此粉末混合物2分鐘。
2b.在高剪切混合器中摻合：將活性成分及內相的賦形劑(乳糖、微晶纖維素、氫氧化鎂及/或醋酸鈣，交聯普維酮，及有需要時的普維酮)分兩部份在高剪切混合器中摻合，先3分鐘，接著4分鐘。
設定值：攪拌器：300 rpm切碎器：1050 rpm
然後將外相的賦形劑(硬脂酸鎂)添加至粉末混合物中，且粉末混合物置於高剪切混合器中(攪拌器：300 rpm，切碎器：1050 rpm)或在容器摻合器中(攪拌速度20 rpm)再摻合2分鐘。
3.將與外相勻化過的粉末混合物在轉動藥片壓機內壓製成藥片。
實施例14膜塗覆藥片的製造(5毫克、10毫克、20毫克及40毫克)用Opadry II White、85F18422的水溶液膜塗覆實施例9－12的核心藥片。
膜衣的量為個別主體量的~3%。
Claims (9)
- 一種含有非晶態羅蘇伐他汀鈣(rosuvastatin calcium)之新穎藥學組成物，其特徵在於含有氫氧化鎂及/或醋酸鈣或甘油磷酸鈣作為穩定化添加劑，及一或多種藥學上可接受的賦形劑。
- 根據申請專利範圍第1項之藥學組成物，其含有氫氧化鎂及/或醋酸鈣作為穩定化添加劑。
- 根據申請專利範圍第1或2項之藥學組成物，其含有稀釋劑及/或黏合劑及/或崩解劑及/或潤滑劑及/或膜塗覆材料作為藥學上可接受的賦形劑，及在所給個例中的另外賦形劑。
- 根據申請專利範圍第1或2項之藥學組成物，其含有乳糖及/或微晶纖維素作為稀釋劑。
- 根據申請專利範圍第1或2項之藥學組成物，其含有普維酮(povidone)作為黏合劑。
- 根據申請專利範圍第1或2項之藥學組成物，其含有交聯普維酮(crospovidone)作為崩解劑。
- 根據申請專利範圍第1或2項之藥學組成物，其含有硬脂酸鎂作為潤滑劑。
- 根據申請專利範圍第1或2項之藥學組成物，其含有膜塗層。
- 一種製造根據申請專利範圍第1項之藥學組成物之方法，其特徵在於：i)篩選活性成分、穩定化添加劑及/或多種穩定化添 加劑以及賦形劑，ii)勻化該活性成分、穩定化添加劑及/或多種穩定化添加劑、稀釋劑、黏合劑以及崩解劑，iii)添加潤滑劑至內相，iv)摻合該混合物，v)在給定個例中將另外賦形劑添加到該混合物中且壓製成藥片，最後vi)膜塗覆該藥片。
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| HU0600728A HU227610B1 (en) | 2006-09-18 | 2006-09-18 | Pharmaceutical compositions containing rosuvastatin potassium |
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| EP2138165A1 (en) | 2008-06-27 | 2009-12-30 | KRKA, tovarna zdravil, d.d., Novo mesto | Pharmaceutical composition comprising a statin |
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| ATE489078T1 (de) | 2010-12-15 |
| CA2662919C (en) | 2013-04-30 |
| TW200829246A (en) | 2008-07-16 |
| PT2063868E (pt) | 2010-12-23 |
| ME01944B (me) | 2011-08-31 |
| PL2063868T3 (pl) | 2011-05-31 |
| EP2063868A1 (en) | 2009-06-03 |
| HUP0600728A2 (en) | 2008-06-30 |
| EA014451B1 (ru) | 2010-12-30 |
| AR062874A1 (es) | 2008-12-10 |
| CY1114533T1 (el) | 2016-10-05 |
| WO2008035128A1 (en) | 2008-03-27 |
| US8221788B2 (en) | 2012-07-17 |
| ES2357263T3 (es) | 2011-04-20 |
| DK2063868T3 (da) | 2011-02-07 |
| SI2063868T1 (sl) | 2011-03-31 |
| EP2063868B1 (en) | 2010-11-24 |
| DE602007010797D1 (de) | 2011-01-05 |
| HU0600728D0 (en) | 2006-11-28 |
| CA2662919A1 (en) | 2008-03-27 |
| HU227610B1 (en) | 2011-09-28 |
| HRP20110125T1 (hr) | 2011-03-31 |
| CN101516349A (zh) | 2009-08-26 |
| UA97489C2 (ru) | 2012-02-27 |
| EA200970291A1 (ru) | 2009-06-30 |
| US20090297599A1 (en) | 2009-12-03 |
| AU2007298751A1 (en) | 2008-03-27 |
| RS51563B (sr) | 2011-08-31 |
| JP5534812B2 (ja) | 2014-07-02 |
| AU2007298751B2 (en) | 2013-05-02 |
| JO2641B1 (en) | 2012-06-17 |
| JP2010503723A (ja) | 2010-02-04 |
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