TWI239839B - Pharmaceutical composition - Google Patents
Pharmaceutical composition Download PDFInfo
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- TWI239839B TWI239839B TW091109135A TW91109135A TWI239839B TW I239839 B TWI239839 B TW I239839B TW 091109135 A TW091109135 A TW 091109135A TW 91109135 A TW91109135 A TW 91109135A TW I239839 B TWI239839 B TW I239839B
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 25
- 150000002337 glycosamines Chemical class 0.000 claims abstract description 17
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims abstract description 16
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims abstract description 12
- 239000004480 active ingredient Substances 0.000 claims abstract description 11
- 239000000945 filler Substances 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 19
- 239000003795 chemical substances by application Substances 0.000 claims description 18
- 239000007937 lozenge Substances 0.000 claims description 16
- 239000000314 lubricant Substances 0.000 claims description 14
- 239000011230 binding agent Substances 0.000 claims description 13
- 239000007884 disintegrant Substances 0.000 claims description 11
- 235000000346 sugar Nutrition 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000003826 tablet Substances 0.000 claims description 10
- -1 Avastar Chemical compound 0.000 claims description 9
- 229940123934 Reductase inhibitor Drugs 0.000 claims description 9
- 239000001913 cellulose Substances 0.000 claims description 9
- 239000006185 dispersion Substances 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 159000000000 sodium salts Chemical class 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 7
- 102000004316 Oxidoreductases Human genes 0.000 claims description 6
- 108090000854 Oxidoreductases Proteins 0.000 claims description 6
- 239000008116 calcium stearate Substances 0.000 claims description 6
- 239000003112 inhibitor Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 5
- 239000000853 adhesive Substances 0.000 claims description 5
- 230000001070 adhesive effect Effects 0.000 claims description 5
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 5
- 235000013539 calcium stearate Nutrition 0.000 claims description 5
- 239000003729 cation exchange resin Substances 0.000 claims description 5
- 229920002678 cellulose Polymers 0.000 claims description 5
- 238000004132 cross linking Methods 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000000377 silicon dioxide Substances 0.000 claims description 5
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 235000010980 cellulose Nutrition 0.000 claims description 4
- 229910052681 coesite Inorganic materials 0.000 claims description 4
- 229910052906 cristobalite Inorganic materials 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 4
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- 229920003124 powdered cellulose Polymers 0.000 claims description 4
- 235000019814 powdered cellulose Nutrition 0.000 claims description 4
- 235000012239 silicon dioxide Nutrition 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 229910052682 stishovite Inorganic materials 0.000 claims description 4
- 229910052905 tridymite Inorganic materials 0.000 claims description 4
- 229940100445 wheat starch Drugs 0.000 claims description 4
- 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 claims description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 claims description 3
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 claims description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 3
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 claims description 3
- 235000019359 magnesium stearate Nutrition 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 150000003872 salicylic acid derivatives Chemical class 0.000 claims description 3
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 claims description 2
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 2
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 2
- AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 claims description 2
- 206010040844 Skin exfoliation Diseases 0.000 claims description 2
- 229960005370 atorvastatin Drugs 0.000 claims description 2
- GPUADMRJQVPIAS-QCVDVZFFSA-M cerivastatin sodium Chemical compound [Na+].COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 GPUADMRJQVPIAS-QCVDVZFFSA-M 0.000 claims description 2
- 230000035618 desquamation Effects 0.000 claims description 2
- 229960003765 fluvastatin Drugs 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 claims description 2
- 229950009116 mevastatin Drugs 0.000 claims description 2
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 claims description 2
- 229940058287 salicylic acid derivative anticestodals Drugs 0.000 claims description 2
- 229960002797 pitavastatin Drugs 0.000 claims 3
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 claims 2
- OIEWLITYBUYJOH-UHFFFAOYSA-N 2,3-bis(ethenyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C=C)=C1C=C OIEWLITYBUYJOH-UHFFFAOYSA-N 0.000 claims 1
- 241000228347 Monascus <ascomycete fungus> Species 0.000 claims 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 claims 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims 1
- 102400001190 Vastatin Human genes 0.000 claims 1
- 101800000422 Vastatin Proteins 0.000 claims 1
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- 229920003303 ion-exchange polymer Polymers 0.000 claims 1
- 229960004844 lovastatin Drugs 0.000 claims 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 claims 1
- 229940100629 oral lozenge Drugs 0.000 claims 1
- RHGYHLPFVJEAOC-FFNUKLMVSA-L pitavastatin calcium Chemical compound [Ca+2].[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1.[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 RHGYHLPFVJEAOC-FFNUKLMVSA-L 0.000 claims 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims 1
- 229960002965 pravastatin Drugs 0.000 claims 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 claims 1
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- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 22
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Classifications
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- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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Description
1239839
本發明有關一種醫藥組合物，包括作為活性成分之 HMG-CoA還原酶抑制劑。 血漿膽固醇量與冠狀心臟疾病（CHD)有關之臨床事件發 生有正面關聯。因此，可於哺乳類中降低膽固醇量之醫藥 插入物對CHD有正面效益。尤其，降低之血漿低密度脂蛋 白質（LDL)膽固醇量與降低動脈硬化及降低CHD危險性有 關，且用於單一療法或組合療法之血脂肪降低劑可有效降 低LDL膽固醇量及降低隨後之chd危險性。 哺乳類中膽固醇代謝機制涉及一系列路徑，包含小腸中 膽固醇吸收、數種組織（主要為肝及小腸）中膽固醇生合 成、肝臟.中膽汁酸生合成及小腸中再吸收、含膽固醇之: 漿脂蛋白藉肝及腸合成、含膽固醇之血漿脂蛋白藉肝及肝 臟外組織之分解代謝及膽固醇及膽汁酸藉肝之分泌作用。 膽固醇合成發生於多種組織，但主要在肝及腸。其為多 步驟製程藉一系列酵素包含羥甲基榖胺醯基_輔酶a(hmg_ C〇A)還原酶、HMG_c〇A合成酶、角鯊烯合成酶、角鯊晞 %氧酶、角鯊晞環酶及羊毛脂醇去甲基酶所催化之乙醯基-輔酵素A起始。該等酵素催化作用之抑制或阻斷HMg_c 〇A 遂原酶基因表現被認為為降低膽固醇生合成之有效方法且 可引起膽固醇量減少。已知之111^(^(：〇八還原酶抑制劑包 έ斯達/Γ (statin)如維瓦斯達汀（i〇vastatin)、希瓦斯達汀 (mvastatin)帕瓦斯達〉'丁（pravastatin)、氟瓦斯達汀 (uvastatin)阿技瓦斯達汀（atorvastatin)、美瓦斯達；丁 (meVaStatin)、利瓦斯達汀（rivastatin)(色瓦斯達汁 - 4 · 本纸張尺度適用中國國家標準(CNS) A4規格------ 1239839 A7 B7 五、發明説明（3 ) -包括脫氫表睪丸酮（DHEA)、選自類視黃醇、醯化水楊酸 衍生物或HMG-C οA還原酶抑制劑之脫屑劑及糖衍生物， 及 -包括造麴原料之胚芽及紅曲素（monacolin) K。 包括脫氫表睪丸酮（DHEA)、選自類視黃醇、醯化水楊 酸衍生物或HMG-C οA還原酶抑制劑之脫屑劑及糖衍生物 之組合物述於WO 0 1266 19。此組合物描述可用於化妝品工 業。包括造麴原料之胚芽（該胚芽包括葡糖胺）如小麥或稻 米胚芽及紅曲素（monacolin) K(羅瓦斯達汁）之組合物述於 JP 2000106834。JP 2000106834中亦描述此組合物可藉使 小麥胚芽及稻米胚芽與水之混合物加熱，以紅曲科 (Monascus pilosus) IFO4520培育該混合物，培養4至8天.， 加熱至110°C歷時20分鐘，使所得混合物乾燥例如減少溼 氣含量至10°/〇或以下，及粉碎而獲得。 依據本發明，HMG-C oA還原酶抑制劑包含例如在酸性 環境不安定之一或多種，較好一種HMG-C oA還原酶抑制 劑，如述於HMG-C oA還原酶抑制劑專利申請中之化合物 包含斯達汀。此專利申請包含如US423 1938(包含如羅瓦斯 達汀）；EP0033538(包含如希瓦斯達汀）；GB2077264(包含 如帕瓦斯達汀）；ΕΡ01 14027(包含如氟瓦斯達汀）； EP0247633(包含如阿拢瓦斯達汀）；US3983 140(包含美瓦 斯達汀）；EP0491226(包含如利瓦斯達汀；色瓦斯達汀）； US501 1930(包含如比塔瓦斯達汀，日產/三共尼瓦斯達汀 (NK-104)或塔瓦斯達汀）；US5260440(包含 Shionogi· -6- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 裝 訂
1239839 一(，
Astra/Zeneca之羅蘇你、本 及_細（包含與上===斤達/⑽-㈣⑴ 之專利申請内容併本文供二丁二斯達;丁)；該引證 制劑係選自斯達汁如羅瓦斯達考。較：HMG-C。Α還原酶抑 ;丁、氣瓦斯達汀、阿=，、希瓦斯達红、帕瓦斯達 ，、丁 β…、、斯達汁、美瓦斯達疗、利瓦斯達 ，丁（色瓦斯達>Τ)、比塔瓦斯達汀（尼 汀）、羅蘇瓦斯達汁（必沙斯、查、… ^ 丁 J斯達 好選自羅瓦斯料、希瓦斯/)關斯心7化合物；更 卜阿托瓦斯㈣、美瓦=、：瓦斯達"瓦斯達 汀）、比m去、達瓦斯達汀（色瓦斯達 二二=(尼瓦斯達汁、塔瓦斯達汀)及羅蘇瓦斯 、彳#^、斤達/丁），又更好為帕瓦斯達汀。 、=目的巾’本發明提供_種包括斯料作為活性成分 醫藥組合物，該斯達#為例如羅瓦斯達汀、希瓦 斯達，丁 Φ白瓦斯達>丁、氣瓦斯達;丁、阿托瓦斯達汁、美瓦 斯達^利瓦斯達厅（色瓦斯達汁）、比塔瓦斯達汀（尼瓦斯 達>丁、塔瓦斯達汁）或羅蘇瓦斯達汁（必沙斯達汁），更好為 帕瓦斯達>'丁。 … 本發明之醫藥組合物可藉混合hmg_c〇a還原酶抑制劑 與胺基糖混合而製備。較好該胺基糖為可調節該水性分散 液之、·且口物之pH至少為7.0之胺基糖。較好該胺基糖使用 作為pH-調節（鹼化）劑。本發明較佳之胺基糖包含n_甲基 葡糖胺。 & 於水性分散液中獲得pH至少7.0之胺基糖相對於111^(}-C oA還原酶抑制劑量之必要量具重要性且可藉預先測試獲 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1239839 五 、發明説明（ 、二A甲基葡糖胺作為胺基糖及帕瓦斯達汀作為HMG-旦A遂原酶抑制劑時，較好相對於〇A還原酶抑制劑 量之胺基糖量為每重量15%及以下，如6%至15%。 本：明《醫藥組合物除了活性成分及胺基糖以外，可包 括醫藥可接雙性賦型劑如可用於製造醫藥組合物之一或多 型劑。適當賦型劑可藉預先測試決定。此賦型劑實例 匕。士或夕種填充劑及/或黏合劑及/或崩解劑及/或潤滑 劑，如 -纖維素例如包含 -粉末纖維素作為填充劑； _微晶纖維素如AWeel例如包含AWW⑽⑧作為填充劑； -羧甲基纖维素如包含交聯羧甲基纖維素鈉(交聯羧 維素鈉）作為崩解劑； -經垸基纖維素如包含㈣基纖維素作為黏合劑，· -澱粉如包含小麥澱粉作為填充劑或黏合劑； 乙婦t各燒酮作為黏合劑如包含交聯聚乙締基心垸 -二氧化矽如包含Si〇2膠體作為崩解劑； -丙婦酸及甲基丙缔酸共聚物如均·:共聚物如" 酸，二以希基苯製備之低交聯羧酸陽離子交換樹脂之神鹽 如聚丙稀琳（polyacrilin)鉀作為崩解劑； -乳糖作為填充劑； -硬脂酸鎂、硬脂酸鈣作為潤滑劑； -硫酸躬作為填充劑； 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐） -8 - 1239839 五、 發明説明（ -CAHP〇4亦稱為鱗_或鱗酸二㈣為填充劑； •矽酸鎂鋁作為崩解劑。 一本發明另_目的係提供本發明之醫藥組合物及又包 樂可接受性賦型劑如包括愛 ' W ^ ^ 括選自一或多種填充劑及/或黏合 劑及/或朋解劑及/或潤滑劑，例如 一種由下列組成之醫藥組合物： -HMG-CoA還原酶抑制劑作為活性成分， -胺基糖，及 選自或夕種填充劑及’或黏合劑及/或崩解劑及/或潤 劑之醫藥可接受性賦型劑。 本發明.較佳具體例中’該醫藥組合物除了 HMG-COA還 原酶抑制劑及胺基糖以外又包括一或多種填充劑、黏合 劑、崩解劑及潤滑劑。 訂 本發明 < 醫藥組合物可為任何型態如固態或液態，如呈 口服投藥之懸浮液或乳液態。 本發明又一目的係提供一種呈固態之本發明醫藥組合 物。 固態包含例如顆粒、粉劑、鍵劑，較好為錠劑。本發明 之固態較好包含口服投藥之固態。 本發明又一目的係提供成錠劑態供口服投藥之本發明醫 藥組合物。 本發明之錠劑包含非可分散及可分散錠劑。可分散錠劑 需了解包含於水性溶劑中形成（均勻）分散液之錠劑，如獲 得供口服投藥之乳液或懸浮液。較佳之HMG-C oA還原酶 -9- 本紙張尺度適用中國菌家標準(CNS) A4規格(21〇 X 297公釐） 1239839
抑制劑包含帕瓦斯達汀如呈鈉鹽態。 n日月齋]包含其中胺基糖量為錠劑總重之0%及以 下’如2·0%及以下，如0.5%至5.0%且其中HMG-CoA還原 酶抑制劑為如呈鈉鹽態帕瓦斯達汀之錠劑。 本發明較佳具體例中，呈錠劑供口服投藥之本發明醫藥 組合物可如下製備： HMG-C οA還原酶抑制劑如斯達汀例如帕瓦斯達汀如呈 鈉鹽之帕瓦斯達汀可與填充劑及/或黏合劑混合。所得混 合物可以水造粒。或者HMG-CoA還原酶抑制劑可與填充 劑及/或黏合劑混合及所得混合物可以其中溶解一或多種 (車又好韓）胺基糖作為pH-調節（驗化）劑之水造粒。所得顆 粒可乾燥及視情況經過篩加工，較好孔徑為丨〇至3 〇毫米 如2.0毫米之網篩。所得顆粒可視情況再與作為pH_調節（鹼 化）劑之胺基糖混合（造粒期間胺基糖已存在之例及在造粒 期間胺基糖不存在之例），所得顆粒與作為pH_調節（鹼化） 劑之胺基糖混合。所得混合物可壓縮獲得錠劑。 較佳之劑量單位包含正常可用如已知可用於特定hmg_ CoA還原酶抑制劑者。在使用φ白瓦斯達㈣作顧腦心八 還原酶抑制劑之例中，^好一錠劑+有1〇、2〇或4〇毫克帕 瓦斯達、;丁鋼。 本發明另一具體例提供一種供口服投藥之本發明錠劑， 包括例如由呈鈉鹽態之帕瓦斯斬所構成且又包括填充劑 及/或黏合劑及/或崩解劑及/或潤滑劑；及胺基糖作為例如 ΡΗ·調節（鹼化）劑，其量為使該錠劑於水中分散液之阳為
-裝 訂
-10-
1239839 A7 B7
7.0至8.7，較好8.〇至8.7。 本發明另一具體例提供一種供口服投藥之錠劑，包括例 如由呈鋼鹽態之帕瓦斯達汁、填充劑、黏合劑、崩解劑、 潤滑劑及胺基糖作為例如pH_調節（鹼化）劑所構成，該胺 基糖量為使該錠劑於水中分散液之？11為7 〇至8 7，較好8 〇 至 8.7 。 ’ 本發明另一目的系提供本發明之錠劑，包括例如由下所 成分所構成： 成鈉鹽態之帕瓦斯達汀作為活性成分，及 -乳糖、微晶纖維素、聚乙埽基吡咯烷酮、交聯幾甲基纖維 素鈉及硬脂酸鎂，或 -磷酸氫二鈣、粉末纖維素、羥丙基纖維素、Si〇2、硬脂酸 鈣及由甲基丙晞酸及二乙晞基苯製備之低交聯幾酸陽離子 交換樹脂之鉀鹽，或 -磷酸氫二鈣、粉末纖維素、小麥澱粉、Si〇2、硬脂酸鈣及 由甲基丙晞酸及二乙缔基苯製備之低交聯羧酸陽離子交換 樹脂之鉀鹽，及 N-甲基葡糖胺作為pH調節（鹼化）劑，其量為使該錠劑於水 中分散液之pH為7.0至8.7。 本發明另一目的係提供一種製造供口服投藥且包括 HMG-C οA還原酶抑制劑作為活性成分之錠劑之方法，該 方法包括下列步驟： a·使HMG-CoA還原酶抑制劑與填充劑及/或黏合劑混合， 如與填充劑與黏合劑混合， -11- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)
裝 訂
線 1239839
所，顆粒乾燥及經孔徑2.0毫米之㈣過篩。所得粒化顯粒 A崩解h彳、潤滑劑及胺基糖混合。或活性成分與填充劑及 t合劑混合及所得混合物以其中溶解胺基糖之水依濕造粒 造粒。所得顆粒乾燥及經孔徑2.0毫米之網篩過篩。所得粒 化顆粒與崩解劑及潤滑劑混合。 本發明所得混合物壓縮成包括1 0、2 0或4 0毫克帕瓦斯 達汀鈉鹽之錠劑。 上述本發明所得3種不同錠劑組成成分（以一錠劑每重量 %)概述於下表i : 13- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1239839 A7 B7 五、發明説明（n 表1 製劑1 製劑2 製劑3 帕瓦斯達汀鈉鹽 10.00 10.00 10.00 乳糖作為填充劑 68.20 • 祕 微晶纖維素*)作為填充 劑 13.50 - - 磷酸氫二鈣作為填充劑 • 65.00 65.00 粉末纖維素作為填充劑 - 17.00 17.00 聚乙晞基P比洛燒酮作為 黏合劑 0.50 - - 羥丙基纖維素作為黏合 劑 - 1.00 - 小麥澱粉作為黏合劑 - 晒 1.00 交聯羧甲基纖維素鈉作 為崩解劑 6.00 3102膠體作為崩解劑 - 2.50 2.50 聚丙烯琳鉀***)作為崩 解劑 - 2.50 2.50 硬脂酸鎂作為潤滑劑 1.00 - - 硬脂酸鈣作為潤滑劑 • 1.00 1.00 Meglumine**)作為 pH 調節劑 0.80 1.00 1.00 裝 訂
*)Avicel pH 102 **)N-甲基葡糖胺 ***)由甲基丙烯酸及二乙烯基苯製備之低交聯羧酸陽離子 交換樹脂之鉀鹽 包括述於上表1之製劑1、製劑2、製劑3之成分之實例中 -14- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1239839 A7 B7 五、發明説明（12 ) 所得之錠劑之水性分散劑之pH予以測定且介於8.0至8.7之 間。製劑1、製劑2及製劑3在正常環境溼度條件下安定超 過1個月。 -15- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)
Claims (1)
- I23983髮〇__號專利申請案D。 中文申請專利範圍替換本(94年5月）5 A8 B8 丨修正 補充 申請專利範園 1· 一種包括HMG-CoA還原酶抑制劑作為活性成分之安定 醫藥組合物，其特徵為該醫藥組合物包括胺基糖，但下 列組合物除外： 包括脫氫表睪丸酮（DHEA)、選自類視黃醇、醯化水 杨酸衍生物或HMG-C oA還原酶抑制劑之脫屑劑及糖衍 生物，及 -包括造麴原料之胚芽及紅曲素㈤⑽扣……K 〇 2.如申請專利範圍第1項之醫藥組合物，又包括醫藥可接 受性賦型劑。 3·如申請專利範圍第2項之醫藥組合物，其中該醫藥可接 受性賦型劑係選自一或多種填充劑及/或黏合劑及/或崩 解劑及/或潤滑劑。 4· 一種安定醫藥組合物，包括·· -HMG-C oA還原酶抑制劑作為活性成分， -胺基糖，及 •選自一或多種填充劑及/或黏合劑及/或崩解劑及/或 潤滑劑之醫藥可接受性賦型劑。 5·如申請專利範圍第2至4項任一磺之醫藥組合物，其中該 醫藥可接受性賦型劑係選自一或多種填充劑、黏合劑、 崩解劑及潤滑劑。 6.如申請專利範圍第1至4項任一項之醫藥組合物，其中該 HMG-CoA還原酶抑制劑為斯達汀（statin)。 7·如申請專利範圍第6項之醫藥組合物，其中該斯達汀係 選自羅瓦斯達丁（lovastatin)、希瓦斯達、;丁 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1239839 as B8 C8 D8 六、申請專利範圍 (simvastatin)、帕瓦斯達汁（pravastatin)、氟瓦斯達 ί丁 (fluvastatin)、阿技瓦斯達、;丁（atorvastatin)、美瓦斯達 ;丁（mevastatin)、利瓦斯達 丁（rivastatin)(色瓦斯達、;丁 (cer(i)vastatin))、比塔瓦斯達，;丁（pitavastatin)(尼瓦斯 達、;丁（ nisvastatin)、塔瓦斯達;丁（ itavastatin))及羅蘇瓦斯 達汀（rosuvastatin)(必沙斯達 ί丁（ visastatin))。 8·如申請專利範圍第6項之醫藥組合物，其中該斯達汀為 帕瓦斯達汀。 9·如申請專利範圍第1至4項任一項之醫藥組合物，係成固 態。 10.如申請專利範圍第9項之醫藥組合物，係成錠劑態。 11· 一種口服錠劑，係由鈉鹽態之帕瓦斯達汀、一或多種填 充劑、黏合劑、崩解劑及/或潤滑劑、及作為pH調整（鹼 化）劑之胺基糖，該糖之量為使該錠劑於水中分散液之 pH為 7.0至 8.7。 12·如申請專利範圍第11項之錠劑，係由下列所構成： 成鈉鹽態之帕瓦斯達汀作為活性成分，及 -乳糖、微晶纖維素、聚乙晞基p比嘻燒酮、交聯叛甲 基纖維素鈉及硬脂酸鎂，或 -磷酸氫二鈣、粉末纖維素、羥丙基纖維素、Si02、 硬脂酸鈣及由甲基丙烯酸及二乙晞基苯製備之低交聯羧 酸陽離子交換樹脂之鉀鹽，或 -磷酸氫二鈣、粉末纖維素、小麥澱粉、Si02、硬脂 酸鈣及由甲基丙婦酸及二乙烯基苯製備之低交聯羧酸陽 -2- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐）8 8 8 8 A BCD 1239839 々、申請專利範圍 離子交換樹脂之钾鹽，及 N-甲基葡糖胺作為pH調節（鹼化）劑，其量為使該錠 劑於水中分散液之pH為7.0至8.7。 -3 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐)
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| GBGB0111077.4A GB0111077D0 (en) | 2001-05-04 | 2001-05-04 | Organic compounds |
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| EP (1) | EP1392277A2 (zh) |
| AR (1) | AR035875A1 (zh) |
| AU (1) | AU2002310798A1 (zh) |
| GB (1) | GB0111077D0 (zh) |
| TW (1) | TWI239839B (zh) |
| WO (1) | WO2002089788A2 (zh) |
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| USRE44578E1 (en) | 2000-04-10 | 2013-11-05 | Teva Pharmaceutical Industries, Ltd. | Stable pharmaceutical compositions containing 7-substituted-3,5-dihydroxyheptanoic acids or 7-substituted-3,5-dihydroxyheptenoic acids |
| WO2003000239A1 (en) * | 2001-06-21 | 2003-01-03 | Andrx Pharmaceuticals, Inc. | Stable pharmaceutical compositions containing pravastatin |
| IL158790A0 (en) | 2001-06-29 | 2004-05-12 | Warner Lambert Co | Crystalline forms of [r-(*,r*)]-2-(4-fluorophenyl) -beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1h-pyrrole-1-heptanoic acid calcium salt (2:1) (atorvastatin) |
| US7790197B2 (en) | 2003-06-09 | 2010-09-07 | Warner-Lambert Company Llc | Pharmaceutical compositions of atorvastatin |
| JP2007536373A (ja) | 2004-05-05 | 2007-12-13 | ファイザー・プロダクツ・インク | アトルバスタチンの塩形態 |
| WO2006006021A2 (en) * | 2004-06-28 | 2006-01-19 | Glenmark Pharmaceuticals Limited | Stabilized pharmaceutical compositions of preferably a statin |
| WO2006054308A2 (en) | 2004-11-22 | 2006-05-26 | Dexcel Pharma Technologies Ltd. | Stable atorvastatin formulations |
| GB0516604D0 (en) * | 2005-08-12 | 2005-09-21 | Sandoz Ag | Rapidly dispersing/disintegrating compositions |
| WO2007071357A2 (en) * | 2005-12-20 | 2007-06-28 | Lek Pharmaceuticals D.D. | Pharmaceutical composition comprising (e) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5 -yl- (3r, 5s) -3, 5-dihydr0xyhept-6-en0ic acid |
| HU227610B1 (en) * | 2006-09-18 | 2011-09-28 | Richter Gedeon Nyrt | Pharmaceutical compositions containing rosuvastatin potassium |
| DE102007007865A1 (de) * | 2007-02-14 | 2008-08-21 | Jennissen, Herbert, Prof. Dr. | Verfahren zur Herstellung von lagerfähigen Implantaten mit einer ultrahydrophilen Oberfläche |
| CZ300047B6 (cs) * | 2007-03-02 | 2009-01-21 | Zentiva, A. S. | Farmaceutická kompozice s obsahem úcinné látky atorvastatinu |
| EP2192920A4 (en) * | 2007-08-21 | 2010-09-01 | Univ Virginia Commonwealth | METHOD AND COMPOSITIONS FOR TREATING OR PREVENTING RADIATION-INDUCED FIBROSIS |
| MX344885B (es) * | 2008-11-10 | 2017-01-10 | Psicofarma S A De C V | Proceso para la obtencion de una composicion de rosuvastatina calcica y producto obtenido. |
| UA108742C2 (uk) | 2009-09-23 | 2015-06-10 | Фармацевтична композиція для лікування запальних захворювань, опосередкованих mcp-1 | |
| KR101298788B1 (ko) * | 2011-03-15 | 2013-08-22 | 보령제약 주식회사 | 안정성이 개선된 복합제제 |
| TWI636783B (zh) * | 2012-04-18 | 2018-10-01 | 友霖生技醫藥股份有限公司 | 含匹伐他汀（ｐｉｔａｖａｓｔａｔｉｎ）穩定配方的醫藥組合物 |
| CN108118042B (zh) * | 2016-11-30 | 2021-01-15 | 中国科学院青岛生物能源与过程研究所 | 2-甲基丁酸侧链水解酶和产莫纳可林j的曲霉菌株及其构建方法与应用 |
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| US5030447A (en) * | 1988-03-31 | 1991-07-09 | E. R. Squibb & Sons, Inc. | Pharmaceutical compositions having good stability |
| HU217629B (hu) * | 1991-12-12 | 2000-03-28 | Novartis Ag. | Eljárás fluvasztatint tartalmazó stabilizált gyógyszerkészítmények előállítására |
| SG45369A1 (en) | 1993-01-19 | 1998-10-16 | Warner Lambert Co | Stable oral ci-981 formulation and process of preparing same |
| SI20109A (sl) * | 1998-12-16 | 2000-06-30 | LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. | Stabilna farmacevtska formulacija |
| US6551617B1 (en) * | 2000-04-20 | 2003-04-22 | Bristol-Myers Squibb Company | Taste masking coating composition |
| US6531507B1 (en) * | 2000-06-09 | 2003-03-11 | Lek Pharmaceuticals D.D. | Stabilized pharmaceutically effective composition and pharmaceutical formulation comprising the same |
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- 2002-05-03 WO PCT/EP2002/004891 patent/WO2002089788A2/en not_active Ceased
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| AU2002310798A1 (en) | 2002-11-18 |
| EP1392277A2 (en) | 2004-03-03 |
| WO2002089788A2 (en) | 2002-11-14 |
| AR035875A1 (es) | 2004-07-21 |
| GB0111077D0 (en) | 2001-06-27 |
| WO2002089788A3 (en) | 2002-12-12 |
| US6911472B2 (en) | 2005-06-28 |
| US20040167085A1 (en) | 2004-08-26 |
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