TW202128148A - 製造含有活性物質之結晶與非晶質部分之藥物配製物的方法 - Google Patents
製造含有活性物質之結晶與非晶質部分之藥物配製物的方法 Download PDFInfo
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- TW202128148A TW202128148A TW109134691A TW109134691A TW202128148A TW 202128148 A TW202128148 A TW 202128148A TW 109134691 A TW109134691 A TW 109134691A TW 109134691 A TW109134691 A TW 109134691A TW 202128148 A TW202128148 A TW 202128148A
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- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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Abstract
一種製造藥物配製物之方法，其包括以下步驟：A)提供聚合物顆粒，其中藥物活性物質顆粒額外至少部分嵌入聚合物顆粒中，B)將聚合物顆粒加熱至預定溫度長達預定時間，及C)在預定時間後將聚合物顆粒冷卻至18℃至24℃的溫度，其中聚合物至少部分溶於水且活性物質至少部分溶於聚合物。
微粒狀藥物活性物質係以粒徑分佈具有d90值
1μm之顆粒形式存在。預定溫度係在低於聚合物之玻璃轉移溫度(由DSC根據DIN EN ISO 11357-2以10K/min加熱率決定)10K至活性物質之熔融溫度之範圍內。聚合物中活性物質總比例大於在預定溫度下可溶於聚合物之活性物質的量。
本發明進一步有關一種包括塗有至少部分水溶性聚合物的微粒狀藥物活性物質之藥物配製物、製造藥物配製物懸浮液之方法及藥物活性物質之懸浮液。
Description
本發明有關一種製造藥物配製物之方法，其包括以下步驟：A)提供聚合物顆粒，其中藥物活性物質顆粒額外至少部分嵌入聚合物顆粒中，B)將聚合物顆粒加熱至預定溫度長達預定時間，及C)在預定時間後將聚合物顆粒冷卻至18℃至24℃的溫度，其中聚合物至少部分溶於水且活性物質至少部分溶於聚合物。本發明進一步有關一種包括塗有至少部分水溶性聚合物的微粒狀藥物活性物質之藥物配製物、製造藥物配製物懸浮液之方法及藥物活性物質之懸浮液。
藥物活性物質之高溶解率通常造成生物可用率增加或至少造成生物可用率動力學改良。例如，此可藉由增加活性物質-顆粒集體之比表面積來實現。因而，活性物質奈米懸浮液較微粉化懸浮液具有相當高溶解率。增加溶解率與溶解度之另一種方法係製造非晶質固體形式之活性物質-聚合物分散液。在此方式中，在聚合物基質中製造活性物質之分子分散液，此提供非晶質穩定性。僅當聚合物能夠完全溶解存在的活性物質時，此系統為熱力學穩定。在室溫下聚合物中活性物質之低溶解度意指通常僅少量活性物質以穩定方式溶於聚合物基質中。
Wang等人在「Stability of nanosuspensions in drug delivery」於Journal of Controlled Release 172(2013)1126-1141文章中，報導由冷凍乾燥製
造含有可再分散奈米顆粒之粉末。除了常用穩定劑外，此處亦使用額外基質形成劑。SDS僅用作研磨添加劑。
S.Baghel等人在「Polymeric Amorphous Solid Dispersions：A Review of Amorphization,Crystallization,Stabilization,Solid-State Characterization,and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs」於the Journal of Pharmaceutical Sciences 105,9,2016,pp.2527-2544回顧文章中，敘述製造非晶質固體分散液。回顧未提及任何混成系統。
Van Duong等人在「Polymorphism of Indomethacin in Semicrystalline Dispersions：Formation,Transformation,and Segregation」於Mol.Pharmaceutics 2018,15,1037-1051文章中，報導一種半結晶聚合物-活性物質系統，其中從非晶質固體分散液開始，可由改變活性物質含量形成不同同質多形體。此方法缺點在於未控制生長，因而形成尺寸變化之微晶體。此外，使用結晶質PEG。再者，形成不同同質多形體。最後，非晶質相幾乎完全結晶質。
本發明目的係提供改良藥物配製物，其與可變的釋放動力學一起允許較高的活性物質負載。
根據本發明，該目的藉由根據請求項1之方法、根據請求項11之配製物、根據請求項13之方法及根據請求項15之分散液來實現。在附屬請求項中載述有利發展。除非從上下文清楚相反的情況，否則其等可自由組合。
一種製造藥物配製物之方法，該藥物配製物呈由非晶質固體溶液與結晶質奈米顆粒混合組成的混成系統形式，其包括以下步驟：
A)提供聚合物顆粒，其中藥物活性物質的顆粒額外至少部分嵌入聚合物顆粒中；
B)將聚合物顆粒加熱至預定溫度長達預定時間；
C)在預定時間後將聚合物顆粒冷卻至18℃至24℃的溫度，以產生呈由非晶質固體溶液與結晶質奈米顆粒混合組成的混成系統形式的藥物配製物，
其中聚合物至少部分溶於水，且活性物質至少部分溶於聚合物，
微粒狀藥物活性物質係以粒徑分佈具有d90值
1μm(基於體積；根據ISO 13320：2009由雷射繞射測定)之顆粒形式存在，
預定溫度係在低於聚合物玻璃轉移溫度(由DSC根據DIN EN ISO 11357-2以10K/min加熱率決定)10K至活性物質熔融溫度(由DSC根據DIN EN ISO 11357-2以10K/min加熱率決定)之範圍，且
聚合物中活性物質總比例大於在預定溫度下可溶於聚合物之活性物質的量。
本發明提供包括非晶質與奈米微粒活性物質之藥物活性物質系統。此處微粒分率係以嵌入非晶質固體溶液之單離奈米顆粒形式存在。此種非晶質與奈米微粒分率組合結合各自性質。此外，活性物質含量高於純非晶質固體溶液中含量。釋放動力學亦有優勢，因為不僅存在固體活性物質奈米顆粒(經由粒徑調節溶解率)，而且存在具有其典型「彈跳與降落傘(spring and parachute)」效果之非晶質固體溶液。
在方法步驟A)中，提供至少部分嵌入活性物質顆粒之聚合物顆粒。相等敘述係活性物質顆粒至少部分被聚合物包裝。聚合物至少部分為水溶性。此處「水溶性」應理解意指在20℃，至少0.5g、較佳至少2g聚合物溶於100g水或溶解形成凝膠。
聚合物可為中性聚合物或陽離子或陰離子聚電解質，且可選自以下組群：烷基纖維素、羥烷基纖維素、羥烷基烷基纖維素、羧烷基纖維素、羧烷基纖維素的鹼金屬鹽、羧烷基烷基纖維素、羧烷基纖維素酯、澱粉、果膠、幾丁質衍生物、多醣、聚丙烯酸及其鹽、聚甲基丙烯酸及其鹽、聚乙烯醇、聚乙烯基吡咯烷酮、聚環氧烷、載述聚合物類型的共聚物或至少兩種上述聚合物的混合物。
活性物質至少部分可溶於聚合物。在預定溫度下活性物質於聚合物之溶解度較佳每100g聚合物大於0.5g活性物質，更佳每100g聚合物大於2g活性物質。在活性物質混合物情況中，此係指最難溶的組分。
適合活性物質等級實例為苯二氮卓類、抗高血壓藥、維生素、細胞增殖抑制劑、尤其是紫杉醇、麻醉劑、精神安定劑、抗抑鬱劑、抗病毒劑(例如抗HIV劑)、抗生素、抗真菌劑、抗失智劑、殺黴劑、化學治療劑、泌尿藥、血小板聚集抑制劑、磺胺類、解痙藥、激素、免疫球蛋白、血
清、甲狀腺治療劑、精神藥、抗帕金森病藥與其他動功能抗進藥(antihyperkinetics)、眼藥、神經病產品、鈣代謝調節劑、肌肉鬆弛劑、降脂劑、肝臟治療劑、抗心絞痛藥、心臟劑、免疫治療劑、調節肽與其抑制劑、安眠藥、鎮靜劑、婦科劑、抗痛風劑、血纖蛋白分解藥、酶產品與運輸蛋白、酶抑抑制劑、催吐藥、血液循環促進劑、利尿劑、診斷劑、皮質類固醇、類膽鹼藥、膽道治療劑、平喘劑、祛痰藥(broncholytics)、β受器阻斷劑、鈣離子通道阻斷劑、ACE抑制劑、抗動脈硬化劑、抗炎藥、抗凝血劑、抗低血壓藥、抗高血糖藥、抗高血壓藥、抗血纖蛋白分解藥、抗癲癇藥、止吐劑、解毒劑、抗糖尿病藥、抗心律不整劑、抗貧血藥、抗過敏藥、驅蟲劑、止痛藥、興奮劑、醛固酮拮抗劑、減肥劑或至少兩種上述活性物質等級之混合物。
難溶於水之活性物質特別適合作為活性物質。此處活性物質應理解意指在20℃ 100g水中，溶解度不大於1g、較佳不大於0.1g、更佳不大於0.01g者。
關於活性物質粒徑，較佳粒徑分佈之d90值(在本發明上下文中，d90意指基於體積，90%所有顆粒具有不大於此值之直徑；根據ISO 13320：2009由雷射繞射決定)
10nm至
1μm、較佳
50nm至
500nm、更佳
30nm至
300nm。此等活性物質顆粒較佳至少部分結晶質、更佳為結晶質。當此情況時，其等亦可敘述為奈米結晶質活性物質顆粒。
步驟B)為熱平衡步驟，包括持續預定時間從低於聚合物玻璃轉移溫度10K加熱至到活性物質熔融溫度之溫度。在聚合物混合物情況中，選擇存在組分之最低玻璃轉移溫度作為參考，在活性物質混合物情況中，則為存在組分之最低熔融溫度。加熱較佳為±10K Tg、更佳為±5K Tg，但不高於低於活性物質熔融溫度10K，因為驚人地發現在此溫度範圍內，對形成由非晶質固體溶液與結晶質奈米顆粒混合組成的混成系統之影響特別有益。不受任何特別理論束縛，假設聚合物允許在Tg區域中增加流動性，結果聚合物對活性物質之溶解性質(亦即活性物質分子嵌入聚合物基質)變得重要。
如引言已提及，此處敘述一種製造藥物配製物之方法，其中將聚合物顆粒加熱至預定溫度持續預定時間。聚合物顆粒本身達到預定溫度至關重要。因此，例如，僅在預定溫度範圍內的某個溫度進行方法期間乾燥、
但聚合物顆粒本身之溫度不在預定溫度範圍內是不足夠的。為了在熱平衡步驟後仍存在微粒狀活性物質且並非所有的活性物質已溶於聚合物，可設想聚合物中活性物質之總比例大於在預定溫度下可溶於聚合物之活性物質的量。活性物質較佳分散於聚合物中直至其熱力學飽和，更佳呈分子分散液形式。
在實施例中，步驟B)之預定時間為
1秒至
10小時。預定時間較佳為
1分鐘至
5小時、更佳
1小時至
4小時。
在進一步實施例中，藉由研磨包括活性物質顆粒及聚合物水溶液之懸浮液，然後乾燥獲得步驟A)提供之材料。聚合物水溶液可額外用作將表面活性劑(特別是離子界面活性劑)導入系統之手段。
在進一步實施例中，步驟B)中，從多物質噴嘴之噴嘴霧化(atomize)包括活性物質顆粒及聚合物水溶液之懸浮液，並從多物質噴嘴之另一個噴嘴排出溫度高於預定溫度之氣體，結果懸浮液被乾燥，且乾燥材料被加熱至預定溫度。在藉由噴霧乾燥(兩種物質噴嘴)之活性物質奈米懸浮液製造混成系統中，懸浮液噴霧較佳在高於聚合物玻璃轉移溫度舉行。以類似方式從粉末製造時，部分活性物質在此亦溶於聚合物，造成形成非晶質-結晶質混成系統。此外，維持結晶質形式。
在進一步實施例中，步驟B)中，從多物質噴嘴之噴嘴霧化包括活性物質顆粒之懸浮液，並從多物質的噴嘴之另一個噴嘴霧化聚合物與活性物質之水溶液，造成含有霧化顆粒懸浮液之混合物，並從多物質噴嘴之另一個噴嘴另外排出溫度高於預定溫度之氣體，結果混合物被乾燥，且乾燥材料被加熱至預定溫度。在藉由噴霧乾燥(三種物質噴嘴)之活性物質奈米懸浮液與活性物質-聚合物溶液製造混成系統中，懸浮液(較佳為水性)及溶液在低於聚合物玻璃轉移溫度之溫度下一起噴霧。使用適合於活性物質-聚合物系統之溶劑(例如乙醇、丙酮)製造活性物質-聚合物溶液。活性物質及添加劑必須以完全溶解形式存在。固態存在者係與結晶質奈米顆粒組合之非晶質固體溶液。此外，較佳維持結晶質形式。
在進一步實施例中，藥物活性物質選自：環孢素A、環孢素G、雷帕黴素(rapamycin)、他克莫司(tacrolimus)、晶狀去氧史帕胍啉(deoxyspergualin)、黴酚酸嗎啉乙酯(mycophenolate mofetil)、脈立莫司
(gusperimus)；乙醯柳酸、伊布洛芬(ibuprofen)、S(+)-伊布洛芬、吲哚美辛(indometacin)、雙氯芬酸(diclofenac)、匹洛西卡(piroxicam)、美洛昔康(meloxicam)、替諾昔康(tenoxicam)、萘普生(naproxen)、可多普洛菲(ketoprofen)、氟比洛芬(flurbiprofen)、芬諾洛芬(fenoprofen)、聯苯乙酸(felbinac)、舒林酸(sulindac)、依托度酸(etodolac)、羥基保泰松(oxyphenbutazone)、保泰松(phenylbutazone)、萘丁美酮(nabumetone)；硝苯地平(nifedipine)、尼托地平(nitrendipine)、尼莫地平(nimodipine)、尼索地平(nisoldipine)、伊拉地平(isradipine)、非洛地平(felodipine)、氨氯地平(amlodipine)、尼伐地平(nilvadipine)、拉西地平(lacidipine)、貝尼地平(benidipine)、樂卡地平(lercanidipine)、呋尼地平(furnidipine)、尼古地平(niguldipine)；α-硫辛酸；胞壁醯二肽或三肽、羅莫肽(romurtide)；維生素A、D、E或F；凡克派丁(vincopectin)、長春新鹼(vincristine)、長春花鹼(vinblastine)、利血平(reserpine)、可待因(codeine)；溴隱亭(bromocriptine)、二氫麥角胺(dihydroergotamine)、二氫麥角鹼(dihydroergocristine)；氯芥苯丁酸(chlorambucil)、依託泊苷(etoposide)、替尼泊苷(teniposide)、艾多昔芬(idoxifene)、他莫司汀(tallimustine)、替洛蒽醌(teloxantrone)、替拉扎明(tirapazamine)、卡折来新(carzelesin)、右尼古地平(dexniguldipine)、茚托利辛(intoplicine)、艾達黴素(idarubicin)、米替福新(miltefosine)、曲磷胺(trofosfamide)、黴法蘭(melphalan)、洛莫司汀(lomustine)、4,5-雙(4-氟苯胺基)鄰苯二甲醯亞胺；4,5-二苯胺基鄰苯二甲醯亞胺；胸腺托南(thymoctonan)、醋肽铜(prezatide-copper acetate)；紅黴素(erythromycin)、道諾黴素(daunorubicin)、短桿菌素(gramicidin)、阿黴素(doxorubicin)、兩性黴素B(amphotericin B)、正大黴素(gentamicin)、白黴素(leucomycin)、鏈黴素(streptomycin)、加奈黴素(ganefromycin)、利福克昔(rifamexil)、雷莫拉寧(ramoplanin)、螺旋黴素(spiramycin)；氟康那唑(fluconazole)、酮康唑(ketoconazole)、艾妥可那唑(itraconazole)；啡莫替定(famotidine)、希美替定(cimetidine)、雷尼替丁(ranitidine)、羅沙替丁(roxatidine)、尼扎替丁(nizatidine)、奧美拉唑(omeprazole)；N-[4-甲基-3-(4-吡啶-3-基嘧啶-2-基胺基)苯基]苯甲醯胺、N-苄醯基星形孢菌素(N-benzoylstaurosporine)；
BOC-PhecPhe-Val-Phe-嗎啉或其O-[2-(2-甲氧基乙氧基)乙醯氧基]衍生物；N-[4-(5-環戊基氧基羰基胺基-1-甲基吲哚-3-基甲基)-3-甲氧基苄醯基]-2-乙烯基氧基]苯磺醯胺或至少兩種上述活性物質之混合物。
在進一步實施例中，聚合物選自：甲基纖維素、羥甲基纖維素、羥乙基纖維素、羥丙基纖維素、羥丁基纖維素、羥乙基甲基纖維素、羥丙基甲基纖維素、羧甲基纖維素、羧甲基纖維素鈉、羧甲基乙基纖維素、羧烷基纖維素酯、澱粉、羧甲基分枝澱粉鈉、聚葡萄胺糖、藻酸、藻酸之鹼金屬鹽及銨鹽、角叉菜膠、半乳甘露聚糖、黃蓍膠、瓊脂、阿拉伯膠、瓜爾膠、三仙膠、聚丙烯酸及其鹽、聚甲基丙烯酸及其鹽、聚乙烯醇、聚乙烯基吡咯烷酮、聚環氧乙烷、聚環氧丙烷、環氧乙烷與環氧丙烷之共聚物、N-乙烯基吡咯烷酮-乙酸乙烯酯共聚物或至少兩種上述聚合物之混合物。特別佳者給予聚乙烯基吡咯烷酮(特別是K12及K30類型)與N-乙烯基吡咯烷酮-乙酸乙烯酯共聚物。
在進一步實施例中，聚合物顆粒額外含有離子界面活性劑。離子界面活性劑可為陰離子、陽離子或兩性離子(兩性)界面活性劑。不受任何特別理論束縛，假定離子界面活性劑與聚合物組合在乾燥期間對活性物質顆粒穩定性具有有益作用。因此，靜電與空間穩定性之組合使顆粒可幾乎完全再分散。亦可觀察到顆粒保持多形態。此可由X射線粉末繞射測定法及傅立葉轉換紅外光譜術記錄。
在步驟A)之聚合物/活性物質顆粒中，聚合物含量可為
0.1重量%至
40重量%，界面活性劑
0.001重量%至
10重量%，各情況中基於步驟A)之懸浮液總重。劑量之進一步實例係活性物質：聚合物：界面活性劑之重量比率
0.01至
5：1：
0.001至
1。
在進一步實施例中，離子界面活性劑選自：
醯基胺基酸(及其鹽)，例如：醯基麩胺酸鹽，例如醯基麩胺酸鈉、二-TEA-棕櫚醯基天冬胺酸鹽及癸醯基麩胺酸鈉；醯基肽，例如棕櫚醯基水解的乳蛋白、椰油醯基水解的大豆蛋白鈉及椰油醯基水解的膠原蛋白鈉/鉀；肌胺酸鹽，例如肉荳蔻醯基肌胺酸鹽、TEA-月桂醯基肌胺酸鹽、月桂醯基肌胺酸鈉與椰油醯基肌胺酸鈉；牛磺酸鹽，例如月桂醯基牛磺酸鈉與甲基椰油醯基牛
磺酸鈉；醯基乳酸鹽、月桂醯基乳酸鹽、己醯基乳酸鹽、丙胺酸鹽；羧酸及衍生物，例如：羧酸，例如月桂酸、硬脂酸鋁、烷醇鎂及十一烯酸鋅、羧酸酯，例如硬脂醯乳酸鈣及PEG月桂醯胺羧酸鈉，羧酸醚，例如月桂醇聚醚羧酸鈉及PEG椰油醯胺羧酸鈉；磷酸酯與磷酸鹽，例如DEA油醇聚醚磷酸酯及二月桂醇聚醚磷酸酯；磺酸與磺酸鹽，例如醯基羥乙基磺酸鹽，例如椰油基羥乙基磺酸鈉/銨，烷基芳基磺酸鹽、烷基磺酸鹽，例如椰油單甘油酯硫酸鈉、C-烯烴磺酸鈉、月桂基磺基乙酸鈉及PEG椰油醯胺硫酸鎂，磺基琥珀酸鹽，例如磺基琥珀酸二辛基鈉、月桂醇聚醚磺基琥珀酸二鈉、月桂基磺基琥珀酸二鈉及十一烯醯胺基MEA-磺基琥珀酸二鈉；及亦硫酸酯，例如烷基醚硫酸鹽，例如月桂醇聚醚硫酸鈉、月桂醇聚醚硫酸銨、月桂醇聚醚硫酸鎂、MIPA月桂醇聚醚硫酸鹽、TIPA月桂醇聚醚硫酸鹽、肉豆蔻醇聚醚硫酸鈉及C-pareth硫酸鈉，烷基硫酸鹽，例如月桂基硫酸鈉、月桂基硫酸銨及TEA月桂基硫酸鹽。
根據發明，離子界面活性劑可進一步有利選自陽離子界面活性劑組群。可有利使用之陽離子界面活性劑為烷基胺、烷基咪唑、乙氧基化胺、四級界面活性劑及酯基四級銨鹽。
四級界面活性劑含有至少一個與4個烷基或芳基共價鍵結之N原子。不論pH值，此會造成正電荷。有利者為烷基甜菜鹼、烷基醯胺基丙基甜菜鹼及烷基醯胺基丙基羥基磺基甜菜鹼。根據發明使用之陽離子界面活性劑可額外較佳選自以下組群：四級銨化合物，特別是苄基三烷基氯化銨或溴化銨(例如苄基二甲基硬脂基氯化銨)、及亦烷基三烷基銨鹽(例如鯨蠟基三甲基氯化銨或溴化銨)、烷基二甲基羥乙基氯化銨或溴化銨、二烷基二甲基氯化銨或溴化銨、烷基醯胺基乙基三甲基銨醚硫酸鹽、烷基吡啶鎓鹽(例如月桂基氯化吡啶或鯨蠟基氯化吡啶)、咪唑啉衍生物及具有陽離子特性之化合物，例如氧化胺，例如烷基二甲基氧化胺或烷基胺基乙基二甲基氧化胺。特別有利者係使用鯨蠟基三甲基銨鹽。
根據發明，離子界面活性劑可有利選自兩性界面活性劑組群。
可有利使用之兩性界面活性劑為：醯基乙二胺或二烷基乙二胺，例如醯基兩性乙酸鈉、醯基兩性二丙酸二鈉、烷基兩性二乙酸二鈉、醯
基兩性羥丙基磺酸鈉、醯基兩性二乙酸二鈉及醯基兩性丙酸鈉，及亦N-烷基胺基酸，例如胺基丙基烷基麩醯胺、烷基胺基丙酸、烷基亞胺基二丙酸鈉及月桂兩性羧基甘胺酸鹽。
特佳為界面活性劑者給予十二烷基硫酸鈉(SDS)、多庫酯鈉(sodium docusate)、油酸鈉及/或去氧膽酸鈉。
在進一步實施例中，活性物質與聚合物係以相對重量比率
1：4至
9：1(較佳
1：3至
3：1)存在。
在進一步實施例中，聚合物與界面活性劑係以相對重量比率
10：1至
300：1(較佳
20：1至
70：1)存在。
發明進一步態樣為藥物配製物，包括塗有至少部分水溶性聚合物之微粒狀藥物活性物質，該微粒狀藥物活性物質係以粒徑分佈具有d90值
1μm(基於體積；根據ISO 13320：2009由雷射繞射測定)之顆粒形式存在，相同活性物質額外以非晶質形式分散於聚合物中，且活性物質於聚合物中之總比例大於在20℃下可溶於聚合物之活性物質的量。
配製物可由根據發明方法獲得。因此，以上闡述方法之定義及實施例亦適用於配製物。聚合物中存在活性物質之非晶質分散液可由X射線粉末繞射測定法(XRPD；Cu-K α 輻射)，基於缺乏結晶質活性物質之反射來鑑定。聚合物進一步含有離子界面活性劑之實體化值得特別提及。
發明進一步有關一種製造藥物配製物懸浮液之方法，包括將根據發明配製物懸浮於懸浮媒質之步驟。乾燥後活性物質含量可為
50重量%、較佳
60重量%，基於乾燥物質總重。懸浮媒質較佳為水性懸浮媒質。進一步較佳使用無進一步添加劑之水。
發明同樣有關一種藉由根據發明方法可獲得之藥物活性物質懸浮液。
藉由以下實施例及圖示詳細闡明本發明，但不限於此。縮寫「重量%」意指重量百分比，並基於水性懸浮液總重。PVP K12為具有Fikentscher K值(DIN EN ISO 1628-1)12之聚乙烯基吡咯烷酮。SDS為十二烷基硫酸鈉。
KVA 64為Kollidon® VA64，乙烯基吡咯烷酮-乙酸乙烯酯共聚物。藉由傅立葉轉換紅外光譜儀(FTIR)及X射線粉末繞射儀(XRPD)進行儀器分析。
根據DIN EN ISO 11357-2，藉由動態微差掃描熱量法(動態DSC)，以10K/min加熱率決定PVP K12及KVA 64之玻璃轉移溫度Tg。針對PVP K12，Tg為107℃，針對KVA 64，Tg為101℃。
實施例1：吲哚美洒辛(indomethacin)-PVP K12系統
使用行星式球磨機(Fritsch Pulverisette 5)製備奈米懸浮液。為此，用6重量% PVP K12及0.1重量% SDS穩定10重量%吲哚美辛(indomethacin)。分別製備與溶解聚合物-界面活性劑溶液。然後將溶液與吲哚美辛粉末混合，並將所得懸浮液於攪拌板上均質化。用0.4至0.6mm研磨珠(SiLibeads，氧化鋯，經釔穩定)填充60%(按體積計)研磨室，並用懸浮液填充剩餘體積，注意排除氣泡。在400rpm研磨1小時30分鐘後，呈現可用於乾燥且含有d90<500nm顆粒(Malvern，Mastersizer 2000)之奈米懸浮液。
為了冷凍乾燥，在3ml小瓶填充0.7g懸浮液(填充水平<1cm)，置入預先冷卻至-40℃之冷凍乾燥器，並乾燥。然後將所得含有活性物質奈米顆粒之粉末用於製造混成系統。
然後將含有活性物質奈米顆粒之粉末(活性物質含>60重量%活性物質，PVP K12，SDS)在約100℃烘烤持續高達4小時。此提供由非晶質固體溶液及精細分散結晶相兩者組成之非晶質-結晶質混成系統。由XRPD及FTIR測量證明混合系統。
圖1顯示非晶質及結晶質吲哚美洒辛(IMC)，含有吲哚美洒辛奈米顆粒的熱平衡粉末(IMC：PVP K12：SDS)及未熱平衡之含有奈米顆粒的粉末之FTIR光譜。圖2顯示含有吲哚美洒辛奈米顆粒的熱平衡粉末及未熱平衡之含有吲哚美洒辛奈米顆粒的粉末之XRP繞射圖案。
檢查純非晶質與純結晶質活性物質之FTIR光譜清楚顯示，在994cm-1波峰為非晶質吲哚美洒辛特徵，在904cm-1波峰為結晶質吲哚美洒辛特徵。
若比較熱平衡樣品與無熱平衡樣品，從圖1可見熱平衡後存在非晶質與結晶質部分兩者。再者，從圖2可見在熱平衡樣品中非晶質與結晶質部分皆存在，而結晶質形式不受影響。
實施例2：吲哚美辛(Indometacin)-KVA 64系統
以類似實施例1的方式製備含有奈米顆粒之粉末，不同處在於使用KVA 64代替PVP K12。
然後將含有活性物質奈米顆粒之粉末(活性物質含>60重量%活性物質，KVA 64(<40重量%)，SDS)在約100℃烘烤。此提供由非晶質固體溶液及精細分散結晶相兩者組成之非晶質-結晶質混成系統。由XRPD及FTIR測量證明混合系統。
圖3顯示非晶質及結晶質吲哚美洒辛(IMC)，含有吲哚美洒辛奈米顆粒的熱平衡粉末(IMC：KVA 64：SDS)及未熱平衡之含有奈米顆粒的粉末的FTIR光譜。圖4顯示含有吲哚美洒辛奈米顆粒的熱平衡粉末及未熱平衡之含有吲哚美洒辛奈米顆粒的粉末之XRP繞射圖案。
檢查純非晶質與純結晶質活性物質之FTIR光譜清楚顯示，在994cm-1波峰為非晶質吲哚美洒辛特徵，在904cm-1波峰為結晶質吲哚美洒辛特徵。若比較熱平衡樣品與無熱平衡樣品，從圖3可見熱平衡後非晶質與結晶質部分皆存在。再者，從圖4可見在熱平衡的樣品中非晶質與結晶質部分皆存在，而結晶質形式不受影響。
圖5顯示根據發明方法之圖示代表，其中提供至少部分水溶性聚合物如PVP K12或KVA 64之顆粒100，其中藥物活性物質係以複數個奈米結晶質顆粒200形式存在。適合活性物質特別是吲哚美洒辛或萘普生(naproxen)。
接近聚合物玻璃轉移溫度Tg之溫度△T增加造成活性物質部分溶於聚合物。此由中間圖片中顆粒200上的彎曲箭頭指示。
底部圖片描述由方法可獲得之發明藥物配製物。除了活性物質奈米顆粒200外，聚合物110中存在溶解的活性物質。此可特徵化為單分子分離活性物質或「固體分散體」。
圖6為圖5代表之變化，其中僅單一活性物質奈米顆粒存在於聚合物100、110。此圖5及6描述不一定是相同標規。
100:聚合物顆粒
110:聚合物
200:奈米顆粒
100:聚合物顆粒
110:聚合物
200:奈米顆粒
Claims (15)
- 一種製造藥物配製物之方法，該藥物配製物係呈由非晶質固體溶液與結晶質奈米顆粒混合組成的混成系統形式，其包括以下步驟：A)提供聚合物顆粒，其中藥物活性物質的顆粒額外至少部分嵌入該聚合物顆粒中；B)將該聚合物顆粒加熱至預定溫度長達預定時間；C)在預定時間後將該聚合物顆粒冷卻至18℃至24℃的溫度，以產生呈由非晶質固體溶液與結晶質奈米顆粒混合組成的混成系統形式的藥物配製物，其中該聚合物至少部分溶於水，且該活性物質至少部分溶於該聚合物，特徵在於該微粒狀藥物活性物質係以粒徑分佈(基於體積；根據ISO 13320：2009由雷射繞射測定)具有d90值1μm之顆粒形式存在，
該預定溫度係在低於該聚合物之玻璃轉移溫度(由DSC根據DIN EN ISO 11357-2以10K/min加熱率決定)10K至該活性物質之熔融溫度(由DSC根據DIN EN ISO 11357-2以10K/min加熱率決定)之範圍，且該聚合物中之活性物質總比例大於在預定溫度下可溶於該聚合物之活性物質的量。 - 根據請求項1之方法，其中該預定溫度係在該聚合物之玻璃轉移溫度(由DSC根據DIN EN ISO 11357-2以10K/min加熱率決定)±10K至不高過低於該活性物質之熔融溫度(由DSC根據DIN EN ISO 11357-2以10K/min加熱率決定)10K之範圍。
- 根據請求項1或2之方法，其中步驟B)之預定時間為1秒至
10小時。
- 根據請求項1至3中任一項之方法，其中步驟A)中提供之材料係藉由研磨包括該活性物質顆粒及該聚合物水溶液之懸浮液，然後乾燥而獲得。
- 根據請求項1至4中任一項之方法，其中步驟B)中，從多物質噴嘴之噴嘴霧化(atomize)包括該活性物質顆粒及該聚合物水溶液之懸浮 液，並從多物質噴嘴之另一個噴嘴排出溫度高於預定溫度之氣體，使該懸浮液被乾燥，且經乾燥之材料係被加熱至預定溫度。
- 根據請求項1至5中任一項之方法，其中步驟B)中，從多物質噴嘴之噴嘴霧化包括該活性物質顆粒之懸浮液，並從多物質的噴嘴之另一個噴嘴霧化該聚合物與該活性物質之水溶液，使含有霧化顆粒懸浮液之混合物產生，並從多物質噴嘴之另一個噴嘴另外排出溫度高於預定溫度之氣體，使混合物被乾燥，且經乾燥之材料係被加熱至預定溫度。
- 根據請求項1至6中任一項之方法，其中藥物活性物質選自：環孢素A、環孢素G、雷帕黴素(rapamycin)、他克莫司(tacrolimus)、晶狀去氧史帕胍啉(deoxyspergualin)、黴酚酸嗎啉乙酯(mycophenolate mofetil)、胍立莫司(gusperimus)；乙醯柳酸、伊布洛芬(ibuprofen)、S(+)-伊布洛芬、吲哚美辛(indometacin)、雙氯芬酸(diclofenac)、匹洛西卡(piroxicam)、美洛昔康(meloxicam)、替諾昔康(tenoxicam)、萘普生(naproxen)、可多普洛菲(ketoprofen)、氟比洛芬(flurbiprofen)、芬諾洛芬(fenoprofen)、聯苯乙酸(felbinac)、舒林酸(sulindac)、依托度酸(etodolac)、羥基保泰松(oxyphenbutazone)、保泰松(phenylbutazone)、萘丁美酮(nabumetone)；硝苯地平(nifedipine)、尼托地平(nitrendipine)、尼莫地平(nimodipine)、尼索地平(nisoldipine)、伊拉地平(isradipine)、非洛地平(felodipine)、氨氯地平(amlodipine)、尼伐地平(nilvadipine)、拉西地平(lacidipine)、貝尼地平(benidipine)、樂卡地平(lercanidipine)、呋尼地平(furnidipine)、尼古地平(niguldipine)；α-硫辛酸；胞壁醯二肽或三肽、羅莫肽(romurtide)；維生素A、D、E或F；凡克派丁(vincopectin)、長春新鹼(vincristine)、長春花鹼(vinblastine)、利血平(reserpine)、可待因(codeine)；溴隱亭(bromocriptine)、二氫麥角胺(dihydroergotamine)、二氫麥角鹼(dihydroergocristine)；氯芥苯丁酸(chlorambucil)、依託泊苷(etoposide)、替尼泊苷(teniposide)、艾多昔芬(idoxifene)、他莫司汀(tallimustine)、替洛蒽醌(teloxantrone)、替拉扎明(tirapazamine)、卡折来新(carzelesin)、右尼古地平(dexniguldipine)、茚托利辛(intoplicine)、艾達黴素(idarubicin)、米替福新(miltefosine)、曲磷胺(trofosfamide)、黴法蘭(melphalan)、洛莫司汀(lomustine)、4,5-雙(4-氟苯胺基) 鄰苯二甲醯亞胺；4,5-二苯胺基鄰苯二甲醯亞胺；胸腺托南(thymoctonan)、醋肽铜(prezatide-copper acetate)；紅黴素(erythromycin)、道諾黴素(daunorubicin)、短桿菌素(gramicidin)、阿黴素(doxorubicin)、兩性黴素B(amyhotericin B)、正大黴素(gentamicin)、白黴素(leucomycin)、鏈黴素(streptomycin)、加奈黴素(ganefromycin)、利福克昔(rifamexil)、雷莫拉寧(ramoplanin)、螺旋黴素(spiramycin)；氟康那唑(fluconazole)、酮康唑(ketoconazole)、艾妥可那唑(itraconazole)；啡莫替定(famotidine)、希美替定(cimetidine)、雷尼替丁(ranitidine)、羅沙替丁(roxatidine)、尼扎替丁(nizatidine)、奧美拉唑(omeprazole)：N-[4-甲基-3-(4-吡啶-3-基嘧啶-2-基胺基)苯基]苯甲醯胺、N-苄醯基星形孢菌素(N-benzoylstaurosporine)；BOC-PhecPhe-Val-Phe-嗎啉或其O-[2-(2-甲氧基乙氧基)乙醯氧基]衍生物；N-[4-(5-環戊基氧基羰基胺基-1-甲基吲哚-3-基甲基)-3-甲氧基苄醯基]-2-乙烯基氧基]苯磺醯胺或至少兩種上述活性物質之混合物。
- 根據請求項1至7中任一項之方法，其中該聚合物選自甲基纖維素、羥甲基纖維素、羥乙基纖維素、羥丙基纖維素、羥丁基纖維素、羥乙基甲基纖維素、羥丙基甲基纖維素、羧甲基纖維素、羧甲基纖維素鈉、羧甲基乙基纖維素、羧烷基纖維素酯、澱粉、羧甲基分枝澱粉鈉、聚葡萄胺糖、藻酸、藻酸之鹼金屬鹽及銨鹽、角叉菜膠、半乳甘露聚糖、黃蓍膠、瓊脂、阿拉伯膠、瓜爾膠、三仙膠、聚丙烯酸及其鹽、聚甲基丙烯酸及其鹽、聚乙烯醇、聚乙烯基吡咯烷酮、聚環氧乙烷、聚環氧丙烷、環氧乙烷與環氧丙烷之共聚物、N-乙烯基吡咯烷酮-乙酸乙烯酯共聚物或至少兩種上述聚合物之混合物。
- 根據請求項1至8中任一項之方法，其中該聚合物顆粒額外包含離子界面活性劑。
- 根據請求項1至9中任一項之方法，其中該活性物質與該聚合物係以相對重量比率1：4至
9：1存在。
- 根據請求項8至10中任一項之方法，其中該聚合物與該界面活性劑係以相對重量比率10：1至
300：1存在。
- 一種藥物配製物，其包括以至少部分水溶性聚合物(110)塗佈之微粒狀藥物活性物質，特徵在於該微粒狀藥物活性物質係以粒徑分佈具有d90值1μm之顆粒(200)形式存在，在該聚合物(110)中，相同活性物質亦額外以非晶質形式分散，及
於該聚合物(110)中該活性物質之總比例大於在20℃下可溶於該聚合物(110)之活性物質的量。 - 根據請求項12之配製物，其中該聚合物(110)額外包括離子界面活性劑。
- 一種製造藥物配製物懸浮液之方法，其包括將根據請求項12或13之配製物懸浮於懸浮媒質之步驟。
- 一種藥物活性物質懸浮液，其可藉由根據請求項14之方法獲得。
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