TWI462752B - 包覆疏水性藥物之膠囊粒子製造方法 - Google Patents
包覆疏水性藥物之膠囊粒子製造方法 Download PDFInfo
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Description
本發明係關於一種包覆疏水性藥物之膠囊粒子製造方法,尤指藉由低溫震盪而形成穩定之包覆疏水性藥物之膠囊粒子。
隨著藥物發展趨勢漸漲,藥物攜帶系統的發展需求亦日趨漸增,目前對包覆或攜帶藥物之載體研究,主要著重於解決藥物表面的物理或化學特性,以使其更容易與生物體相容,而促進進行目標病灶之治療。
一般來說疏水性藥物可透過凝膠相分離法、乳化法、氧化還原法等物理或化學方法進行藥物包覆,藉此以增加維持藥物本身效用,延長藥物作用時間以及提高藥物到達目標細胞之目的。
用來包覆疏水性藥物之生物可相容性材料有許多種,例如聚乳酸甘油醇(Poly-(D,L-lactide-co-glycolide,PLGA)、微脂體等,其主要技術係於室溫下,藉由添加界面活性劑以促進疏水性藥物之包覆,最後以過濾方式篩選適當大小的藥物包覆粒子。然而,事實上對於具有溫度敏感性的藥物,室溫下的包覆製程有可能會破壞藥物本身的藥效性,且包覆過程所使用的介面活性劑,亦有可能因為去除不完全而對生物體產生毒性,或者與藥物作用而產生不良的藥理作用。
有鑑於此,目前極需發展一種藥物包覆技術,以解決疏水性藥物之包覆技術問題,在不破壞藥物本身藥理功效下進行藥物包覆,並藉由藥物包覆之量產自動化製程,以利藥性維持並長期保存。
本發明之主要目的係在提供一種包覆疏水性藥物之膠囊粒子製造方法,俾能透過低溫超音波震盪方式,以製造包覆有疏水性藥物之穩定且利於保存之膠囊粒子。
為達成上述目的,本發明係提供一種包覆疏水性藥物之膠囊粒子製造方法,包括步驟:(A)提供含有一生物相容性聚合物以及一疏水性藥物之一有機溶液;(B)將上述有機溶液於3至10℃低溫下攪拌,並以一醇類溶液滴定,以使上述生物相容性聚合物包覆上述疏水性藥物,形成一膠囊微粒;(C)於3至10℃低溫下,超音波震盪此膠囊微粒;(D)過濾此膠囊微粒,以使膠囊微粒之平均粒徑為60-450 nm;(E)冷凍乾燥此膠囊微粒,以達到長期保存之目的。
於上述步驟中,生物相容性聚合物可為美國食品藥物管制局所許可之材料,並無特別限制,較佳係選自由:聚乳酸甘油醇(Poly-(D,L-lactide-co-glycolide,PLGA)、聚乳酸(PLA)、以及聚乙二醇-聚乳酸(PEG-PLA)所組成之群組,更佳係聚乳酸甘油醇(Poly-(D,L-lactide-co-glycolide,PLGA)。另外,上述之輸水性藥物只要具有疏水性特質之藥物即可,較佳為具有疏水性質之一抗癌藥物或小分子抑制劑,更佳
之疏水性藥物係至少一選自由:輝克癒蘇(Phyxol)、J-30、LY 294002及AG490所組成之群組。再則,上述之有機溶液並無特別限制,較佳為酮類溶液,更佳為丙酮溶液。
本發明步驟(B)中之醇類滴定溶液並無特別限制,較佳為乙醇溶液,此外,於上述此步驟中,較佳係於4-6℃之低溫下攪拌,並進行醇類溶液滴定。此外,此步驟滴定過程中,需將欲滴定之溶液保持低攪拌速度,較佳之攪拌速度可為3-10 rpm,更佳為5-6 rpm。在此,藉由低溫攪拌,以穩定疏水藥物本身的藥理特性,避免於包覆過程中發生變質而劣化藥物本身之藥理作用。
於本發明步驟(C)中,較佳係於4-6℃下將步驟(B)之膠囊微粒進行超音波震盪,藉由低溫之超音波震盪,一方面可避免疏水性藥物變質,另一方面可透過超音波震盪以降低並均勻化膠囊粒子之粒徑。
上述本發明步驟(D)中,膠囊微粒較佳之平均粒徑係介於90-350 nm間,更佳係介於100-200 nm間,再佳係介於150-250 nm間。
於本發明步驟(C)中,可更包含一步驟(C1):將含有膠囊微粒之有機溶液加入一無菌超純水(M.Q water)中,並超音波震盪此膠囊微粒;除此之外,另可包含一步驟(C2):移除上述無菌超純水中之上述之有機溶液。在此,移除含膠囊微粒之無菌超純水中的有機溶液之方法無特別限制,可例如透過揮發、透析、稀釋等方式移除。較佳係以透析法移除該無菌超純水中殘留之有機溶液。
再則,於上述本發明步驟(E)中,更包含一步驟(E1):將含有膠囊微粒之無菌超純水溶液置換成一含有蔗糖(sucrose)及膠囊微粒之無菌超純水溶液,藉此以形成等張溶液之外,亦可作為賦形劑。
以上述本發明之方法所製得之包覆有疏水性藥物之膠囊微粒,其包覆率可由下式1計算,其可介於10-90%間,較佳包覆率係介於30-80%間,更佳係介於40-60%間。
[式1]包覆率%=包覆於生物相容性聚合物之藥物量/總藥量
本發明主要係透過於低溫環境且無需使用介面活性劑情況下,配合超音波震盪,進行自動化製程以達到疏水性藥物之包覆,並改變疏水性藥物之表面特性,如親水特性等,本發明之方法可增加疏水性藥物之包覆率(由習知技術20%包覆率上升至50%左右包覆率),透過生物相容性聚合物(例如聚乳酸甘油醇)來包覆疏水性之藥物。以本發明所提供之方法,其包覆之疏水性藥物可具有改善藥物動力學之特性,增加其於血液中的滯留時間,以及增加腫瘤治療劑量之維持時間,並得以改善腫瘤對藥物的抗藥性問題,以於低副作用下,提升藥物的治療效果。此外,於低溫下進行超音波震盪之包覆製程,不但能確保藥物維持之藥性,且可形成具有均勻粒徑之包覆有疏水性藥物之膠囊微粒,更可透過冷凍乾燥,以達到長期常溫保存的功效,待需要時再以適當之等張溶液(如生理食鹽水溶液)回溶使用,同樣能達到預期功效。
以下係藉由具體實施例說明本發明之實施方式,熟習此技藝之人士可由本說明書所揭示之內容輕易地了解本發明之其他優點與功效。此外,本發明亦可藉由其他不同具體實施例加以施行或應用,在不悖離本發明之精神下進行各種修飾與變更。
本實施例係以聚乳酸甘油醇(Poly-(D,L-lactide-co-glycolide,PLGA)之生物相容性聚合物包覆輝克癒蘇(Phyxol)疏水性藥物,形成膠囊微粒之示範實施態樣。
將2.5克PLGA(乳酸(lactide):甘醇酸(glycolide)=50:50,4.5 A,M.W.=66 kDa)以及50 mg輝克癒蘇(Phyxol=pacilitaxel)溶於250 mL添加有機酸之丙酮溶液中後,以200-3000 rpm轉速,於4℃下攪拌5-30分鐘,以形成透明之PLGA/輝克癒蘇/丙酮混合溶液。接著,降低攪拌轉速至5 rpm,並以蠕動幫浦滴定50%乙醇(24 μl/每滴)至上述混合溶液中,同時,利用超音波震盪(最大瞬間功率=2000 W)震盪預成形之PLGA膠囊微粒,以降低膠囊微粒之粒徑,持續滴定乙醇至混合溶液,使其由透明轉變為半透明後,停止滴定並繼續進行低溫超音波震盪15分鐘。接下來,將上述半透明混合溶液快速以針筒(23G針)注入1 L無菌超純水(M.Q.water)中,形成白色膠狀溶液,然後,再將此白色膠
狀溶液維持於4℃超音波震盪環境下30分鐘,以穩定包覆有輝克癒蘇之PLGA膠囊微粒之結構。接著,透過揮發的方式將白色膠狀溶液中的丙酮溶液揮發移除。
將上述白色膠狀的產物,以40 μm孔徑之過濾器過濾去除聚集黏結之膠囊微粒後,測量其膠囊微粒之大小,結果如圖1所示,此粒徑測量結果具有一個波峰,標準差為90.1,膠囊微粒之平均粒徑分布為217.7 nm,,且此膠囊微粒具有負電之表面電荷特性。
為了移除未包覆有疏水性藥物之PLGA、未被包覆之輝克癒蘇、以及混合溶液中之有機酸,因此透過進行TFF系統(tangential flow filtration)滲濾(diafiltration),以去除小於100 nm大小之物質。在完成滲濾後,包覆有輝克癒蘇疏水性藥物之PLGA膠囊微粒之粒徑大小約170 nm,以穿透式電子顯微鏡TEM觀測膠囊微粒之形狀,發現其係呈現如橢圓形等不規則形狀。
為了使包覆於PLGA之輝克癒蘇疏水性藥物更穩定,故將滲濾之白色膠狀溶液溶於5%蔗糖溶液中,再進行冷凍乾燥,待維持冷凍乾燥兩天後,以形成粉狀固體。再欲使用此膠囊微粒之前,可將此粉狀固體回溶於無菌超純水(M.Q.water)或等張溶液中,以供使用。
將實施例1之膠囊微粒回溶,以AS-2肺癌細胞模型檢測其胞外藥理功效,其結果如圖2所示。
本實施例係將AS-2肺癌細胞培養48小時後,加入不同條件之樣品,以觀察細胞存活率。本實施例實驗共分成三組,第一組係僅添加PLGA樣品;第二組係添加無進行包覆之輝克癒蘇(Phyxol)樣品;第三組係添加本發明實施例1之含有輝克癒蘇(Phyxol)之膠囊微粒樣品,且三組實驗添加之樣品濃度皆為0 nM、2.5 nM、12.5 nM、62.5 nM及312.5 nM。由圖2之結果可明顯發現,隨著添加樣品濃度的提升,第一組細胞存活率幾乎維持不變,第二組與第三組細胞存活率皆明顯由100%降低至小於20%,此結果證實本發明之方法不劣化包覆藥物之藥效外,且由本發明之方法所製成之膠囊微粒(即實施例1之膠囊微粒)幾乎具有與原藥物相同藥效,其與與無進行包覆之輝克癒蘇(第二組)藥效幾乎相同。
上述實施例僅係為了方便說明而舉例而已,本發明所主張之權利範圍自應以申請專利範圍所述為準,而非僅限於上述實施例。
圖1係本發明實施例1之膠囊微粒粒徑分布圖。
圖2係本發明實施例2之in-vitro
藥理功效結果圖。
Claims (13)
- 一種包覆疏水性藥物之膠囊粒子製造方法,包括下列步驟:(A)提供含有一生物相容性聚合物以及一疏水性藥物之一有機溶液,其中,生物相容性聚合物係選自由:聚乳酸甘油醇(Poly-(D,L-lactide-co-glycolide,PLGA)、聚乳酸(PLA)、以及聚乙二醇-聚乳酸(PEG-PLA)所組成之群組;(B)將該有機溶液於3至10℃低溫下攪拌,並以一醇類溶液滴定,以使該生物相容性聚合物包覆該疏水性藥物,形成一膠囊微粒;(C)於3至10℃低溫下,超音波震盪該膠囊微粒;(D)過濾該膠囊微粒,以使該膠囊微粒之平均粒徑為60-450nm;以及(E)冷凍乾燥該膠囊微粒。
- 如申請專利範圍第1項所述之製造方法,其中,該疏水性藥物係為一抗癌藥物。
- 如申請專利範圍第2項所述之製造方法,其中,該抗癌藥物係至少一選自由:輝克癒蘇(Phyxol)、J-30、LY 294002及AG490所組成之群組。
- 如申請專利範圍第1項所述之製造方法,其中,該有機溶液係丙酮溶液。
- 如申請專利範圍第1項所述之製造方法,其中,步驟(B)係於4-6℃低溫下攪拌該有機溶液。
- 如申請專利範圍第1項所述之製造方法,其中,該醇類係為一乙醇溶液。
- 如申請專利範圍第1項所述之製造方法,其中,步驟(C)係於4-6℃低溫下,超音波震盪該膠囊微粒。
- 如申請專利範圍第1項所述之製造方法,於步驟(C)中,更包含一步驟(C1):(C1)將含有該膠囊微粒之該有機溶液加入一無菌超純水(M.Q water)中,並超音波震盪該膠囊微粒。
- 如申請專利範圍第8項所述之製造方法,於步驟(C)中,更包含一步驟(C2):(C2)移除該無菌超純水中之該有機溶液。
- 如申請專利範圍第9項所述之製造方法,於步驟(C2)中,係透過透析法移除該無菌超純水中殘留之該有機溶液。
- 如申請專利範圍第1項所述之製造方法,其中,該膠囊微粒之平均粒徑為150-250nm。
- 如申請專利範圍第9項所述之製造方法,步驟(E)更包含一步驟(E1):(E1)將含有該膠囊微粒之該無菌超純水溶液置換成一含有蔗糖(sucrose)及該膠囊微粒之該無菌超純水溶液。
- 如申請專利範圍第1項所述之製造方法,其中,該生物相容性聚合物包覆該疏水性藥物之包覆率為10-90%。
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