TWI651101B - 包含阿托發司他汀(atorvastatin)、厄貝沙坦(irbesartan)及碳酸鎂之雙層複合片劑調配物 - Google Patents
包含阿托發司他汀(atorvastatin)、厄貝沙坦(irbesartan)及碳酸鎂之雙層複合片劑調配物 Download PDFInfo
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- TWI651101B TWI651101B TW102131243A TW102131243A TWI651101B TW I651101 B TWI651101 B TW I651101B TW 102131243 A TW102131243 A TW 102131243A TW 102131243 A TW102131243 A TW 102131243A TW I651101 B TWI651101 B TW I651101B
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- Prior art keywords
- irbesartan
- pharmaceutically acceptable
- layer
- tablet formulation
- acceptable salt
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- 229960002198 irbesartan Drugs 0.000 title claims abstract description 39
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Abstract
本發明係揭示一種雙層複合片劑調配物,包含(a)一包含厄貝沙坦或其藥學上可接受之鹽的第一層;及(b)一以1:4至1:5之重量比包含阿托發司他汀或其藥學上可接受之鹽與碳酸鎂(MgCO3)的第二層;及製備該雙層複合片劑調配物的方法。該雙層複合片劑調配物展現優異的溶離率及生體可用率,可用於高血壓及高膽固醇症的治療。
Description
本發明係有關於一種包含阿托發司他汀(ATORVASTATIN)、厄貝沙坦(IRBESARTAN)及碳酸鎂之雙層複合片劑調配物,其係於生體可用率及溶離率上有所改良。
阿托發司他汀或其藥學上可接受之鹽,係一種選擇性及競爭性的HMG-CoA還原酶抑制劑。尤其,以下式(I)表示的阿托發司他汀鈣(IUPAC學名:[R-(R*,R*)]-2-(4-氟苯基)-β,δ-二羥基-5-(1-甲基乙基)-3-苯基-4-[(苯胺)羰基]-1H-吡咯-1-庚酸鈣(2:1)),會降低血液中低密度脂蛋白膽固醇的濃度,作用如適用於異常血脂症之治療的降血脂劑。另外,阿托發司他汀鈣為人著稱的是降低心血管疾病所致死亡率、以及減少風險族群的中風機率。
厄貝沙坦是一種強效第二型血管收縮素受體拮抗劑,其阻斷第二型血管收縮素(血管收縮之致因)與第二型血管收縮素AT1受體的交互作用以誘使血壓降低。厄貝沙坦選擇性抑制AT1受體,但並不阻斷第二型血管收縮素結合至AT2受體,故能在維持血管擴張活動的同時,抑制內皮細胞生長、血管收縮及組織再生。
國際專利公開案WO 03/011283揭示一種包含阿托發司他汀鈣及苯磺酸氨氯地平(amlodipine besylate)的複合調配物,其中係使用一形成pH 5以上的鹼化劑作為阿托發司他汀鈣的安定劑。在該複合調配物中,係使用碳酸鈣、磷酸二鈣或磷酸三鈣作為鹼化劑。阿托發司他汀或其藥學上可接受之鹽及碳酸鈣使以約1:1至1:4(w/w)的比率使用。根據上述方法,該鹼化劑確保阿托發司他汀安定性的增進。然而,由藥物動力學或臨床觀點,鹼化劑的使用造成需要較大劑量的阿托發司他汀以達所欲療效。
韓國專利早期公開案第2011-126020號說明一種雙層複合片劑調配物,其由包含厄貝沙坦或其藥學上可接受之鹽的第一層、及包含HMG-CoA還原酶抑制劑及一鹼劑
的第二層所構成,該案揭示該鹼劑增進該HMG-CoA還原酶抑制劑的安定性,而CaCO3、MgCO3或其等之混合物可作為該鹼劑。
雖然已知所述鹼劑可安定包含阿托發司他汀的HMG-CoA還原酶抑制劑,但仍需進一步研發以改良使用該鹼劑下HMG-CoA還原酶抑制劑的溶離率或生體可用率。
本發明人已致力改良包含厄貝沙坦及阿托發司他汀之複合調配物的溶離率及生體可用率,並已發現在一特定重量比下碳酸鎂與阿托發司他汀於一層中的共存,在藥物溶離與體內攝取的改良方面發揮了極佳的影響,從而完成本發明。
據此,本發明之一目的在於提供一種包含厄貝沙坦及阿托發司他汀的藥學複合調配物,其展現優異的生體可用率及最適的溶離曲線。
本發明之另一目的在於提供一種用於製造該藥學複合調配物的方法。
根據本發明之一面向,本發明係提供一種雙層複合片劑調配物,包含:(a)一第一層,包含厄貝沙坦或其藥學上可接受之鹽;及(b)一第二層,以1:4至1:5的重量比,包含阿托發司他汀或其藥學上可接受之鹽與碳酸鎂。
根據本發明之另一面向,本發明係提供一種用於
製作該雙層複合片劑調配物的方法,包含:1)形成顆粒,其包含厄貝沙坦或其藥學上可接受之鹽;2)形成顆粒,其包含1:4至1:5之重量比的阿托發司他汀或其藥學上可接受之鹽與碳酸鎂;及3)將在步驟1)所形成的厄貝沙坦顆粒及在步驟2)所形成的阿托發司他汀顆粒壓製成一雙層片劑。
從本發明後述說明並結合隨附圖式,本發明之上述及其他標的及特徵會為顯明,該等圖式係分別顯示:
圖1:比較例1至3及實施例1至3製備的厄貝沙坦-阿托發司他汀雙層片劑以及市售產品(立普妥錠,Lipitor Tab.)的溶離曲線比較。
圖2:比較例1至3及實施例1至3製備的厄貝沙坦-阿托發司他汀雙層片劑以及市售產品(立普妥錠,Lipitor Tab.)的阿托發司他汀10分鐘溶離率比較。
圖3:比較例1至3及實施例1至3製備的厄貝沙坦-阿托發司他汀雙層片劑以及市售產品(立普妥錠,Lipitor Tab.)的血中阿托發司他汀濃度經時曲線比較。
本發明提供一種雙層複合片劑調配物,包含:(a)一第一層,其包含厄貝沙坦或其藥學上可接受之鹽;及(b)一第二層,其包含重量比1:4至1:5阿托發司他汀或其藥學上可接受之鹽與碳酸鎂。
以下提供用於本發明之雙層複合片劑調配物之性質及成分種類的詳細說明。
(i)第一層
根據本發明之雙層複合片劑調配物的第一層,包含厄貝沙坦或其藥學上可接受之鹽。
厄貝沙坦(IUPAC學名:2-丁基-3-({4-[2-(2H-1,2,3,4-四唑-5-基)苯基]苯基}甲基)-1,3-二氮螺環[4.4]壬-1-烯-4-酮)是一種長效型第二型血管收縮素-受體拮抗劑,具有對血管收縮素受體的高度特異性。厄貝沙坦作用於阻障血管收縮素的活動,包括血管收縮、醛固酮的釋出、及水和鈉的再吸收,因此厄貝沙坦適用於治療心血管疾病,特別是如高血壓及心衰竭。厄貝沙坦具有下式(II)之結構,並揭示於美國專利US 5,270,317中。
在本發明中,只是要習於此藝者可輕易獲得者,任何厄貝沙坦之藥學上可接受之鹽均可使用,包括氫氯酸、鈉鹽、鉀鹽、鎂鹽及銨鹽。
根據本發明之第一層中,以該第一層之總重量計,可包含含量從20至80wt%的厄貝沙坦或其藥學上可接受之鹽,而較佳係從50至70wt%之量,對應每單位調配物之範圍從8至600mg的治療上有效量,較佳為從100至200
mg,但並不限於此。
另外,該第一層可進一步包含一藥學上可接受之添加劑。該藥學上可接受的的添加劑可選自於由下述所構成的群組:一水性烯釋劑、一黏結劑、一崩解劑、一潤滑劑、一界面活性劑及其混合物。
在本發明中,該水性稀釋劑可選自於由下列所構成的群組:微晶纖維素、羥丙基纖微素、預糊化澱粉、葡萄糖、蔗糖、乳糖、山梨糖醇、甘露糖醇、半乳糖醇、核糖醇、木糖醇及其混合物,但不限於此。該水性稀釋劑可以從5至50wt%之量而使用,以該第一層之總量計,而較佳係從8至30wt%之量。
在本發明中,該黏結劑可選自於由下列所構成的群組:藻酸、藻酸鈉、羧甲基纖微素鈉、乙基纖微素、羥乙基纖微素、羥丙基纖微素、羥甲基纖微素、甲基纖微素、明膠、聚維酮、澱粉、預糊化澱粉及其混合物,但不限於此。該黏結劑可使用自0.5至10wt%之量,以該第一層之總重量計,而較佳係自2至5wt%之量。
本發明中的該崩解劑係可選自於由下列所構成的群組:藻酸、藻酸鈉、羧甲基纖微素鈉、微晶纖微素、粉末化纖微素、交聯羧甲基纖維素鈉、交聯聚維酮、預糊化澱粉、羥乙酸鈉、澱粉、及其混合物,但不限於此。該崩解劑可使用自0.5至20wt%之量,以該第一層之總重量計,而較佳係自2至10wt%之量。
本發明中,該潤滑劑可選自於由下列所構成的群
組,但不限於此:硬脂酸鈣、甘油單硬脂酸酯、棕櫚酸硬脂酸甘油酯、硬脂酸鎂、月桂硫酸鈉、硬脂醯延胡索酸鈉、硬脂酸鋅、硬脂酸、氫化植物油、聚乙二醇、苯甲酸鈉、滑石、及其混合物。該潤滑劑可使用自0.1至10wt%之量,以該第一層之總重量計,而較佳係自0.5至2wt%之量。
在本發明中,該界面活性劑可選自於由下列所構成的群組:月桂硫酸鈉,泊洛沙姆(poloxamer),聚乙二醇、及其混合物,但不限於此。該界面活性劑可使用自0.5至20wt%之量,以該第一層之總重量計,而較佳係自2至5wt%之量。
(ii)第二層
在本發明之該雙層複合片劑調配物的第二層中,阿托發司他汀或其藥學上可接受之鹽係以自1:4至1:5的重量比與碳酸鎂混合。
阿托發司他汀作用在降低血脂蛋白或血脂濃度,並用於預防或治療高血脂病及動脈硬化症。
任何習於此藝者可輕易獲得的阿托發司他汀之藥學上可接受之鹽,皆可用於本發明中,代表性如鈣鹽、氫氯酸、鈉鹽、鉀鹽、鎂鹽、及銨鹽,而以鈣鹽為佳。阿托發司他汀係以酸酐形式較佳。
在本發明之第二層中,阿托發司他汀或其藥學上可接受之鹽係含自0.5至20wt%之量,以該第二層之總重量計,而較佳係自2至5wt%,對應每單位調配物之範圍從1至80mg的治療上有效量,較佳為從5至50mg,但不限於此。
根據本發明,僅存在於與含阿托發司他汀同一層的碳酸鎂,不僅提高阿托發司他汀的安定性並伴隨阿托發司他汀於溶離率及生體可用率的增進,亦防止阿托發司他汀與厄貝沙坦發生反應。
如前所述,在該第二層中,阿托發司他汀對碳酸鎂的重量比範圍為自1:4至1:5。若該阿托發司他汀對碳酸鎂的重量比低於1:4,則需要較高劑量的阿托發司他汀才能達到治療有效濃度、或所欲療效。另一方面,當阿托發司他汀對碳酸鎂的重量比超過1:5,則溶離曲線或血中濃度沒有觀察到進一步增進。另外,過量的碳酸鎂不利於服藥順從性及生產效率。還有,當重量比遠逾該範圍時,則該固體劑型的Cmax會超過現存市售藥劑(如立普妥錠)的125%,這會造成該調配物視為與現存、市面上可獲得者不同的藥物。若如此,則必須呈送另行實驗而獲得的安全性曲線(safety profile)報告。據此,本發明中,阿托發司他汀對碳酸鎂的重量比較佳係於1:4至1:5之範圍。
另外,該第二層可進一步包含藥學上可接受的添加劑。該藥學上可接受的添加劑可選自於由下列所構成的群組:水性稀釋劑、黏結劑、崩解劑、潤滑劑、及其混合物。
在本發明中,該水性稀釋劑可選自於由下列所構成的群組:微晶纖微素、羥丙基纖微素,預糊化澱粉、葡萄糖、蔗糖、乳糖、山梨糖醇、甘露糖醇、半乳糖醇、核糖醇、木糖醇,及其混合物,但不限於此。該水性稀釋劑
可使用自5至80wt%之量,以該第二層之總重量計,而較佳係自10至50wt%之量。
在本發明中,該黏結劑可選自於由下列所構成的群組,但不限於此:藻酸、藻酸鈉,羧甲基纖微素鈉、乙基纖微素、羥乙基纖微素、羥丙基纖微素、羥甲基纖微素、甲基纖微素,明膠、聚維酮、澱粉、預糊化澱粉,及其混合物。該黏結劑可使用自0.1至5wt%之量,以該第二層之總重量計,以及自0.5至2wt%之量。
本發明中該崩解劑崩解劑可選自於由下列所構成的群組:藻酸、藻酸鈉、羧甲基纖維素鈉、微晶纖微素、粉末化纖微素、交聯羧甲基纖維素鈉、交聯聚維酮、預糊化澱粉、羥乙酸鈉、澱粉、及其混合物,但不限於此。該崩解劑可使用自2至50wt%之量,以該第二層之總重量計,而較佳係自5至20wt%之量。
本發明中,潤滑劑可選自於由下列所構成的群組,但不限於此:硬脂酸鈣、甘油單硬脂酸酯、棕櫚酸硬脂酸甘油酯、硬脂酸鎂、月桂硫酸鈉、硬脂醯延胡索酸鈉、硬脂酸鋅、硬脂酸、氫化植物油、聚乙二醇、苯甲酸鈉、滑石、及其混合物。該潤滑劑可使用自0.1至5wt%之量,以該第二層之總重量計,而較佳係自0.5至2wt%之量。
(iii)雙層片劑
本發明之雙層複合片劑調配物具有雙層結構,其中厄貝沙坦或其藥學上可接受之鹽的顆粒係存在於第一層,而阿托發司他汀或其藥學上可接受之鹽及碳酸鎂之混
合物的顆粒係以1:4至1:5重量比形成第二層,藉此可以盡可能地阻障兩種顆粒的相互接觸,同時改善阿托發司他汀之溶離率及生體可用率。
特別是,特徵在於阿托發司他汀及碳酸鎂以1:4至1:5之重量比共存於該第二層的本發明之雙層複合片劑調配物,能夠免除安定性及溶離率的問題,此等係複合劑型之藥物動力學中最重要的因素。
根據本發明一實施態樣的雙層複合片劑調配物,可在10分鐘內以30%或更高的速率釋放阿托發司他汀,其為溶離曲線上最具區辨性之時間範圍(見圖1及2),在藥效方面其係相似或優於市場可獲得之商品立普妥錠。
本發明之雙層複合片劑調配物可使用一方法製備,其包含以下步驟:1)形成包含厄貝沙坦或其藥學上可接受之鹽的顆粒;2)以1:4至1:5之重量比,形成包含阿托發司他汀或其藥學上可接受之鹽與碳酸鎂的顆粒;及3)使用雙層片劑壓錠機將步驟1)所形成之厄貝沙坦顆粒及步驟2)所形成之阿托發司他汀顆粒壓製成雙層片劑。
本發明之製備方法的步驟可使用傳統方法進行。
在本發明之一實施態樣中,厄貝沙坦或阿托發司他汀之顆粒可依據包含下述步驟的成粒方法來形成:(a)摻混厄貝沙坦或阿托發司他汀與一崩解劑及可擇地部份或全部的用於最終組成物之其他必要添加劑(該添加劑可包含稀釋劑、黏結劑及其他在可處理性、流動性、安定性及單位劑型之形成上必要的藥劑);
(b)添加一成粒溶劑至步驟(a)所形成之摻混物中(較佳的成粒溶劑可為水、乙醇、異丙醇或其等之混合物,而其他習知之成分(如黏結劑、潤濕劑、界面活性劑等)可添加至該成粒溶劑中);(c)乾燥由步驟(b)所獲致之軟材,該乾燥係使用空氣乾燥器、盤式乾燥器、流體化床乾燥器或微波乾燥器(該乾燥方法可在例如40至60℃下進行);(d)碎化或過篩該步驟(c)所獲得的經乾燥物質(使用14至40目的篩網,如30目);以及(e)混合該步驟(d)所獲得的粉末及一添加劑(如潤滑劑)並將該混合物形成為顆粒。
若一新穎複合調配物的AUC或Cmax超過先前存在之市面可獲得之藥劑調配物的125%,則該新穎複合調配物係被認為與該市面可獲得之藥劑調配物在安定性曲線方面並不相同。在此情況下,必須呈送該複合調配物之安定性曲線之報告供獲取許可證的官方核准。然而,提供調配物毒性相關數據的實驗,就時間及財務觀點而言是無效益的。再者,即便為一新穎複合調配物進行額外的臨床試驗,這也不保證該複合調配物的安全性。因此,AUC或Cmax,相較他者,係開發一複合調配物時需考量的重要因素。本發明之雙層複合片劑調配物,其厄貝沙坦及阿托發司他汀係分別侷限於第一及第二層內,該調配物AUC T/R比範圍為自0.85至1.18,在90%的信賴區間下,具有與市面可獲得商品(立普妥錠)相等的Cmax值(見圖3及表5),因而展現相等
於該市面可獲得商品的安全性曲線。
因此,具優異生體可用率及溶離率的本發明之複合調配物,係可使用在對高血壓及高膽固醇的治療。
在下文中進一步詳述本發明。以下實施例僅供例示之目的,非意欲限制本發明之範圍
如表1之組成物所示,厄貝沙坦(韓美精密化學,韓國)係與甘露醇、預糊化澱粉及交聯羧甲基纖維素鈉(DMV國際)摻混,添加液體黏結劑普維酮(BASF,德國)及Poloxamer 188(BASF,德國)於水中並乾燥,然後以30目篩網過篩該軟材以獲得濕顆粒。接著,該濕顆粒係與硬脂酸鎂混合以製備厄貝沙坦顆粒。
依據表2所示數據,阿托發司他汀鈣(TEVA,印度)係與乳糖、微晶纖微素,交聯普維酮(BASF,德國)及碳酸鎂(Tomita,日本)摻混,添加液體黏結劑HPC(日本曹達,日本)及聚山梨醇酯80(Croda,美國)並乾燥,然後以30目篩網過篩該軟材以獲得濕顆粒。接著,該濕顆粒係與硬脂酸鎂混合以製備阿托發司他汀顆粒。
如下表3所示,於製備例1及製備例2-1、2-5或2-6所製備的顆粒,係經結合以製備包含厄貝沙坦及阿托發司他汀的複合調配物。
使用一雙層片劑壓錠機,厄貝沙坦顆粒及阿托發司他汀顆粒係經壓制成雙層片劑,其由每片劑包含150mg厄貝沙坦之第一層及包含10mg阿托發司他汀之第二層所構成。
如下表3所示,於製備例1及製備例2-2、2-3或2-4所製備的顆粒,係經結合以製備包含厄貝沙坦及阿托發司他汀的複合調配物。
使用一雙層片劑壓錠機,厄貝沙坦顆粒及阿托發司他汀顆粒係經壓制成雙層片劑,其由每片劑包含150mg厄貝沙坦之第一層及包含10mg阿托發司他汀之第二層所構成。
於比較例1至3及實施例1至3所製備的雙層片劑,係經試驗阿托發司他汀之溶離率。依據USP溶離率裝置2(漿板法),溶離率測試係使用900mL之溶離液、pH 1.2,同時以25rpm攪拌。在溶離後5、10、15、30、45、60及90分鐘收樣本,並量測阿托發司他汀之溶離率。結果顯示於表1。如圖1所示,觀察到阿托發司他汀的溶離率隨碳酸鎂含量增加而增加。
另外,於比較例1至3及實施例1至3製備之雙層片劑的溶離率數據係顯示於圖2,而t試驗之p值列於下表4。供比較之用,市面可獲得商品立普妥錠係作為對照組。
由該數據可知,實施例1至3所有複合調配物係經證實在溶離率方面實質上同等於對照組,具5%之有效性認為其溶離率與對照組相似,於10分鐘內的時間點(最具區辨性之時間範圍),p值0.05。另一方面,比較例1至3所有複合調配物係證實與對照組有顯著不同,p值<0.05。在圖2中,具顯著不同的調配物係以星號(*)指示。
為評估比較例1至3及實施例1至3所製備之雙層片劑的阿托發司他汀生體可用率,該經製備之調配物係投
予米格魯犬以監測血中阿托發司他汀濃度。供比較之用,市面可獲得商品立普妥錠(輝端)係使用為對照組。
共28隻米格魯犬被分為4隻7組。該片劑經碎化並分散於0.5%羧甲基纖微素(CMC)中,以對應於10mg/kg阿托發司他汀之劑量口服投藥予該米格魯犬。血中阿托發司他汀濃度係於投藥後經時量測並就阿托發司他汀之藥物動力學參數作分析。結果顯示於圖3及表5。
由圖3及表5之數據可顯知,實施例1至3之複合調配物在AUC T/R比率係於自0.85至1.18之範圍,在90%之信賴區間下,具有同等於市面可獲得商品(立普妥錠)之Cmax值。
Claims (7)
- 一種雙層複合片劑調配物,其包含:(a)一第一層,其包含厄貝沙坦或其藥學上可接受之鹽;及(b)一第二層,其包含重量比為1:4至1:5的阿托發司他汀或其藥學上可接受之鹽與碳酸鎂。
- 如請求項1之雙層複合片劑調配物,其中該阿托發司他汀係呈酸酐形式。
- 如請求項1之雙層複合片劑調配物,其中該厄貝沙坦或其藥學上可接受之鹽係以每單位調配物自8mg至600mg的量被包含其中。
- 如請求項1之雙層複合片劑調配物,其中該阿托發司他汀或其藥學上可接受之鹽係以每單位調配物自1mg至80mg的量被包含其中。
- 如請求項1之雙層複合片劑調配物,其中該第一層進一步包含一藥學上可接受的添加劑,該添加劑係選自於由水性稀釋劑、黏結劑、崩解劑、潤滑劑、界面活性劑及其等之混合物所構成之群組。
- 如請求項1之雙層複合片劑調配物,其中該第二層進一步包含一藥學上可接受的添加劑,該添加劑係選自於由水性稀釋劑、黏結劑、崩解劑、潤滑劑及其等之混合物所構成之群組。
- 一種用於製備如請求項1之雙層複合片劑調配物的方法,其包含下列步驟:1)形成包含厄貝沙坦或其藥學上可接受之鹽的顆粒;2)形成包含阿托發司他汀或其藥學上可接受之鹽與碳酸鎂重量比為1:4至1:5的顆粒;以及3)將步驟1)所形成之厄貝沙坦顆粒及步驟2)所形成之阿托發司他汀顆粒壓製成一雙層片劑。
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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TW201200166A (en) * | 2010-05-14 | 2012-01-01 | Hanmi Holdings Co Ltd | Pharmaceutical formulation in the form of bilayered tablets comprising HMG-CoA reductase inhibitor and irbesartan |
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