TWI697339B - 醫藥製劑 - Google Patents
醫藥製劑 Download PDFInfo
- Publication number
- TWI697339B TWI697339B TW108114949A TW108114949A TWI697339B TW I697339 B TWI697339 B TW I697339B TW 108114949 A TW108114949 A TW 108114949A TW 108114949 A TW108114949 A TW 108114949A TW I697339 B TWI697339 B TW I697339B
- Authority
- TW
- Taiwan
- Prior art keywords
- layer
- pharmaceutically acceptable
- acid
- fimasartan
- amlodipine
- Prior art date
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- 239000000825 pharmaceutical preparation Substances 0.000 title description 6
- AMEROGPZOLAFBN-UHFFFAOYSA-N fimasartan Chemical compound CCCCC1=NC(C)=C(CC(=S)N(C)C)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 AMEROGPZOLAFBN-UHFFFAOYSA-N 0.000 claims abstract description 68
- 229960003489 fimasartan Drugs 0.000 claims abstract description 68
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- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 claims abstract description 54
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Abstract
本發明提供一種包含非馬沙坦(fimasartan)、胺氯地平(amlodipine)及羅素他汀(rosuvastatin)作為有效組分之製劑。本發明提供該製劑,其中各有效組分顯示優異溶解速率及高穩定性,從而顯著增進用藥順從性。
Description
本發明係關於一種含有非馬沙坦(fimasartan)、胺氯地平(amlodipine)及羅素他汀(rosuvastatin)作為有效組分之組合製劑。更特定言之,本發明係關於單位劑型,其含有非馬沙坦、胺氯地平及羅素他汀作為有效組分,顯示優異溶解模式及穩定性,且增強用藥順從性。
針對高血壓,重要的是藉由維持血壓於其正常範圍內而非治療血壓本身來預防冠狀動脈疾病及心血管併發症(諸如危及生命之中風、心機能不全、心肌梗塞等)。因此,更多焦點應放在調整血壓在恆定壓力以下。
一般而言,患有高血壓之患者經常伴有其他類型之心血管疾病(包括高脂血症),因此顯示兩種合併藥物或更多之高處方率。亦要求彼等患者服藥持續長時間段。因此,更多關注應放在選擇治療性藥物。結果,需要同時使用具有不同機理之藥物及減少使用之單一藥物之量而非簡單選擇一種藥物,從而減少由長期使用藥物產生之可能副作用。
已知非馬沙坦係為治療高血壓及其他醫學徵兆開發之血管收縮素II受體拮抗劑(專利註冊號10-1058284)。
已知胺氯地平係為治療高血壓及其他醫學徵兆開發之鈣通道阻斷劑。
羅素他汀為HMG-CoA還原酶抑制劑,其防止HMG-CoA還原成甲羥戊酸,因此顯示降低血脂濃度及膽固醇之效果,使得羅素他汀係用於高脂血症、高膽固醇血症、動脈粥樣硬化及類似者。
針對心血管疾病等(包括高血壓)之更有效治療,可考慮含有具有如上彼此不同機理之非馬沙坦、胺氯地平及羅素他汀全體之組合製劑。然而,於此情況下,可存在問題,因為各自組分之相互干擾對各自活性組分之溶解有影響。特定言之,Kanarb (其在市場上作為非馬沙坦之單藥製劑發佈)顯示在低pH (例如,pH 1.2至1.4)下之低溶解度。然而,若用作與其他藥理學活性組分之組合製劑,則Kanarb可顯示較單藥製劑更低之溶解速率。
該各組分亦具有不同溶解度,因此使其難以將彼等三種組分調配成各自顯示有效溶解模式之此種製劑。因此,單位劑型尚未以含有非馬沙坦、胺氯地平及羅素他汀全體作為有效組分之組合製劑之形式進行商業化。
本發明提供一種製劑,其包含:
第一層,該第一層含有非馬沙坦、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物;及
第二層,該第二層含有羅素他汀、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物,及胺氯地平、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物,
其中該第二層含有經低取代之羥丙基纖維素。
下文中,將更詳細描述本發明。
本發明提供一種製劑,其包含:
第一層,該第一層含有非馬沙坦、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物;及
第二層,該第二層含有羅素他汀、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物,及胺氯地平、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物,
其中該第二層含有經低取代之羥丙基纖維素。
於本發明之製劑中,含有經低取代之羥丙基纖維素之第二層與水接觸後快速溶脹,使得第一層與第二層可立即彼此分離,及因此可各自崩解,同時彼此分離。
結果,該第一層及該第二層在彼此不影響下各自崩解,使得可溶離屬於各層之活性組分。換言之,雖然第一層及第二層之崩解模式彼此不同,但是添加劑(諸如醫藥上可接受之載劑、崩解劑等)或屬於該各層之藥理學活性組分不具有對另一層之崩解模式及溶解之影響。特定言之,可甚至於胃液中於pH 3或更低之酸性狀態中立即分離各層,使得第一層及第二層之各自崩解不具有對另一層之活性組分之崩解及溶解之影響且各組分顯示優異溶解模式。結果,含於本發明製劑中之三種藥理學活性組分可顯示與含有各組分之單藥製劑幾乎相同或相似之溶解模式。
因此,含於本發明之組合製劑之第一層及第二層中之各自組分可以充分有效方式展示各藥理學活性而彼此不干擾;可不造成任何問題,諸如由藥物干擾造成之穩定性下降等;可顯著增強用藥順從性;且可容易投入大量生產。
本發明之製劑亦可顯示優異穩定性及因此維持穩定狀態達長時間段而不具有彼此分離之層。
於本說明書中,該等術語(諸如第一、第二等)僅用於彼此區分各種層、膜、步驟等,但是不意欲指示其順序或指示其重要程度,且彼等層、膜、步驟等之特徵不受限於該等術語(諸如第一、第二等)。因此,該等術語(諸如第一、第二等)於實施方式、實例、申請專利範圍等中可不全部相等使用且只要彼等層、膜、步驟等可藉由該等術語(諸如第一、第二等)彼此區分就足夠。
如本文中所用,術語「醫藥上可接受的」可意指以下者:生理學上可接受;當投與人類時,習知上不造成過敏反應(諸如胃腸道紊亂及頭暈),或隨附其他類似反應;及由熟習此項技術者習知用於製備醫藥製劑中。
如本文中所用,術語「水合物」可意指以下者:其中非馬沙坦、其醫藥上可接受之鹽或其光學異構體;胺氯地平、其醫藥上可接受之鹽或其光學異構體;羅素他汀、其醫藥上可接受之鹽或其光學異構體;或類似者藉助非共價分子間力結合至水且含有化學計量或非化學計量量之水。特定言之,該水合物可含有基於1 mol活性組分計約0.25 mol至約10 mol之莫耳比率之水,更特定言之約0.5 mol、約1 mol、約1.5 mol、約2 mol、約2.5 mol、約3 mol、約5 mol等之水。
如本文中所用,術語「溶劑化物」可意指以下者:其中非馬沙坦、其醫藥上可接受之鹽或其光學異構體;胺氯地平、其醫藥上可接受之鹽或其光學異構體;或羅素他汀、其醫藥上可接受之鹽或其光學異構體藉助分子間力結合至非水溶劑且其可含有化學計量或非化學計量量之溶劑。特定言之,該溶劑化物可含有基於1 mol活性組分計約0.25 mol至約10 mol之莫耳比率之溶劑分子,更特定言之約0.5 mol、約1 mol、約1.5 mol、約2 mol、約2.5 mol、約3 mol、約5 mol等之溶劑分子。
如本文中所用,術語「含有非馬沙坦作為有效組分」可意指「含有非馬沙坦游離鹼、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物」。例如,「含有非馬沙坦作為有效組分之層」係指含有非馬沙坦游離鹼、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物之層,及「含有非馬沙坦之混合物作為有效組分」係指含有非馬沙坦游離鹼、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物之混合物。
如本文中所用,術語「含有胺氯地平作為有效組分」可意指「含有胺氯地平游離鹼、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物」。例如,「含有胺氯地平作為有效組分之層」係指含有胺氯地平游離鹼、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物之層,及「含有胺氯地平之混合物作為有效組分」係指含有胺氯地平游離鹼、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物之混合物。
如本文中所用,術語「含有羅素他汀作為有效組分」可意指「含有羅素他汀游離鹼、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物」。例如,「含有羅素他汀作為有效組分之層」係指含有羅素他汀游離鹼、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物之層,及「含有羅素他汀之混合物作為有效組分」係指含有羅素他汀游離鹼、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物之混合物。
於本發明之示例性實施例中,該製劑可為含有非馬沙坦、羅素他汀及胺氯地平全體作為有效組分之單位劑型。
於本發明之示例性實施例中,該第二層可含有基於該第二層之重量計3至50重量%之量,特定言之5至40重量%之量之經低取代之羥丙基纖維素。若以以上含量之量包含該經低取代之羥丙基纖維素,則第二層之溶脹可迅速進展,使得第一層及第二層可彼此快速分離。因此,即使該第二層較該第一層崩解更快,該第一層不受該第二層之崩解影響,且含於該第一層及第二層中之各活性組分可顯示優異溶解模式。
除此之外,若以以上含量之量包含該經低取代之羥丙基纖維素,則錠劑可維持適宜大小,因此增強患者用藥順從性及促進錠劑壓縮。亦可極佳地維持含於各錠劑中之各組分之含量均勻度,及因此使其經濟上易於實施其大量生產。
於本發明之示例性實施例中,該第一層及第二層可顯示於溶解介質中彼此不同之溶解速率。此時,該溶解介質可為pH 1.2之鹽酸水溶液。
於本發明之示例性實施例中,該第二層可較該第一層於溶解介質中崩解更早,其中該溶解介質可為pH 1.2之鹽酸水溶液。
於本發明之示例性實施例中,該製劑可為錠劑,特定言之雙層錠劑。於本發明之示例性實施例中,該雙層錠劑之第一層可含有非馬沙坦作為有效組分,及該第二層可含有胺氯地平及羅素他汀作為有效組分,使得該第一層之有效組分(即,非馬沙坦)及該第二層之有效組分(即,胺氯地平及羅素他汀)彼此分離而不混合在一起。
一般而言,於雙層錠劑之情況下,具有不同性質之兩層藉助物理力彼此結合。在崩解期間,該兩層於該兩層之間之介面中不彼此分離及移動分開,從而造成含於各層中之組分降低另一層之崩解及溶解的問題。
然而,儘管含有三種組分於一個呈雙層錠劑形式之錠劑中,本發明之製劑可顯示優異溶解模式,使得本發明製劑可顯示與採用所有各自含有非馬沙坦、胺氯地平及羅素他汀之製劑之情況相同或相似之溶解模式及生物可利用率,從而顯著增強患者用藥順從性。
於本發明之示例性實施例中,該第一層可包含含有非馬沙坦作為有效組分之顆粒。該等顆粒可為乾顆粒或濕顆粒,特定言之濕顆粒。
於本發明之示例性實施例中,該第二層可具有於其中混合在一起之羅素他汀、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物;及胺氯地平、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物。
本發明之製劑含有於該第二層中簡單混合之各自組分,但是顯示優異穩定性,其中特定言之,有效組分(即,羅素他汀)可維持穩定狀態達長時間段。同樣,含於第二層中之有效組分不必呈顆粒形式製備,從而導致簡單製備、高生產效率及容易大量生產。
於本發明之示例性實施例中,非馬沙坦之該等醫藥上可接受之鹽可係選自由無機離子鹽、無機酸鹽、有機酸鹽、磺酸鹽、胺基酸鹽及胺鹽組成之群。特定言之,非馬沙坦之此等醫藥上可接受之鹽可為自鈣、鉀、鈉、鎂或類似者製備之無機離子鹽;自鹽酸、硝酸、磷酸、溴酸、碘酸、高氯酸、硫酸或類似者製備之無機酸鹽;自以下製備之有機酸鹽:乙酸、三氟乙酸、檸檬酸、馬來酸、琥珀酸、草酸、苯甲酸、酒石酸、富馬酸、丙酸、乳酸、乙醇酸、葡萄糖酸、半乳糖醛酸、麩胺酸、戊二酸、葡萄糖醛酸、天冬胺酸、抗壞血酸、碳酸、香草酸、扁桃酸、黏酸、撲酸、泛酸或類似者;自甲磺酸、乙磺酸、乙二磺酸、苯磺酸、對甲苯磺酸、樟腦磺酸、萘二磺酸、萘磺酸或類似者製備之磺酸鹽;自甘胺酸、精胺酸、離胺酸或類似者製備之胺基酸鹽;自三甲胺、甲葡胺、三乙胺、氨、吡啶、甲基吡啶、膽鹼或類似者製備之胺鹽;或類似者,但是本發明中意指之鹽之類型不限於彼等所列鹽。特定言之,非馬沙坦之該等醫藥上可接受之鹽可為非馬沙坦鉀、非馬沙坦甲苯磺酸鹽或非馬沙坦氨鹽,更特定言之非馬沙坦鉀鹽。
於本發明之示例性實施例中,該非馬沙坦、其醫藥上可接受之鹽或其光學異構體之水合物可為單水合物或三水合物,特定言之非馬沙坦鉀之單水合物或三水合物,及更特定言之非馬沙坦鉀之三水合物。
於本發明之示例性實施例中,非馬沙坦、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物之每日劑量可為作為非馬沙坦鉀約0.5 mg至約240 mg,特定言之約10 mg至約180 mg,更特定言之約20 mg至約120 mg,及仍更特定言之約30 mg至約60 mg,及例如,可為作為非馬沙坦鉀約30 mg至約60 mg。
於本發明之示例性實施例中,該第二層之胺氯地平可含有胺氯地平、(S)-胺氯地平或(R)-胺氯地平之外消旋體及特定言之可含有胺氯地平或(S)-胺氯地平之外消旋體。
於本發明之示例性實施例中,可含於該第二層中之胺氯地平之醫藥上可接受之鹽可係選自由無機離子鹽、無機酸鹽、有機酸鹽、磺酸鹽、胺基酸鹽及胺鹽組成之群。特定言之,胺氯地平之醫藥上可接受之鹽可為自以下製備者:鹽酸、氫溴酸、硫酸、磷酸、乙酸、馬來酸、富馬酸、乳酸、酒石酸、檸檬酸、葡萄糖酸、苯磺酸、樟腦磺酸或類似者,及更特定言之苯磺酸胺氯地平。
於本發明之示例性實施例中,胺氯地平、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物之每日劑量可為作為胺氯地平約0.1 mg至約20 mg,特定言之約3 mg至約15 mg,及更特定言之約5 mg至約10 mg,及例如,可為作為胺氯地平約5 mg或約10 mg。
於本發明之示例性實施例中,該第二層中之羅素他汀之醫藥上可接受之鹽可係選自由無機離子鹽、無機酸鹽、有機酸鹽、磺酸鹽、胺基酸鹽及胺鹽組成之群。特定言之,該羅素他汀之醫藥上可接受之鹽可為自鈣、鉀、鈉、鎂或類似者製備之無機離子鹽,及更特定言之羅素他汀鈣鹽。
於本發明之示例性實施例中,羅素他汀、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物之每日劑量可為作為羅素他汀約1 mg至約40 mg,特定言之約3 mg至約30 mg,及更特定言之約5 mg至約20 mg,及例如,可為作為羅素他汀約5 mg、約10 mg或約20 mg。
於本發明之示例性實施例中,該製劑可含有以下量之非馬沙坦、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物/單位劑型:作為非馬沙坦鉀約0.5 mg至約240 mg,特定言之約10 mg至約180 mg,更特定言之約20 mg至約120 mg,及仍更特定言之約30 mg至約60 mg,及例如,可含有作為非馬沙坦鉀約30 mg至約60 mg之量。
於本發明之示例性實施例中,該製劑可含有以下量之胺氯地平、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物/單位劑型:作為胺氯地平約0.1 mg至約20 mg,特定言之約3 mg至15 mg,及更特定言之約5 mg至約10 mg,及例如,可含有作為胺氯地平約5 mg或約10 mg之量。
於本發明之示例性實施例中,該製劑可含有以下量之羅素他汀、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物/單位劑型:作為羅素他汀約1 mg至約40 mg,特定言之約3 mg至約30 mg,及更特定言之約5 mg至約20 mg,及例如,可含有作為該羅素他汀約5 mg、約10 mg或約20 mg之量。
於本發明之示例性實施例中,該製劑可一天一次至一天若干次,特定言之一天一次至一天三次,更特定言之一天一次至一天兩次,及仍更特定言之一天一次投與,但是不限於此,且可根據患者之狀態適當調整。
於本發明之示例性實施例中,該製劑可治療或預防心血管疾病,其中該心血管疾病可為高血壓、動脈痙攣、深靜脈、心機能不全、心肥大、腦梗塞、糖尿病、肥胖症、高脂血症、冠狀動脈疾病、慢性穩定性心絞痛、血管痙攣性心絞痛、中風、心肌梗塞、暫時性腦缺血、充血性心臟衰竭、胰島素耐性、葡萄糖耐受性不良、糖尿病前期、2型糖尿病、糖尿病性腎病、血脂異常、認知衰退、癡呆等,特定言之高血壓、動脈痙攣、深靜脈、心肥大、腦梗塞、脂血症、冠狀動脈疾病、慢性穩定性心絞痛、血管痙攣性心絞痛、中風、心肌梗塞、暫時性腦缺血、充血性心臟衰竭等,及更特定言之高血壓、高脂血症等。
於本發明之示例性實施例中,該第一層及第二層還可各自含有醫藥上可接受之添加劑。含於該第一層及該第二層中之醫藥上可接受之添加劑可係彼此相同或不同。
該等醫藥上可接受之添加劑可為載劑、賦形劑、稀釋劑、增量劑、抗氧化劑、穩定劑、溶解助劑、緩衝液、填料、抗凝劑、潤滑劑、崩解劑、潤濕劑、調味劑、乳化劑、懸浮劑、表面活性劑、防腐劑或其混合物。可將該等添加劑調配至製劑中以便藉由選擇含有習知範圍之劑量於其中。
於本發明之示例性實施例中,該第二層可含有穩定劑作為醫藥上可接受之添加劑。
特定言之,該等添加劑可為乳糖、右旋糖、矽酸鈣、玉米澱粉、澱粉乙醇酸鈉、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藻糖醇、麥芽糖醇、澱粉、相思樹橡膠、藻酸鹽、預凝膠澱粉、明膠、磷酸鈣酐、磷酸二氫鈣、磷酸氫鈣、纖維素、甲基纖維素、微晶纖維素、交聯羧甲基纖維素鈉、交聯聚維酮、膠體二氧化矽、聚維酮(povidone)、共聚維酮、聚乙烯吡咯啶酮、羥丙基纖維素、羥丙基甲基纖維素、羥丙基乙基纖維素、羥基苯甲酸甲酯、羥基苯甲酸丙酯、輕質無水矽酸、滑石粉、滑石、硬脂酸、硬脂酸鎂、硬脂酸鈣、氫化蓖麻油、聚乙二醇、膠體化二氧化矽或其混合物,但不限於此。例如,該等添加劑不與含於製劑中作為有效組分之非馬沙坦、羅素他汀或胺氯地平反應且可為不降低製劑穩定性之物質。
更特定言之,用該等添加劑,下列可用作該等穩定劑:甲葡胺、磷酸鈣酐、磷酸二氫鈣、磷酸氫鈣、磷酸三鎂、磷酸三鋁或其混合物,特定言之甲葡胺、磷酸鈣酐、磷酸二氫鈣、磷酸氫鈣或其混合物。於該等添加劑中,下列可用作黏合劑:羥丙基纖維素、羥丙基甲基纖維素、澱粉、明膠、葡萄糖糖漿、聚乙烯吡咯啶酮、聚乙二醇6000、甲基纖維素、乙基纖維素、羧甲基纖維素、其混合物或類似者。用該等添加劑,下列可用作該等崩解劑:澱粉或改質澱粉,諸如澱粉乙醇酸鈉、玉米澱粉、馬鈴薯澱粉、預凝膠澱粉或類似者;黏土,諸如膨潤土、微晶高嶺石、矽酸鎂鋁或類似者;纖維素,諸如微晶纖維素、羧甲基纖維素或類似者;藻素,諸如藻酸鈉、藻酸或類似者;交聯纖維素,諸如交聯羧甲基纖維素鈉等;樹膠,諸如瓜爾膠、黃原膠等;交聯聚合物,諸如交聯聚維酮等;碳酸氫鈉;檸檬酸;或其混合物。作為該等助流劑,可使用下列:硬脂酸鎂、硬脂酸鈣、硬脂酸、硬脂酸富馬酸鈉、聚乙二醇、二氧化矽、其混合物或類似者。作為該等稀釋劑,可使用下列:纖維素、乳糖、澱粉、微晶纖維素、乳糖水合物、葡萄糖、甘露醇、藻酸鹽、鹼土金屬鹽、黏土、聚乙二醇、磷酸二鈣、其混合物或類似者。作為該等溶解助劑,可使用下列:月桂基硫酸鈉、聚氧乙烯脫水山梨糖醇脂肪酸酯(諸如聚山梨醇酯等)、多庫酯鈉、其混合物或類似者。作為該等表面活性劑,可使用下列:月桂基硫酸鈉、克列莫佛(cremophor)、泊洛沙姆(poloxamer)、多庫酯及醫藥上可接受之多庫酯鹽或其混合物等。
於本發明之示例性實施例中,該第一層可含有黏合劑、崩解劑、潤滑劑、稀釋劑、助流劑或其混合物作為醫藥上可接受之添加劑,及該第二層可含有崩解劑、潤滑劑、稀釋劑、助流劑或其混合物作為醫藥上可接受之添加劑(除了經低取代之羥丙基纖維素外)。
根據本發明之示例性實施例,除了經低取代之羥丙基纖維素外,該第二層還可含有各種類型之澱粉、蔗糖、澱粉1500、磷酸氫鈣、山梨糖醇、磷酸鈣、碳酸鈣、甘露醇、乳糖、微晶纖維素或其混合物。特定言之,除了經低取代之羥丙基纖維素外,該第二層還可含有甘露醇、乳糖、微晶纖維素或其混合物,特定言之微晶纖維素。
例如,含有非馬沙坦作為有效組分之第一層可含有交聯羧甲基纖維素鈉、羥丙基纖維素、硬脂酸鎂、微晶纖維素、甘露醇、乳糖、乳糖水合物或其混合物,及含有羅素他汀及胺氯地平作為有效組分之第二層可含有交聯聚維酮、甘露醇、微晶纖維素、乳糖、乳糖水合物、甲葡胺、膠體二氧化矽、硬脂酸鎂或其混合物(除經低取代之羥丙基纖維素以外)。
於本發明之示例性實施例中,除了該第一層及第二層外,該錠劑還可含有外部包衣層。形成該包衣層之方法可適宜選自由熟習此項技術者用於在錠劑層表面上形成膜相包衣層之方法,及可應用諸如流化床塗覆方法、鍋塗覆方法、乾塗覆方法等之方法。該包衣層可含有羥丙基甲基纖維素、乙基纖維素、聚乙酸乙烯酯、聚乙二醇、二氧化鈦、氧化鐵等或在專有名稱下之歐巴代(Opadry)。可(例如)以基於錠劑之總重量計0.5至10.0重量%,特定言之1.0至6.0重量%,及更特定言之2.0至5.0重量%之量包含該包衣層。
一種用於製備根據本發明之製劑之方法包括:
藉由組合非馬沙坦、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物及醫藥上可接受之添加劑製備混合物之第一步驟;
藉由組合羅素他汀、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物;胺氯地平、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物;及醫藥上可接受之添加劑製備混合物之第二步驟;及
將該第一步驟中製備之混合物及該第二步驟中製備之混合物壓縮成錠劑之步驟。
於本發明之示例性實施例中,於該第二步驟中,該等醫藥上可接受之添加劑包括經低取代之羥丙基纖維素。
於本發明之示例性實施例中,該第二步驟中製備之混合物可含有基於該混合物之總重量計約3重量%至約50重量%之量,特定言之約5至40重量%之量之經低取代之羥丙基纖維素。
於本發明之示例性實施例中,該第一步驟可包含製備含有非馬沙坦、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物之顆粒之步驟。特定言之,可藉助濕法製粒或乾法製粒,更特定言之濕法製粒進行該製備顆粒之步驟。
若彼此不矛盾,則於本發明之製劑中提及之物質亦同樣適用於該等製備方法。
本發明提供一種用於治療或預防心血管疾病之醫藥組合物,其包含:
第一層,該第一層含有非馬沙坦作為有效組分;及
第二層,該第二層含有胺氯地平及羅素他汀作為有效組分,
其中該第二層含有經低取代之羥丙基纖維素。
本發明提供一種藉由投與治療上有效量之醫藥組合物預防或治療心血管疾病之方法,該醫藥組合物包含:
第一層,該第一層含有非馬沙坦作為有效組分;及
第二層,該第二層含有胺氯地平及羅素他汀作為有效組分,
其中該第二層含有經低取代之羥丙基纖維素。
本發明提供一種組合物用於預防或治療心血管疾病之用途,該組合物包含:
第一層,該第一層含有非馬沙坦作為有效組分;及
第二層,該第二層含有胺氯地平及羅素他汀作為有效組分,
其中該第二層含有經低取代之羥丙基纖維素。
若彼此不矛盾,則於本發明之製劑中提及之物質亦同樣適用於醫藥組合物、治療方法及治療用途。
有利效應
本發明提供一種含有非馬沙坦、羅素他汀及胺氯地平全體作為有效組分之單位製劑,其中所有三種組分顯示優異溶解速率及穩定性,從而顯著增進用藥順從性,而無干擾現象,儘管該等三種組分含於一種單位劑型中。
本發明之最佳模式
下文中,將經由實例詳細描述本發明以更為理解本發明。然而,僅出於說明本發明之目的提供下列實例,及因此本發明之範圍不限於此。提供本發明之實例以對一般技術者更完整描述本發明。
如該等實例及比較例中所用,非馬沙坦鉀三水合物係購自Boryung Pharmaceutical Co., Ltd.;苯磺酸胺氯地平係購自Dr. Reddy;羅素他汀鈣係購自MSN;甲葡胺係購自Merck;及交聯聚維酮係購自ISP,及本文中使用之該經低取代之羥丙基纖維素為NBD-021 (來自ShinEtsu Co., Ltd.)。
實例 1. (1) 製備含有非馬沙坦作為有效組分之顆粒
藉助下列方法製備含有非馬沙坦作為有效組分之顆粒使得其組分及含量/單位劑型(400 mg)可遵從下表1中所述之彼等。
將非馬沙坦鉀三水合物、微晶纖維素及交聯羧甲基纖維素鈉混合在一起約10分鐘,之後將該混合物進一步放入高速混合器中約3分鐘,從而製備含有非馬沙坦作為有效組分之混合物。
除此之外,將羥丙基纖維素溶解於60 ml經純化之水中,從而製備黏合劑溶液。
將該經製備之黏合劑溶液放入高速混合物中,然後與該含有非馬沙坦作為有效組分之混合物進行濕法製粒,通過20目篩調節大小,及然後乾燥。於乾燥後,向其中添加交聯羧甲基纖維素鈉及於雙錐形混合器中混合約5分鐘,之後向其中添加硬脂酸鎂及進一步混合約5分鐘,從而製備含有非馬沙坦作為有效組分之顆粒。
(2) 製備含有胺氯地平及羅素他汀作為有效組分之混合物
製備實例1中之含有胺氯地平及羅素他汀作為有效組分之混合物使得其含量/單位劑型可遵從下表1中所述之彼等。
首先,向其中放入苯磺酸胺氯地平、羅素他汀鈣、穩定劑(即,甲葡胺)及膠體二氧化矽並混合在一起約5分鐘,及通過30目篩過篩。將所得經過篩之混合物連同微晶纖維素、經低取代之羥丙基纖維素及交聯聚維酮放入雙錐形混合器中,及混合約15分鐘。作為助流劑,向其中添加硬脂酸鎂及進一步混合約5分鐘,從而製備含有胺氯地平及羅素他汀作為有效組分之混合物。
3. 錠劑壓縮
將含有非馬沙坦作為有效組分之顆粒及含有胺氯地平及羅素他汀作為有效組分之混合物各自放入各沖模中,及壓縮以製備雙層錠劑。
藉助多層壓錠機(Piccola雙層壓錠機)製備雙層錠劑,使得該一個雙層錠劑之硬度可達到10至15 kp。藉助脆度測試儀(在25 rpm下100次自由降落)量測此等所得錠劑之脆度。脆度為0.1%或更低,使得該等錠劑之硬度係合理。藉助VARIAN VK200量測硬度。
實例 2.
藉助與以上實例1中所示相同之方法製備雙層錠劑,不同之處在於其組分及含量/單位劑型遵從表1之實例2中所述之彼等。
實例 3.
藉助與以上實例1中所示相同之方法製備雙層錠劑,不同之處在於其組分及含量/單位劑型遵從表1之實例3中所述之彼等。
實例 4.
藉助與以上實例1中所示相同之方法製備雙層錠劑,不同之處在於其組分及含量/單位劑型遵從表1之實例4中所述之彼等。
比較例 1 (1) 含有非馬沙坦作為有效組分之顆粒
製備比較例1中之含有非馬沙坦作為有效組分之顆粒使得其組分及含量/單位劑型(400 mg)可遵從下表2中所述之彼等。
將非馬沙坦鉀三水合物、微晶纖維素及交聯羧甲基纖維素鈉混合在一起約10分鐘,之後將該所得混合物進一步放入高速混合器中約3分鐘,從而製備含有非馬沙坦作為有效組分之混合物。
除此之外,將羥丙基纖維素溶解於60 ml經純化之水中,從而製備黏合劑溶液。
將該經製備之黏合劑溶液放入高速混合物中,然後與該含有非馬沙坦之混合物進行濕法製粒,然後通過20目篩調節大小,及然後乾燥。於乾燥後,向其中添加交聯羧甲基纖維素鈉及於雙錐形混合器中混合約5分鐘,之後向其中添加硬脂酸鎂及進一步混合約5分鐘,從而製備含有非馬沙坦作為有效組分之顆粒。(2) 製備含有胺氯地平及羅素他汀作為有效組分之混合物
製備比較例1中之含有胺氯地平及羅素他汀之混合物使得其組分及含量/單位劑型可遵從下表2中所述之彼等。
向其中放入苯磺酸胺氯地平、羅素他汀鈣、穩定劑(即,甲葡胺)及膠體二氧化矽並混合在一起約5分鐘,從而製備混合物。放入該混合物及通過30目篩過篩。將所得經過篩之混合物連同甘露醇及交聯聚維酮放入雙錐形混合器中,及混合約15分鐘。作為助流劑,向其中添加硬脂酸鎂及進一步混合約5分鐘,從而製備含有胺氯地平及羅素他汀作為有效組分之混合物。
3. 錠劑壓縮
將含有非馬沙坦作為有效組分之顆粒及含有胺氯地平及羅素他汀作為有效組分之混合物各自放入各沖模中,及壓縮以製備雙層錠劑。
藉助雙層壓錠機(Piccola雙層壓錠機)製備雙層錠劑使得該一個經壓製之雙層錠劑之硬度可達到10至15 kp。藉助脆度測試儀(在25 rpm下100次自由降落)量測此等所得錠劑之脆度。脆度為0.1%或更低,使得該等錠劑之硬度係合理。藉助VARIAN VK200量測硬度。
比較例 2
藉助與比較例1中所示相同之方法製備雙層錠劑,不同之處在於使用乳糖代替甘露醇,且不同之處在於含於單位劑型中之組分及含量遵從該表2之比較例2中所述之彼等。
比較例 3
藉助與比較例1中所示相同之方法製備雙層錠劑,不同之處在於使用微晶纖維素代替甘露醇,且不同之處在於含於單位劑型中之組分及含量遵從該表2之比較例3中所述之彼等。
[實驗實例]實例及比較例之錠劑中之各組分之溶解速率
藉助實例1至4、比較例1至3及市售對照藥物(即,Kanarb錠劑、Norvasc錠劑及Crestor錠劑)各者進行溶解測試。溶解測試方法述於表3中。溶解測試結果述於圖1至3中,其指示平均溶解速率。
根據韓國藥典(Korean Pharmacopoeia)之溶解測試方法II (槳法),在與下表3中所述相同之條件下,對含有非馬沙坦、胺氯地平及羅素他汀作為有效組分之組合製劑進行溶解測試,該組合製劑於實例及比較例中製備。為與本發明之組合製劑比較溶解速率,在與本發明之組合製劑相同之條件下,對非馬沙坦之單藥劑產品(即,Boryung Pharmaceutical之「Kanarb 60 mg」),胺氯地平之單藥劑產品(即,Pfizer之「Norvasc 10 mg」)及羅素他汀之單藥劑產品(即,AstraZeneca之「Crestor 20 mg」進行測試。
如該圖1至3中所示,來自實例1至4之錠劑之非馬沙坦、胺氯地平及羅素他汀之溶解幾乎類似於各組分之單藥製劑(即,Kanarb 60 mg,Norvasc及Crestor)之彼等,且各製劑之溶解速率幾乎不存在差異。
因此,可看出本發明之錠劑顯示與單藥製劑相同程度之優異溶解而無各自組分之間的干擾現象,儘管此等錠劑採取組合製劑之形式。
另一方面,根據比較例之錠劑顯示其中所含之有效組分之溶解速率相較於單藥製劑顯著降低。
自該等結果,確定的是三種有效組分具有不同機理之根據本發明之組合製劑之單位劑型顯示優異溶解模式而無彼此干擾現象且顯著改善用藥順從性。
自以上描述,熟習此項技術者將瞭解,本發明可以其他特定形式實踐而不改變其技術範圍或基本特徵。就此而言,應瞭解,上述實例於所有態樣中係說明性且不設計限制本發明。本發明之範圍應解釋為包含源自下述專利申請專利範圍之含義及範圍之所有經修改或改變之形式以及其等效概念而非實施方式。
圖1顯示根據實例之錠劑及根據比較例之錠劑中之非馬沙坦之溶解速率。
圖2顯示根據實例之錠劑及根據比較例之錠劑中之胺氯地平之溶解速率。
圖3顯示根據實例之錠劑及根據比較例之錠劑中之羅素他汀之溶解速率。
於該等圖1至3中,垂直軸指示溶解速率(%)及水平軸指示分鐘。
Claims (5)
- 一種雙層錠劑,其包含:第一層,該第一層含有非馬沙坦(fimasartan)、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物;及第二層,該第二層含有羅素他汀(rosuvastatin)、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物,及胺氯地平(amlodipine)、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物,其中該第二層含有經低取代之羥丙基纖維素。
- 如請求項1之雙層錠劑,其中該第二層包含基於該第二層之重量計3至50重量%之量的經低取代之羥丙基纖維素。
- 如請求項1之雙層錠劑,其中該第二層還包含選自由微晶纖維素、甘露醇及乳糖組成之群之至少一者。
- 如請求項1之雙層錠劑,其中該第二層具有:羅素他汀、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物;及胺氯地平、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物,於其中混合在一起。
- 如請求項1之雙層錠劑,其中該第一層包含含有非馬沙坦、其醫藥上可接受之鹽、其光學異構體、或其水合物或溶劑化物之顆粒。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103156842A (zh) * | 2013-03-08 | 2013-06-19 | 南开大学 | 牛蒡子苷元在制备抗心律失常药物中的新用途 |
WO2017007287A1 (ko) * | 2015-07-08 | 2017-01-12 | 씨제이헬스케어 주식회사 | 암로디핀, 발사르탄 및 로수바스타틴을 포함하는 약학적 조성물 |
US20170027871A1 (en) * | 2013-11-29 | 2017-02-02 | Hanmi Pharm. Co., Ltd. | Pharmaceutical combination formulation comprising amlodipine, losartan and rosuvastatin |
Family Cites Families (7)
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RU2639818C2 (ru) * | 2013-03-14 | 2017-12-22 | Борюн Фармасьютикал Ко., Лтд. | Фармацевтическое комбинированное лекарственное средство |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103156842A (zh) * | 2013-03-08 | 2013-06-19 | 南开大学 | 牛蒡子苷元在制备抗心律失常药物中的新用途 |
US20170027871A1 (en) * | 2013-11-29 | 2017-02-02 | Hanmi Pharm. Co., Ltd. | Pharmaceutical combination formulation comprising amlodipine, losartan and rosuvastatin |
WO2017007287A1 (ko) * | 2015-07-08 | 2017-01-12 | 씨제이헬스케어 주식회사 | 암로디핀, 발사르탄 및 로수바스타틴을 포함하는 약학적 조성물 |
Non-Patent Citations (2)
Title |
---|
Combination of Fimasartan/Amlodipine/Rosuvastatin in Patients With Essential Hypertension and Dyslipidemia (FIRST),https://clinicaltrials.gov/ct2/show//5/17 * |
Combination of Fimasartan/Amlodipine/Rosuvastatin in Patients With Essential Hypertension and Dyslipidemia (FIRST),https://clinicaltrials.gov/ct2/show/NCT03156842,2017/5/17 |
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