TWI733299B - 普加巴林的持續-釋放配方 - Google Patents
普加巴林的持續-釋放配方 Download PDFInfo
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- TWI733299B TWI733299B TW109100420A TW109100420A TWI733299B TW I733299 B TWI733299 B TW I733299B TW 109100420 A TW109100420 A TW 109100420A TW 109100420 A TW109100420 A TW 109100420A TW I733299 B TWI733299 B TW I733299B
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- sustained
- pregabalin
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Abstract
本發明揭示一種持續-釋放配方,以該配方的總重量為基礎,其包含有:呈一數量落在5%至40%之範圍內的普加巴林,或者它的一藥學上可接受的鹽類、溶劑合物或水合物;呈一數量落在0.1%至5%之範圍內的卡波姆;以及呈一數量落在20%至60%之範圍內的聚氧化乙烯;其中,該配方不含有聚乙酸乙烯酯。
Description
本發明是有關於一種持續-釋放配方(sustained-release formulation),以該配方的總重量為基礎,其包含有:呈一數量落在5%至40%之範圍內的普加巴林(pregabalin),或者它的一藥學上可接受的鹽類、溶劑合物或水合物;呈一數量落在0.1%至5%之範圍內的卡波姆(carbomer);以及呈一數量落在20%至60%之範圍內的聚氧化乙烯(polyethylene oxide);其中,該配方不含有聚乙酸乙烯酯(polyvinyl acetate)。
普加巴林(pregabalin){化學名稱為(S)-(+)-3-氨甲基-5-甲基己酸[(S)-(+)-3-aminomethyl-5-methylhexanoic acid]}是一種γ-胺基丁酸(γ-aminobutyric acid, GABA)的類似物(analog),它會結合至中樞神經系統(central nerve system)中的突觸前鈣離子通道(presynaptic calcium channel)的α2-δ單元(α2-δ subunit)以降低在神經末梢處的鈣離子內流(calcium influx),而鈣離子內流的降低會減少興奮性神經傳導物(excitatory neurotransmitters)的釋出,進而使得神經細胞的功能能夠回復到正常位準。
普加巴林具有抗癲癇活性(anti-seizure activity)並且可供用於治療各種不同的神經性疾病(neurological diseases)[例如,神經性病變疼痛(neuropathic pain)、癲癇(epilepsy)、纖維肌痛(fibromyalgia)、杭丁頓氏舞蹈症(Huntington's chorea)、大腦缺血(cerebral ischemia)以及巴金森氏症(Parkinson's disease)等]。目前市售的普加巴林係呈立即-釋放硬殼膠囊(immediate-release hard shell capsules)的劑型(商品名為Lyrica
®),該膠囊以每日二或三次的方式而被投藥給病患。然而,每日投藥二或三次會對病患造成不便,特別是,當病患需要長時間服藥或大量服藥時,這種多次給藥(multiple administrations)的方式會降低病患的藥物順從性(drug compliance)。因此,本領域的相關研究人員皆致力於發展出新穎的普加巴林持續-釋放配方(sustained-release formulation of pregabalin)以供用於每日一次投藥(once-daily administration)。
US 9144559 B2揭示一種供用於每日一次投藥的藥學組成物,其包含有普加巴林、基質形成劑(matrix forming agent)以及膨脹劑(swelling agent),其中該基質形成劑包括聚乙酸乙烯酯(polyvinyl acetate, PVAc)以及聚乙烯吡咯烷酮(polyvinylpyrrolidone, PVP),該膨脹劑包括交聯的聚乙烯吡咯烷酮(crosslinked polyvinylpyrrolidone, PVPP)。特別是,US 9144559 B2教示該基質形成劑能賦予固態劑型結構完整性並有助於控制或延緩藥物的釋放速率。另外,除了該基質形成劑以及該膨脹劑之外,該藥學組成物可選擇性地包含一膠凝劑(gelling agent),其可延長藥物從劑型中釋出的時間。適用的膠凝劑包括卡波姆(carbomers)[諸如卡伯波(carbopol)]、多醣[諸如羥乙基纖維素(hydroxyethyl cellulose)],或此等之組合。US 9144559 B2的實施例24係為含有卡伯波(Carbopol
®71G)的藥學組成物,實施例25係為含有羥乙基纖維素(Natrosol
®250)的藥學組成物,從表11的溶離試驗(dissolution test)結果可見,實施例24的藥學組成物在開始進行溶離試驗之後的第20小時,普加巴林的溶出百分比為102.7%,而實施例25的藥學組成物在開始進行溶離試驗之後的第24小時,普加巴林的溶出百分比才會達至99.3%。
在本發明中,申請人嘗試提供一種新穎的普加巴林持續-釋放配方,特別地,該配方含有普加巴林、卡波姆以及聚氧化乙烯(polyethylene oxide, PEO),但是不含有PVAc。申請人進一步經由實驗證實,該配方能夠有效地延緩普加巴林的釋出,因而可供用於每日一次投藥。
發明概要
於是,本發明提供一種持續-釋放配方(sustained-release formulation),以該配方的總重量為基礎,其包含有:
呈一數量落在5%至40%之範圍內的普加巴林(pregabalin),或者它的一藥學上可接受的鹽類、溶劑合物或水合物;
呈一數量落在0.1%至5%之範圍內的卡波姆(carbomer);以及
呈一數量落在20%至60%之範圍內的聚氧化乙烯(polyethylene oxide);
其中,該配方不含有聚乙酸乙烯酯(polyvinyl acetate)。
發明的詳細說明
要被瞭解的是:若有任何一件前案刊物在此被引述,該前案刊物不構成一個下述承認:在台灣或任何其他國家之中,該前案刊物形成本技藝中的常見一般知識之一部分。
為了這本說明書之目的,將被清楚地瞭解的是:文字“包含有(comprising)”意指“包含但不限於”,以及文字“包括(comprises)”具有一對應的意義。
除非另外有所定義,在本文中所使用的所有技術性與科學術語具有熟悉本發明所屬技藝的人士所共同瞭解的意義。一熟悉本技藝者會認知到許多與那些被描述於本文中者相似或等效的方法和材料,它們可被用於實施本發明。當然,本發明決不受到所描述的方法和材料之限制。
除非另外有所定義,在本文中所使用的任何百分比(percentages)(%)皆意指重量百分比(percentages by weight)。
在開發普加巴林的持續-釋放配方(sustained-release formulation of pregabalin)上,申請人經由實驗而發現到,一含有普加巴林、卡波姆(carbomer)以及聚氧化乙烯(polyethylene oxide, PEO)的配方能夠有效地延緩普加巴林的釋出,特別是,該配方不含有聚乙酸乙烯酯(polyvinyl acetate, PVAc)。該配方被預期可供用於每日一次投藥(once-daily administration)。
於是,本發明提供一種持續-釋放配方,以該配方的總重量為基礎,其包含有:
呈一數量落在5%至40%之範圍內的普加巴林,或者它的一藥學上可接受的鹽類、溶劑合物(solvate)或水合物(hydrate);
呈一數量落在0.1%至5%之範圍內的卡波姆;以及
呈一數量落在20%至60%之範圍內的PEO;
其中,該配方不含有PVAc。
依據本發明,卡波姆可選自於由下列所構成的群組:Acrypol
®、Acritamer
®、Carbopol
®、Pemulen
®,以及它們的組合。較佳地,卡波姆是選自於由下列所構成的群組:Acrypol
®974P、Acrypol
®934P、Acrypol
®971P,以及它們的組合。在本發明的一個較佳具體例中,該卡波姆是Acrypol
®974P。
如本文中所使用的,術語“持續-釋放配方(sustained-release formulation)”與“控制-釋放配方(controlled-release formulation)”可被交換地使用,並且意指任何可藉由在一段延長的期間內逐漸釋放藥物,而使得該藥物在血中維持恆定位準(constant levels)的配方。較佳地,該持續-釋放配方可在至少12至24小時的期間內逐漸釋放藥物。在本發明的一個較佳具體例中,該持續-釋放配方會在至少24小時的期間內逐漸釋放藥物。
依據本發明,以該配方的總重量為基礎,該配方進一步包含有:
呈一數量落在5%至60%之範圍內的稀釋劑(diluent);
呈一數量落在1%至10%之範圍內的黏合劑(binder);
呈一數量落在0.01%至2%之範圍內的抗氧化劑(antioxidant);以及
呈一數量落在0.1%至5%之範圍內的潤滑劑(lubricant)。
較佳地,該稀釋劑是選自於由下列所構成的群組:澱粉、微晶型纖維素(microcrystalline cellulose)、無水磷酸氫鈣(anhydrous dicalcium phosphate)、右旋糖(dextrose)、乳糖(lactose)、蔗糖(sucrose)、甘露醇(mannitol)、木糖醇(xylitol)、山梨糖醇(sorbitol),以及它們的組合。
較佳地,該黏合劑是選自於由下列所構成的群組:聚乙烯吡咯烷酮(polyvinylpyrrolidone, PVP)、共聚維酮(copovidone)、羥丙纖維素(hydroxypropyl cellulose)、羥丙基甲基纖維素(hydroxypropylmethyl cellulose)、羥乙基纖維素(hydroxyethyl cellulose)、甲基纖維素(methylcellulose),以及它們的組合。
較佳地,該抗氧化劑是選自於由下列所構成的群組:二丁基羥基甲苯(butylated hydroxytoluene, BHT)、丁基羥基甲氧苯(butylated hydroxyanisole, BHA)、抗壞血酸(ascorbic acid)、五倍子酸丙酯(propyl gallate),以及它們的組合。
較佳地,該潤滑劑是選自於由下列所構成的群組:硬脂酸(stearic acid)、硬脂酸鎂(magnesium stearate)、硬脂酸鈣(calcium stearate)、硬脂酸鋅(zinc stearate)、甘油單硬脂酸酯(glyceryl monostearate)、硬脂醯延胡索酸鈉(sodium stearyl fumarate)、甘油二十二烷酸酯(glyceryl behenate),以及它們的組合。
依據本發明,該配方可進一步包含有其他被廣泛地使用於藥物製造技術之藥學上可接受的載劑(pharmaceutically acceptable carrier)。例如,該藥學上可接受的載劑可包含一或多種選自於下列的試劑:溶劑(solvent)、緩衝液(buffer)、乳化劑(emulsifier)、懸浮劑(suspending agent)、分解劑(decomposer)、崩解劑(disintegrating agent)、分散劑(dispersing agent)、安定劑(stabilizing agent)、螯合劑(chelating agent)、膠凝劑(gelling agent)、防腐劑(preservative)、潤濕劑(wetting agent)、吸收延遲劑(absorption delaying agent)、脂質體(liposome)以及類似之物。有關這些試劑的選用與數量是落在熟習此項技術之人士的專業素養與例行技術範疇內。
在本發明的一個較佳具體例中,以該配方的總重量為基礎,該配方包含有29.5%普加巴林、0.4%卡波姆、20% PEO、13.9%澱粉、32.5%微晶型纖維素、2.7% PVP、0.1% BHT以及0.9%硬脂酸鎂。
在本發明的另一個較佳具體例中,以該配方的總重量為基礎,該配方包含有29.5%普加巴林、0.4%卡波姆、40% PEO、7.9%澱粉、18.5%微晶型纖維素、2.7% PVP、0.1% BHT以及0.9%硬脂酸鎂。
在本發明的又另一個較佳具體例中,以該配方的總重量為基礎,該配方包含有29.5%普加巴林、0.4%卡波姆、60% PEO、1.9%澱粉、4.5%微晶型纖維素、2.7% PVP、0.1% BHT以及0.9%硬脂酸鎂。
依據本發明,該配方可利用熟習此技藝者所詳知的技術而被製造成一適合於口服投藥(oral administration)之劑型(dosage form),這包括,但不限於:錠劑(tablet)、口含錠(lozenge)、丸劑(pellet)以及膠囊(capsule)。在本發明的一個較佳具體例中,該劑型是錠劑。
較佳實施例之詳細說明
本發明將就下面的實施例來做進一步說明,但應瞭解的是,該等實施例僅是供例示說明用,而不應被解釋為本發明的實施上的限制。
實施例 一般實驗材料: 1. 下面表1顯示供用於製備出本發明的普加巴林持續-釋放配方(sustained-release formulation of pregabalin)的組分及其來源。
表1. 本發明的普加巴林持續-釋放配方的組分及其來源
實施例1. 製備本發明的 普加巴林 錠劑 (pregabalin tablet)
組分 | 購買來源 |
普加巴林(pregabalin) | MSN Pharmaceuticals Inc. |
澱粉(starch) (商品名為Starch 1500 ®) | Colorcon Inc. |
卡波姆(carbomer) (商品名為Acrypol ®974P) | Corel Pharma Chem |
微晶型纖維素(microcrystalline cellulose) (商品名為Comprecel M101D+ ®) | Mingtai Chemical Co., Ltd. |
聚乙烯吡咯烷酮(polyvinylpyrrolidone, PVP) (商品名為Povidone K‐30 ®) | Anhui Sunhere Pharmaceutical Excipients Co., Ltd. |
二丁基羥基甲苯(butylated hydroxytoluene, BHT) | Spectrum Chemical |
聚氧化乙烯(polyethylene oxide, PEO) (商品名為Polyox WSR 303) | Dow Chemical |
硬脂酸鎂(magnesium stearate) | Sigma-Aldrich |
在本實施例中,申請人依據下面表2中所示配方來製備3種含有普加巴林的錠劑(亦即錠劑1至錠劑3)。
表2. 本發明的普加巴林錠劑的配方實例
組分 | 錠劑1 | 錠劑2 | 錠劑3 |
含量(mg/錠劑) | |||
普加巴林 | 330 | 330 | 330 |
澱粉 | 156 | 88.5 | 21.6 |
卡波姆 | 5 | 5 | 5 |
微晶型纖維素 | 364 | 207.5 | 50.4 |
PVP | 30 | 30 | 30 |
BHT | 1 | 1 | 1 |
PEO | 224 | 448 | 672 |
硬脂酸鎂 | 10 | 10 | 10 |
每個錠劑重量為1120 mg |
有關錠劑1至錠劑3的製備方法是依照下面所示的步驟而被進行:首先,將普加巴林與澱粉、卡波姆、微晶型纖維素、PVP以及BHT充分混合製粒,而形成含有普加巴林的顆粒。之後,所得到的顆粒被混合以PEO以及硬脂酸鎂,繼而使用一混合器(mixer)來進行混合,而得到一最終混合物。該最終混合物接而被壓製成錠劑。
實施例2. 本發明的 普加巴林錠劑 的活體外溶離試驗(
in vitrodissolution test)
為了探討本發明的普加巴林錠劑在延緩普加巴林釋出上之效用,申請人將依據上面實施例所得到的3種錠劑拿來進行活體外溶離試驗。另外,為供比較,市售Lyrica
®普加巴林膠囊(75 mg)(購自於Pfizer)被拿來進行相同的溶離試驗。
實驗方法:
有關普加巴林的溶出百分比(percentage of dissolution of pregabalin)是參照「FDA-Recommended Dissolution Methods」資料庫中所規範之有關普加巴林的延續釋放錠劑(extended release tablet)的活體外溶離試驗條件來進行檢測。簡言之,將本發明的錠劑1至錠劑3以及市售Lyrica
®普加巴林膠囊各取1顆作為待測樣品。然後,分別將900 mL的溶離介質(dissolution medium)(0.06 N鹽酸溶液)加入至一USP旋轉攪拌裝置(USP rotating paddle apparatus)中的4個容器(vessel)中。接著,將各個待測樣品分別置於該等容器中並在轉速設定為50 rpm以及溫度設定為37℃的條件下進行溶離試驗,總試驗時間為24小時。
在開始進行溶離試驗之前(亦即第0小時)以及在開始進行溶離試驗之後的第0.5、1、2、3、4、6、8、10以及24小時,從分別含有錠劑1至錠劑3的容器中各自取出1.5 mL的溶離液(dissolution solution)。此外,在開始進行溶離試驗之後的第0、0.16、0.25、0.5以及0.75小時,從含有市售Lyrica
®普加巴林膠囊的容器中取出1.5 mL的溶離液。
之後,對各個時間點所取出的溶離液予以離心,繼而收取上清液並將之拿來進行高效能液相層析(high performance liquid chromatography, HPLC)分析。
接著,將所得到的普加巴林的溶出百分比相對於時間來作圖,而繪製出一溶離曲線(dissolution profile)。
結果:
圖1顯示本發明的普加巴林錠劑以及市售Lyrica
®普加巴林膠囊的溶離試驗結果。從圖1可見,在開始進行溶離試驗之後的第0.5小時,市售Lyrica
®普加巴林膠囊中的普加巴林已完全釋出,而本發明之錠劑1至錠劑3中普加巴林的溶出百分比分別僅有10.7%、10.4%以及7.3%。事實上,錠劑1與錠劑2中的普加巴林在開始進行溶離試驗之後的第24小時才會完全釋出,而錠劑3中的普加巴林甚至在超過24小時之後才會完全釋出。依據這個實驗結果,申請人認為:依據本發明的持續-釋放配方能夠有效地延緩普加巴林的釋出,因而可供用於每日一次投藥(once-daily administration)。
於本說明書中被引述之所有專利和文獻以其整體被併入本案作為參考資料。若有所衝突時,本案詳細說明(包含界定在內)將佔上風。
雖然本發明已參考上述特定的具體例被描述,明顯地在不背離本發明之範圍和精神之下可作出很多的修改和變化。因此意欲的是,本發明僅受如隨文檢附之申請專利範圍所示者之限制。
本發明的上述以及其它目的、特徵與優點,在參照以下的詳細說明與較佳實施例和隨文檢附的圖式後,將變得明顯,其中:
圖1顯示本發明的普加巴林錠劑以及市售Lyrica
®普加巴林膠囊的溶離試驗結果。
Claims (7)
- 一種持續-釋放配方,以該配方的總重量為基礎,其包含有: 呈一數量落在5%至40%之範圍內的普加巴林,或者它的一藥學上可接受的鹽類、溶劑合物或水合物; 呈一數量落在0.1%至5%之範圍內的卡波姆;以及 呈一數量落在20%至60%之範圍內的聚氧化乙烯; 其中,該配方不含有聚乙酸乙烯酯。
- 如請求項1的持續-釋放配方,以該配方的總重量為基礎,其進一步包含有: 呈一數量落在5%至60%之範圍內的稀釋劑; 呈一數量落在1%至10%之範圍內的黏合劑; 呈一數量落在0.01%至2%之範圍內的抗氧化劑;以及 呈一數量落在0.1%至5%之範圍內的潤滑劑。
- 如請求項2的持續-釋放配方,其中該稀釋劑是選自於由下列所構成的群組:澱粉、微晶型纖維素、無水磷酸氫鈣、右旋糖、乳糖、蔗糖、甘露醇、木糖醇、山梨糖醇,以及它們的組合。
- 如請求項2的持續-釋放配方,其中該黏合劑是選自於由下列所構成的群組:聚乙烯吡咯烷酮、共聚維酮、羥丙纖維素、羥丙基甲基纖維素、羥乙基纖維素、甲基纖維素,以及它們的組合。
- 如請求項2的持續-釋放配方,其中該抗氧化劑是選自於由下列所構成的群組:二丁基羥基甲苯、丁基羥基甲氧苯、抗壞血酸、五倍子酸丙酯,以及它們的組合。
- 如請求項2的持續-釋放配方,其中該潤滑劑是選自於由下列所構成的群組:硬脂酸、硬脂酸鎂、硬脂酸鈣、硬脂酸鋅、甘油單硬脂酸酯、硬脂醯延胡索酸鈉、甘油二十二烷酸酯,以及它們的組合。
- 如請求項1的持續-釋放配方,它是呈一供口服投藥的劑型。
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TW109100420A TWI733299B (zh) | 2020-01-07 | 2020-01-07 | 普加巴林的持續-釋放配方 |
CN202010082826.2A CN113143874A (zh) | 2020-01-07 | 2020-02-07 | 普加巴林的持续-释放配方 |
US16/832,071 US20210205247A1 (en) | 2020-01-07 | 2020-03-27 | Sustained-release formulation containing pregabalin |
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TW109100420A TWI733299B (zh) | 2020-01-07 | 2020-01-07 | 普加巴林的持續-釋放配方 |
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WO2020006372A1 (en) * | 2018-06-28 | 2020-01-02 | Mylan Inc. | Pregabalin extended-release fomulations |
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CN1857244A (zh) * | 2006-03-06 | 2006-11-08 | 重庆医药工业研究院有限责任公司 | 普瑞巴林缓释药物组合物 |
AU2013213859A1 (en) * | 2012-01-30 | 2014-08-21 | Sun Pharmaceutical Industries Limited | Pregabalin GR tablets |
CN104840443B (zh) * | 2015-05-27 | 2018-04-27 | 齐鲁制药有限公司 | 含活性成分普瑞巴林的药物组合物 |
CN110585153A (zh) * | 2018-06-13 | 2019-12-20 | 北京泰德制药股份有限公司 | 一种普瑞巴林缓释组合物及其制备方法 |
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- 2020-02-07 CN CN202010082826.2A patent/CN113143874A/zh active Pending
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WO2020006372A1 (en) * | 2018-06-28 | 2020-01-02 | Mylan Inc. | Pregabalin extended-release fomulations |
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