TWI543779B - 獲得莫達非尼之醫藥組成物之方法、如此獲得之醫藥組成物及其應用 - Google Patents
獲得莫達非尼之醫藥組成物之方法、如此獲得之醫藥組成物及其應用 Download PDFInfo
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Description
本發明係有關於獲得莫達非尼之醫藥組成物之方法、如此獲得之醫藥組成物及其應用。
莫達非尼(modafinil)為2-[(二苯基甲基)亞磺醯基)]乙醯胺，其分子式為C15H15NO2S及其結構式為：
1970年，法國拉鳳藥廠(Lafon)發展二苯甲基亞磺醯基衍生物。1986年，亞茁非尼(Adrafinil)測試用於發作性睡病及被放棄，原因在於胃腸道本質的問題，出現發疹現象及有顯著皮膚過敏。1992年以來莫達非尼在歐洲用作為清醒藥；其增加清醒及白晝警覺度，因而目前處方用於治療發作性睡病。作用模式未經全然解說，但涉及在腹側前光核的誘導睡眠核抑制正腎上腺素的重新捕捉；也將具有擬腎上腺素α1促效劑效應，對擬麩胺酸傳輸具有正面效應，其係結合至多巴胺的載體，
減少其重新捕捉。
莫達非尼係以莫迪歐達(Modiodal)、普維吉爾(Provigil)及雅樂泰(Alertec)上市。投藥劑量從每日服用一次100毫克變化至每日服用兩次200毫克；清除半生期於人類約為14小時。
莫達非尼係以其外消旋形式分銷，具有一個對掌中心，實際上是個硫原子；但存在有兩種旋光性異構物：右旋-對映異構物(S)及左旋-對映異構物(R)，兩種形式係以等量存在於外消旋形式。
兩種對映異構物於動物體具有相同的藥理活性；但用於人類，左旋對映異構物(R)具有10至14小時的半生期。右旋對映異構物(S)具有3至4小時的半生期[參考文獻：Wong等人，J.Clin.pharmacol.,39：30-40(1999)；Wong等人，J.Clin.pharmacol.,39：281-288(1999)；Robertson等人，Clin.Pharmacokinet.,42：123-137(2003)]。
投藥後，R對映異構物具有比較外消旋型更大的曲線下方面積(AUC)及更少的血漿濃度變異度。
莫達非尼係用於治療與有或無僵直的發作性睡病相關聯的過度白晝嗜睡。過度白晝嗜睡的特徵是難以維持清醒及在不定時的瞬間進入睡眠週期的增加。初始推薦劑量為早晨單次服用200毫克，或早晨及中午分兩次服用，依據病人的反應決定。對反應不足的病人劑量可提高至600毫克。
目前可得的商業形式的問題在於莫達非尼的
效果持續超過病人所期望的時間週期。此種持久的警覺性最終可能變成干擾病人的正常睡眠週期且甚至誘發失眠。
莫達非尼也成功地用於兒童治療ADHD(注意力不足過動症)；全部此等病理中，有關臨床徵象皆觀察得強力變異性，因此證實需要做個別的治療調整。
本發明之一目的係讓病人有一種S莫達非尼的新穎口服藥物劑型可資利用，其比較外消旋劑型具有增高的生物利用率及縮短的作用時間。
本發明之一目的也係提供一種配方其可滿足個人間強力變異的需求，因而讓病人有一種許可容易調整投藥劑量的相似配方可資運用。
本發明之另一目的係給予病人一種治療製劑，其比較外消旋劑型許可極為快速的治療效果及與單獨投予S莫達非尼可相媲美的功效。
如此，本發明係有關於S莫達非尼的口服治療劑型，呈含有25至200毫克活性成分及較佳為50至100毫克劑量的錠劑、藥包或明膠膠囊劑劑型。
此處呈示的配方為相似物，因此無論投予病人的劑量為何皆相同，其造成先前報導之強力變異度的減低。
此處描述的組成物係特別開發獲得試管試驗中極為快速的溶解，總而言之，溶解度係大於市售劑型的溶解度；因此特別發展出區別溶解方法，許可做賦形劑及製造方法的選擇。
於先前技術中描述多種莫達非尼口服配方；如此，專利案US 7,297,346描述莫達非尼組成物包含乳糖、玉米澱粉、矽酸鎂、交聯甲基纖維素鈉、PVP、滑石及硬脂酸鎂。
本組成物使用呈外消旋形式的莫達非尼，及相對應於商業配方普維吉爾。
文件US No.RE37516呈示使用明確界定粒徑的粒子的醫藥組成物，及特別95%粒子具有小於200微米大小的組成物。於本文件中，所得藥理效果係與活性成分的最終粒子大小有關；如此描述具有經界定粒徑的粒子係藉多次連續研磨與過篩操作獲得。此等操作笨重而煩瑣，經濟上難以與工業製造的現實妥協。該配方方法，即本發明之目的，係使用相當不同的技術，隨後會敘述所謂的超臨界流體技術。
專利案US 6,919,378、US 6,489,363、EP 1 562 572 B1家族係針對偏好投予非水溶液劑型，其範圍極廣：溶液呈兩種或數種物質的混合物，該等溶液可呈固體分散於液體、固體、或半固體介質。如此，專利案EP 1 562 572敘述包含至少一個固體撐體的固體分散體，相同撐體係屬具有3,000至8,000道爾頓的分子量之PEG家族，PEG 400除外。
專利案US 6,919,378描述非水性組成物。專利案US 6,489,363描述包含莫達非尼於溶液較佳為非水溶液的醫藥組成物，但也請求水性組成物的專利。
專利申請案US 2007/0275057描述一種口服
組成物包含一種或數種醫藥賦形劑，其中至少65%莫達非尼粒子具有大於220微米直徑。於該本發明之目的組成物中，S莫達非尼溶解於超臨界流體，流體膨脹後在撐體上結晶。次此一方法中，所得S莫達非尼粒子約為1微米。
專利案EP 1 542 666描述一種醫藥組成物包含具有有限尺寸範圍的至少兩個莫達非尼粒子族群，部分此等範圍係從最終醫藥組成物排除。就製造而言，如此需要數個分離及晶粒大小檢查步驟，涉及長期而困難的處理程序。
專利申請案US 2004/0121003描述一種獲得具有10至500微米的平均大小的活性成分與至少一種賦形劑的混合物之特殊方法；該混合物係經研磨(空氣噴射研磨)以維持個別粒子的大小及外觀。
國際專利申請案WO 2008/008879係有關包含莫達非尼或其鹽類中之一者的奈米粒子及至少一種表面安定劑吸收在相同奈米粒子的組成物；粒子的平均晶粒奈係為至少2,000奈米。於本發明之組成物中，活性成分係溶解於超臨界流體及然後吸收在撐體上。
現在利用後述事實將更為瞭解本發明。
莫達非尼呈結晶性白色粉末，實質上不溶於水，部分可溶於甲醇及丙酮。結果導致莫達非尼的生物利用率低，估計約為40%；確實因活性成分的溶解度低，故無法決定絕對生物利用率。
因而尋求改良莫達非尼的溶解度；更明確言之，此乃本發明之目的中之一者，莫達非尼的溶解度係於超臨界流體中作研究。
此等超臨界流體中，值得一提者為二氧化碳；該超臨界二氧化碳技術係基於二氧化碳的溶解度可依據施用的壓力及溫度條件而予調整。
於超臨界態(超過74巴及31℃)，二氧化碳具有極為特殊的性質。所得流體之特徵在於具有高擴散性(約為氣體的擴散性)使其獲得良好擴散能力，及高密度因而具有顯示轉送及萃取能力。
一種使用超臨界二氧化碳萃取方法係在閉路中操作。該閉路包括加壓單元(泵浦)及溫度設定單元(交換器)以將二氧化碳調整至高於其臨界點。
欲處理的產物置於萃取器內，藉超臨界二氧化碳流橫過其中。可溶解於超臨界二氧化碳及因而可被萃取的分子乃具有低分子量的非具極高極性的化合物。
超臨界流體比較液態流體具有數項優點：˙擴散係數高及黏度係數低；˙不存在有表面張力，提高超臨界流體的穿透力。
超臨界流體比較其它溶劑具有另一項優點：其溶解度的改變係取決於其溫度或其壓力的變動。因而能夠確定超臨界流體乃某些物質在某個瞬間的溶劑而非
下個瞬間的溶劑。如此有助於已經溶解的物質之回收。
如此，瞭解莫達非尼於二氧化碳具有可接收的溶解度，如下圖所示。
然後尋求噴霧已溶解的活性成分在惰性撐體上而獲得由該撐體所組成的顆粒，依據前述方法獲得的莫達非尼粒子係吸收在該顆粒表面上。此等粒子的晶粒大小以其結晶型乃綜合研究的主題。
進行數項測試，首先使用無水乳糖作為撐體。
藉變更下列參數而製造不同樣本：萃取溫度及壓力、膨脹前溫度、膨脹壓力、液體二氧化碳百分比。
藉示差熱分析或X光繞射研究粉末的結晶型，及藉比較此等資料與參考文獻的資料，因而獲得結論：其結晶型輪廓為相同且係相對應於無水乳糖及相對應於外消旋莫達非尼的IV型。
然後於HPLC研究溶解度，籃50 rpm；溶解介質：HCl 0.1N；浴溫：37℃；體積：450毫升；試樣相
當於約50毫克S莫達非尼；配方置於尺寸000之明膠膠囊(2個明膠膠囊)內。
所得結果見下圖：
觀察到比較單獨混合物(SAD P1/拉托普斯(lactopress))於試管試驗中的溶解度增高。
然後修正不同參數：-改變撐體為甘露糖醇，-增加載荷程度高達活性成分負荷的30%，-使用S莫達非尼，-二氧化碳以外的溶劑，值得一提者為四氟乙烷，更明確言之，1,1,1,2-四氟乙烷。
下表重複當使用S莫達非尼，及甘露糖醇替代無水乳糖，又復，載荷程度增至約30%時的結果。
下列曲線例示說明使用超臨界二氧化碳或四氟乙烷方法所製備的S莫達非尼/甘露糖醇型配方的DSC輪廓與參考品物理混合物的比較。獲得此等配方之莫達非尼的操作程序請參考國際申請案WO 2010/112702。
利用掃描電子顯微鏡(SEM)從30% S莫達非尼/甘露糖醇配方獲得S莫達非尼粒子的不同顯微照片；此等顯微照片複製如下，樣本2係使用二氧化碳作為超臨界溶劑而獲得，而樣本4係使用四氟乙烷而獲得。
下列圖式連續地例示說明使用超臨界二氧化碳法(介質HCl 0.1N)製備的30% S莫達非尼/甘露糖醇配方亦即樣本2與藉使用四氟乙烷方法製備的樣本4之溶解動力學的比較。
該等配方的分析結果證實先前研究期間所得結果，但捕捉賦形劑已經改變：-製備具有一致效價的配方，其具有對S莫達非尼粒子的良好捕捉效果；-DSC輪廓類似先前研究工作期間在相同操作條件下所製備的配方之輪廓；-配方之SEM觀察似乎指示S莫達非尼係結晶成具有約1微米大小的粒子形式；-針對兩型配方的溶解動力學為可再現性且類似先前獲得的結果。超臨界二氧化碳配方的溶解速率相當慢。使用四氟乙烷的配方具有較快的溶解輪廓。
前述獲得的製劑係經配方而獲得含2毫克S莫達非尼劑量之錠劑，此等錠劑意圖用於藥力學研究期間投予大鼠。
使用的方法如下：-秤重各個成分後，賦形劑係以遞增重量順序連續地導入混合器內；-然後混合物經過篩去除可能的簇狀粒子；-然後所得混合物經緊壓及然後於具有1.25毫米孔徑的格網上以250 rpm校準；-然後進行在施維亞(SVIAC)打錠機上壓縮。
製備配方
DASC00512：
莫達非尼、配方4(散劑)與化合物DASC 00512(錠劑於籃內溶解)比較的溶解結果見下圖。
依據超臨界流體法所得的S莫達非尼配方實際上證實其許可極為快速釋放(少於1小時)及具有有限持續時間的效果(3至4小時間)：此等雙重特徵讓依據本發明之配方令人矚目。
本配方包含形成顆粒的撐體，例如甘露糖醇或無水乳糖或任何其它惰性撐體，於其表面上已經吸收使用超臨界流體技術所得的S莫達非尼粒子。
優異地，由此配方獲得的錠劑將以25至200毫克S莫達非尼，甚至更佳地使用50至100毫克劑量。一旦消費者需要提高短期的清醒度，換言之，極為快速地(少於1小時)歷經短時間週期(3至4小時間)時，前述特徵許可此等錠劑的使用。
Claims (10)
- 一種獲得醫藥組成物之方法，其特徵在於該方法係包括將S莫達非尼(modafinil)溶解於超臨界態的流體中，及接著在該流體膨脹之後，藉由以呈顆粒的惰性撐體使得S莫達非尼在表面上被吸收而回收之。
- 如申請專利範圍第1項之方法，其中該超臨界流體係為二氧化碳。
- 如申請專利範圍第1項之方法，其中該超臨界流體係為四氟乙烷。
- 如申請專利範圍第1至3項中任一項之方法，其中該撐體係為甘露糖醇。
- 如申請專利範圍第1至3項中任一項之方法，其中該撐體係為無水乳糖。
- 一種醫藥組成物，其係依據如申請專利範圍第1至5項中任一項之方法而獲得。
- 如申請專利範圍第6項之醫藥組成物，其係呈口服劑型。
- 如申請專利範圍第7項之醫藥組成物，其中該口服劑型係含有25至200毫克S莫達非尼。
- 如申請專利範圍第8項之醫藥組成物，其中該口服劑型係含有50至100毫克S莫達非尼。
- 如申請專利範圍第7至9項中任一項之醫藥組成物，其中該口服劑型係為錠劑。
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| US6489363B2 (en) | 2000-10-11 | 2002-12-03 | Cephalon, Inc. | Pharmaceutical solutions of modafinil compounds |
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| US20040048931A1 (en) | 2002-07-12 | 2004-03-11 | Craig Heacock | Modafinil pharmaceutical compositions |
| US20040121003A1 (en) | 2002-12-19 | 2004-06-24 | Acusphere, Inc. | Methods for making pharmaceutical formulations comprising deagglomerated microparticles |
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| WO2007011707A2 (en) * | 2005-07-15 | 2007-01-25 | Micell Technologies, Inc. | Polymer coatings containing drug powder of controlled morphology |
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