TWI626042B - 莫達非尼於古柯鹼成癮替代治療之醫藥組成物 - Google Patents
莫達非尼於古柯鹼成癮替代治療之醫藥組成物 Download PDFInfo
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- YFGHCGITMMYXAQ-UHFFFAOYSA-N 2-[(diphenylmethyl)sulfinyl]acetamide Chemical group C=1C=CC=CC=1C(S(=O)CC(=O)N)C1=CC=CC=C1 YFGHCGITMMYXAQ-UHFFFAOYSA-N 0.000 title claims abstract description 49
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Abstract
本發明係有關於莫達非尼(modafinil)於古柯鹼成癮之應用。
所使用之莫達非尼係其右旋對映異構物(S莫達非尼)，其具有少於1小時及較佳為15至30分鐘之極為快速的釋放時間，及少於4小時及較佳少於2小時之極為有限的清醒效應。其係呈口服吸收的醫藥組成物，各個單位劑量包括25至200毫克，較佳地50至100毫克S莫達非尼。
此種醫藥組成物之用途係作為古柯鹼成癮替代治療。
Description
本發明係有關於莫達非尼於古柯鹼成癮替代治療之應用。
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：
目前，古柯鹼的使用係許多內科病症及精神科合併症的起因，諸如成癮。因此，古柯鹼成癮乃嚴重公共衛生問題且正在不斷增加當中。據報告美國在2002年有超過20萬人由於使用古柯鹼所繼發的內科或精神科問題而送急診。今日多種分子可使用在古柯鹼成癮的治療。確實，古柯鹼在大腦層面的作用模式涉及至少三種神經媒介物質：γ-胺基丁酸(GABA)、麩胺酸酯、及多巴胺(DA)。因此在此等媒介物質上的不同活性分子已經成為用在人體的功效研究的主題。此等分子包括巴克羅芬(baclofene)、托比拉美(topiramate)、莫達非尼
(modafinil)、迪薩非朗(disulfiram)[BH Herman、A.Elkashef、F.Vocci-古柯鹼成癮的治療藥物：萌生候選者，今日藥物探索：治療策略，第2卷第1期2005年]，[P.Tahsili-Fahadan、GV Carr、GC Harris及G.Aston-Jones-莫達非尼阻擋在大鼠體追尋已消失的鴉片劑的復位：藉麩胺酸機轉投藥，神經精神藥理學，25,2010,2203-2210],[J.M.Martizez-Raga、C.Knecht及S.Cepeda-莫達非尼：古柯鹼成癮的有用藥物？得自神經藥理、實驗及臨床研究之證據綜論-目前藥物濫用綜論，2008,1,213-221]。
莫達非尼乃一種清醒藥，自九零年代以來已經在歐洲使用；莫達非尼增加清醒及白晝警覺程度，因此目前處方用於發作性睡病的治療。
其作用模式尚未完全知曉，但係出現在擬腎上腺素及擬麩胺酸的傳輸。結合至多巴胺的攜帶者而減少其之再度捕捉。
其也造成在負責誘導入睡的腹側光核抑制正腎上腺素的再度捕捉。
莫達非尼係以莫迪歐達(Modiodal)、波維吉爾(Provigil)及雅樂泰(Alertec)之名稱上市。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；於人類之清除半生期約為14小時。
莫達非尼係以其外消旋形式被販售，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，對映異構物R具有10至14小時的半生期。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，對映異構物R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導失眠。
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到強力變異性，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供利用，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，因而讓病人有一種允許容易調整投藥劑量的相似配方可供運用。
本發明之另一目的係給予病人一種治療製劑，其與外消旋劑型相較允許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。
不同的先前技術文件描述莫達非尼用於古柯鹼成癮的治療；如此，專利申請案US2001/0034373描述少於100毫克及更特別為1至75毫克每日有效劑量的使用。該文件未曾教示有關配方資料或藥力學資料。
PCT國際專利案WO99/25329述及二苯甲基磺醯基衍生物包括莫達非尼用以減少因使用鴉片劑治療所誘發的嗜眠效應。該文件並未更特別地描述醫藥組成物或任何藥力學效應。
專利申請案US2004/06532描述一種每個治療服用單位含有250至450毫克莫達非尼的藥物劑型的應用。有關該點本發明係有關於含有100毫克活性成分或甚至更低的S莫達非尼劑量之藥物劑型。
專利申請案US2009/0123545係有關於莫達非尼化合物的一種聯合物其中該S莫達非尼係占大於50%濃度。此等組成物係用於增加警覺清醒狀況，更通用地用以增加中樞神經系統(CNS)的興奮。所述藥物資料教示S莫達非尼組成物係高於80%及半生期係少於4小時。針對此點本發明係有關於特別調配的製劑因而獲得
小於或等於1小時的迅速作用，及少於2小時半生期的短效作用時間。
文件WO2007/01362本身也描述含100毫克S莫達非尼的組成物，但教示誘導效果持續長達4小時。
本發明效果為作用極為快速同時短暫。
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，因而無論投予病人的劑量如何皆相同，因而促成觀察到之強力變異度的減低。
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。
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。
一種新穎使用超臨界二氧化碳的技術之配方方法乃本發明之目的，該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。
超臨界流體具有優於其它溶劑的另一項優點：其溶解度的改變係取決於其溫度或其壓力是否改變。如此可確保針對某種物質在某個瞬間，該超臨界流體為溶劑而在下個瞬間則非為該物質的溶劑。如此協助回收所溶解的物質。
其顯示莫達非尼於二氧化碳具有可接受的溶解度。
圖1顯示莫迪歐達、配方4(散劑)與化合物DASC 00512(錠劑於籃內溶解)的錠劑溶解結果之比較。
圖2顯示參考品與配方的膠囊溶解輪廓之比較。
如下步驟包含噴霧已溶解的活性成分在惰性撐體上，及然後，研究所得粒子的晶粒大小以及該等粒子的結晶型。
進行不同測試，首先係使用無水乳糖作為惰性撐體。
然後，修正不同參數：-改變惰性撐體(無水乳糖以甘露糖醇置換)，-提高載荷程度至高達活性成分負荷的30%，-使用S莫達非尼，-二氧化碳以外的超臨界溶劑。
測試係藉使用S莫達非尼及甘露糖醇摘述於下表：
前述獲得的配方4係經調配而獲得含4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250rpm校準；-然後進行在施維亞(SVIAC)打錠機上壓縮。
製備配方7
DASC00512
莫迪歐達、配方4(散劑)與DASC 00512(錠劑於籃內溶解)比較的溶解結果見圖1。
同樣也製造與測試另一型配方，即半固體明膠膠囊劑。
舉個實例，現在描述製造配方8之方法，須瞭解其它配方也遵照相同方法，亦即稱重原料及雙重研磨活性成分(類似錠劑)，所得粉末分散於賦形劑內及分配為明膠膠囊劑。
1. 於100毫升燒杯內摻混25克利普索400 MED(聚乙二醇400)。
2. 以250rpm攪拌。
3. 於室溫摻混25克之聚山梨醇酯80及攪拌2分鐘。
4. 徐緩摻混20克已研磨的活性成分。
5. 分散後於350rpm攪拌10分鐘。
於室溫獲得均質且略為黏稠的帶白色分散液，滴定於285.7毫克/克活性成分。
此種分散液將摻混入喜巴爾(HIBAR)型半固體明膠膠囊劑內，利用設有船舶用推進器的攪拌器以200rpm維持攪拌以進行明膠膠囊劑的填充。
料斗及注入器的溫度將調整至27℃。然後將進行明膠膠囊劑的封閉及穩定化。
圖2可比較參考品與配方的溶解輪廓。
DASC=S-莫達非尼，DASB=外消旋物。
由本圖可知於100毫克劑量，四種明膠膠囊劑配方具有比較參考品ASB更快速的溶解輪廓。
全部明膠膠囊劑配方皆具有比較內部參考品更高的溶解度。
在配方中，以ASB(外消旋物)為基的配方具有比較三個ASC(S-莫達非尼)配方更慢的溶解度，三個ASC配方的溶解輪廓為相同。
藉由比較所得之溶解輪廓，觀察到使用此處顯示的ASB之S莫達非尼及特定配方的S莫達非尼，比較參考產品及於相同配方中的外消旋混合物，獲得試管
試驗中極為快速的溶解結果，在30分鐘內溶解約90%。
如此，無論此乃藉使用超臨界流體之方法所獲得的S莫達非尼配方，或為半固體明膠膠囊劑，就藥力學輪廓而言達成相同結果，亦即在少於1小時及更特別約為30分鐘以內極快速釋放，及效果短暫，該醫藥組成物被病人吸收後4小時有關莫達非尼的清醒度增高的持續性效果消失。
其在古柯鹼成癮的治療上就極為快速釋放及暫時性效果的雙重特徵特別令人關注。
如前文已述，古柯鹼成癮已經變成全球主要公共衛生毒害，目前對古柯鹼成癮尚無有效的基本治療。藉由醫院環境裡重複的且昂貴的戒毒，病人確實能從戒毒中獲益，但最終仍然無可避免地故態復萌。
此外，治療限於戒毒期間使用非專一性精神治療藥，及介於此等戒毒週期間進行各項心理治療，但效果未經證實。
已經測試多項治療，但成功情況有限，對國際專家而言莫達非尼顯然為最具展望者。
確實，古柯鹼的特異性標靶乃大腦中涉及成癮現象的該等區域的擬多巴胺系統。古柯鹼抑制神經元細胞膜的多巴胺(DA)載體，因而放大擬多巴胺反應。
莫達非尼乃非安非它命的精神興奮藥，其作用機轉尚未完全明瞭，但含有大量擬多巴胺成分，特別在DAT。莫達非尼的其它非擬腎上腺素效果及擬麩胺酸效果也係與古柯鹼的非擬多巴胺作用相聯結。
此種神經藥理上的相似性已經導致將莫達非尼視為古柯鹼成癮的潛在替代治療。
公元2000年期間已經在數個臨床試驗中測試莫達非尼用於古柯鹼成癮病人。在美國對有限數目的病人進行的此等測試獲得令人振奮但孤立的結果，再度發現對某些臨床及生物學評估標準有效但非全部。
此等陽性結果但仍然不足，解釋應係由於置換的不完美。莫達非尼模擬古柯鹼的藥理效應，但其藥力學輪廓與古柯鹼的藥力學輪廓之差異過大，因而無法達成充分「勸阻性」取代成癮病人的「強烈渴癮」感覺及古柯鹼的使用。
目標係希望獲得在15至30分鐘以內極為快速開始作用，允許強烈渴癮的窗口縮小，讓病人有能力對抗對毒品成癮的強迫行為。所得產品比較天然分子達成遠更有效的替代。
依據本發明之藥物劑型結果所獲得藥力學輪廓允許滿足此等雙重需求：S莫達非尼的作用起始極為迅速而清醒效應有限，少於4小時及更佳地少於2小時，以避免具有R莫達非尼的長期清醒效應相聯結的失眠風險。確實，涵蓋夜晚時間，亦即強烈渴癮與故態復萌的敏感時刻中之一者，要求該產品係在黃昏時服用。因而每天在此時病人服用一劑依據本發明之組成物不會帶來任何不便。因此該藥物劑型實際上為古柯鹼成癮的治療性替代劑型；包裝呈非水性劑型，亦即固體或半固體劑型，每單位劑型將含有25至200毫克S莫達非尼，及較
佳為50毫克至100毫克。
較佳地，依據本發明之藥物劑型將呈口服劑型，例如錠劑或明膠膠囊劑，因此避免藉注射投藥可能導致的健康風險。
Claims (6)
- 一種基於S莫達非尼(S modafinil)於古柯鹼成癮替代治療使用之醫藥組成物，其特徵在於該S莫達非尼係藉超臨界流體技術所獲得，該S莫達非尼係在以惰性撐體所製成之顆粒表面被吸收，且病人所吸收的S莫達非尼劑量係為每單位劑量50毫克至100毫克。
- 如申請專利範圍第1項之醫藥組成物，其中該流體為二氧化碳。
- 如申請專利範圍第1項之醫藥組成物，其中該撐體為無水乳糖。
- 如申請專利範圍第1項之醫藥組成物，其中該撐體為甘露糖醇。
- 如申請專利範圍第1至4項中任一項之醫藥組成物，其中該醫藥組成物係呈錠劑型式。
- 如申請專利範圍第1至4項中任一項之醫藥組成物，其中該錠劑含有25至200毫克之S莫達非尼。
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| WO2008127679A1 (en) * | 2007-04-11 | 2008-10-23 | Cephalon, Inc. | Lyophilized pharmaceutical compositions and methods of making and using same |
| US20090123545A1 (en) * | 2005-07-21 | 2009-05-14 | Ron Eyal S | Rapid Onset and Short Term Modafinil Compositions and Methods of Use Thereof |
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| US20010034373A1 (en) | 2000-02-09 | 2001-10-25 | Matthew Miller | Low dose modafinil for enhancement of cognitive function |
| US20040006532A1 (en) | 2001-03-20 | 2004-01-08 | David Lawrence | Network access risk management |
| US20060024370A1 (en) * | 2004-07-29 | 2006-02-02 | Cephalon France | Modafinil oral lyophilizate |
| US7093476B2 (en) | 2004-09-15 | 2006-08-22 | Ut-Battelle, Llc | Method for fabricating thin californium-containing radioactive source wires |
| BRPI0714173A2 (pt) * | 2006-07-12 | 2012-12-25 | Elan Pharma Int Ltd | composiÇço nanoparticulada estÁvel,mÉtodos para preparar a composiÇço, para prevenir e/ou tratar estados de doenÇas, sintomas, sÍndromes e condiÇÕes do sistema nervoso central, para melhorar ou manter a biodisponibilidade de modafinil, e para tratar distérbio com base neurolàgica, composiÇço farmacÊutica, e forma de dosagem |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002030414A1 (en) * | 2000-10-11 | 2002-04-18 | Cephalon, Inc. | Compositions comprising modafinil compounds |
| US20090123545A1 (en) * | 2005-07-21 | 2009-05-14 | Ron Eyal S | Rapid Onset and Short Term Modafinil Compositions and Methods of Use Thereof |
| WO2008127679A1 (en) * | 2007-04-11 | 2008-10-23 | Cephalon, Inc. | Lyophilized pharmaceutical compositions and methods of making and using same |
Non-Patent Citations (1)
| Title |
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| Current Drug Abuse Reviews, 2008, 1, 213-221 * |
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