TWI838826B - Lsd的固體口服立即釋放配製物的組成物及製作lsd的固體口服立即釋放配製物之方法 - Google Patents
Lsd的固體口服立即釋放配製物的組成物及製作lsd的固體口服立即釋放配製物之方法 Download PDFInfo
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- TWI838826B TWI838826B TW111131360A TW111131360A TWI838826B TW I838826 B TWI838826 B TW I838826B TW 111131360 A TW111131360 A TW 111131360A TW 111131360 A TW111131360 A TW 111131360A TW I838826 B TWI838826 B TW I838826B
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Abstract
一種LSD的固體口服立即釋放配製物,其中該組成物是藉由在預成型模具中凍乾原料以形成口腔崩散錠而生產的。一種製作LSD的固體口服立即釋放配製物之方法,該方法藉由在預成型模具中凍乾LSD包括非膠化的基質形成劑、填料和黏合劑和賦形劑的速凍儲備溶液,以及形成口腔崩散錠。一種藉由投與LSD的固體口服立即釋放配製物治療個體之方法,其中該組成物係藉由在預成型模具中凍乾原料以形成口腔崩散錠而生產的,並且治療該個體。
Description
本發明關於藥物的配製物。更特別地,本發明關於d-麥角酸二乙胺(LSD)藥物配製物的立即釋放配製物。
口服溶液配製物方便在小數量的地點和有限數量的患者中研究(主要是早期開發研究),但由於產品穩定性和供應鏈方面的挑戰(如對冷鏈儲存的潛在需要),可能不適用於在許多中心和跨越廣泛地域進行的晚期開發研究,也不適用於商業化。
固體口服配製物(像片劑或膠囊)由於在生產、供應鏈、及患者方便性方面的優勢在晚期臨床開發和商業上更常見。固體口服配製物可以立即釋放(瞬時地溶解於嘴或胃中)或緩釋(其中藥物釋放隨時間延長)。
口腔崩散錠(ODT)係另一種固體劑型,該等口腔崩散錠之配製目的係增加藥物產品的溶出速率並促進胃前吸收。為了實現快速崩散速率,ODT
配製物必須提供高孔隙率、低密度、及低硬度(Berthoumieu等人2010;Bandari等人2008)。可以選擇這種劑型來改變吸收或用於吞咽困難的患者群體(Lindgren等人1993),並且也適用於在老年和兒科患者中使用,或用於患有如吞嚥困難病症的患者(Sastry等人2000)。
從成本和簡單性的角度來看,直接壓片係製備ODT的常見方法。然而,以這種方式生產的ODT的崩散能力被所得片劑的大小和硬度所限制。一種製備ODT之可替代的方法係冷凍乾燥。例如,Zydis® ODT(口腔溶解片)即溶配製物係一種在口腔中不需要水幾乎就能立即分散的冷凍乾燥口服固體劑型。
LSD衍生自其德文名稱LysergSäureDiethylamid(麥角酸二乙胺)。麥角二乙胺屬於吲哚烷基胺家族,該家族包括許多取代色胺,如二甲-4-羥色胺(psilocin)(賽洛西賓的活性部分)和N,N-二甲基色胺(DMT)。LSD的IUPAC名稱係9,10-雙脫氫-N,N-二乙基-6-甲基麥角靈-8β-甲醯胺。
LSD可用於輔助針對許多適應證(包括焦慮、憂鬱、成癮、人格障礙等)的心理療法,還可用於治療叢集性頭痛、偏頭痛等其他疾病(Passie等人2008;Hintzen等人2010;Nichols,2016;Liechti,2017)。LSD的作用可包括想法、感受、對周圍環境的意識發生改變,瞳孔放大,血壓升高和體溫升高。LSD的治療性用途在治療各種神經和行為障礙中顯示出有前景的結果。然而由於其效力,在開發和製造符合藥學上可接受的含量均一性和化學穩定性限制的LSD的固體口服配製物方面可能存在挑戰。
LSD的臨床研究已經集中在口服溶液的藥物產品形式上。幾乎沒有LSD的配製物開發工作。歷來使用口服溶液且幾乎所有的舊研究和傳聞數據都是口服溶液或浸漬紙/紙箱。
需要既對廣泛的患者群體具有商業吸引力又符合對適應性和穩健性的管控/品質期望的LSD劑型和藥物產品。d-麥角酸二乙胺(LSD)(呈游離鹼或以鹽形式)的商業上可行的固體口服的立即釋放藥物配製物,目前不存在市場產品或無文獻報導。LSD的期望治療劑量在10至100微克,實現可接受的藥物含量均一性和化學穩定性存在挑戰。此外,先前的研究已經顯示口服溶液中的LSD在室溫下不穩定(Holze等人2019)。
除了實現均一的和穩定的立即釋放藥物產品配製物之外,最終的藥物產品應處於對廣泛的患者群體容易投與的形式,該等患者群體包括但不限於老年人、小兒、和患有可能限制他們吞嚥能力的病症的患者。
本發明提供了LSD的固體口服立即釋放配製物,該配製物包括用於口腔崩散錠劑型的LSD配製物,其中該組成物係藉由在預成型模具中凍乾原料以形成口腔崩散錠而生產的。
本發明進一步提供了一種製作LSD的固體口服立即釋放配製物之方法,該方法藉由在預成型模具中凍乾LSD和賦形劑(非膠化的基質形成劑、填料、黏合劑和緩衝劑)以及另外的賦形劑(如抗氧化劑、光敏試劑、滲透增強劑和調味劑)的速凍儲備溶液,以及形成口腔崩散錠。
本發明還提供了一種藉由投與LSD的固體口服立即釋放配製物治療個體之方法,其中該組成物係藉由在預成型模具中凍乾原料以形成口腔崩散錠而生產的,並且治療該個體。
在與附圖結合考慮時,參照以下詳細描述,會容易認識到並更好地理解本發明的其他優點,其中:[圖1]係D-LSD D-酒石酸鹽之示意圖;並且[圖2]係含有LSD的Zydis ODT的相片。
本發明提供了一種迅速釋放或立即釋放劑型(如口腔崩散錠)的LSD的配製物。術語「迅速釋放片劑」係立即遞送藥物的機制(與立即釋放劑型相似),這與在其投與後延緩(緩釋劑型)或用於延長時間段(延長釋放(ER、XR、XL)劑型)或針對體內特異性靶點(靶向釋放劑型)相反。較佳的是,其係指口服劑量配製物中最小的時間依賴性釋放。本發明提供一種一旦口服攝取就相對迅速地溶解的組成物,較佳的是包括LSD作為其活性成分或其活性成分之一。這提供了容易投與但預期有效且有用的治療效果。
LSD可為鹼形式或呈結晶或非結晶固體的鹽形式。鹽可為但不限於鹽酸鹽、氫溴酸鹽、馬來酸鹽、酒石酸鹽(包括D-酒石酸和內消旋酒石酸)、檸檬酸鹽、磷酸鹽、富馬酸鹽、硫酸鹽、甲磺酸鹽、醋酸鹽、草酸鹽、苯甲酸鹽、苯磺酸鹽、昔萘酸鹽(xinafoate)、1,5-萘二磺酸鹽、抗壞血酸鹽、和萘-2-磺酸鹽。LSD的劑量較佳的是可為0.01-1mg(10-1000μg)。然而,取決於適應症、年齡、體重、和影響藥理學、生理學及藥物/藥物相互作用的其他因素,在給定患者中可以調整劑量。
較佳的固體口服配製物係例如使用在美國專利案號US 9,192,580 B2(將其藉由引用併入本文)中描述的ZYDIS®(Catalent公司)技術的口腔崩散錠(ODT)。這在實例1中進一步示出。典型的ZYDIS® ODT配製物包括非膠化
的基質形成劑、填料、黏合劑和pH改性劑(即緩衝液)。另外,抗氧化劑、光敏試劑、滲透增強劑、著色劑和甜味劑/調味劑可以包括在ZYDIS® ODT配製物中。
使用的非膠化的基質形成劑之實例包括但不限於非膠化的明膠(包括魚膠)、麥芽糖糊精、改性澱粉、澱粉醚、低分子量右旋糖酐以及低至中分子量纖維素膠(美國專利案號10,548,839 B2)。
使用的填料之實例包括乳糖(包括無水的)、甘露醇、磷酸二鈣、硫酸鈣、澱粉(如本文使用的澱粉,可以包括乾澱粉或預膠化澱粉)、纖維素(包括微晶纖維素)、高嶺土、氯化鈉、山梨醇、海藻糖、蔗糖等。
黏合劑之實例包括阿拉伯膠、甲基纖維素、羥丙基甲基纖維素、羥丙基纖維素、黃蓍膠、聚乙烯吡咯啶酮(PVP)、澱粉等。
添加緩衝劑以使配製物達到特定pH。目前,三種緩衝劑(檸檬酸、磷酸鹽及醋酸鹽)構成了FDA批准的腸胃外藥物中使用的緩衝劑的大多數,但少有先例的賦形劑肯定可在商用劑型中使用。可替代地,配製物的pH可用無緩衝酸(即鹽酸)或無緩衝鹼(即氫氧化鈉)調節。
為了最小化由於氧化應激引起的降解,可以將抗氧化劑添加至配製物中。術語氧化可以被定義為氧摻入至藥物結構中,或定義為將一種化學物質轉變為另一種含有少量電子的衍生物的過程。這種抗氧化劑之實例係抗壞血酸、檸檬酸、丁基羥基甲氧苯(BHA)、和丁羥甲苯(BHT)。
許多藥物對光敏感,因此它們的配製產品在製造、儲存、和投與期間可能降解。藥物物質的光穩定性可以被定義為藥物或藥物產品以固體、半固體、或液體狀態暴露於太陽、UV和可見光的反應,導致物理或化學變化。過度的光暴露可能導致效力喪失、功效改變、和不良的生物效應。為了最小化由於光暴露引起的任何降解,可以使用各種添加劑或包囊方法和組成物(即光穩定劑)以保護活性產品免受光照。
光降解也可能與氧暴露組合發生,這導致光氧化降解。一些常用的防止光氧化的抗氧化劑係抗壞血酸、α-生育酚、丁基羥基甲氧苯(BHA)、丁羥甲苯(BHT)、L-組胺酸、沒食子酸丙酯、和硫化物。抗壞血酸、α-生育酚、β-胡蘿蔔素、和BHT充當自由基清除劑和單線態氧猝滅劑,並因此抑制光敏反應。如果藥物物質充當光敏劑並啟動藥物產品內的連鎖反應,一些賦形劑可能被氧化,而該藥物可以被保護免受光降解。
配製物還可以含有滲透性增強劑以增加吸收的程度和/或速率。這種增強劑之實例係亞碸(如二甲基亞碸,DMSO)、月桂氮酮(例如月桂氮卓酮)、吡咯啶酮(例如2-吡咯啶酮,2P)、醇和烷醇(乙醇或癸醇)、乙二醇(例如丙二醇、PG,外用劑型中常見的賦形劑)、界面活性劑(劑型中也常見)和萜。
為了改善患者的識別度和可接受性,還可以將著色劑、甜味劑、和調味劑添加至固體口服配製物中。
考慮到個體患者的臨床狀況投與和給藥本發明的化合物,投與的部位和方法,投與的時間安排,患者年齡、性別、體重,以及執業醫師已知的其他因素。因此,用於本文目的的藥學上「有效量」由本領域已知的該等考慮來確定。該量必須有效實現改善,包括但不限於改善的生存率或更快的恢復,或者改善或消除症狀和熟悉該項技術者根據適當措施選擇的其他指標。
在本發明的方法中,本發明之化合物能以各種方式投與。應注意,其可作為化合物投與,並且可單獨投與或作為活性成分與藥學上可接受的載體、稀釋劑、佐劑和媒介物組合投與。所治療的患者係溫血動物,特別是哺乳動物,包括人。藥學上可接受的載體、稀釋劑、佐劑和媒介物通常係指不與本發明的活性成分反應的惰性、無毒固體或液體填料、稀釋劑或封裝材料。
劑量可為單劑量或在幾天時段內的多劑量。治療的時間長度通常與疾病過程的時間長度和藥物有效性以及所治療的患者種類成比例。
可以靶向活性藥物的吸收。藥物吸收由藥物的理化特性、劑型、和投與途徑確定。配製待藉由各種途徑(例如,口服、含服、舌下、直腸、腸胃外、外用、吸入)給與的由藥物和其他成分組成的劑型(例如,片劑、膠囊、溶液)。無論投與途徑如何,藥物必須處於可被吸收的溶液中。因此,固體形式(例如,片劑、膠囊)必須能夠崩散和分解。典型地,固體口服片劑和膠囊配製物具有胃吸收,而可以配製ODT配製物來靶向胃前或含服吸收,這可以進一步增強生體可用率。
本發明提供了一種製作呈游離鹼或鹽形式的LSD的固體口服立即釋放配製物之方法,該方法藉由在預成型模具中凍乾藥物和賦形劑的速凍儲備溶液來形成口腔崩散錠。這種方式考慮了配製低劑量產品相關的、同時維持LSD的含量均一性和化學完整性的挑戰。
本發明提供了一種治療個體之方法,該方法藉由投與LSD的固體口服立即釋放配製物治療該個體,其中該組成物係藉由在預成型模具中凍乾原料以形成口腔崩散錠而生產的,並且治療該個體。
治療的病症或疾病可以包括但不限於:焦慮障礙(包括晚期疾病如癌症中的焦慮、以及廣泛性焦慮障礙)、憂鬱(包括產後憂鬱、嚴重憂鬱障礙和難治性憂鬱)、頭疼障礙(包括叢集性頭痛和偏頭痛)、強迫症(OCD)、人格障礙(包括行為規範障礙症)、壓力障礙(包括適應障礙和創傷後壓力障礙)、藥物障礙(包括酒精依賴或戒斷、尼古丁依賴或戒斷、類鴉片藥物依賴或戒斷、可卡因依賴或戒斷、甲基苯丙胺依賴或戒斷)、其他成癮(包括賭博障礙、飲食障礙和身體變形症)、疼痛、神經退行性障礙(如癡呆、阿茲海默氏症、帕金森氏症)、泛自閉症障礙、飲食障礙或神經障礙(如中風)。
藉由參考以下實驗實例進一步詳細描述本發明。提供該等實例僅用於說明之目的,除非另有說明,否則無意為限制性的。因此,本發明決不應被
解釋為限於以下實例,而是應該被解釋為涵蓋由於本文提供的傳授內容而變得明顯的任何和所有變化。
實例1:凍乾d-LSD D-酒石酸儲備溶液來配製口腔崩散錠
按以下方法生產快速分散口腔崩散錠(ODT)中之d-LSD D-酒石酸的固體口服配製物:A)產生含有d-LSD D-酒石酸、非膠化的基質形成賦形劑、填料賦形劑和完全溶解於水的黏合劑的速凍儲備溶液;B)在預成型模具中計量該儲備溶液;以及C)凍乾給藥的配製物以藉由昇華去除水。在表1中提供了配製物組成物。配製物1的圖像在圖2中示出。所有配製物在小於60秒的時間內分解,這說明立即釋放。
該等配製物被保護以免水分進入,在40℃下保持穩定,並且一個月後測試化學降解。總化學雜質呈現於表2中。該等結果顯示在加速條件下儲存一個月後總雜質中較少的變化,這表明了d-LSD D-酒石酸的凍乾ODT配製物的適用性。
在整個申請中,將包括美國專利在內的各種出版物均藉由作者和年份以及專利案號進行援引。下面列出了該等出版物的完整引文。該等出版物和專利的揭露內容以其全文藉由援引特此併入本申請中,以便更全面地描述本發明所屬領域的現狀。
已經以示例性的方式描述了本發明,並且應理解,已經使用的術語意在具有說明性詞語的性質,而非限制性的。
顯而易見地,能夠根據以上傳授內容進行本發明的很多修改和變化。因此,應當理解,在所附請求項之範圍內可以用不同於特定描述的方式來實踐本發明。
Claims (10)
- 一種LSD的固體口服立即釋放配製物的組成物,該組成物包括包含在口腔崩散錠的立即釋放劑型內的大於0重量份至小於1重量份的LSD、2至10重量份的非膠化的基質形成劑、1至5重量份的黏合劑及2至10重量份的填料,其中所述組成物係藉由在預成型模具中凍乾原料以形成口腔崩散錠而生產的,其中該非膠化的基質形成劑為魚膠或麥芽糖糊精,該黏合劑為甲基纖維素,該填料為甘露醇或海藻糖。
- 如請求項1所述之組成物,該組成物進一步包括選自由以下組成之群組的緩衝劑:檸檬酸鹽、磷酸鹽和醋酸鹽。
- 如請求項1所述之組成物,該組成物進一步包括選自由以下組成之群組的抗氧化劑:抗壞血酸、丁基羥基甲氧苯(BHA)和丁羥甲苯(BHT)。
- 如請求項1所述之組成物,該組成物進一步包括光敏試劑。
- 如請求項1所述之組成物,該組成物進一步包括選自由以下組成之群組的滲透增強劑:硫酸鹽、月桂氮酮、吡咯啶酮、醇、界面活性劑和萜。
- 如請求項1所述之組成物,該組成物進一步包括著色劑、甜味劑和調味劑。
- 一種製作LSD的固體口服立即釋放配製物之方法,該方法包括以下步驟:在預形成模具中提供含有大於0重量份至小於1重量份的LSD和2至10重量份的非膠化的基質形成劑、2至10重量份的填料、1至5重量份的黏合劑和緩衝劑的賦形劑之速凍儲備溶液,其中該非膠化的基質形成劑為魚膠或麥芽糖糊精,該黏合劑為甲基纖維素,該填料為甘露醇或海藻糖;並且 在預形成模具中凍乾含有該LSD和該非膠化的基質形成劑、該填料、該黏合劑和該緩衝劑的賦形劑之速凍儲備溶液,形成口腔崩散錠。
- 如請求項7所述之方法,其中該緩衝劑選自由以下組成之群組:檸檬酸鹽、磷酸鹽和醋酸鹽。
- 如請求項7所述之方法,其中該LSD處於選自游離鹼和鹽的形式。
- 如請求項7所述之方法,其中該LSD處於鹽形式,並且該鹽選自由以下組成之群組:鹽酸鹽、氫溴酸鹽、馬來酸鹽、酒石酸鹽、檸檬酸鹽、磷酸鹽、富馬酸鹽、硫酸鹽、甲磺酸鹽、醋酸鹽和草酸鹽。
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