相關申請之交叉參考
本文主張於2013年3月15申請之美國臨時專利申請案第61/801,896號之35 U.S.C.§119 (e)的權益，且其揭示內容以引用的方式併入本文中。
如本文所用，術語「控制釋放」及「修飾釋放」為可互換使用且係指以脫離立即釋放之方式釋放所投與之維他命D化合物。如本文所用，術語「持續釋放」及「延伸釋放」可互換使用且係指與可比較的立即釋放調配物相比，釋放所投與之維他命D化合物歷經更長時間，從而導致與可比較的立即釋放調配物相比，維他命D化合物之血清濃度在基線上保持升高更長時間。前述術語視情況包括延緩釋放特徵。舉例而言，延緩釋放類型之控制釋放調配物將藉由在一時間時Cmax
大於立即釋放調配物之Cmax
表徵。作為另一實例，25-羥基維他命D化合物之釋放將較佳地以使25-羥基維他命D之總血清或血液含量在延伸之時間(例如4至24小時或甚至更長)內維持或升高超過預給藥量的此類速率。
如本文所用，除非另外規定，否則術語「纖維素化合物」可包括纖維素(C6
H10
O5
)n
或纖維素衍生物。「纖維素醚」為已經化學改質以引起纖維素分子中羥基局部或完全醚化之纖維素衍生物。可用作穩定藥劑之纖維素衍生物之實例例如包括(但不限於)纖維糖醛酸、羧甲基纖維素、乙基纖維素、羥乙基纖維素、羥丙基纖維素、羥丙基甲基纖維素、甲基纖維素、聚陰離子纖維素及其組合。藉由術語亦包涵對應於例如分子量、黏度、溶解度之變量之不同級的各纖維素化合物或穩定劑。
任何適用於預防預防及/或治療用途之維他命D化合物及其組合預期包括在本文所述之調配物中。維他命D、25-羥基維他命D、1,25-二羥基維他命D及其他代謝物及維他命D類似物亦用作醫藥組合物中之活性化合物。特定實例包括(但不限於)維他命D3
(膽鈣化醇)、維他命D2
(麥角鈣化醇)、25-羥基維他命D3
、25-羥基維他命D2
、25-羥基維他命D4
、25-羥基維他命D5
、25-羥基維他命D7
、1α,25-二羥基維他命D3
、1α,25-二羥基維他命D2
、1α,25-二羥基維他命D4
及維他命D類似物(包括所有羥基及二羥基形式)，該等維他命D類似物包括1,25-二羥基-19-去甲-維他命D2
及1α-羥基維他命D3
。在一種實施例中，維他命D化合物包括一或多個羥基形式，諸如25-羥基維他命D3
及25-羥基維他命D2
之組合。
尤其預期用於本文所揭示之調配物之維他命D化合物的類型可包括25-羥基維他命D2
、25-羥基維他命D3
或其組合。尤其考慮25-羥基維他命D3
。如本文所用，術語25-羥基維他命D係指25-羥基維他命D3
、25-羥基維他命D2
、25-羥基維他命D4
、25-羥基維他命D5
或25-羥基維他命D7
中之一或多者，且意欲在任何提及尚未較佳實施例中為25-羥基維他命D3
及25-羥基維他命D2
中之一或多者、較佳為25-羥基維他命D3
。由此，在本文所述之任何及所有調配物中，特定預期活性劑可包括25-羥基維他命D2
及25-羥基維他命D3
，尤其25-羥基維他命D3
中之一者或兩者。在本發明中，維他命D化合物(或其組合)亦稱為調配物(或「活性」藥劑)之「活性」部分，以區別於控制釋放基質、穩定劑及其他賦形劑。在本文所報導之關於使用25-羥基維他命D3
作為活性劑之樣品的藥物動力學測試中，25-羥基維他命D之參考應解釋為意謂25-羥基維他命D3
，且與之有關之所有藥物動力學(PK)結果(例如tmax
、Cmax
、AUC)應理解為基於25-羥基維他命D3
。
如本文所用，「經穩定之」調配物係指展現穩定的活體外溶解特徵(根據本文進一步所述之參數中之任一者)及在初始製造之後(例如在實際貨架儲存或加速穩定儲存條件之後)的一段時間，活體內維他命D化合物之控制釋放(例如持續釋放)之調配物。活性成分之釋放可使用合適之活體外溶解法量測，諸如此項技術中已知之方法中之一種。原則上，若調配物為穩定的，則可使用以下溶解研究中之任一者進行測定，該等溶解研究描述於美國藥典，USP 29-NF 24，溶解＜711＞物理試驗及測定，美國藥典公約公司，Rockville，MD，2006，第2673-2682頁；歐洲藥典2.9.3固體劑型之溶解試驗或日本藥典6.10溶解試驗中。出於本發明之目的，活體外溶解法為美國藥典，USP 29-NF 24，溶解＜711＞物理試驗及測定，美國藥典公約公司，Rockville，MD，2006，第2673-2682頁，使用以下實例中如所述之設備2 (攪拌槳法)。
如本文所用，tmax
(或Tmax)定義為在投與本發明之調配物之後，活性化合物之血漿濃度以劑量間隔達到其最大值的時間。當投與單一的25-羥基維他命D化合物(例如25-羥基維他命D3
)時，除非另外規定，否則tmax
定義為在投與調配物之後，血清25-羥基維他命D3
之血漿濃度以劑量間隔達到其最大值的時間。
符合NKF K/DOQI指南，如本文所用將維他命D充足定義為血清25-羥基維他命D含量≥ 30 ng/mL，將維他命D不足定義為血清25-羥基維他命D含量為16-30 ng/mL，將輕度維他命D缺乏定義為血清25-羥基維他命D含量為5-15 ng/mL，且將嚴重的維他命D缺乏定義為25-羥基維他命D含量小於5 ng/mL。
在禁止授予在人體上實踐之方法專利權的權限中，對於人類個體「服用」組合物之含義應受限於開(藥)人類個體將藉由任何技術(例如經口、吸入、表面塗覆、注射、插入等)自我服用之受控物質。預期採用與界定可獲專利之標的物之法律或法規一致的最廣泛合理的解釋。在不禁止授予在人體上實踐之方法專利權的權限中，「服用」組合物包括在人體上實踐之兩種方法以及前述活動。
特定瞭解本文所述之任何數值包括下限值至上限值之所有值，亦即所列舉最低值與最高值之間的數值之所有可能組合欲視為在本申請案中明確陳述。舉例而言，若濃度範圍或有利的效應範圍陳述為1%至50%，則希望在本說明書中明確地列舉諸如2%至40%、10%至30%或1%至3%等之值。作為另一實例，約20%之所述濃度意欲包括19.5%至至多20.5%之值。此等實例僅為特定預期之實例。
本文中所揭示為用於維他命D化合物在攝入調配物之個體之胃腸道中控制釋放的調配物。調配物將包括如本文所述之維他命D化合物、可釋放地結合維他命D化合物及可控制地釋放維他命D化合物之基質組分(例如親脂性基質)及穩定劑(例如纖維素化合物)。
本發明之經穩定之調配物在儲存一段時間之後，在活體外溶解中釋放一定量之25-羥基維他命D，該溶解非實質上不同於僅在製造之後及在儲存之前之相同調配物的溶解。舉例而言，在一個實施例中，調配物在暴露於25℃及60%相對濕度下之儲存條件兩個月之後的活體外溶解期間釋放一定量之25-羥基維他命D，與在將調配物暴露於儲存條件之前(亦即新鮮製得的產物)所進行的活體外溶解期間，在同一溶解時間點時的釋放量相比，該釋放量在四小時之後的任何給定溶解時間點變化30%或小於30%。
下表提供在初始製造之後在25℃及60%RH下及或者在40℃及75%RH下多次儲存之後，及在溶解試驗期間之不同時間時，本發明之實施例所預期之儲存穩定性之有利程度的實例。儲存穩定性之程度以與標稱活性效能偏離之最大值表示，亦即自LC變化之最大值%。亦提供最大值偏離之替代性實施例。 時間(h) 1 個月 3 個月 6 個月 9 個月 12 個月 18 個月 24 個月
在25℃及60% RH下儲存
2 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10%
4 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10%
6 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10%
8 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10%
12 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10%
在40℃及75% RH下儲存
2 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10%
4 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10%
6 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10%
8 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10%
12 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10% 30%，或25%，或20%，或15%，或10%
在一種實施例中，調配物在整個溶解試驗中多個時間點時將具有緊接著以上表中所述之穩定性的有利程度，例如至少在2及4小時之兩個時間點、視情況亦在6小時時間點、進一步視情況亦在8小時時間點及進一步視情況亦在12小時時間點，以使得儲存之後的溶解特徵遵循新鮮產物之溶解特徵。或者，調配物至少在2、6及12小時時間點時將具有緊接著以上表中所述之穩定性的有利程度。或者，調配物至少在4、8及12小時時間點時將具有緊接著以上表中所述之穩定性的有利程度。或者，調配物至少在2、4及6小時時間點時將具有緊接著以上表中所述之穩定性的有利程度。或者，調配物至少在4、6、8及12小時時間點或4小時之所有時間時及其後將具有緊接著以上表中所述之穩定性的有利程度。
在緊接著以上表中所述之任何及所有實施例中，就新鮮產物而言偏離意欲可為正(更多釋放)或為負(較少釋放)。在一種實施例中，偏離意欲在多個時間點將處於負方向(較少釋放)。再者，在一種實施例中，若調配物中不存在穩定劑，則在溶解釋放中之偏離意欲在多個時間點將已為負(較少釋放)。
在本文涵蓋之任何實施例中，調配物之溶解釋放曲線可具有以下本文所提供之實例中之任一者的特徵。舉例而言，調配物可藉由溶解釋放曲線表徵，該溶解釋放曲線提供在2小時時小於30%、在6小時時大於45%及在12小時時大於80%及在6小時時進一步視情況小於60%之維他命D化合物的釋放。
在另一種實施例中，調配物可藉由提供在100至140分鐘時小於30%、在5至7小時時大於45%及在11至13小時時大於80%之維他命D化合物之釋放的活體外溶解特徵表徵。在另一種實施例中，調配物可藉由提供在2小時時小於30%、在6小時時大於45%及在12小時時大於80%之維他命D化合物之釋放的活體外溶解特徵表徵。在此等類型之實施例中，視情況維他命D化合物之釋放在5至7小時時小於60%或在6小時時小於60%。
在另一種實施例中，調配物可藉由提供在2小時為約20%至約40%、在6小時時至少為35%及在12小時時至少為70%之維他命D化合物之釋放的活體外溶解特徵表徵。在另一種實施例中，調配物可藉由提供在2小時時為約25%至約35%、在6小時時至少為40%及在12小時時至少為75%之維他命D化合物之釋放的活體外溶解特徵表徵。在此等類型之實施例中，視情況維他命D化合物之釋放例如在6小時時為75%或小於75%、或在6小時時為65%或小於65%、或在6小時時為60%或小於60%。
在本文所述之任何實施例中，經穩定之調配物可藉由投與人類患者劑型之後的tmax
表徵，該tmax
為至少4小時、或至少8小時、或至少12小時、或至少18小時、或至少20小時、或至少24小時、或至少28小時，例如在4至96小時範圍內、或在18至30小時範圍內、或在13至28小時範圍內、或例如為28小時。
在本文所涵蓋之任何實施例中，包含25-羥基維他命D之調配物，其特徵在於提供每微克25-羥基維他命D經基線調整之Cmax
，當投與成人時，該Cmax
在約0.0133 ng/mL至約0.04 ng/mL範圍內。
在本文所涵蓋之方法中之任一種中，該方法可包括向人類患者投與包含25-羥基維他命D化合物之經穩定之持續釋放劑型，包含向患者投與有效量之調配物以提供經基線調整之Cmax
，該Cmax
至少為約0.2 ng/mL、及視情況小於110 ng/mL、及進一步視情況為24 ng/mL或小於24 ng/mL，例如在約0.2至約24 ng/mL範圍內。
在本文所涵蓋之方法中之任一種中，該方法可包括向人類患者投與包含25-羥基維他命D化合物之經穩定之持續釋放劑型，包含向患者投與有效量之調配物以提供經基線調整之AUC0-inf
，該AUC0-inf
至少為52 ng*h/mL、及視情況小於34,500 ng*h/mL、及進一步視情況為約12,000 ng*h/mL或小於12,000 ng*h/mL，例如在約52 ng*h/mL至約12,000 ng*h/mL範圍內。
在本文所述之任何實施例中，經穩定之調配物意欲在儲存之後可生物等效於新鮮製得的產物。由此，例如經穩定之調配物在儲存之後可提供活性劑之曲線下面積(或血清中總25-羥基維他命D)，AUC(例如AUC0-inf
或AUC0-t
)在90%信賴區間內、或在新鮮產物之平均值之80%至125%內、或在其平均值之80%至120%內。另外或在替代方案中，經穩定之調配物在儲存之後可提供活性劑(或血清總25-羥基維他命D)之最大血清濃度，Cmax
(例如絕對Cmax
或相比於基線之Cmax
)在90%信賴區間內、或在新鮮產物之平均值之80%至125%內、或在其平均值之80%至120%內。
在一個實施例中，經穩定之調配物包含25-羥基維他命D2
及25-羥基維他命D3
、蠟基質及纖維素化合物中之一者或兩者。在一個態樣中，經穩定之調配物包含25-羥基維他命D2
及25-羥基維他命D3
、蠟基質及纖維素穩定劑中之一者或兩者。在另一態樣中，調配物包含25-羥基維他命D2
及25-羥基維他命D3
、蠟基質及有效量之纖維素化合物中之一者或兩者以提供如本文所述之有利的穩定度，例如根據緊接著以上表格或符合以下所述之實例中之任一者。舉例而言，該量可有效提供在暴露於25℃及60%相對濕度之儲存條件至少一個月之後的活體外溶解期間，在溶解時間點時所釋放之活性劑的量與在調配物暴露於儲存條件之前所進行之活體外溶解期間，在同一溶解時間點時所釋放之量之間30%或小於30%之差異，而比較調配物缺乏穩定劑將在相同儲存條件之後的溶解釋放中產生更大的差異。
在一個態樣中，調配物為經改良之調配物，其用於在攝入該調配物之個體之胃腸道中維他命D化合物的控制釋放。在一個實施例中，改良包含將纖維素穩定劑摻和至調配物中以用於在攝入該調配物之個體之胃腸道中維他命D化合物的控制釋放。在另一實施例中，改良包含將有效量之纖維素化合物混雜至調配物中以用於攝入該調配物之個體之胃腸道中維他命D化合物的控制釋放，從而提供如本文所述之有利的穩定度，例如根據緊接著以上表格或符合以下所述之實例中之任一者。舉例而言，該量可有效提供在暴露於25℃及60%相對濕度之儲存條件至少一個月之後的活體外溶解期間，在溶解時間點時所釋放之活性劑的量與在調配物暴露於儲存條件之前所進行之活體外溶解期間，在同一溶解時間點時所釋放之量之間30%或小於30%之差異，而比較調配物缺乏穩定劑將在相同儲存條件之後的溶解釋放中產生更大的差異。
穩定劑可包括纖維素化合物。用於本發明之經穩定之調配物的纖維素化合物及穩定劑之實例可包括(但不限於)纖維糖醛酸、羧甲基纖維素、乙基纖維素、羥乙基纖維素、羥丙基纖維素、羥丙基甲基纖維素、甲基纖維素、聚陰離子纖維素及其組合。亦涵蓋泊洛沙姆(poloxamer)(例如polaxamer 407)、聚(環氧乙烷)聚合物(例如Dow's POLYOX polymers)、普維酮(povidones)及煙霧狀二氧化矽(例如AEROSIL 200, Evonik Industries AG, Essen, Germany)中之一或多者。穩定劑(例如纖維素化合物)較佳以基於除任何其他包衣或外殼外之調配物的總重量，調配物之至少約5%之量(wt%)的形式存在。舉例而言，纖維素化合物可以調配物之至少5 wt%、或調配物之至少10 wt%、或調配物之至少15 wt%、或大於調配物之5 wt%、或大於調配物之10 wt%、或大於調配物之15 wt%之量的形式存在。合適之範圍包括5 wt%至30 wt%、10 wt%至20 wt%、10 wt%至15 wt%、5 wt%至15 wt%及7.5 wt%至12.5 wt.%。實例包括約5 wt%、約6 wt%、約7 wt%、約8 wt%、約9 wt%、約10 wt%、約11 wt%、約12 wt%、約13 wt%、約14 wt%及約15 wt%。應瞭解本文中所提及之穩定劑為針對在儲存條件(例如典型的貨架儲存條件)期間隨時間推移產生之實質性變化，使溶解釋放曲線(及由此亦為活體內釋放曲線)穩定之試劑。用於預防活性組分本身降解之作為防腐劑之此項技術中已知的其他藥劑並不意欲包涵在術語「穩定劑(stabilizing agent)」及「穩定劑(stabilizer)」內,儘管該等防腐劑亦預期用於本發明之調配物。
在一類實施例中，纖維素化合物為纖維素醚。纖維素醚之實例包括(但不限於)甲基纖維素、羥丙基甲基纖維素、羥乙基甲基纖維素、羥乙基纖維素、羥丙基纖維素及其組合。
尤其考慮羥丙基甲基纖維素(HPMC)。HPMC可藉由以下特徵中之一或多者表徵，該等特徵單獨地及以組合形式特定預期。HPMC中之甲氧基組分%可在19至24範圍內。羥丙基組分%可在7至12範圍內。視黏度(在20℃下2%水溶液)可為至少50,000厘泊、或至少80,000厘泊、或在約80至120,000厘泊、或3000至120,000厘泊、或11,000至120,000厘泊、或80,000至120,000厘泊範圍內。特定而言，視黏度(在20℃下2%水溶液)可在80,000至120,000厘泊範圍內。pH值(1%水溶液)可在5.5至8.0範圍內。舉例而言，具有所有上述性質，包括80,000至120,000厘泊範圍內之視黏度(在20℃下2%水溶液)之合適的羥丙基甲基纖維素為METHOCEL K100M CR (Dow Wolff Cellulosics, Midland, Michigan)。
在一種實施例中，纖維素化合物在基質之主要組分的熔點(例如在65℃下或在60℃至75℃範圍內)下，在基質調配物中將為不溶的。
在一種實施例中，纖維素化合物將為親水性的。
包含25-羥基維他命D2
及25-羥基維他命D3
及纖維素化合物中之一者或多者之本發明的醫藥調配物，與缺少纖維素化合物之調配物相比，出乎意料地具有經改良之穩定性。在一個實施例中，本發明之經穩定之調配物包含包含25-羥基維他命D2
及25-羥基維他命D3
及纖維素穩定劑中之一者或兩者之活性裝載之親脂性基質的混合物，其中在暴露於25℃及60%相對濕度下之儲存條件至少一個月之後的活體外溶解期間，調配物釋放一定量之25-羥基維他命D，與在新鮮製得的產物上所進行之活體外溶解期間的相同溶解時間點時的釋放量相比，該釋放量在任何給定溶解時間點時變化30%或小於30%。
未經穩定之調配物在組合物儲存一段時間之後所釋放之活性成分的量上呈現變化，如以下實例中所示。未經穩定之調配物在暴露於儲存條件之後釋放一定量之25-羥基維他命D，該釋放量可在給定溶解時間點時變化，例如與在新鮮製得的產物上所進行之活體外溶解期間的相同溶解時間點時的釋放量相比，變化超過30%。在給定時間點時變化可為溶解速率之增加或降低，且該等變化產生溶解特徵之曲線不同於最初溶解特徵之形狀的溶解特徵。與本發明之經穩定之調配物相比，未經穩定之調配物在如本文所述之儲存之後(例如在25℃及60%RH下儲存3個月或更長時間之後)亦展現不同的活體內效應。與未經穩定之調配物相比，經穩定之調配物在如本文所述之儲存之後(例如在25℃及60%RH下儲存3個月或更長時間之後)展示不同的臨床藥物動力學參數，諸如經改良之生物可用性。本發明之經穩定之調配物可具有儲存不穩定之基礎調配物以及如本文所述使調配物儲存穩定之穩定劑。
可釋放地結合及可控制地釋放活性組分之基質可例如為親脂性基質，包括蠟基質。蠟基質可提供室溫下固體或半固體之調配物且提供體溫下固體、半固體或液體之調配物，較佳提供體溫下半固體或液體之調配物。在一個態樣中，蠟基質包含控制釋放試劑、乳化劑及吸收增進劑。
適用於該用途之控制釋放試劑之實例包括(但不限於)蠟(包括合成蠟、微晶蠟、固體石臘、巴西棕櫚蠟及蜂臘)；聚乙氧基化蓖麻油衍生物、經氫化之植物油、甘油單-、雙-或三蘿酸酯；長鏈醇(諸如硬脂醇、鯨蠟醇及聚乙二醇)；及上述中之任一者之混合物。較佳為非消化性蠟質物質(諸如硬石臘)。
控制釋放試劑可以調配物之至少5 wt%或大於調配物之約5 wt%之量的形式存在。舉例而言，視所使用之控制釋放試劑而定，控制釋放試劑可包含調配物之至少5 wt%或調配物之至少10 wt%、或調配物之至少15 wt%、或調配物之至少20 wt%、或調配物之至少25 wt%、或大於調配物之5 wt%、或大於調配物之10 wt%、或大於調配物之15 wt%、或大於調配物之20 wt%及或大於調配物之25 wt%。控制釋放試劑可以50 wt%或小於50 wt%、40 wt%或小於40 wt%、35 wt%或小於35 wt%或30 wt%或小於30 wt%之量的形式存在。合適之範圍包括5 wt%至40 wt%、10 wt%至30 wt%及15 wt%至25 wt%。實例包括約15 wt%、約16 wt%、約17 wt%、約18 wt%、約19 wt%、約20 wt%、約21 wt%、約22 wt%、約23 wt%、約24 wt%及約25 wt%。
適用於調配物之乳化劑之實例包括(但不限於)具有小於7之HLB的親脂性試劑(諸如混合性脂肪酸單甘油酯；混合性脂肪酸二甘油酯；脂肪酸單及二甘油酯之混合物)；親脂性聚甘油酯；包括甘油單油酸酯、甘油二油酸酯、甘油單硬脂酸酯、甘油二硬脂酸酯、甘油單棕櫚酸酯及甘油二棕櫚酸酯之甘油酯；脂肪酸甘油乳酸酯；包括丙二醇單棕櫚酸酯、丙二醇單硬脂酸酯及丙二醇單油酸酯之丙二醇酯；包括脫水山梨糖醇單硬脂酸酯、脫水山梨糖醇倍半油酸酯之脫水山梨糖醇酯；包括硬脂酸、棕櫚酸及油酸之脂肪酸及其皂類；及其混合物；甘油單油酸酯、甘油二油酸酯、甘油單硬脂酸酯、甘油二硬脂酸酯、甘油單棕櫚酸酯、及甘油二棕櫚酸酯；脂肪酸甘油乳酸酯；包括丙二醇單棕櫚酸酯、丙二醇單硬脂酸酯及丙二醇單油酸酯之丙二醇酯；包括脫水山梨糖醇單硬脂酸酯、脫水山梨糖醇倍半油酸酯之脫水山梨糖醇酯；包括硬脂酸、棕櫚酸及油酸之脂肪酸及其皂類；及其混合物。
較佳親脂性試劑係選自甘油酯及其衍生物。較佳甘油酯係選自由中鏈或長鏈甘油酯、辛醯己醯聚乙二醇甘油酯及其混合物組成之群。
較佳中鏈甘油酯包括(但不限於)中鏈單甘油酯、中鏈二甘油酯、辛酸/癸酸三甘油酯、單月桂酸甘油酯、單硬脂酸甘油酯、辛酸/癸酸甘油酯、單辛酸甘油酯、單二辛酸甘油酯、辛酸/癸酸亞麻油酸三甘油酯及辛酸/癸酸/丁二酸三甘油酯。
具有低熔點之單甘油酯較佳用於製備調配物。較佳單甘油酯包括(但不限於)單硬脂酸甘油酯、單棕櫚酸甘油酯、單油酸甘油酯、單辛酸甘油酯、單癸酸甘油酯、單月桂酸甘油酯等，較佳為單硬脂酸甘油酯(GMS)。GMS為天然乳化劑。其為油溶性但難溶於水。GMS之HLB值為3.8。親脂性乳化劑可例如以約10 wt%至約40 wt%或約20 wt%至約25 wt%之量的形式存在。其他實例包括約20 wt%、約21 wt%、約22 wt%、約23 wt%、約24 wt%及約25 wt%。
合適之吸收增進劑之實例包括(但不限於)諸如聚乙烯糖基化甘油酯之辛醯己醯聚乙二醇甘油酯，亦稱為聚乙二醇化(polyglycolized)甘油酯或聚乙二醇化(PEGylated)甘油酯。可在組合物中採用之聚乙二醇化甘油酯包括(但不限於)單甘油酯、二甘油酯及三甘油酯及聚乙二醇之單酯及二酯之混合物、聚乙烯糖基化杏仁甘油酯、聚乙烯糖基化玉米甘油酯及聚乙烯糖基化辛酸/癸酸三甘油酯。吸收增進劑之HLB值可為13至18或為13至15。
已知的一個較佳吸收增進劑係在商標名GELUCIRE(Gattefossé Corporation, Paramus, New Jersey, USA)下。GELUCIRE為熟知的賦形劑，其為甘油及PEG酯之脂肪酸酯之家族，亦稱為聚乙二醇化甘油酯。GELUCIRE用於不同的應用(包括製備持續釋放醫藥組合物)中。GELUCIRE化合物為惰性、半固體蠟質材料，其為兩性的且可獲得不同溶劑中之變化的物理特徵(諸如熔點、HLB及溶解度)。其實際上為界面活性劑且在水性介質中分散或溶解進而形成微胞、顯微小球體或微脂粒。其藉由其熔點/HLB值識別。熔點以攝氏度表示。可選擇不同等級之GELUCIRE賦形劑中之一種或混合物以達成熔點及/或HLB值之所需特徵。較佳GELUCIRE組合物為GELUCIRE 44/14 (十二醯聚乙二醇甘油酯及十二醯聚氧甘油酯之混合物)，其具有44℃之熔點及14之HLB。吸收增進劑可例如以約5 wt%至約20 wt%或約8 wt%至約15 wt%之量的形式存在。其他實例包括約8 wt%、約9 wt%、約10 wt%、約11 wt%、約12 wt%、約13 wt%、約14 wt%及約15 wt%。
蠟基質之低熔點提供在約0℃至約50℃高於蠟基質之熔點的溫度下，結合醫藥學活性成分(例如諸如25-D2
、25-D3
或二者之維他命D化合物)，且隨後將熔融物(溶液及/或分散液)填充進合適之膠囊中之方法。膠囊可為與熔融物填充之溫度相容之任何品種，包括軟或硬明膠膠囊及動物或植物明膠膠囊。熔融物在冷卻至室溫時於膠囊內固化。
在一個態樣中，經穩定之調配物可進一步包含用於25-羥基維他命D2
及/或25-羥基維他命D3
之油性媒劑。可使用任何醫藥學可接受之油。實例包括動物(例如魚)、植物(例如大豆)及礦物油。油較佳地將易於溶解所使用之25-羥基維他命D化合物。較佳油性媒劑包括非消化性油，諸如礦物油，特定而言，液體石蠟及角鯊烯。油性媒劑可例如以調配物之約10 wt%至約50 wt%、或約15 wt%至約45 wt%、或約20 wt%至約40 wt%、或約30 wt%至約40 wt%範圍內之濃度的形式存在。在一種實施例中，合適之液體石蠟可藉由以下參數中之一或多者表徵：比重約為0.88至0.89；運動黏度(40℃)為約64 cSt至約70 cSt；分子量為424；石蠟烴%為約59；及傾點為-24℃。蠟基質與油性媒劑之間的比率可經優化為了達成維他命D化合物之釋放之所需速率。由此，若使用較重的油組分，則可使用相對較少之蠟基質，且若使用較輕的油組分，則可使用相對較多之蠟基質。
本發明之經穩定之控制釋放組合物較佳地經設計以例如使每單位劑量含有1至1000 μg之25-羥基維他命D2
及/或25-羥基維他命D3
之濃度，且以此方式製備以達成25-羥基維他命D2
/25-羥基維他命D3
之效應受控或實質上恆定釋放，視情況歷經延伸之時間段釋放至人類或動物之胃腸道之迴腸中。劑量之實例包括每單位劑量1 μg至1000 μg、1 μg至600 μg、1 μg至400 μg、1 μg至200 μg、1 μg至100 μg、5 μg至90 μg、30 μg至80 μg、20 μg至60 μg、30 μg至60 μg、35 μg至50 μg、5 μg至50 μg及10 μg至25 μg，例如20 μg、25 μg、30 μg、40 μg、50 μg、60 μg、70 μg、80 μg、90 μg及100 μg。
在一個較佳類別之實施例中，控制釋放調配物在給藥後的第一24小時內釋放至少70%之維他命D化合物，更佳至少80%。
有利的是，可例如經口，根據上述實施例，例如以每天1至100 μg劑量投與25-羥基維他命D2
、25-羥基維他命D3
或其組合連同其他治療劑。在一種實施例中，將選擇劑量以提供劑量間隔中約1至3 ng/ml之血清25-羥基維他命D3
的平均升高。
在實施例中，本文所述之調配物可投與升高及較佳地亦使血液中1,25-二羥基維他命D含量維持在25 pg/mL、30 pg/mL或更高(例如25-65 pg/mL)持續一段延伸之時間段，例如至少一個月、至少三個月、至少六個月或更長時間。
在一個態樣中，可向患者投與本文所述之調配物以降低或維持降低之血清副甲狀腺激素含量，較佳為PTH含量降低至少30%之量，或者使PTH之血清含量降至CKD期之目標範圍(例如對於3期為35-70 pg/mL (相當於3.85-7.7 pmol/L)、對於4期為70-110 pg/mL (相當於7.7-12.1 pmol/L)及對於5期為150-300 pg/mL (相當於16.5-33.0 pmol/L) (K/DOQI指南1號中所定義))所需的量。
在另一態樣中，可向罹患慢性腎病之繼發性甲狀腺高能症(例如3或4期，或3、4或5期)之患者投與本發明的調配物以降低血清PTH含量。
本文所述之劑量預期用於本文所述之治療方法中之任一者。應瞭解在特定情況下維他命D化合物之實際較佳量將根據所調配之特定組合物、應用模式及經治療之特定部位而變化。劑量可使用習知考慮進行測定，例如藉由習用比較激素及已知試劑之不同活性，例如藉助於恰當的習知藥理學方案。
用於各特定患者之特定劑量可視各種因素而定，例如年齡、體重、一般健康狀況、性別、飲食、投與之時序及模式、排泄速率、組合使用之藥劑及施用療法之特定病症的嚴重度。
需要維他命D補充之患者包括健康個體及處於維他命D不足或缺乏之風險中的個體，例如患有1、2、3、4或5期CKD之個體；不飲用維他命D強化乳之嬰兒、兒童及成人(例如乳糖不耐受個體、牛奶過敏個體、不食用牛奶之素食者及母乳餵養之嬰兒)；患有佝僂病個體；深色皮膚個體 (例如在美國，42%介於15歲與49歲年齡之間的非洲裔美國女性與4%白人女性相比為維他命D缺乏)；老人(合成維他命D能力降低以及更可能待在室內)；機構化之成人(可能待在室內之成人，包括患有阿茲海默氏(Alzheimer)病或精神病之個體)；覆蓋所有裸露皮膚之個體(諸如某些宗教或文化之人員)；總是使用防曬劑之個體(例如塗覆防曬係數(SPF)值為8的防曬劑減少95%維他命D之產生，且較高的SPF值可進一步減少維他命D)；患有脂肪吸收障礙症候群(包括(但不限於)囊腫性纖維化、膽汁鬱滯性肝病、其他肝病、膽囊疾病、胰酶缺乏症、克羅恩氏(Crohn)病、發炎性腸道疾病、口炎性腹瀉或乳糜瀉或手術移除部分或所有胃及/或腸)之個體；患有發炎性腸道疾病之個體；患有克羅恩氏(Crohn)病之個體；已將小腸切除之個體；患有齒齦病之個體；服用增加維他命D代謝之藥物(包括苯妥英(phenytoin)、磷苯妥英(fosphenytoin)、苯巴比妥(phenobarbital)、卡馬西平(carbamazepine)及利福平(rifampin))之個體；服用降低維他命D吸收之藥物(包括消膽胺(cholestyramine)、考來替潑(colestipol)、羅氏鮮(orlistat)、礦物油及脂肪替代物)之個體；服用抑制維他命D活化之藥物(包括酮康唑(ketoconazole))之個體；服用降低鈣吸收之藥物(包括皮質類固醇)之個體；患有肥胖症之個體(沈積於身體脂肪儲存中之維他命D為較少生物可用的)；患有骨質疏鬆症之個體；患有低骨礦物質密度及骨質疏鬆症之患者；及/或停經後女性。根據關於維他命D之膳食參考攝入量之醫學學會報告，食品食用資料表明年輕及年長女性之維他命D的中值攝入量低於當前建議的攝入量；資料表明超過50%之年輕及年長女性未食用所建議之維他命D的量。
視情況自本文所述之本發明之方法排除的為治療處理罹患腎性骨營養不良(包括軟骨病及囊性纖維性骨炎)之個體。
在其他態樣中，本發明之組合物及方法適用於預防或治療處理維他命D反應性疾病，亦即其中維他命D、25-羥基維他命D或活性維他命D (例如1,25-二羥基維他命D)防止疾病發作或發展或減少疾病之徵象或症狀的疾病。該等維他命D反應性疾病包括癌症(例如乳房、肺、皮膚、黑素瘤、結腸、結腸直腸、直腸、前列腺、及骨癌)。已觀察1,25-二羥基維他命D在活體外誘發多個細胞之細胞分化及/或抑制細胞增殖。維他命D反應性疾病亦包括自體免疫疾病，例如I型糖尿病、多發性硬化、類風濕性關節炎、多發性肌炎、皮肌炎、硬皮病、纖維化、格雷弗氏(Grave)病、橋本氏(Hashimoto)病、急性或慢性移植排斥反應、急性或慢性移植物抗宿主疾病、發炎性腸道疾病、克羅恩氏(Crohn)病、全身性紅斑狼瘡、休格連氏症候群、濕疹及銀屑病、皮膚炎(包括異位性皮膚炎、接觸性皮炎、過敏性皮炎及/或慢性皮炎)。維他命D反應性疾病亦包括其他發炎性疾病，例如哮喘、慢性阻塞性肺病、多囊性腎病、多囊性卵巢症候群、胰臟炎、腎炎、肝炎及/或感染。亦已報導維他命D反應性疾病包括高血壓及心血管病。由此，本發明涵蓋預防或治療處理處於罹患心血管病之風險中的個體，例如患有動脈粥樣硬化、動脈硬化、冠狀動脈疾病、腦血管疾病、周邊血管疾病、心肌梗塞、心肌缺血、大腦缺血、中風、充血性心臟衰竭、心肌症、肥胖症或其他體重病症、脂質病症(例如高脂質血症、包括相關之糖尿病性血脂異常及混合性血脂異常低α-脂蛋白血症之血脂異常、高三酸甘油酯血症、高膽固醇血症及低HDL (高密度脂蛋白))、代謝障礙(例如代謝症候群、II型糖尿病、I型糖尿病、高胰島素血症、葡萄糖耐受性異常、胰島素抗性、糖尿病併發症(包括神經病、腎病、視網膜病、糖尿病性足部潰瘍及白內障))及/或血塞之個體。
可受益於維他命D化合物之含量調整之疾病包括(但不限於)：(i)呈副甲狀腺-副甲狀腺低能症、假副甲狀腺低能症、繼發性副甲狀腺高能症形式；(ii)呈胰腺糖尿病形式；(iii)呈甲狀腺髓性癌形式；(iv)呈皮膚銀屑病；創傷癒合形式；(v)呈肺類肉瘤病及肺結核形式；(vi)呈腎慢性腎病、低磷酸鹽VDRR、維他命D依賴性佝僂病形式；(vii)呈骨骼抗驚厥治療、骨纖維生成不良、囊性纖維性骨炎、軟骨病、骨質疏鬆症、骨質減少、骨硬化病、腎性骨營養不良、佝僂病形式；(viii)呈腸糖皮質激素拮抗、嬰兒期自發性高鈣血症、吸收障礙症候群、脂肪痢、熱帶口炎性腹瀉形式；及(ix)自體免疫病症。
在本發明之實施例中，受益於維他命D化合物之含量調整之疾病係選自癌症、皮膚病症(例如銀屑病)、副甲狀腺病症(例如副甲狀腺高能症及繼發性副甲狀腺高能症)、骨骼病症(例如骨質疏鬆症)及自體免疫病症。
調配物可藉由正好在一般熟習此項技術者之能力範圍內的程序製備。舉例而言，視需要可將基質之組分(例如蠟及油性媒劑)進行熔融以提供可流動液體由此使其更容易獲得均質混合物。將活性劑(例如25-羥基維他命D2
及/或25-羥基維他命D3
)添加至液體載劑中，例如溶解於諸如無水乙醇之醇中，且混合成分以提供均質混合物。在一種實施例中，穩定劑可在所有基質組分(例如蠟及油)摻合之後及在與活性劑組合之前添加。混合物可經冷卻且儲存，稍後分成單位劑型(諸如經填充之明膠膠囊)。
在一種方法中，將油性媒劑、控制釋放試劑及乳化劑之一部分加熱至相對較高的溫度(例如65℃)且在添加吸收增進劑之前混合，隨後再混合直至均質，隨後冷卻至中等高溫(例如50℃至55℃)。在獨立容器中，將抗氧化防腐劑及油性媒劑之剩餘部分混合及加熱至中等高溫(例如50℃)，隨後與蠟混合物組合及混合直至獲得均質溶液。然後，添加穩定劑及混合。然後，使於乙醇中之維他命D化合物溶液與均勻蠟質溶液組合，混合直至獲得均質溶液，較佳地填充至膠囊中，且隨後冷卻至室溫。在另一較佳方法中，油性媒劑、控制釋放試劑及乳化劑之一部分在55℃至60℃之溫度下加熱且在添加吸收增進劑之前混合，隨後再混合直至均質。在獨立容器中，將抗氧化防腐劑、油性媒劑之剩餘部分及穩定劑混合及加熱至55℃至60℃之溫度，隨後與蠟混合物組合及混合直至獲得均質溶液。然後，使於乙醇中之維他命D化合物溶液與均勻蠟質溶液組合，混合直至獲得均質溶液，較佳地填充至膠囊中，且隨後冷卻至室溫。
在向需要治療之患者投與之前調配物較佳地置放於膠囊中。該等膠囊可為硬或軟的，且尤其考慮軟膠囊。可使用標準膠囊填充機將調配物填充至明膠膠囊中，諸如藉由熔化調配物及將其注射填充至軟膠囊外殼中。軟膠囊外殼之實例包括VEGICAPS及OPTISHELL技術(Catalent, Somerset, NJ, USA)。在替代方案中，可藉由任何其他合適之製程將調配物製成單位劑型，例如以產生錠劑、藥囊、糖衣藥丸、栓劑或其類似物。
在一種實施例中，製備調配物用於口服遞送且藉由口服遞送進行投與。在另一種實施例中，調配物製備用於栓劑且以栓劑形式投與，例如直腸栓劑。
除非另外說明，否則使用及製備之調配物及方法預期包括包括以下進一步所述之其他視情況選用之要素、特徵及步驟中之一或多者的任何組合之實施例。
由此，在一種實施例中，調配物進一步包括防腐劑(諸如抗氧化劑)。丁基化羥基甲苯(BHT)為較佳。
在另一種實施例中，維他命D化合物與一或多個其他治療劑組合投與。
若維他命D化合物與一或多個其他治療劑組合投與，則所投與之組合中之化合物中的每一者之比例將視所處理之特定疾病病況而定。舉例而言，吾人可選擇與一或多個鈣鹽(預期作為鈣補充物或膳食磷酸鹽黏結劑)、雙膦酸鹽、擬鈣劑(calcimimetics)、菸鹼酸、鐵、磷酸鹽黏結劑、膽鈣化醇、麥角鈣化醇、活性維他命D固醇、血糖及高血壓控制劑、可降解維他命D藥劑之CYP24及其他細胞色素P450酶類之不同抗贅生性藥劑及抑制劑一起投與25-羥基維他命D2
及/或25-羥基維他命D3
(例如經口)。另外，吾人可選擇與膽鈣化醇、麥角鈣化醇、活性維他命D固醇、血糖及高血壓控制劑、可降解維他命D藥劑之CYP24及其他細胞色素P450酶類之不同抗贅生性藥劑及抑制劑一起經靜脈內投與25-羥基維他命D2
及/或25-羥基維他命D3
。實際上，在疾病病況之治療處理為所需終點時，使用較高劑量之本發明之化合物，同時較低劑量通常用於預防目的，亦即在任何給定情況下，所投與之特定劑量將根據所投與之特定化合物、待治療之疾病、個體情況及其他可改變藥物活性或個體反應之相關醫學事實調整，正如熟習此項技術者所熟知。
如上所述，調配物較佳填充至明膠膠囊中，但其亦可以純的形式或以一或多個外塗膜(諸如腸溶塗膜)投與。亦預期調配物可壓製成錠劑，且在該情況下可包括一或多個錠劑壓製賦形劑。
在本文所述之組合物及方法中，上述較佳步驟、較佳組分、其較佳組成範圍及較佳組合可選自本文所提供之各種特定實例。舉例而言，較佳調配物包括25-羥基維他命D(例如約30 μg、約60 μg或約90 μg 25-羥基維他命D3
)、約2 wt% (例如2.32 wt%)無水乙醇、約10 wt%(例如9.75wt%) GELUCIRE 44/14、約20 wt%(例如20.00 wt.%)硬石蠟、約23 wt%(例如22.55 wt%)GMS、約35 wt% (例如35.36 wt%)液體石蠟或礦物油、約10 wt%HPMC及視情況少量防腐劑(例如0.02 wt%BHT)。此調配物之變型將包括約15%(例如15.29 wt%)HPMC及約30wt%(例如29.88 wt%)液體石蠟或礦物油。實例
以下實例說明特定調配物及其製備方法。提供實例係用於說明且並不意欲限制本發明之範疇。
在實例中使用如USP 29-NF 24，通則＜711＞溶解中所述之USP設備2 (攪拌槳法)，使用下文所述之溶解介質進行活體外溶解試驗。一般而言，根據以下步驟進行方法。將所述體積之溶解介質(±1%)置放於指定設備之容器中，組裝設備，平衡溶解介質至37±0.5℃且移除溫度計。將劑量單位置放於設備中，注意自劑量單位之表面除去氣泡且緊接著按指定速率操作設備。在所述時間中之每一處，自溶解介質表面與旋轉葉片頂部之間的中間區域(離容器壁不小於1 cm)抽取標本。在37℃下用相同體積之新鮮溶解介質替換用於分析所抽取之等分試樣。在試驗持續期間保持容器覆蓋且核實在合適之時間時受測試混合物之溫度。在此情況下使用合適之分析方法(超高效液相層析(UPLC))進行分析。
在每個時間點測試各調配物之六個膠囊。溶解介質為在37±0.5℃下0.05 M pH 6.8之磷酸鹽緩衝液/1%十二烷基硫酸鈉溶解介質且以每分鐘100轉操作設備。在2、4、6、8及12小時取出樣品且使用UPLC測定各樣品之25-羥基維他命D含量。實例 1-25- 羥基維他命 D 之未經穩定之持續釋放調配物之活體外溶解
測試由90 µg 25-羥基維他命D3
、19.98 wt%硬石蠟、37.85 wt%GMS、9.76 wt%GELUCIRE 44/14、2.36 wt%無水乙醇、29.88 wt%液體石蠟及0.02 wt%BHT(比較調配物1)的混合物製成之調配物的溶解。調配物不包含纖維素化合物。所釋放之25-羥基維他命D3
之平均量概述於下表中，該等平均量按在T = 0時及在調配物在5℃及環境濕度下受控儲存至多12個月之後，每個劑型標稱載藥量之平均百分比(標示量之平均%，%LC)計算。在試驗之前確定樣品在15℃至30℃範圍內之溫度及環境濕度下儲存持續約3個月之時間段。由此，將應表示時間零點之樣品標記為T = 0p
(偽時間零點)且應瞭解經標稱1個月、3個月、6個月、9個月及12個月老化之樣品亦經歷剛才所述之大約3個月老化時間段。為提供較多精確基線，不經任何老化對新鮮批次相同類型之樣品進行製備及測試，此資料標記為T = 0f
以指示新鮮樣品。亦報告變異係數(%CV)。自藉由T = 0p
及T = 0f
批次所釋放之25-羥基維他命D3
之最初量變化之百分比分別在括號及雙括號中提供。 在 5 ℃ / 環境濕度下儲存之後溶解
時間
(小時) T=0p
偽 T=0f
新鮮 1個月
(%CV)
[自T=0p
變化%]
[[自T=0f
變化%]] 3個月
(%CV)
[自T=0p
變化%]
[[自T=0f
變化%]] 6個月
(%CV)
[自T=0p
變化%]
[[自T=0f
變化%]] 9個月
(%CV)
[自T=0p
變化%]
[[自T=0f
變化%]] 12個月
(%CV)
[自T=0p
變化%]
[[自T=0f
變化%]]
2 6.1
(29.6) 22.1
(17.2) 8.9
(13.4)
[45.9]
[[59.7]] 15.7
(27.4)
[157.4]
[[29.0]] 9.1
(23)
[49.2]
[[58.8]] 15.2
(47.2)
[149.2]
[[31.2]] 12.7
(16.8)
[108.2]
[[42.5]]
4 14.5
(15.7) 52.0
(4.6) 20.7
(19.1)
[42.8]
[[60.2]] 22.3
(15.6)
[53.8]
[[57.1]] 22.9
(7.1)
[57.9]
[[56.0]] 25.2
(19.2)
[73.8]
[[51.5]] 24.7
(13.5)
[70.3]
[[52.5]]
6 27.6
(21.2) 77.9
(4.6) 35.7
(9.6)
[29.3]
[[54.2]] 33.5
(2.6)
[21.4]
[[57.0]] 34.1
(7.1)
[23.6]
[[56.2]] 36.2
(20.5)
[31.2]
[[53.5]] 34.8
(14.6)
[26.1]
[[55.3]]
8 45.7
(23.6) 96.8
(2.9) 53.0
(9.9)
[16.0]
[[45.2]] 47.4
(3.7)
[3.7]
[[51.0]] 46.8
(6)
[2.4]
[[51.7]] 47.8
(18.6)
[4.6]
[[50.6]] 46.4
(8.9)
[1.5]
[[52.1]]
12 89.7
(15.6) 112.3
(1.6) 100.0
(4.8)
[11.5]
[[11.0]] 78.9
(8.1)
[12.0]
[[29.7]] 76.9
(5.7)
[14.3]
[[31.5]] 74.1
(17.3)
[17.4]
[[34.0]] 78.8
(5.3)
[12.2]
[[29.8]]
測試在25℃及60%相對濕度下儲存0至12個月之後比較調配物1之溶解。結果概述於下表中。 在 25 ℃ /60% 相對濕度下儲存之後溶解
溶解時間(小時) T=0p
偽 T=0f
新鮮 1個月
(%CV)
[自T=0p
變化%]
[[自T=0f
變化%]] 3個月
(%CV)
[自T=0p
變化%]
[[自T=0f
變化%]] 6個月
(%CV)
[自T=0p
變化%]
[[自T=0f
變化%]] 9個月
(%CV)
[自T=0p
變化%]
[[自T=0f
變化%]] 12個月
(%CV)
[自T=0p
變化%]
[[自T=0f
變化%]]
2 6.1
(29.6) 22.1
(17.2) 7.6
(7.7)
[24.6]
[[65.6]] 10.8
(15.7)
[77.0]
[[51.1]] 8.5
(19.2)
[39.3]
[[61.5]] 10.8
(15.8)
[77.0]
[[51.1]] 13.5
(24.7)
[121.3]
[[38.9]]
4 14.5
(15.7) 52.0
(4.6) 18.7
(18.6)
[29.0]
[[64.0]] 22.8
(23.7)
[57.2]
[[56.2]] 17.9
(11.9)
[23.4]
[[65.6]] 21.4
(5.5)
[47.6]
[[58.8]] 24.5
(17.4)
[69.0]
[[52.9]]
6 27.6
(21.2) 77.9
(4.6) 27.1
(22.7)
[1.8]
[[65.2]] 30.7
(29.6)
[11.2]
[[60.6]] 23.8
(11.6)
[13.8]
[[69.4]] 27.0
(7.3)
[2.2]
[[65.3]] 30.0
(15.7)
[8.7]
[[61.5]]
8 45.7
(23.6) 96.8
(2.9) 37.1
(18.1)
[18/8]
[[61.7]] 40.6
(29.9)
[11.2]
[[58.1]] 28.5
(13.2)
[37.6]
[[70.6]] 32.3
(6.4)
[29.3]
[[66.6]] 35.6
(14.7)
[22.1]
[[63.2]]
12 89.7
(15.6) 112.3
(1.6) 61.6
(16.6)
[31.3]
[[45.1]] 53.0
(32.2)
[40.9]
[[52.8]] 38.5
(12.2)
[57.1]
[[65.7]] 38.9
(6)
[56.6]
[[65.4]] 44.2
(12.2)
[50.7]
[[60.6]]
測試在40℃及75%相對濕度下儲存0、1、3及6個月之後比較調配物1之溶解。結果概述於下表中。 在 40 ℃ /75% 相對濕度下儲存之後溶解
溶解時間(小時) T=0p
偽 T=0f
新鮮 1個月
(%CV)
[自T=0p
變化%]
[[自T=0f
變化%]] 3個月
(%CV)
[自T=0p
變化%]
[[自T=0f
變化%]] 6個月
(%CV)
[自T=0p
變化%]
[[自T=0f
變化%]]
2 6.1
(29.6) 22.1
(17.2) 11.7
(50)
[91.8]
[[47.1]] 16.9
(36.3)
[177.0]
[[23.5]] 1.8
(75)
[70.5]
[[91.9]]
4 14.5
(15.7) 52.0
(4.6) 52.0
(45.1)
[258.6]
[[0]] 59.8
(31.3)
[312.4]
[[15.0]] 36.2
(21.8)
[149.7]
[[30.4]]
6 27.6
(21.2) 77.9
(4.6) 87.0
(21.5)
[215.2]
[[11.7]] 97.8
(24)
[254.3]
[[25.5]] 76.7
(12.3)
[177.9]
[[1.5]]
8 45.7
(23.6) 96.8
(2.9) 107.3
(8.1)
[134.8]
[[10.8]] 110.9
(13)
[142.7]
[[14.6]] 101.2
(6.1)
[121.4]
[[4.5]]
12 89.7
(15.6) 112.3
(1.6) 118.7
(1.7)
[32.3]
[[5.7]] 115.1
(3.7)
[28.3]
[[2.5]] 112.6
(2.1)
[25.5]
[[0.3]]
不意欲藉由任何特定理論束縛，與偽T = 0值相比在40℃下儲存之後溶解程度之增加認為歸因於所測試之偽T = 0樣品之上文所述之老化效應與當在40℃下儲存時調配物中之溫度依賴性相變之組合。
比較調配物1之老化產物經熱固化，且隨後經受溶解試驗。固化由施加熱處理組成且已展示穩定醫藥調配物(見例如美國專利第6,645,527號)。比較調配物1(老化樣品)在40℃下加熱72小時以進行固化，且隨後在室溫下儲存8週。在室溫下儲存0、2、4及8週之後測試25-羥基維他命D3
自固化調配物之釋放。結果概述於下表中。 在 40 ℃ 下固化 72 小時之後溶解
溶解時間(小時) T=0 2週
% LC
[變化%] 4週
% LC
[變化%] 8週
% LC
[變化%]
2 17.4 12.4
[28.7] 11.4
[34.5] 8.2
[52.9]
4 53.3 46.4
[12.9] 40.1
[24.8] 26.6
[50.1]
6 86.2 76.2
[11.6] 69.0
[20.0] 44.8
[48.0]
8 103.8 102.0
[1.7] 95.8
[7.7] 66.6
[35.8]
12 115.7 110.5
[4.5] 119.8
[3.5] 103.3
[10.7]
實例 2-25- 羥基維他命 D 之經穩定之控制釋放調配物之活體外溶解
測試在室溫下儲存0至11週之後，包含90 µg 25-羥基維他命D3
、19.88 wt%硬石蠟、15.29 wt%羥丙基甲基纖維素、22.55 wt%GMS、9.76 wt%GELUCIRE 44/14、2.36 wt%無水乙醇、29.88 wt%液體石蠟及0.02 wt%BHT(實例調配物A)之持續釋放調配物之溶解。結果概述於下表中。 在室溫 / 環境濕度下儲存之後溶解
溶解時間(小時) T=0 3週
% LC
[變化%] 11週
% LC
[變化%]
2 15.45 14.20
[8.1%] 12.08
[21.8%]
4 36.3 38.80
[6.9%] 37.13
[2.3%]
6 56.9 62.70
[10.2%] 59.51
[4.6%]
8 71.1 71.90
[1.1%] 69.76
[1.9%]
12 89.4 91.20
[2.0%] 89.90
[0.6%]
測試在室溫下儲存0至26週之後，包含90 µg 25-羥基維他命D3
、19.88 wt%硬石蠟、10.00 wt%羥丙基甲基纖維素、22.55 wt%GMS、9.76 wt%GELUCIRE 44/14、2.36 wt%無水乙醇、35.17 wt%液體石蠟及0.02 wt%BHT(實例調配物B ))之持續釋放調配物之溶解。結果概述於下表中。 在室溫 / 環境濕度下儲存之後溶解
溶解時間(小時) T=0 6週
% LC
[變化%] 13週
% LC
[變化%] 26週
% LC
[變化%]
2 30.15 25.40
[15.8%] 25.20
[16.4%] 21.10
[30.0%]
4 58.55 51.90
[11.4%] 51.80
[11.5%] 45.20
[22.8%]
6 72.1 74.40
[3.2%] 73.00
[1.2%] 67.63
[6.2%]
8 80.55 84.30
[4.7%] 84.50
[4.9%] 77.30
[4.0%]
12 91.8 94.10
[2.5%] 94.40
[2.8%] 91.16
[0.7%]
實例調配物B顯示在室溫下儲存至少26週之後實質上穩定的溶解特徵。
使用25℃及60%相對濕度及40℃及75%相對濕度之儲存條件測試包含30 µg 25-羥基維他命D3
(實例調配物C)、60 µg 25-羥基維他命D3
(實例調配物D)或90 µg 25-羥基維他命D3
(實例調配物E)之經穩定之調配物的穩定性。實例調配物C至E之組合物概述於下表中： 組分 量
25-羥基維他命D3 30 µg、60 µg或90 µg
固體石臘 20.00 wt%
礦物油 35.36 wt%
羥丙基甲基纖維素K100M CR (METHOCEL) 10.00 wt%
單硬脂酸甘油酯 22.55 wt%
十二醯聚乙二醇甘油酯及聚氧甘油酯(GELUCIRE 44/14) 9.75 wt%
無水乙醇 2.32 wt%
BHT 0.02 wt%
軟膠囊殼(VEGICAPS)
調配物在25℃及60%相對濕度下儲存至少24個月之後實質上展現穩定的溶解特徵(圖1)。溶解結果(%LC及%CV)概述於下表中。 在 25 ℃ /60% 相對濕度下儲存之後溶解
時間( 小時) T=0 %LC (% CV) 1 個月 %LC (% CV) 3 個月 %LC (% CV) 6 個月 %LC (% CV) 9 個月 %LC (% CV) 12 個月 %LC (% CV) 18 個月 %LC (% CV) 24 個月 %LC (% CV)
30 µg 25-羥基維他命D3
(實例調配物C)
2 10.1
(16.1) 12.9
(25.2) 14.0
(48.5) 9.6
(38.3) 10.5
(18.2) 13.5
(35.8) 10.6
(26.5) 7.0
(47.8)
4 43.6
(12.7) 48.8
(10.9) 45.9
(29.9) 36.8
(25) 37.2
(11.1) 50.2
(14.8) 39.3
(22.9) 39.6
(32.3)
6 83.1
(5.7) 73.4
(9.2) 72.4
(7.5) 71.4
(6.8) 66.7
(10.6) 70.6
(11.5) 70.1
(7.2) 69.3
(12.6)
8 96.4
(6.5) 89.6
(4.4) 88.4
(4.7) 88.4
(5.7) 85.2
(4.9) 85.4
(9) 84
(5.1) 85.7
(8.2)
12 115.8
(4.5) 104.2
(1.9) 105.6
(1.4) 106.1
(1.6) 101.5
(1.5) 100.8
(3.9) 100.2
(4.5) 103
(2.6)
60 µg 25-羥基維他命D3
(實例調配物D)
2 17.5
(20) 16.3
(27.4) 16.1
(25.3) 17.7
(34.7) 11.2
(20.2) 14.3
(29.1) 16.1
(25.8) 12.4
(52.3)
4 53.6
(19.6) 55.1
(18.8) 53.8
(12.8) 55.3
(17.9) 43.7
(14) 51
(22.5) 52.9
(16.7) 41
(36.6)
6 83.9
(7.5) 78.7
(8.3) 79.9
(6.6) 78.4
(4.7) 72.2
(7.1) 75
(13) 72
(9.9) 64.7
(29.6)
8 99.2
(3.9) 94.3
(5.2) 97.2
(4.8) 92.5
(3.3) 87
(5.5) 88.9
(6.3) 84.9
(12.3)* 81.3
(21.7)
12 104.8
(3.3) 108.7
(1.8) 111.9
(1.1) 104.5
(0.5) 103.1
(0.8) 104.7
(1.4) 99.8
(4.6)* 101.7
(8)
90 µg 25-羥基維他命D3
(實例調配物E)
2 14.9
(19.9) 14.9
(8.6) 13.3
(41.2) 13.5
(23.4) 14.3
(30.4) 15
(35.1) 9.5
(37.1) 8.5
(53.2)
4 49.9
(16.4) 46.9
(10.2) 52.4
(18.5) 49.7
(16.4) 45.9
(25.6) 51.8
(14) 36.8
(34.5) 34.4
(24.9)
6 89.4
(7.2) 71.4
(4.1) 81.1
(5.6) 74.2
(11.1) 71.6
(17.6) 77
(4.9) 64.4
(10.3) 64.5
(15.1)
8 101.7
(2.5) 84.9
(2.8) 96.1
(2.3) 90.8
(6.4) 89
(9.4) 91.6
(3.3) 77.4
(15.7) 83.6
(11.2)
12 103
(2.1) 99.3
(2.4) 110
(1.3) 104.4
(1.1) 100.5
(2.4) 104.6
(0.3) 96.8
(5) 102.8
(3.4)
* 4次重複代替6次
老化之後所釋放之25-羥基維他命D3
之量與初始釋放量相比之間的變化百分比概述於下表。 時間(h) 1 個月 % 變化 3 個月 變化% 6 個月 變化% 9 個月 變化% 12 個月 變化% 18 個月 變化% 24 個月 變化%
30 µg 25-羥基維他命D3
(實例調配物C)
2 27.7% 38.6% 5.0% 4.0% 33.7% 5.0% 30.7%
4 11.9% 5.3% 15.6% 14.7% 15.1% 9.9% 9.2%
6 11.7% 12.9% 14.1% 19.7% 15.0% 15.6% 16.6%
8 7.1% 8.3% 8.3% 11.6% 11.4% 12.9% 11.1%
12 10.0% 8.8% 8.4% 12.3% 13.0% 13.5% 11.1%
60 µg 25-羥基維他命D3
(實例調配物D)
2 6.9% 8.0% 1.1% 36.0% 18.3% 8.0% 29.1%
4 2.8% 0.4% 3.2% 18.5% 4.9% 1.3% 23.5%
6 6.2% 4.8% 6.6% 13.9% 10.6% 14.2% 22.9%
8 4.9% 2.0% 6.8% 12.3% 10.4% 14.4% 18.0%
12 3.7% 6.8% 0.3% 1.6% 0.1% 4.8% 3.0%
90 µg 25-羥基維他命D3
(實例調配物E)
2 0.0% 10.7% 9.4% 4.0% 0.7% 36.2% 43.0%
4 6.0% 5.0% 0.4% 8.0% 3.8% 26.3% 31.1%
6 20.1% 9.3% 17.0% 19.9% 13.9% 28.0% 27.9%
8 16.5% 5.5% 10.7% 12.5% 9.9% 23.9% 17.8%
12 3.6% 6.8% 1.4% 2.4% 1.6% 6.0% 0.2%
實例調配物C至E在40℃及75%RH下儲存至少6個月之後亦實質上展現穩定的溶解特徵(圖2)。溶解結果概述於下表中。 在 40 ℃ /75% 相對濕度下儲存之後溶解
時間( 小時) 初始 % LC (%CV) 1 個月 % LC (%CV) 3 個月 % LC (%CV) 6 個月 % LC (%CV)
30 µg 25-羥基維他命D3
(實例調配物C)
2 10.1
(16.1) 11.3
(54.3) 13.5
(53.8) 11.1
(14.8)
4 43.6
(12.7) 46
(27.1) 44.4
(23.9) 40.9
(13.9)
6 83.1
(5.7) 72.7
(9.7) 62.8
(20.4) 68.7
(7.3)
8 96.4
(6.5) 88.7
(5) 76.5
(12.5) 82.5
(4.1)
12 115.8
(4.5) 103.1
(0.9) 93.4
(7.6) 96.4
(2.8)
60 µg 25-羥基維他命D3
(實例調配物D)
2 17.5
(20) 12.9
(40.7) 15.5
(37) 13.9
(40)
4 53.6
(19.6) 50.7
(18.5) 54.4
(12) 49.8
(16.3)
6 83.9
(7.5) 75.8
(9.7) 78.3
(10.6) 74.7
(8.1)
8 99.2
(3.9) 91.2
(7.9) 91.6
(9.1) 88.5
(6.5)
12 104.8
(3.3) 100.7
(5.1) 104.1
(6.5) 101.5
(2.3)
90 µg 25-羥基維他命D3
(實例調配物E)
2 14.9
(19.9) 18.5
(32.5) 10.2
(44.6) 8.3
(34.7)
4 49.9
(16.4) 50.7
(12..8) 47
(14.6) 44.8
(10.6)
6 89.4
(7.2) 74.7
(8) 72.9
(5.2) 73
(3.4)
8 101.7
(2.5) 90.5
(5) 86.6
(4.8) 87.9
(3)
12 103
(2.1) 100.1
(1.4) 102.5
(1.6) 101.0
(1.9)
暴露於儲存條件之後所釋放之25-羥基維他命D3
之量與初始釋放量相比之間的變化百分比概述於下表中。 時間(小時) 1 個月 變化% 3 個月 變化% 6 個月 變化%
30 µg 25-羥基維他命D3
(實例調配物C)
2 11.9% 33.7% 9.9%
4 5.5% 1.8% 6.2%
6 12.5% 24.4% 17.3%
8 8.0% 20.6% 14.4%
12 11.0% 19.3% 16.8%
60 µg 25-羥基維他命D3
(實例調配物D)
2 26.3% 11.4% 20.6%
4 5.4% 1.5% 7.1%
6 9.7% 6.7% 11.0%
8 8.1% 7.7% 10.8%
12 3.9% 0.7% 3.1%
90 µg 25-羥基維他命D3
(實例調配物E)
2 24.2% 31.5% 44.3%
4 1.6% 5.8% 10.2%
6 16.4% 18.5% 18.3%
8 11.0% 14.8% 13.6%
12 2.8% 0.5% 1.9%
在25℃及60%相對濕度下儲存12個月之後評價不含纖維素化合物之比較調配物1及包含羥丙基甲基纖維素之實例調配物E之穩定性(圖3)。T溶解結果概述於下表中。 在 25 ℃ /60% 相對濕度下儲存之後溶解
溶解時間 ( 小時) 比較調配物1 實例調配物E
初始
% LC 12個月
% LC 初始
% LC 12個月
% LC
2 22.1 13.5 14.9 15.0
4 52.2 24.5 49.9 51.8
6 77.9 30.0 89.4 77.0
8 96.8 35.6 101.7 91.6
12 112.3 44.2 103.0 104.6
暴露於儲存條件之後所釋放之25-羥基維他命D3
之量與初始釋放量相比之間的變化百分比概述於下表中。 溶解時間 ( 小時) 比較調配物1
自初始變化% 實例調配物E
自初始變化%
2 38.9% 0.7%
4 53.1% 3.8%
6 61.5% 13.9%
8 63.2% 9.9%
12 60.6% 1.6%
實例 3 ：未經穩定之及經穩定之控制釋放調配物之活體內結果
進行活體內研究以評估人類個體中25-羥基維他命D3
之未經穩定之及經穩定之控制釋放調配物之臨床藥代動力學。在研究A中，28名患有3期或4期CKD、繼發性副甲狀腺高能症(3期：70-1000 pg/mL iPTH；4期：110-1000 pg/mL iPTH)及維他命D不足(血清中總基線25-羥基維他命D為15 ng/mL至29 ng/mL)之個體接受控制釋放膠囊之單次口服劑量或於乙醇溶液中之448 µg 25-羥基維他命D3
之單次靜脈內劑量，該膠囊包含450 µg或900 µg 25-羥基維他命D3
、20.00 wt%硬石蠟、37.85 wt%GMS、9.75 wt%GELUCIRE 44/14、2.32 wt%無水乙醇、30.06 wt%礦物油及0.02 wt%BHT (比較調配物3)。調配物均不包含纖維素化合物。
25-羥基維他命D3
之血清濃度在投與口服劑量之後逐漸增加。25-羥基維他命D3
之增加呈劑量比例的且在投與900 µg膠囊之後達到32 ng/mL(血清濃度所觀察到的近似平均最大值(Cmax))。出現Cmax之時間(Tmax)大約為給藥後13個小時。相比之下，25-羥基維他命D3
之濃度在經靜脈內給藥投與之後快速增加。緊接著經靜脈內給藥投與之後(Tmax = 0.5小時))達成最大血清含量且達到134 ng/mL之近似平均Cmax。口服劑量之生物可用性為約6至11%。在口服給藥投與之後25-羥基維他命D3
之終半衰期(t1/2
)為約12至22天。在任何處理組中未觀察到對血清鈣或磷或尿液鈣產生不良作用。
平均血清總1,25-二羥基維他命D之量在經靜脈內注射投與之後快速上升，經給藥後6個小時自預處理基線增加約13 pg/mL。相比之下，平均血清總1,25-二羥基維他命D之量在投與900 µg膠囊之後經給藥後48小時按給藥比例且逐漸增加約7 pg/mL。
血清iPTH展示在歷經經靜脈內給藥投與之後的第一96小時無實際意義變化。相比之下，血清PTH在給藥之後逐漸下降，對於接受900 µg膠囊之個體達到自預處理基線約20%之最大抑制。觀察到的所有處理組之藥物動力學參數概述於下表中。 參數 450 μg 經口 (N=9) 900 μg 經口 (N=9) 448 μg 經靜脈內 (N=9)
n 平均 (SD) n 平均 (SD) n 平均 (SD)
中值 範圍 中值 範圍 中值 範圍
PK/PD群
觀察到的25-羥基維他命D3
AUC0-42 天
(ng*h/mL) 9 13353.12
(10606.47)
12196.45
888.39，32885.95 9 21563.95
(9165.53)
17940.11
9292,88,38631.91 9 43463.51
(12589.57)
47115.66
23340.59，63006.78
AUC0-
last
(ng*h/mL) 9 13353.12
(10606.47)
12196.45
888.39,32885.95 9 21563,95
(9165.53)
17940.11
9292.88，38631.91 9 43463.51
(12589.57)
47115.66
23340.59,63006.78
AUC0-inf
(ng*h/mL) 9 81511.71
(103037,08)
54967.57
4927.95，333366.90 9 122901.73
(114168.13)
79902.04
25729.84，378935.59 9 137955.58
(66746.71)
123580.87
39282.49，243322.76
Cmax
(ng/mL) 9 25.18(10.134)
20.52
15.35,42.24 9 31.54(15.765)
30.12
12.21，67.01 9 133.99(19.311)
133.68
91.71，160.91
Clast
(ng/mL) 9 18.11 (7.846)
15.84
10.30,29.80 9 19.08(7.611)
21.37
7.30，27.93 9 35.07(12.330)
36.9.1
12.68,53.39
tmax
(h) 9 13.11 (9.597)
10.00
6.00,36.00 9 13.56 (9.989)
10.00
2.00，30.00 9 0.49 (0.638)
0.25
0.083，2.00
λ2
(h-1
) 9 0.0015 (0.0028)
0.0003
0.0001,0.0087 9 0.0003 (0.0002)
0.0004
0.0001,0.0005 9 0.0005 (0.0002)
0.0004
0.0002,0.0008
R2 9 0.89(0.130)
0.96
0.662，1.000 9 0.90(0.169)
0.99
0.523,0.998 9 0.91 (0.090)
0.93
0.730,1.000
t1/2
(h) 9 2477.72 (2581.24)
2483.61
79.24，8615.11 9 3228.63 (2734.74) 1937.32
1300.13,9646.71 9 1775.86(779.13)
1694.69
871.46，3297.78
Vd
(L/ng) 9 49.42(18.30)
50.93
23.20，72.76 9 45.06(1938)
40.080
20.77，87.51 9 20.35(7.42)
19.550
13.04,32.68
CL (L/ng*h) 9 0.0499(0.0155)
0.0182
0.0030，0.2029 9 0.0155(0.0119)
0.0125 0.0026,0.0389 9 0.0095 (0.0065)
0.0081
0.0041,0.0255
F 不適用 0.306 (不適用)
不適用
不適用 不適用 0.247 (不適用)
不適用
不適用 不適用 1.000 (不適用)
不適用
不適用
所有處理組之經基線調整之藥物動力學參數概述於下表中。 參數 450 μg 經口 (N=9) 900 μg 經口 (N=9) 448 μg 經靜脈 (N=9)
n 平均 (SD) n 平均 (SD) n 平均 (SD)
中值 範圍 中值 範圍 中值 範圍
AUC0-42 天
(ng*h/mL) 9 1394.89
(1911.41)
605.42
48.87，4956.68 8 4525.43
(3123.29)
4801.54
148.07，8843.74 9 19609.07
(5319.01)
18764.48 11066.02,28611.05
AUC0-last
(ng*h/mL) 9 1257.30
(2047.74)
48.87
-325.43，4956.68 8 4274.27
(3488.40)
4801.54
-877.99，8843.74 9 19609.07
(5319.01)
18764.48
11066.02,28611.05
AUC0-inf
(ng*h/mL) 6 3318.90
(4606.89)
547.25 8 6791.49
(5224.54)
6872.86 9 34543.75
(22103.97)
26962.25
Cmax
(ng/mL)
9 50.78，9878.03
6.90 (4.266)
5.70
2.93，14.87
8 285.04,14979.17
14.17(9.884)
12.30
2.55,35.59
9 16868.97，89126.53
110.33(14.536)
111.08
76.63，127.40
Clast
(ng/mL) 9 2.36 (2.257)
2.05
0.16，5.49 8 2.64(1.784)
3.01
0.42，5.40 9 11.40(5.648)
9.01
5.84，22.86
tmax
(h) 9 13.11(9.597)
10.00
6.00，36.00 8 15.00(9.621)
10.00
8.00，30.00 9 0.49 (0.638)
0.25
0.083,2.00
λ2
(h-1
) 6 0.018 (0.359)
0.0042
0.0008，0.0910 7 0.0020 (0.0013)
0.0016
0.0008,0.0037 9 0.0011 (0.0005)
0.0010
0.0004，0.0021
R2 6 0.92(0.101)
0.96
0.743，0.999 6 0.99 (0.020)
0.99
0.948，1.000 9 0.92 (0.086)
0.95
0.720,0.999
t1/2
(h) 6 307.86(336.42)
165.72
7.61,914.23 6 522.96(320.80)
530.00 189.84,879.31 9 745.86 (437.65)
663.43
337.37，1834.71
Vd
(L/ng) 6 340.42(269.11)
249.77
80.51,771.79 6 82.92 (29.70)
77.11
39.96，127.06 9 32.94 (11.00)
29.70
24.28，58.95
CL (L/ng*h) 6 4.588 (7.525)
2.119
0.101,19.692 6 0.141 (0.080)
0.1200
0.0668，0.2860 9 0.036 (0.014)
0.037
0.011,0.059
F 不適用 0.064 (不適用)
不適用
不適用 不適用 0.109 (不適用)
不適用
不適用 不適用 1.000 (不適用)
不適用
不適用
在研究B中，20名具有約24 ng/mL (範圍在11 ng/mL至45 ng/mL)之平均基線血清25-羥基維他命D之健康個體接受經穩定之控制釋放膠囊之單次口服劑量或乙醇溶液中之448 µg 25-羥基維他命D3
之單次靜脈內劑量，該膠囊包含900 µg 25-羥基維他命D3
、20.00 wt%硬石蠟、10.00 wt%HPMC、22.55 wt%GMS、9.75 wt%GELUCIRE 44/14、2.32 wt%無水乙醇、35.36 wt%礦物油及0.02 wt%BHT(實例調配物F)。
與靜脈內給藥相比，在投與經穩定之口服調配物之後25-羥基維他命D3
含量之逐漸增加藉由延長之Tmax顯示。在投與經穩定之口服調配物之後藥物動力學概況顯示25-羥基維他命D3
濃度逐漸增加，其中平均Tmax為28小時，同時避免大多數個體中血液含量快速增加。經靜脈內給藥之投與導致所有個體中25-羥基維他命D3
濃度快速增加。藉由處理組之間所觀察到的Cmax
中之顯著差異突出顯示避免25-羥基維他命D3
含量快速增加。與經靜脈內給藥之後153 ng/mL之Cmax相比，口服給藥之後的Cmax為58 ng/mL。
投與控制釋放膠囊之後25-羥基維他命D3
之暴露比經靜脈內給藥之後約小兩倍，儘管口服給藥為約兩倍高，從而導致約25%之生物可用性。t1/2
、消除率(CL)及體積分佈(Vd)在處理組之間顯示為類似的。t1/2
及CL之值符合所報導之25-羥基維他命D3
之延長消除。另外，Vd值表明25-羥基維他命D3
維持在體循環中，可能高度束縛於DBP。觀察到的所有處理組之藥物動力學參數概述於下表中。 參數 900 μg CTAP101
膠囊(N=10) 448 μg CTAP101 注射 (N=10)
AUC0-t
(ng.h/mL)
平均(SD) 21545.20(7054.02) 25274.44(7206.93)
中值 19904.00 25810.85
最小值，最大值 10176.40，35885.02 8434.02，35382.55
AUC0-inf
(ng.h/mL)
平均(SD) 77945.13(55896.15) 55234.52(27268.64)
中值 58974.22 51247.29
最小值，最大值 19504.43,194796.33 22979.18，119865.38
Cmax
(ng/mL)
平均(SD) 57.657(39.3810) 153.029(20.8620)
中值 37.925 152.890
最小值，最大值 24.43,146.86 125.94，185.33
tmax
(h)
平均(SD) 28.100(27.4000) 0.272(0.2910)
中值 21.000 0.161
最小值，最大值 4.00，96.00 0.05，1.00
t1/2
(h)
平均(SD) 1389.40(1144.48) 660.23(415.82)
中值 1042.60 607.65
最小值，最大值 557.32，4173.67 238.46，1733.68
λ2
(h-1
)
平均(SD) 0.00072(0,00036) 0.00136(0.00071)
中值 0.00067 0.00115
最小值，最大值 0.00017,0.00124 0.00040,0.00291
CL (L/h)
平均(SD) 0.0064(0.0027) 0.0098 (0.0046)
中值 0.0066 0.0087
最小值，最大值 0.0018，0.0098 0.0037，0.0195
Vd (L)
平均(SD) 9.27(0.97) 7.50(1.19)
中值 9.39 7.24
最小值，最大值 7.93，10.49 6.02，9.77
R2
平均(SD) 0.80(0.24) 0.92 (0.075)
中值 0.88 0.94
最小值，最大值 0.25，0.99 0.74，1.0
F
平均 0.42(0.14) 不適用
中值 0.39 不適用
最小值，最大值 0.20，0.71 不適用
個別個體生物可用性之平均值縮寫：
N/A，不適用
所有處理組之經基線調整之藥物動力學參數概述於下表中。 參數 900 μg CTAP101 膠囊 (N=10) 448 μg CTAP101 注射 (N=10)
AUC0-t
(ng.h/mL)
平均(SD) 6891.81 (6678.97) 13583.95 (3908.42)
中值 4360.23 14853.46
最小值，最大值 1017.88，20340.68 5302.50，17194.59
AUC0-inf
(ng.h/mL)
平均(SD) 9418.00(9410.58) 17735.09(5249.38)
中值 5420.04 18229.25
最小值，最大值 1179.07,28031.64 9820.16，25534.45
Cmax
(ng/mL)
平均(SD) 35.867 (39.3886) 133.653(20.7925)
中值 14.910 133.785
最小值，最大值 6.50，120.52 103.88，166.34
tmax
(h)
平均(SD) 28.100(27.4001) 0.272(0.2914)
中值 21.000 0.167
最小值，最大值 4.00，96.00 0.05，1.00
t1/2
(h)
平均(SD) 270.61 (215.00) 264.08(82.23)
中值 194.00 269.57
最小值，最大值 107.90，832.70 132.46，382.99
λ2
(h-1
)
平均(SD) 0.00362(0.00182) 0.00292(0.00112)
中值 0.00363 0.00257
最小值，最大值 0.00083，0.00624 0.00181，0.00523
CL (L/h)
平均(SD) 0.027 (0.0063) 0.028 (0.0093)
中值 0.028 0.025
最小值，最大值 0.012，0.033 0.018，0.046
Vd (L)
平均(SD) 8.78 (3.08) 9.74(2.02)
中值 8.08 9.47
最小值，最大值 5.06，14.17 6.54，13.27
R2
平均(SD) 0.83 (0.22) 0.92 (0.072)
中值 0.88 0.94
最小值，最大值 0.25，1.0 0.74，1.0
F
平均(SD) 0.25 (0.24) 不適用
中值 0.16 不適用
最小值，最大值 0.037，0.75 不適用
個別個體生物可用性之平均值縮寫：
N/A，不適用
研究顯示經穩定之控制釋放調配物改良25-羥基維他命D3
之吸收速率，從而在血清25-羥基維他命D3
含量中產生更加逐漸之增加同時維持分佈及消除特徵。在研究A中與未經穩定之調配物的相同給藥相比，經穩定之調配物顯示經改良之藥物動力學參數(諸如增加之Tmax、AUC及生物可用性)。
在研究C中，78名患有3期CKD (eGFR 25-70 mL/min/1.73 m2
)、SHPT (＞ 70 pg/mL血漿iPTH)及維他命D不足(血清中總基線25-羥基維他命D為10 ng/mL至29 ng/mL)之個體接受經穩定之控制釋放調配物之每日口服劑量或接受安慰劑持續6週，該等調配物包含30 µg、60 µg或90 µg 25-羥基維他命D3
、20.00 wt%硬石蠟、10.00 wt%HPMC、22.55 wt%GMS、9.75 wt%GELUCIRE 44/14、2.32 wt%無水乙醇、35.36 wt%礦物油及0.02 wt%BHT (來自實例2之實例調配物C、D及E)。
比較所有處理組之平均基線血清25-羥基維他命D3
濃度，且介於約16至20 ng/mL範圍內。經25-羥基維他命D3
處理之後，血清25-羥基維他命D3
之平均含量逐漸增加且在每日反覆投與25-羥基維他命D3
之後以與劑量成比例之方式增加，且經6週開始接近穩態(圖4)。對於投與30 µg、60 µg及90 µg 25-羥基維他命D3
之組，其平均基線調整之Cmax值分別為約28、60及86 ng/mL。在所有劑量組中如本底調整之AUC0-6
週所評估，25-羥基維他命D3
之平均暴露係與劑量成比例。按照最後劑量，平均血清25-羥基維他命D3
含量下降緩慢，但在研究結束時所有組保持在基線以上。平均t1/2
經測定約在25至50天之間。25-羥基維他命D3
之經基線調整之藥物動力學參數概述於下表中。 安慰劑 30 µg 60 µg 90 µg
基線(ng/mL)
平均(SD) 16.4 (8.2) 16.2 (7.3) 19.8 (8.7) 18.4 (9.8)
中值 12.9 17.2 21.2 16.7
最小值，最大值 4.4，30.4 5.0，25.8 5.8，32.5 6.7，38.9
Cmax
(ng/mL)
平均(SD) 4.1 (3.5) 27.8 (8.2) 60.3 (19.0) 85.7 (26.9)
中值 3.1 28.1 60.8 76.0
最小值，最大值 0.6，13.8 10.8，43.4 30.3，89.5 55.4，146.4
AUC0-6 Weeks
(ng ·d/mL)
平均(SD) 45.9 (60.0) 709.2 (246.3) 1531.4 (374.8) 2134.3 (584.3)
中值 32.1 6843.0 1573.0 1963.8
最小值，最大值 -60.1，222.3 307.8，1249.0 712.7，2221.8 1377.5，3207.3
tmax
(d)
平均(SD) 不適用 37.8 (10.4) 41.1 (5.2) 42.6 (5.3)
中值 不適用 42.50 43.0 43.0
最小值，最大值 不適用 8.0，44.0 29.0，45.0 35.0，57.0
t1/2
(d)
平均(SD) 不適用 25.8 (16.3) 33.1 (9.3) 50.1 (51.0)
中值 不適用 24.1 31.6 37.7
最小值，最大值 不適用 5.2，52.6 17.4，52.3 23.2，224.0
比較所有處理組之平均基線血清1,25-二羥基維他命D濃度且濃度逐漸增加，類似於在血清25-羥基維他命D3
濃度上產生之效應。60 µg及90 µg組之平均±SD基線調整之Cmax值與安慰劑及30 µg組(分別為5.7±6.35及6.4±7.66 ng/mL)相比為高的(分別為18.4±6.24及19.9±14.30 ng/mL)。在25-羥基維他命D3
之劑量組中如經基線調整之AUC0-6
週所評估，1,25-二羥基維他命D之平均暴露係與劑量成比例。1,25-二羥基維他命D之經基線調整之藥物動力學參數概述於下表中。 安慰劑 N=23 30 µg N=12 60 µg N=16 90 µg N=14
基線
(pg/mL)
平均(SD) 20.8 (10.11) 18.3 (7.53) 20.6 (7.62) 20.6 (7.29)
中值 17.0 17.0 18.0 21.0
最小值，最大值 7.0，41.4 5.1，30.7 8.2，33.6 9.3，34.5
Cmax
(pg/mL)
平均(SD) 7.6 (5.71) 6.4 (7.66) 18.4 (6.24) 19.9 (14.30)
中值 4.9 5.0 18.4 18.9
最小值，最大值 1.9，22.6 -6.3，21.0 7.3，29.9 -11.6，48.3
AUC0-6 Weeks
(g ·d/mL)
平均(SD) 11.5 (112.97) 100.6 (185.38) 249.9 (198.83) 371.1 (290.81)
中值 16.2 23.0 298.7 352.2
最小值，最大值 -267.1，219.8 -145.4，452.3 -191.7，563.6 -5.8，1235.8
tmax
(d)
平均(SD) 24.4 (15.55) 16.8 (16.09) 26.4 (11.52) 25.5 (13.88)
中值 23.0 12.0 23.0 23.00
最小值，最大值 2.0，45.0 1.0，44.0 8.0，44.0 1.0，44.0
與安慰劑相比在所有活性劑組之明顯更多的個體中，25-羥基維他命D3
之經穩定之控制釋放調配物使血清總25-羥基維他命D含量增加至≥ 30 ng/mL。類似地，與安慰劑相比在所有劑量組中經穩定之調配物使平均血漿iPTH自基線明顯降低。
每日投與於經穩定之控制釋放調配物中之25-羥基維他命D3
增加平均血清總25-羥基維他命D，增加量與與投與劑量成比例。最低投與劑量(30 µg)在處理結束時使血清總25-羥基維他命D自預處理基線(21.7±1.8 ng/mL)增加15.6±1.7(SE) ng/mL，且最高劑量(90 µg)使血清總25-羥基維他命D自21.8±1.2 ng/mL增加61.1±6.1 ng/mL。相比之下，在經組合之安慰劑組中，觀察到在1.2±0.7 ng/mL處理結束時降低。對於所有三個所研究之劑量，處理組與安慰劑組之間的差異顯著(p＜0.0001)。在處理結束時，在30 µg劑量組中平均血清25-羥基維他命D含量為37.3±1.8 ng/mL (略高於K/DOQI規定的30 ng mL之最小適當含量)，表明30 µg為最小有效劑量。
與安慰劑組中之0%相比，在30 µg、60 µg及90 µg劑量組中，在處理結束時達成≥30 ng/mL血清總25-羥基維他命D含量之經處理之個體的百分比為92.3%、100.0%及100.0%。活性劑與安慰劑處理之間的此等反應率差異均為顯著的(p＜0.001)。
處理結束時之平均血漿iPTH與所投與之25-羥基維他命D3
劑量成比例地降低。最低投與劑量(30 µg)使iPTH自預處理基線降低20.2±5.8(SE)%，且最高劑量(90 µg)使iPTH降低35.9±4.2%。在經組合之安慰劑組中，在處理結束時觀察到17.2±7.8%之增加。對於所有三個所研究之劑量，接受25-羥基維他命D3
組與接受安慰劑組之間的差異為顯著的(p＜0.005)，且其有利地與採用更加有效及血鈣口服維他命D激素替代療法(例如度骨化醇、帕立骨化醇及促鈣三醇)在安慰劑對照研究中較長處理所觀察到的差異相比較。
在EOT確認iPTH自預處理基線降低(亦即兩次連續量測)至少20%或30%之接受25-羥基維他命D3
的個體之百分比在劑量到60 µg結束的情況下增加。在60及90 µg處理組中觀察到類似反應率，表明在此研究中對於90 µg劑量未觀察到iPTH降低方面之其他益處。與經組合之安慰劑組中之9.7%相比，對於30 µg、60 µg及90 µg劑量組，確認iPTH降低20%之反應率分別為38.5%、70.6%、及76.5%。對於降低20%所觀察到的反應率之差異僅對於60 µg及90 µg劑量組為顯著的(p＜0.005)且在所有三個劑量組中對於降低30%為顯著的(p＜0.05)。資料支持每天30 µg於經穩定之控制釋放調配物中之25-羥基維他命D3
為最小有效劑量之結論。
25-羥基維他命D3
之經穩定之調配物對經校正之經白蛋白校正的血清鈣、血清磷及尿鈣排泄不具有臨床上顯著作用。在6週處理期期間對血清鈣或血清磷或尿鈣不存在不良作用。
藥物動力學分析揭示在所有三個劑量組中，25-羥基維他命D3
之經穩定之調配物歷經6週以與劑量成比例之方式增加25-羥基維他命D3
暴露(AUC及Cmax
)，t1/2
沒有差異。在投與6週之後，三個處理組尚未完全達到穩態。但是，穩態模型顯示在所有劑量組中到7-9週應已達成穩態。
來自此研究之資料明確顯示25-羥基維他命D3
之經穩定之控制釋放調配物在使血清總25-羥基維他命D升高至30 ng/mL之最小適當含量及降低血漿iPTH方面為有效的。研究亦展示所研究劑量之25-羥基維他命D3
之經穩定之調配物對血清鈣或磷不具有臨床上實際意義的影響。 實例 4 ：在患有繼發性副甲狀腺高能症及維他命 D 不足之 CKD 個體中修飾釋放骨化二醇之藥物動力學及藥效學特徵
在兩組個體中對經穩定之25-羥基維他命D3
(骨化二醇，25D3
)膠囊進行多中心、隨機化、雙盲、安慰劑對照、重複劑量、安全性、功效及PK/PD研究。對於此研究招募患有3期CKD (eGFR為25-70 mL/min/1.73 m2
)、維他命D不足(血清25-羥基維他命D ≥ 10且≤ 29 ng/mL)、SHPT (血漿iPTH ＞ 70 pg/mL)及無需進行定期血液透析之年齡在18歲至85歲的男性及女性個體。將第一組中符合條件之個體按1:1:1比隨機分成3個處理組：兩組分別按每日60或90 μg之口服劑量接受膠囊且一組接受匹配的安慰劑膠囊。將第二組中之個體按1:1比隨機分成兩個處理組：一組每日接受30 μg膠囊且另一組接受安慰劑。各組中之個體完成6週處理且進入6週隨訪時間段，在此期間每週採集PK及PD樣品。在6週處理及6週隨訪期間每週監測血清鈣(Ca)、磷(P)、25D3
、總1,25-二羥基維他命D (1,25D)及血漿iPTH。ANCOVA模型檢測25D3
暴露與自1,25D及iPTH之基線變化之關聯。所包括之共變量為基線eGFR、體重及高度、性別、年齡、人種、糖尿病狀況及1,25D或iPTH之基線濃度。
圖4展示藉由處理組(PK群)所得之平均經基線調整之骨化二醇濃度。血清骨化二醇之平均含量以與劑量成比例之方式逐漸增加且經6週開始接近穩態。在隨訪6週之後，在所有活性劑處理組中含量降低但保持在基線以上。
圖5展示藉由處理組(PK群)所得之骨化二醇濃度之經基線調整的PK參數彙總。
圖6展示在6週處理期間(PK群)所得之平均經基線調整之血清1,25-二羥基維他命D含量。與投與安慰劑之彼等個體相比，在投與活性劑膠囊之彼等個體中，平均基線調整之血清總1,25二羥基維他命D含量隨時間推移而增加。
圖7展示藉由處理組(PK群)所得之血清1,25-二羥基維他命D經基線調整之重複劑量PK參數的彙總。
圖8展示在6週處理(PK群)期間血漿iPTH含量中所得之基線平均百分比。與經組合之安慰劑組中之17%增量相比，在所有劑量組(30、60及90 µg)中活性劑膠囊分別使平均血漿iPTH自基線明顯降低21%、33%及39%。
圖9展示藉由處理組(PK群)所得之血漿iPTH經基線調整之重複劑量PK參數的彙總。
圖10及11展示在PK群中在EOT時血漿iPTH相對於經基線調整之骨化二醇及1,25-二羥基維他命D暴露(AUC0-6wk
)自基線變化的百分比。血漿iPTH自基線至EOT降低之百分比隨處理期間血清骨化二醇及總1,25二羥基維他命D暴露(表示為經基線調整之AUC0-6wk
)增加而增加。
經穩定之、持續釋放25-羥基維他命D3
膠囊使大多數個體中之25D含量正常化且在所有劑量組(30、60及90 µg)中明顯降低iPTH。經穩定之、持續釋放25-羥基維他命D3
膠囊逐漸增加血清25D3
及血清1,25D含量，其中暴露以劑量依賴性增加。25D3
及總1,25D暴露二者為顯著的且與血漿iPTH自基線變化呈負相關。在兩個模型中僅eGFR為顯著共變量。此等結果顯示經穩定之、持續釋放25-羥基維他命D3
膠囊可靠地使25D含量正常化、增加血清1,25D含量且抑制血漿iPTH升高而在進行劑量研究時對血清Ca及P不產生臨床上實際意義的效應。***
給定上述描述僅為了清楚理解，而不應自其理解為不必要的限制，同樣對於彼等一般技術者本發明之範疇內之修改可為顯而易見的。
在整個本說明書及隨後之申請專利範圍中，除非本文另有規定，否則「包含(comprise)」一詞及變型(諸如「包含(comprises/comprising)」)應理解為暗示包括所述整體或步驟或整體或步驟之群組但不排除任何其他整體或步驟或步驟或整體或步驟之群組。
在整個本說明書中，除非以其他方式描述，否則將組合物描述為包括組分或物質，組合物意欲亦可基本上由所述組分或物質之任何組合組成或由該組合組成。同樣，除非以其他方式描述，否則將方法描述為包括特定步驟，方法意欲亦可基本上由所述步驟之任何組合組成或由該組合組成。在不存在非特定揭示於本文中之任何要素或步驟之情況下，可適當地實踐本文所說明性揭示之本發明。
本文所揭示之方法之實踐及其個別步驟可手動及/或憑藉電子設備進行。儘管已參考特定實施例描述製程，但一般技術者將易於瞭解可使用與該等方法有關之其他方式執行行動。舉例而言，除非以其他方式描述，否則在不背離方法之範疇或精神之情況下，可改變各種步驟之次序。另外，可將個別步驟中之一些組合、省略或進一步再分成其他步驟。
本文所引用之所有專利、公開案及參考文獻在此以引用的方式全部併入本文中。在本發明與所併入之專利、公開案及參考文獻之間發生衝突之情況下，應控制本發明。
鑒於上述描述，所涵蓋之實施例包括以下編號段落中所述之彼等實施例。
1. 一種維他命D化合物之控制釋放調配物包含25-羥基維他命D2
及25-羥基維他命D3
中之一者或兩者，該調配物包含可釋放結合及可控制釋放維他命D化合物之基質，該基質包含纖維素衍生物。
2. 一種用於在攝入調配物之個體之胃腸道中控制釋放維他命D化合物的經穩定之調配物，該調配物包含以下之混合物：
25-羥基維他命D2
及25-羥基維他命D3
中之一者或兩者；
及有效量之穩定劑，其視情況為纖維素化合物，以使在暴露於25℃及60%相對濕度之儲存條件兩個月之後的活體外溶解期間，在四小時之後任何給定時間點時所釋放之維他命D化合物的量與在將調配物暴露於儲存條件之前所進行的活體外溶解期間，在同一溶解時間點時的釋放量之間的差異維持小於30%。
3. 一種用於維他命D化合物之控制釋放之經穩定的調配物，該調配物包含以下之混合物：
25-羥基維他命D2
及25-羥基維他命D3
中之一者或兩者；
蠟基質；及
穩定劑，其視情況為纖維素化合物。
4. 一種用於在攝入調配物之個體之胃腸道中控制釋放維他命D化合物的經穩定之調配物，該調配物包含以下之混合物：
25-羥基維他命D2
及25-羥基維他命D3
中之一者或兩者；
蠟基質；及
穩定劑，其視情況為纖維素穩定劑。
5. 一種用於維他命D之控制釋放之經穩定的調配物，該調配物包含以下之混合物：
25-羥基維他命D2
及25-羥基維他命D3
中之一者或兩者；
蠟基質；及
有效量之穩定劑，其視情況為纖維素化合物，以使在暴露於25℃及60%相對濕度之儲存條件兩個月之後的活體外溶解試驗期間，在四小時之後任何給定時間點時所釋放之維他命D化合物的量與在將調配物暴露於儲存條件之前所進行的活體外溶解期間，在同一溶解時間點時的釋放量之間的差異維持小於30%。
6. 一種用於在攝入調配物之個體之胃腸道中控制釋放維他命D化合物的經穩定之調配物，該調配物包含以下之混合物：
活性裝載蠟基質，其包含25-羥基維他命D2
及25-羥基維他命D3
中之一者或兩者；及
纖維素穩定劑；
其中調配物在暴露於25℃及60%相對濕度之儲存兩個月之後的活體外溶解期間釋放一定量之25-羥基維他命D，在不存在纖維素穩定劑之情況下，該釋放量與在將調配物暴露於儲存條件之前所進行之活體外溶解期間之相同溶解時間點時的釋放量相比，在任何給定溶解時間點時變化30%或小於30%。
7. 在用於在攝入調配物之個體之胃腸道中維他命D化合物的控制釋放之調配物中，改良包含將纖維素穩定劑摻和至調配物中。
8. 在用於在攝入調配物之個體之胃腸道中維他命D化合物的控制釋放之調配物中，改良包含將纖維素化合物混雜至調配物中以使在暴露於25℃及60%相對濕度之儲存條件至少一個月之後的活體外溶解期間，在四小時之後任何給定溶解時間點時所釋放之25-羥基維他命D的量，與在將調配物暴露於儲存條件之前所進行的活體外溶解期間的同一溶解時間點時的釋放量相比，變化小於30%。
9. 如前述段落中任一段之調配物，其中纖維素化合物或纖維素穩定劑包含纖維素醚。
10. 如段落9之調配物，其中該纖維素醚係選自由甲基纖維素、羥丙基甲基纖維素、羥乙基甲基纖維素、羥乙基纖維素及羥丙基纖維素組成之群。
11. 如段落9之調配物，其中該纖維素化合物或纖維素穩定劑為羥丙基甲基纖維素。
12. 如前述段落中任一段之調配物，其中該調配物在暴露於25℃及60%相對濕度之儲存條件兩個月之後的活體外溶解期間釋放一定量之25-羥基維他命D，與在將調配物暴露於儲存條件之前所進行之活體外溶解期間之同一溶解時間點時的釋放量相比，該釋放量在四小時之後的任何給定溶解時間點變化30%或小於30%。
13. 如前述段落中任一段之調配物，其中該調配物在暴露於40℃及75%相對濕度之儲存條件一個月之後的活體外溶解期間釋放一定量之25-羥基維他命D，與在將調配物暴露於儲存條件之前所進行之活體外溶解期間之同一溶解時間點時的釋放量相比，該釋放量在四小時之後的任何給定溶解時間點變化30%或小於30%。
14. 如前述段落中任一段之調配物，其中該基質包含蠟基質，該蠟基質包含控制釋放試劑、乳化劑及吸收增進劑。
15. 如段落14之調配物，其中該控制釋放試劑包含石蠟。
16. 如段落14或15之調配物，其中該乳化劑具有小於7之HLB值。
17. 如段落16之調配物，其中該乳化劑包含單硬脂酸甘油酯。
18. 如段落14至17中任一段之調配物，其中該吸收增進劑具有約13至約18範圍內之HLB值。
19. 如段落18之調配物，其中該吸收增進劑為十二醯聚乙二醇甘油酯及十二醯聚氧甘油酯之混合物。
20. 如前述段落中之任一段之調配物，其中該維他命D化合物包含25-羥基維他命D3
。
21. 如前述段落中之任一段之調配物，其進一步包含油性媒劑。
22. 如段落21之調配物，其中該油性媒劑包含礦物油。
23. 如段落22之調配物，其中該調配物包含約20 wt%石蠟、約20 wt%至約25 wt%單硬脂酸甘油酯、約10 wt%十二醯聚乙二醇甘油酯及十二醯聚氧甘油酯之混合物、約30 wt%至約35 wt%礦物油及約10 wt%至約15 wt%羥丙基甲基纖維素。
24. 如前述段落中任一段之調配物，其中該調配物包含單硬脂酸甘油酯。
25. 如前述段落中任一段之調配物，其中該調配物包含一或多種聚乙二醇化甘油酯。
26. 呈膠囊、錠劑、藥囊、糖衣藥丸或栓劑形式之持續釋放劑型包含前述段落中任一段之調配物。
27. 如段落26之劑型，其包含膠囊或錠劑。
28. 如段落27之劑型，其包含膠囊。
29. 如段落26之劑型，其包含口服膠囊、錠劑、藥囊、糖衣藥丸。
30. 一種經穩定之如前述段落中任一段之劑型，其特徵在於提供維他命D化合物之以下釋放之溶解特徵
在2小時時小於30%；
在6小時時大於45%；及
在12小時時大於80%。
31. 如段落26之經穩定之劑型，其中維他命D化合物在6小時時之釋放小於60%。
32. 一種包含維他命D化合物之經穩定之持續釋放口服劑型，其特徵在於提供維他命D化合物之以下釋放之活體外溶解特徵
在100至140分鐘時小於30%；
在5至7小時時大於45%；及
在11至13小時時大於80%。
33. 段落32之劑型，其中維他命D化合物之該釋放為
在2小時時小於30%；
在6小時時大於45%；及
在12小時時大於80%。
34. 如段落32或33之劑型，其中維他命D化合物在5至7小時時之釋放小於60%。
35. 如段落34之劑型，其中維他命D化合物在6小時時之釋放小於60%。
36. 一種包含維他命D化合物之經穩定之持續釋放口服劑型，其特徵在於提供維他命D化合物之以下釋放之活體外溶解特徵
在2小時時約20%至約40%；
在6小時時至少35%；及
在12小時時至少70%。
37. 段落36之劑型，其中維他命D化合物
在2小時時之釋放為約25%至約35%；
在6小時時至少40%；及
在12小時時至少75%。
38. 段落36或37之劑型，其中維他命D化合物在6小時時之釋放為75%或小於75%。
39. 段落38之劑型，其中維他命D化合物在6小時時之釋放為65%或小於65%。
40. 段落39之劑型，其中維他命D化合物在6小時時之釋放為60%或小於60%。
41. 一種包含維他命D化合物之經穩定之持續釋放劑型，其特徵在於在向人類患者投與該劑型之後tmax
至少為4小時。
42. 段落41之劑型，其中tmax
至少為8小時。
43. 段落42之劑型，其中tmax
至少為12小時。
44. 段落43之劑型，其中tmax
至少為18小時。
45. 段落44之劑型，其中tmax
至少為20小時。
46. 段落45之劑型，其中tmax
至少為24小時。
47. 段落46之劑型，其中tmax
至少為28小時。
48. 段落41之劑型，其中tmax
在4至96小時範圍內。
49. 段落48之劑型，其中tmax
在18至30小時範圍內。
50. 段落49之劑型，其中tmax
在13至28小時範圍內。
51. 段落50之劑型，其中tmax
為約28小時。
52. 一種包含25-羥基維他命D化合物之經穩定之持續釋放劑型，該劑型其特徵在於提供每微克25-羥基維他命D經基線調整之Cmax
，當投與成人時，該Cmax
在約0.0133 ng/mL至約0.04 ng/mL範圍內。
53. 向人類患者投與包含25-羥基維他命D化合物之經穩定之持續釋放劑型的方法，其包含向該患者投與有效量之該劑型以提供至少約0.2 ng/mL且小於110 ng/mL之經基線調整之Cmax
。
54. 段落53之方法，其包含投與有效量之該劑型以提供約0.2至約24 ng/mL範圍內之經基線調整之Cmax
。
55. 一種向人類患者投與包含25-羥基維他命D化合物之經穩定之持續釋放劑型的方法，其包含向該患者投與有效量之該劑型以提供至少為52 ng*h/mL且小於34500 ng*h/mL之經基線調整之AUC0-inf
。
56. 段落55之方法，其包含向患者投與有效量之該劑型以提供約52 ng*h/mL至約12,000 ng*h/mL範圍內之經基線調整之AUC0-inf
。
57. 一種維他命D補充之方法，其包含向需要如前述段落中任一段之調配物或劑型之個體投與。
58. 一種處理或預防個體中維他命D反應性疾病之方法，其包含向該個體投與如前述段落中任一段之調配物或劑型。
59. 段落58之方法，其中疾病係選自癌症(例如乳房、肺、皮膚、黑素瘤、結腸、結腸直腸、直腸、前列腺及骨癌症)、自體免疫疾病(例如I型糖尿病、多發性硬化症、類風濕性關節炎、多發性肌炎、皮肌炎、硬皮病、纖維化、格雷弗氏病、橋本氏(Hashimoto)病、急性或慢性移植排斥反應、急性或慢性移植物抗宿主疾病、發炎性腸道疾病、克羅恩氏病、全身性紅斑狼瘡、休格連氏症候群、濕疹及銀屑病、皮炎(包括異位性皮膚炎、接觸性皮炎、過敏性皮炎及/或慢性皮炎)、發炎性疾病(例如哮喘、慢性阻塞性肺病、多囊性腎病、多囊性卵巢症候群、胰臟炎、腎炎、肝炎及/或感染)、高血壓、心血管病(個體患有動脈粥樣硬化、動脈硬化、冠狀動脈疾病、腦血管病、周邊血管疾病、心肌梗塞、心肌缺血、大腦缺血、中風、充血性心臟衰竭、心肌症)、肥胖症或其他體重病症、脂質病症(例如高脂質血症、包括相關之糖尿病血脂異常及混合性血脂異常低α-脂蛋白血症之血脂異常、高三酸甘油酯血症、高膽固醇血症及低HDL(高密度脂蛋白))、代謝障礙(例如代謝症候群、II型糖尿病、I型糖尿病、高胰島素血症、葡萄糖耐受性異常、胰島素抗性、糖尿病併發症(包括神經病、腎病、骨質疏鬆症、視網膜病、糖尿病足部潰瘍及白內障))及/或血塞。
60. 段落59之方法，其中疾病係選自(i)呈副甲狀腺-副甲狀腺低能症、假副甲狀腺低能症、繼發性副甲狀腺高能症形式；(ii)呈胰腺糖尿病形式；(iii)呈甲狀腺髓性癌形式；(iv)呈皮膚銀屑病；創傷癒合形式；(v)呈肺類肉瘤病及肺結核形式；(vi)呈腎慢性腎病、低磷酸鹽VDRR、維他命D依賴性佝僂病形式；(vii)呈骨骼抗驚厥治療、骨纖維生成不良、囊性纖維性骨炎、軟骨病、骨質疏鬆症、骨質減少、骨硬化病、腎性骨營養不良、佝僂病形式；(viii)呈腸糖皮質激素拮抗、嬰兒期自發性高鈣血症、吸收障礙症候群、脂肪痢、熱帶口炎性腹瀉形式；及(ix)自體免疫病症。
61. 段落60之方法，其中疾病係選自癌症、皮膚病症(例如銀屑病)、副甲狀腺病症(例如副甲狀腺高能症及繼發性副甲狀腺高能症)、骨骼病症(例如骨質疏鬆症)及自體免疫病症。
62. 段落61之方法，其中疾病為繼發性副甲狀腺高能症。
63. 段落62之方法，其中個體患有慢性腎病(CKD)。
64. 段落63之方法，其中CKD為3或4期。
65. 段落64之方法，其中患者為維他命D缺乏。
66. 前述段落中任一段之方法，其中患者為人類。
67. 段落66之方法，其中人類為成人。
68. 一種如本文實質上所述之組合物。 Cross-references to related applications
This article claims the rights and interests under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 61/801,896 filed on March 15, 2013, and the disclosure is incorporated herein by reference.
As used herein, the terms "controlled release" and "modified release" are used interchangeably and refer to the release of an administered vitamin D compound in a manner that departs from immediate release. As used herein, the terms "sustained release" and "extended release" are used interchangeably and refer to the release of an administered vitamin D compound over a longer period of time compared to a comparable immediate release formulation, resulting in a Serum concentrations of vitamin D compounds remain elevated above baseline for longer periods of time than with immediate-release formulations. The foregoing terms optionally include delayed release features. For example, a controlled release formulation of the extended release type would be produced by Cmax
Greater than C of immediate release formulationsmax
representation. As another example, the release of the 25-hydroxyvitamin D compound will preferably be such that total serum or blood levels of 25-hydroxyvitamin D are maintained or increased over an extended period of time (eg, 4 to 24 hours or even longer) Such rate exceeds the pre-dose dose.
As used herein, unless otherwise specified, the term "cellulosic compound" may include cellulose (C6
H10
O5
)n
or cellulose derivatives. "Cellulose ethers" are cellulose derivatives that have been chemically modified to cause partial or complete etherification of the hydroxyl groups in the cellulose molecules. Examples of cellulose derivatives useful as stabilizing agents include, but are not limited to, celluronic acid, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose Methylcellulose, methylcellulose, polyanionic cellulose and combinations thereof. Also encompassed by the term are various grades of cellulosic compounds or stabilizers corresponding to variables such as molecular weight, viscosity, solubility.
Any vitamin D compounds and combinations thereof suitable for prophylactic and/or therapeutic use are contemplated to be included in the formulations described herein. Vitamin D, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and other metabolites and vitamin D analogs are also used as active compounds in pharmaceutical compositions. Specific examples include (but are not limited to) vitamin D3
(cholecalciferol), vitamin D2
(ergocalciferol), 25-hydroxyvitamin D3
, 25-hydroxyvitamin D2
, 25-hydroxyvitamin D4
, 25-hydroxyvitamin D5
, 25-hydroxyvitamin D7
, 1α,25-dihydroxyvitamin D3
, 1α,25-dihydroxyvitamin D2
, 1α,25-dihydroxyvitamin D4
and vitamin D analogs (including all hydroxy and dihydroxy forms), including 1,25-dihydroxy-19-nor-vitamin D2
and 1α-hydroxyvitamin D3
. In one embodiment, the vitamin D compound includes one or more hydroxyl forms, such as 25-hydroxyvitamin D3
and 25-hydroxyvitamin D2
combination.
Types of vitamin D compounds particularly contemplated for use in the formulations disclosed herein may include 25-hydroxyvitamin D2
, 25-hydroxyvitamin D3
or combination thereof. Consider especially 25-hydroxyvitamin D3
. As used herein, the term 25-hydroxyvitamin D refers to 25-hydroxyvitamin D3
, 25-hydroxyvitamin D2
, 25-hydroxyvitamin D4
, 25-hydroxyvitamin D5
or 25-hydroxyvitamin D7
one or more of, and is intended to be 25-hydroxyvitamin D in any of the preferred embodiments mentioned3
and 25-hydroxyvitamin D2
One or more of them, preferably 25-hydroxyvitamin D3
. Thus, in any and all formulations described herein, certain contemplated active agents may include 25-hydroxyvitamin D2
and 25-hydroxyvitamin D3
, especially 25-hydroxyvitamin D3
one or both. In the present invention, the vitamin D compound (or combination thereof) is also referred to as the "active" portion of the formulation (or "active" agent) to distinguish it from controlled release matrices, stabilizers and other excipients. What is reported in this article about the use of 25-hydroxyvitamin D3
In pharmacokinetic testing of samples as active agents, references to 25-hydroxyvitamin D should be interpreted to mean 25-hydroxyvitamin D3
, and all pharmacokinetic (PK) results related to it (such as tmax
,Cmax
, AUC) should be understood as based on 25-hydroxyvitamin D3
.
As used herein, a "stabilized" formulation means a formulation that exhibits stable in vitro dissolution characteristics (according to any of the parameters further described herein) and after initial manufacturing (e.g., under actual shelf storage or accelerated stable storage conditions Formulations for controlled release (e.g., sustained release) of vitamin D compounds in vivo over a period of time. The release of the active ingredient can be measured using a suitable in vitro dissolution method, such as one of those known in the art. In principle, if the formulation is stable, it can be determined using any of the following dissolution studies described in United States Pharmacopeia, USP 29-NF 24, Dissolution <711> Physical Tests and Determinations, United States Pharmacopeia Convention, Rockville, MD, 2006, pp. 2673-2682; European Pharmacopoeia 2.9.3 Dissolution Test for Solid Dosage Forms or Japanese Pharmacopoeia 6.10 Dissolution Test. For the purposes of this invention, the in vitro dissolution method is United States Pharmacopeia, USP 29-NF 24, Dissolution <711> Physical Tests and Determinations, USP Convention, Inc., Rockville, MD, 2006, pp. 2673-2682, using the following example Equipment as described in 2 (stirring paddle method).
As used in this article, tmax
(or Tmax) is defined as the time at which the plasma concentration of the active compound reaches its maximum value at a dose interval following administration of a formulation of the invention. When administering a single 25-hydroxyvitamin D compound (e.g., 25-hydroxyvitamin D3
), unless otherwise specified, tmax
Defined as serum 25-hydroxyvitamin D following administration of the formulation3
The time at which the plasma concentration reaches its maximum value between doses.
Consistent with NKF K/DOQI guidelines, as used herein, vitamin D sufficiency is defined as serum 25-hydroxyvitamin D ≥ 30 ng/mL and vitamin D insufficiency is defined as serum 25-hydroxyvitamin D 16-30 ng/mL, Mild vitamin D deficiency is defined as a serum 25-hydroxyvitamin D level of 5-15 ng/mL, and severe vitamin D deficiency is defined as a 25-hydroxyvitamin D level of less than 5 ng/mL.
In the context of prohibiting patents on methods of practice on the human body, the meaning of "administering" a composition to a human subject shall be limited to the extent to which the human subject will prescribe the composition by any technique (e.g., oral, inhaled, surface application) , injection, insertion, etc.) self-administered controlled substances. The broadest reasonable interpretation consistent with the law or regulation defining patentable subject matter is contemplated. In jurisdictions that do not prohibit the granting of patent rights for methods of practice on the human body, "administration" of the composition includes both methods of practice on the human body and the aforementioned activities.
It is specifically understood that any numerical value stated herein includes all values from the lower limit to the upper limit, that is, all possible combinations of the numerical values between the lowest value and the highest value enumerated are intended to be deemed to be expressly stated in this application. For example, if a concentration range or beneficial effect range is stated as 1% to 50%, it is intended that values such as 2% to 40%, 10% to 30%, or 1% to 3% be explicitly recited in this description. . As another example, a concentration of about 20% is intended to include values from 19.5% to up to 20.5%. These examples are only examples of specific expectations.
Disclosed herein are formulations for controlled release of vitamin D compounds in the gastrointestinal tract of an individual who ingests the formulation. The formulation will include a vitamin D compound as described herein, a matrix component (eg, a lipophilic matrix) that releasably binds the vitamin D compound and that controllably releases the vitamin D compound, and a stabilizer (eg, a cellulosic compound).
The stabilized formulations of the present invention release an amount of 25-hydroxyvitamin D in in vitro dissolution after a period of storage that is not materially different from the dissolution of the same formulation only after manufacture and before storage. . For example, in one embodiment, the formulation releases an amount of 25-hydroxyvitamin D during in vitro dissolution after exposure to storage conditions of 25° C. and 60% relative humidity for two months, and the formulation is Changes in release at any given dissolution time point four hours later compared to the amount released at the same dissolution time point during in vitro dissolution prior to exposure to storage conditions (i.e., freshly prepared product)30 % or less than 30%.
The following table provides the expected storage stability of embodiments of the present invention after initial manufacturing at 25°C and 60% RH and or after multiple storages at 40°C and 75% RH, and at various times during dissolution testing. An example of the benefits of sex. The degree of storage stability is expressed as the maximum deviation from the nominal activity potency, that is, the maximum % change from the LC. Alternative embodiments of maximum deviation are also provided. Time(h) 1 month 3 months 6 months 9 months 12 months 18 months 24 months
Store at 25℃ and 60% RH
2 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10%
4 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10%
6 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10%
8 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10%
12 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10%
Store at 40℃ and 75% RH
2 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10%
4 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10%
6 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10%
8 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10%
12 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10% 30%, or 25%, or 20%, or 15%, or 10%
In one embodiment, the formulation will have a favorable degree of stability immediately following that described in the table above at multiple time points throughout the dissolution test, such as at least two time points of 2 and 4 hours, and optionally also at the 6 hour time point, further optionally also at the 8 hour time point and further optionally also at the 12 hour time point, so that the dissolution profile after storage follows that of the fresh product. Alternatively, the formulations will have favorable degrees of stability immediately following those described in the table above at least at the 2, 6 and 12 hour time points. Alternatively, the formulations will have favorable degrees of stability immediately following those described in the table above at least at the 4, 8 and 12 hour time points. Alternatively, the formulations will have favorable degrees of stability immediately following those described in the table above at least at the 2, 4 and 6 hour time points. Alternatively, the formulation will have an advantageous degree of stability immediately described in the table above at least at the 4, 6, 8 and 12 hour time points or at all times of 4 hours and thereafter.
In any and all examples described immediately above in the table, the deviation is intended to be positive (more release) or negative (less release) with respect to fresh product. In one embodiment, the deviation is intended to be in the negative direction (less release) at multiple points in time. Furthermore, in one embodiment, if no stabilizer is present in the formulation, the deviation in dissolution release is expected to have been negative (less release) at multiple time points.
In any of the embodiments contemplated herein, the dissolution release profile of the formulation may be characterized by any of the following examples provided herein. For example, the formulation can be characterized by a dissolution release profile that provides less than 30% at 2 hours, greater than 45% at 6 hours, and greater than 80% at 12 hours and further optionally at 6 hours. Less than 60% of vitamin D compounds released.
In another embodiment, the formulation can be achieved by providing a release of vitamin D compound in vivo by less than 30% at 100 to 140 minutes, greater than 45% at 5 to 7 hours, and greater than 80% at 11 to 13 hours. Characterization of external dissolution characteristics. In another embodiment, the formulation can be characterized by an in vitro dissolution profile that provides less than 30% release at 2 hours, greater than 45% at 6 hours, and greater than 80% release of the vitamin D compound at 12 hours. In these types of embodiments, the release of the vitamin D compound is optionally less than 60% at 5 to 7 hours or less than 60% at 6 hours.
In another embodiment, the formulation may be formulated by providing a release of the vitamin D compound in vivo from about 20% to about 40% at 2 hours, at least 35% at 6 hours, and at least 70% at 12 hours. Characterization of external dissolution characteristics. In another embodiment, the formulation may be formulated by providing from about 25% to about 35% at 2 hours, at least 40% at 6 hours, and at least 75% at 12 hours of release of the vitamin D compound. Characterization of dissolution characteristics in vitro. In these types of embodiments, the release of the vitamin D compound is optionally, for example, 75% or less at 6 hours, or 65% or less at 6 hours, or 60% at 6 hours. or less than 60%.
In any of the embodiments described herein, the stabilized formulation can be prepared by administering the dosage form to a human patient at tmax
Characterization, the tmax
At least 4 hours, or at least 8 hours, or at least 12 hours, or at least 18 hours, or at least 20 hours, or at least 24 hours, or at least 28 hours, such as in the range of 4 to 96 hours, or in the range of 18 to 30 hours range, or in the range of 13 to 28 hours, or for example 28 hours.
In any embodiment contemplated herein, the formulation comprising 25-hydroxyvitamin D is characterized by providing a baseline-adjusted C per microgram of 25-hydroxyvitamin D.max
, when administered to adults, the Cmax
In the range of about 0.0133 ng/mL to about 0.04 ng/mL.
In any of the methods encompassed herein, the method may comprise administering to a human patient a stabilized sustained release dosage form comprising a 25-hydroxyvitamin D compound, comprising administering to the patient an effective amount of the formulation to provide a baseline Adjustment Cmax
, the Cmax
At least about 0.2 ng/mL, and optionally less than 110 ng/mL, and further optionally 24 ng/mL or less, such as in the range of about 0.2 to about 24 ng/mL.
In any of the methods encompassed herein, the method may comprise administering to a human patient a stabilized sustained release dosage form comprising a 25-hydroxyvitamin D compound, comprising administering to the patient an effective amount of the formulation to provide a baseline Adjusted AUC0-inf
, the AUC0-inf
At least 52 ng*h/mL, and optionally less than 34,500 ng*h/mL, and further optionally about 12,000 ng*h/mL or less, such as at about 52 ng*h/mL to approximately 12,000 ng*h/mL.
In any embodiment described herein, the stabilized formulation is intended to be bioequivalent to the freshly prepared product upon storage. Thus, for example, a stabilized formulation may provide, after storage, the area under the curve of the active agent (or total 25-hydroxyvitamin D in serum), AUC (e.g., AUC0-inf
or AUC0-t
) is within a 90% confidence interval, or within 80% to 125% of the mean value of fresh produce, or within 80% to 120% of its mean value. Additionally or in the alternative, the stabilized formulation provides a maximum serum concentration of the active agent (or total serum 25-hydroxyvitamin D) after storage, Cmax
(e.g. absolute Cmax
or C compared to the baselinemax
) is within a 90% confidence interval, or within 80% to 125% of the mean value of fresh produce, or within 80% to 120% of its mean value.
In one embodiment, the stabilized formulation includes 25-hydroxyvitamin D2
and 25-hydroxyvitamin D3
One or both of , wax matrix and cellulose compounds. In one aspect, the stabilized formulation includes 25-hydroxyvitamin D2
and 25-hydroxyvitamin D3
, one or both of wax matrix and cellulose stabilizer. In another aspect, the formulation includes 25-hydroxyvitamin D2
and 25-hydroxyvitamin D3
, one or both of a wax matrix and an effective amount of a cellulosic compound to provide advantageous stability as described herein, such as according to the table immediately above or in accordance with any of the examples described below. For example, the amount is effective to provide an amount of active agent released at the time point of dissolution during in vitro dissolution after exposure to storage conditions of 25° C. and 60% relative humidity for at least one month that is consistent with the amount of active agent released when the formulation is exposed to storage conditions of 25° C. and 60% relative humidity. A 30% or less difference between the amounts released at the same dissolution time point during in vitro dissolution performed prior to storage conditions, whereas the lack of stabilizer in the comparative formulation would result in dissolution release after the same storage conditions Bigger difference.
In one aspect, the formulation is a formulation modified for controlled release of a vitamin D compound in the gastrointestinal tract of an individual who ingests the formulation. In one embodiment, the modification includes incorporating a cellulose stabilizer into the formulation for controlled release of the vitamin D compound in the gastrointestinal tract of the individual ingesting the formulation. In another embodiment, the improvement comprises admixing into the formulation an effective amount of a cellulosic compound for controlled release of a vitamin D compound in the gastrointestinal tract of a subject ingesting the formulation, thereby providing the advantageous benefits as described herein. Stability, for example, according to the table immediately above or in accordance with any of the examples described below. For example, the amount is effective to provide an amount of active agent released at the time point of dissolution during in vitro dissolution after exposure to storage conditions of 25° C. and 60% relative humidity for at least one month that is consistent with the amount of active agent released when the formulation is exposed to storage conditions of 25° C. and 60% relative humidity. A 30% or less difference between the amounts released at the same dissolution time point during in vitro dissolution performed prior to storage conditions, whereas the lack of stabilizer in the comparative formulation would result in dissolution release after the same storage conditions Bigger difference.
Stabilizers may include cellulosic compounds. Examples of cellulosic compounds and stabilizers useful in stabilized formulations of the present invention may include, but are not limited to, cellulonic acid, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyanionic cellulose and combinations thereof. Also covered are poloxamer (e.g. polaxamer 407), poly(ethylene oxide) polymers (e.g. Dow's POLYOX polymers), povidones and fumed silicas (e.g. AEROSIL 200, Evonik Industries AG, Essen, Germany). Stabilizers (eg, cellulosic compounds) are preferably present in an amount of at least about 5% (wt%) of the formulation, based on the total weight of the formulation excluding any other coatings or shells. For example, the cellulosic compound may be at least 5 wt% of the formulation, or at least 10 wt% of the formulation, or at least 15 wt% of the formulation, or greater than 5 wt% of the formulation, or greater than 10 wt% of the formulation. %, or in an amount greater than 15 wt% of the formulation. Suitable ranges include 5 wt% to 30 wt%, 10 wt% to 20 wt%, 10 wt% to 15 wt%, 5 wt% to 15 wt%, and 7.5 wt% to 12.5 wt.%. Examples include about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt% % and about 15 wt%. It is understood that stabilizers as referred to herein are those that stabilize the dissolution release profile (and thus the in vivo release profile) against substantial changes over time during storage conditions (e.g., typical shelf storage conditions). Reagents. Other agents known in the art as preservatives for preventing the degradation of the active ingredient itself are not intended to be included in the terms "stabilizing agent" and "stabilizer", although such preservatives Agents are also contemplated for use in the formulations of the present invention.
In one type of embodiment, the cellulose compound is a cellulose ether. Examples of cellulose ethers include, but are not limited to, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and combinations thereof.
Hydroxypropyl methylcellulose (HPMC) is particularly considered. HPMC may be characterized by one or more of the following characteristics, which are specifically intended individually and in combination. The methoxy component % in HPMC can range from 19 to 24. The hydroxypropyl component % can range from 7 to 12. The apparent viscosity (2% aqueous solution at 20°C) may be at least 50,000 centipoise, or at least 80,000 centipoise, or between about 80 and 120,000 centipoise, or between 3000 and 120,000 centipoise, or between 11,000 and 120,000 centipoise, or between 80,000 and 80,000 centipoise. Within 120,000 centipoise. Specifically, apparent viscosity (2% aqueous solution at 20°C) may range from 80,000 to 120,000 centipoise. The pH value (1% aqueous solution) can range from 5.5 to 8.0. By way of example, a suitable hydroxypropyl methylcellulose having all of the above properties, including an apparent viscosity in the range of 80,000 to 120,000 centipoise (2% aqueous solution at 20°C) is METHOCEL K100M CR (Dow Wolff Cellulosics, Midland, Michigan).
In one embodiment, the cellulosic compound will be insoluble in the matrix formulation at the melting point of the major component of the matrix (eg, at 65°C or in the range of 60°C to 75°C).
In one embodiment, the cellulosic compound will be hydrophilic.
Contains 25-hydroxyvitamin D2
and 25-hydroxyvitamin D3
Pharmaceutical formulations of the invention that contain one or more of a cellulose compound and a cellulose compound surprisingly have improved stability compared to formulations lacking a cellulose compound. In one embodiment, the stabilized formulations of the present invention comprise 25-hydroxyvitamin D.2
and 25-hydroxyvitamin D3
and a mixture of an active loaded lipophilic matrix of one or both of a cellulose stabilizer, wherein the formulation is released during in vitro dissolution after exposure to storage conditions of 25° C. and 60% relative humidity for at least one month. An amount of 25-hydroxyvitamin D that changes by 30% at any given dissolution time point compared to the amount released at the same dissolution time point during in vitro dissolution on freshly prepared product or less than 30%.
Unstabilized formulations exhibit changes in the amount of active ingredient released after the composition has been stored for a period of time, as shown in the following examples. Unstabilized formulations release an amount of 25-hydroxyvitamin D after exposure to storage conditions that may vary at a given dissolution time point, e.g., as compared to in vitro dissolution on freshly prepared product Compared with the release amount at the same dissolution time point during the period, the change was more than 30%. A change may be an increase or decrease in the rate of dissolution at a given point in time, and such changes produce a dissolution profile whose curve is different from the shape of the original dissolution profile. Non-stabilized formulations also exhibit different performance compared to stabilized formulations of the invention after storage as described herein (eg, after storage at 25°C and 60% RH for 3 months or longer). In vivo effects. Stabilized formulations exhibit different clinical pharmacokinetics compared to non-stabilized formulations after storage as described herein (e.g., after storage at 25°C and 60% RH for 3 months or longer) Parameters such as improved bioavailability. Stabilized formulations of the present invention may have a storage-labile base formulation and a stabilizer that renders the formulation storage-stable as described herein.
The matrix to which the active ingredient is releasably bound and to which the active ingredient is controllably released may be, for example, a lipophilic matrix, including a wax matrix. The wax matrix may provide formulations that are solid or semi-solid at room temperature and may provide formulations that are solid, semi-solid or liquid at body temperature, preferably semi-solid or liquid at body temperature. In one aspect, the wax matrix includes controlled release agents, emulsifiers, and absorption enhancers.
Examples of controlled release agents suitable for this purpose include, but are not limited to, waxes (including synthetic waxes, microcrystalline waxes, paraffins, carnauba waxes, and beeswax); polyethoxylated castor oil derivatives, hydrogenated Vegetable oils, glycerol mono-, di-, or triglycerides; long-chain alcohols (such as stearyl alcohol, cetyl alcohol, and polyethylene glycol); and mixtures of any of the above. Preferred are non-digestible waxy materials (such as paraffin).
The controlled release agent may be present in an amount of at least 5 wt% of the formulation or greater than about 5 wt% of the formulation. For example, depending on the controlled release agent used, the controlled release agent may comprise at least 5 wt% of the formulation, or at least 10 wt% of the formulation, or at least 15 wt% of the formulation, or at least 20 wt% of the formulation. wt%, or at least 25 wt% of the formulation, or greater than 5 wt% of the formulation, or greater than 10 wt% of the formulation, or greater than 15 wt% of the formulation, or greater than 20 wt% of the formulation, and or greater 25 wt% of formulation. The controlled release agent may be present in an amount of 50 wt% or less, 40 wt% or less, 35 wt% or less, or 30 wt% or less. Suitable ranges include 5 wt% to 40 wt%, 10 wt% to 30 wt%, and 15 wt% to 25 wt%. Examples include about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt% % and about 25 wt%.
Examples of emulsifiers suitable for use in formulations include, but are not limited to, lipophilic agents with an HLB of less than 7 (such as mixed fatty acid monoglycerides; mixed fatty acid diglycerides; mixtures of fatty acid mono- and diglycerides); Lipophilic polyglyceryl esters; glyceryl esters including glyceryl monooleate, glyceryl dioleate, glyceryl monostearate, glyceryl distearate, glyceryl monopalmitate and glyceryl dipalmitate; fatty acid glycerol Lactic acid esters; including propylene glycol esters of propylene glycol monopalmitate, propylene glycol monostearate and propylene glycol monooleate; including sorbitan monostearate, sorbitan sesquioleate and sorbitan Sugar alcohol esters; fatty acids including stearic acid, palmitic acid and oleic acid and their soaps; and their mixtures; glyceryl monooleate, glyceryl dioleate, glyceryl monostearate, glyceryl distearate , glyceryl monopalmitate, and glyceryl dipalmitate; fatty acid glyceryl lactate; propylene glycol esters including propylene glycol monopalmitate, propylene glycol monostearate and propylene glycol monooleate; including sorbitan monostearate Fatty acid esters, sorbitan esters of sorbitan sesquioleate; fatty acids including stearic acid, palmitic acid and oleic acid and their soaps; and mixtures thereof.
Preferred lipophilic agents are selected from glycerides and their derivatives. Preferred glycerides are selected from the group consisting of medium or long chain glycerides, octanoyl hexanoyl polyethylene glycol glycerides and mixtures thereof.
Preferred medium chain glycerides include (but are not limited to) medium chain monoglycerides, medium chain diglycerides, caprylic/capric triglycerides, glyceryl monolaurate, glyceryl monostearate, and glyceryl caprylic/capric acid. Ester, glyceryl monocaprylate, glyceryl monocaprylate, caprylic/capric linoleic acid triglyceride and caprylic/capric/succinic acid triglyceride.
Monoglycerides with low melting points are preferred for preparing formulations. Preferred monoglycerides include (but are not limited to) glyceryl monostearate, glyceryl monopalmitate, glyceryl monooleate, glyceryl monocaprylate, glyceryl monocaprate, glyceryl monolaurate, etc., preferably It is glyceryl monostearate (GMS). GMS is a natural emulsifier. It is oil-soluble but poorly soluble in water. The HLB value of GMS is 3.8. The lipophilic emulsifier may be present, for example, in an amount from about 10 wt% to about 40 wt% or from about 20 wt% to about 25 wt%. Other examples include about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, and about 25 wt%.
Examples of suitable absorption enhancers include, but are not limited to, octanoylhexanoyl polyethylene glycol glycerides such as polyglycosylated glycerides, also known as polyglycolized glycerides or pegylated (PEGylated)glycerides. PEGylated glycerides that may be used in the composition include, but are not limited to, monoglycerides, diglycerides, and triglycerides and mixtures of mono- and diesters of polyethylene glycol, polyglycosylated almonds Glycerides, polyvinyl glycosylated corn glycerides and polyvinyl glycosylated caprylic/capric triglycerides. The absorption enhancer may have an HLB value of 13 to 18 or 13 to 15.
One preferred absorption enhancer is known under the tradename GELUCIRE (Gattefossé Corporation, Paramus, New Jersey, USA). GELUCIRE is a well-known excipient, which is a family of fatty acid esters of glycerol and PEG esters, also known as PEGylated glycerides. GELUCIRE is used in a variety of applications including the preparation of sustained release pharmaceutical compositions. GELUCIRE compounds are inert, semi-solid waxy materials that are amphoteric and can exhibit varying physical characteristics (such as melting point, HLB, and solubility) in different solvents. It is actually a surfactant and disperses or dissolves in an aqueous medium to form microcells, microscopic spheres or liposomes. It is identified by its melting point/HLB value. Melting point is expressed in degrees Celsius. One or a mixture of different grades of GELUCIRE excipients can be selected to achieve the desired characteristics of melting point and/or HLB value. A preferred GELUCIRE composition is GELUCIRE 44/14 (a mixture of dodecyl polyethylene glycol glyceride and dodecyl polyoxyglyceride), which has a melting point of 44°C and an HLB of 14. The absorption enhancer may be present, for example, in an amount from about 5 wt% to about 20 wt% or from about 8 wt% to about 15 wt%. Other examples include about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, and about 15 wt%.
The low melting point of the wax matrix provides for binding of pharmaceutically active ingredients such as 25-D at temperatures from about 0°C to about 50°C above the melting point of the wax matrix.2
,25-D3
or both vitamin D compounds), and then filling the melt (solution and/or dispersion) into suitable capsules. The capsules may be of any type compatible with the temperature at which the melt is filled, including soft or hard gelatin capsules and animal or vegetable gelatin capsules. The melt solidified inside the capsules on cooling to room temperature.
In one aspect, the stabilized formulation may further comprise 25-hydroxyvitamin D.2
and/or 25-hydroxyvitamin D3
Oily medium. Any pharmaceutically acceptable oil can be used. Examples include animal (eg fish), plant (eg soybean) and mineral oils. The oil will preferably readily dissolve the 25-hydroxyvitamin D compound used. Preferred oil vehicles include non-digestible oils such as mineral oil, specifically liquid paraffin and squalene. The oily vehicle may, for example, comprise from about 10 wt% to about 50 wt%, or from about 15 wt% to about 45 wt%, or from about 20 wt% to about 40 wt%, or from about 30 wt% to about 40 wt% of the formulation. concentration within the % range. In one embodiment, a suitable liquid paraffin can be characterized by one or more of the following parameters: specific gravity is about 0.88 to 0.89; kinematic viscosity (40°C) is about 64 cSt to about 70 cSt; molecular weight is 424; paraffin wax The hydrocarbon % is about 59; and the pour point is -24°C. The ratio between wax base and oil vehicle can be optimized to achieve the desired rate of release of the vitamin D compound. Thus, if a heavier oil component is used, a relatively less wax base can be used, and if a lighter oil component is used, a relatively more wax base can be used.
The stabilized controlled release composition of the present invention is preferably designed, for example, to contain 1 to 1000 μg of 25-hydroxyvitamin D per unit dose.2
and/or 25-hydroxyvitamin D3
concentration and prepared in such a manner to achieve 25-hydroxyvitamin D2
/25-Hydroxyvitamin D3
The effects are controlled or substantially constant release, as appropriate, over an extended period of time into the ileum of the gastrointestinal tract of humans or animals. Examples of dosages include 1 μg to 1000 μg, 1 μg to 600 μg, 1 μg to 400 μg, 1 μg to 200 μg, 1 μg to 100 μg, 5 μg to 90 μg, 30 μg to 80 μg, 20 μg to 60 μg, 30 μg to 60 μg, 35 μg to 50 μg, 5 μg to 50 μg and 10 μg to 25 μg, such as 20 μg, 25 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg , 80 μg, 90 μg and 100 μg.
In a preferred class of embodiments, the controlled release formulation releases at least 70%, more preferably at least 80%, of the vitamin D compound within the first 24 hours after administration.
Advantageously, 25-hydroxyvitamin D can be administered, for example orally, according to the above embodiments, for example in a dose of 1 to 100 μg per day.2
, 25-hydroxyvitamin D3
or combinations thereof together with other therapeutic agents. In one embodiment, the dosage will be selected to provide about 1 to 3 ng/ml of serum 25-hydroxyvitamin D over the dosage interval.3
average increase.
In embodiments, the formulations described herein can be administered to increase and preferably also maintain blood levels of 1,25-dihydroxyvitamin D at 25 pg/mL, 30 pg/mL, or higher (e.g., 25 -65 pg/mL) for an extended period of time, such as at least one month, at least three months, at least six months, or longer.
In one aspect, a formulation described herein can be administered to a patient to reduce or maintain reduced serum parathyroid hormone levels, preferably by an amount that reduces PTH levels by at least 30%, or to reduce serum levels of PTH to CKD Target range for phase 3 (e.g. 35-70 pg/mL (equivalent to 3.85-7.7 pmol/L) for phase 3, 70-110 pg/mL (equivalent to 7.7-12.1 pmol/L) for phase 5 and 5 The amount required for a period of 150-300 pg/mL (equivalent to 16.5-33.0 pmol/L) (as defined in K/DOQI Guideline No. 1)).
In another aspect, a patient suffering from hyperthyroidism secondary to chronic kidney disease (eg, stage 3 or 4, or stage 3, 4, or 5) may be administered a formulation of the invention to reduce serum PTH levels.
The dosages described herein are contemplated for use in any of the treatment methods described herein. It is understood that the actual preferred amount of vitamin D compound in a particular situation will vary depending on the particular composition formulated, the mode of application and the particular site being treated. Doses may be determined using conventional considerations, eg by conventional comparison of the different activities of hormones and known agents, eg by means of appropriate conventional pharmacological protocols.
The specific dosage for each particular patient will depend on a variety of factors, such as age, weight, general health, sex, diet, timing and mode of administration, rate of excretion, agents used in combination, and the severity of the particular condition for which the therapy is being administered. .
Patients requiring vitamin D supplementation include healthy individuals and individuals at risk of vitamin D insufficiency or deficiency, such as individuals with stage 1, 2, 3, 4, or 5 CKD; infants, children, and children who do not drink vitamin D-fortified milk; Adults (e.g., lactose intolerant individuals, individuals with milk allergies, vegetarians who do not consume milk, and breastfed infants); individuals with rickets; dark-skinned individuals (e.g., in the United States, 42% between the ages of 15 and 49 African American women compared with 4% of white women are vitamin D deficient); the elderly (reduced ability to synthesize vitamin D and more likely to stay indoors); institutionalized adults (adults who are likely to stay indoors, including those with Individuals with Alzheimer's disease or mental illness); Individuals who cover all exposed skin (such as those of certain religions or cultures); Individuals who always use sunscreen (e.g., apply a sun protection factor (SPF) value of 8 sunscreens reduce the production of vitamin D by 95%, and higher SPF values can further reduce vitamin D); people with fat malabsorption syndrome (including (but not limited to) cystic fibrosis, cholestatic liver disease, others Individuals with liver disease, gallbladder disease, pancreatic enzyme deficiency, Crohn's disease, inflammatory bowel disease, sprue or celiac disease or surgery to remove part or all of the stomach and/or intestines); Individuals with inflammatory bowel disease; individuals with Crohn's disease; individuals who have had their small intestines removed; individuals with gum disease; individuals taking drugs that increase vitamin D metabolism (including phenytoin, phosphorus Individuals taking phenytoin, phenobarbital, carbamazepine and rifampin); individuals taking drugs that reduce the absorption of vitamin D (including cholestyramine, colestiped) (colestipol, orlistat, mineral oil and fat substitutes); individuals taking drugs that inhibit vitamin D activation (including ketoconazole); individuals taking drugs that reduce calcium absorption (including corticosteroids) Individuals with obesity (vitamin D deposited in body fat stores is less bioavailable); Individuals with osteoporosis; Individuals with low bone mineral density and osteoporosis; and /or postmenopausal women. According to the Academy of Medicine Report on Dietary Reference Intakes of Vitamin D, food consumption data indicate that the median intake of vitamin D for young and older women is lower than the current recommended intake; data indicate that more than 50% of younger and older women Older women do not consume the recommended amount of vitamin D.
Optionally excluded from the methods of the invention described herein is the treatment of individuals suffering from renal osteodystrophy, including rickets and osteitis fibrosus cystica.
In other aspects, the compositions and methods of the present invention are suitable for preventing or treating vitamin D-responsive diseases, namely, in which vitamin D, 25-hydroxyvitamin D or active vitamin D (such as 1,25-dihydroxyvitamin D )A disease that prevents the onset or progression of a disease or reduces the signs or symptoms of a disease. Such vitamin D-responsive diseases include cancers (eg, breast, lung, skin, melanoma, colon, colorectum, rectum, prostate, and bone cancers). 1,25-dihydroxyvitamin D has been observed to induce cell differentiation and/or inhibit cell proliferation in multiple cells in vitro. Vitamin D-responsive diseases also include autoimmune diseases, such as type 1 diabetes, multiple sclerosis, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma, fibrosis, and Grave's disease , Hashimoto's disease, acute or chronic transplant rejection, acute or chronic graft-versus-host disease, inflammatory bowel disease, Crohn's disease, systemic lupus erythematosus, Sugar Ray syndrome, Eczema, psoriasis, dermatitis (including atopic dermatitis, contact dermatitis, allergic dermatitis and/or chronic dermatitis). Vitamin D-responsive diseases also include other inflammatory diseases, such as asthma, chronic obstructive pulmonary disease, polycystic kidney disease, polycystic ovary syndrome, pancreatitis, nephritis, hepatitis and/or infection. Vitamin D-responsive diseases including hypertension and cardiovascular disease have also been reported. Thus, the present invention encompasses the prevention or therapeutic treatment of individuals at risk of developing cardiovascular disease, such as atherosclerosis, arteriosclerosis, coronary artery disease, cerebrovascular disease, peripheral vascular disease, myocardial infarction, myocardial ischemia , cerebral ischemia, stroke, congestive heart failure, cardiomyopathy, obesity or other weight disorders, lipid disorders (such as hyperlipidemia, including related diabetic dyslipidemia and mixed dyslipidemia, hypoalphalipoproteinemia dyslipidemia, hypertriglyceridemia, hypercholesterolemia and low HDL (high-density lipoprotein)), metabolic disorders (such as metabolic syndrome, type II diabetes, type I diabetes, hyperinsulinemia, glucose tolerance Individuals with abnormalities, insulin resistance, complications of diabetes (including neuropathy, nephropathy, retinopathy, diabetic foot ulcers and cataracts)) and/or blood clots.
Diseases that may benefit from modification of levels of vitamin D compounds include (but are not limited to): (i) in the form of parathyroid-hypoparathyroidism, pseudohypoparathyroidism, secondary parathyroid hyperactivity; (ii) in the form of pancreatic hypoparathyroidism Diabetic form; (iii) As medullary thyroid carcinoma form; (iv) As cutaneous psoriasis; Wound healing form; (v) As pulmonary sarcoidosis and tuberculosis form; (vi) As renal chronic kidney disease, hypophosphate VDRR , vitamin D-dependent forms of rickets; (vii) in the form of skeletal anticonvulsant therapy, bone fibrogenesis dysgenesis, cystic fibrous osteitis, rickets, osteoporosis, osteopenia, osteosclerosis, renal osteodystrophy, rickets forms; (viii) in the form of intestinal glucocorticoid antagonism, spontaneous hypercalcemia of infancy, malabsorption syndrome, steatorrhea, tropical sprue; and (ix) autoimmune disorders.
In embodiments of the present invention, diseases that benefit from modulation of levels of vitamin D compounds are selected from the group consisting of cancer, skin disorders (such as psoriasis), parathyroid disorders (such as parathyroid hyperactivity and secondary parathyroid hyperactivity) , bone disorders (such as osteoporosis) and autoimmune disorders.
The formulations may be prepared by procedures well within the ability of one of ordinary skill in the art. For example, components of the matrix (eg, waxes and oily vehicles) may be melted if desired to provide a flowable liquid thereby making it easier to obtain a homogeneous mixture. Active agents such as 25-hydroxyvitamin D2
and/or 25-hydroxyvitamin D3
) is added to a liquid carrier, for example dissolved in an alcohol such as absolute ethanol, and the ingredients are mixed to provide a homogeneous mixture. In one embodiment, the stabilizer can be added after blending of all matrix components (eg, waxes and oils) and before combining with the active agent. The mixture can be cooled and stored and later divided into unit dosage forms (such as filled gelatin capsules).
In one method, the oil vehicle, controlled release agent, and part of the emulsifier are heated to a relatively high temperature (e.g., 65°C) and mixed before adding the absorption enhancer, then mixed until homogeneous, and then cooled to a moderately high temperature. (e.g. 50℃ to 55℃). In a separate container, combine the antioxidant preservative and the remainder of the oil vehicle and heat to moderately high temperature (eg, 50°C), then combine with the wax mixture and mix until a homogeneous solution is obtained. Then, add stabilizer and mix. The vitamin D compound solution in ethanol is then combined with the homogeneous wax solution, mixed until a homogeneous solution is obtained, preferably filled into capsules, and then cooled to room temperature. In another preferred method, a portion of the oil vehicle, controlled release agent and emulsifier are heated at a temperature of 55°C to 60°C and mixed before adding the absorption enhancer and then mixed until homogeneous. In a separate container, combine the antioxidant preservative, the remainder of the oil vehicle and the stabilizer and heat to a temperature of 55°C to 60°C, then combine with the wax mixture and mix until a homogeneous solution is obtained. The vitamin D compound solution in ethanol is then combined with the homogeneous wax solution, mixed until a homogeneous solution is obtained, preferably filled into capsules, and then cooled to room temperature.
The formulation is preferably placed in a capsule prior to administration to a patient in need of treatment. The capsules may be hard or soft, and soft capsules are particularly contemplated. The formulation can be filled into gelatin capsules using standard capsule filling machines, such as by melting the formulation and injection filling it into a soft capsule shell. Examples of soft capsule shells include VEGICAPS and OPTISHELL technology (Catalent, Somerset, NJ, USA). In the alternative, the formulations may be formulated into unit dosage form by any other suitable process, for example to produce tablets, sachets, dragees, suppositories, or the like.
In one embodiment, the formulations are prepared for oral delivery and administered by oral delivery. In another embodiment, the formulations are prepared for and administered as suppositories, such as rectal suppositories.
Unless otherwise indicated, formulations and methods of use and preparation are contemplated to include embodiments including any combination of one or more of the other optional elements, features and steps described further below.
Thus, in one embodiment, the formulation further includes a preservative (such as an antioxidant). Butylated hydroxytoluene (BHT) is preferred.
In another embodiment, the vitamin D compound is administered in combination with one or more other therapeutic agents.
If a vitamin D compound is administered in combination with one or more other therapeutic agents, the proportion of each of the compounds in the combination administered will depend on the specific disease condition being treated. For example, one may choose to combine it with one or more calcium salts (intended as calcium supplements or dietary phosphate binders), bisphosphonates, calcimimetics, niacin, iron, phosphate binders , cholecalciferol, ergocalciferol, active vitamin D sterols, blood sugar and hypertension control agents, CYP24 degradable vitamin D agents and other anti-neoplastic agents and inhibitors of other cytochrome P450 enzymes are administered together25 -Hydroxyvitamin D2
and/or 25-hydroxyvitamin D3
(e.g. orally). In addition, we can choose different anti-neoplastic agents and inhibitors of cholecalciferol, ergocalciferol, active vitamin D sterols, blood sugar and hypertension control agents, CYP24 and other cytochrome P450 enzymes that degrade vitamin D. 25-hydroxyvitamin D administered intravenously2
and/or 25-hydroxyvitamin D3
. In practice, higher doses of the compounds of the invention are used where therapeutic management of a disease condition is the desired endpoint, while lower doses are generally used for prophylactic purposes, ie, the specific dose administered in any given situation Adjustments will be made based on the specific compound administered, the disease to be treated, the individual condition, and other relevant medical facts that may alter the activity of the drug or the response of the individual, as will be understood by those skilled in the art.
As mentioned above, the formulations are preferably filled into gelatin capsules, but they may also be administered in pure form or with one or more external coatings, such as enteric coatings. It is also contemplated that the formulations may be compressed into tablets, and in such case may include one or more tablet compression excipients.
In the compositions and methods described herein, the above-mentioned preferred steps, preferred components, preferred composition ranges and preferred combinations thereof can be selected from various specific examples provided herein. For example, preferred formulations include 25-hydroxyvitamin D (e.g., about 30 μg, about 60 μg, or about 90 μg 25-hydroxyvitamin D3
), about 2 wt% (for example 2.32 wt%) absolute ethanol, about 10 wt% (for example 9.75wt%) GELUCIRE 44/14, about 20 wt% (for example 20.00 wt.%) hard paraffin, about 23 wt% (for example 22.55 wt%) GMS, approximately 35 wt% (e.g., 35.36 wt%) liquid paraffin or mineral oil, approximately 10 wt% HPMC, and optionally a small amount of preservative (e.g., 0.02 wt% BHT). A variation of this formulation would include about 15% (eg, 15.29 wt%) HPMC and about 30% (eg, 29.88 wt%) liquid paraffin or mineral oil.Example
The following examples illustrate specific formulations and methods of preparation thereof. The examples are provided for illustration and are not intended to limit the scope of the invention.
In the examples, USP apparatus 2 (stirring paddle method) as described in USP 29-NF 24, General Chapter <711> Dissolution was used, and in vitro dissolution testing was performed using the dissolution medium described below. Generally speaking, proceed according to the following steps. Place the stated volume of dissolution medium (±1%) into the container of the designated equipment, assemble the equipment, equilibrate the dissolution medium to 37±0.5°C and remove the thermometer. Place the dosage unit in the device, taking care to remove air bubbles from the surface of the dosage unit and then operate the device at the specified rate. At each of these times, a sample is withdrawn from the intermediate area between the surface of the dissolution medium and the top of the rotating blade (not less than 1 cm from the container wall). The aliquots withdrawn for analysis were replaced with the same volume of fresh dissolution medium at 37°C. Keep the container covered for the duration of the test and verify the temperature of the test mixture at the appropriate time. In this case an appropriate analytical method (Ultra Performance Liquid Chromatography (UPLC)) is used for analysis.
Six capsules of each formulation were tested at each time point. The dissolution medium was 0.05 M phosphate buffer pH 6.8/1% sodium dodecyl sulfate at 37±0.5°C and the device was operated at 100 rpm. Samples were taken out at 2, 4, 6, 8 and 12 hours and the 25-hydroxyvitamin D content of each sample was determined using UPLC.Example 1-25- Hydroxyvitamins D In vitro dissolution of unstabilized sustained-release formulations
Tested by 90 µg 25-hydroxyvitamin D3
, 19.98 wt% hard paraffin, 37.85 wt% GMS, 9.76 wt% GELUCIRE 44/14, 2.36 wt% absolute ethanol, 29.88 wt% liquid paraffin and 0.02 wt% BHT (comparative formulation 1). Dissolve. The formulation contains no cellulosic compounds. Released 25-hydroxyvitamin D3
The average amounts are summarized in the table below as the average percentage of the nominal drug loading for each dosage form at T = 0 and after controlled storage of the formulations at 5°C and ambient humidity for up to 12 months. (Average % of labeled amount, %LC) calculation. It was determined before the test that the sample was stored at a temperature and ambient humidity in the range of 15°C to 30°C for a period of approximately 3 months. Therefore, the sample that should represent the zero point of time is marked as T = 0p
(pseudo time zero) and it should be understood that samples that were nominally aged for 1 month, 3 months, 6 months, 9 months and 12 months also experienced the approximately 3 month aging period just mentioned. In order to provide more accurate baselines, fresh batches of the same type of samples were prepared and tested without any aging. This data is marked as T = 0f
to indicate fresh samples. The coefficient of variation (%CV) is also reported. Since T = 0p
and T = 0f
25-hydroxyvitamin D released from batch3
The percentage change in the initial quantity is provided in parentheses and double brackets respectively. Dissolve after storage at 5 °C / ambient humidity
time(hour) T=0 ppseudo T=0 ffresh 1 month (%CV) [% change from T=0 p ] [[% change from T=0 f ]] 3 months (%CV) [% change from T=0 p ] [[% change from T=0 f ]] 6 months (%CV) [% change from T=0 p ] [[% change from T=0 f ]] 9 months (%CV) [% change from T=0 p ] [[% change from T=0 f ]] 12 months (%CV) [% change from T=0 p ] [[% change from T=0 f ]]
2 6.1 (29.6) 22.1 (17.2) 8.9 (13.4) [45.9] [[59.7]] 15.7 (27.4) [157.4] [[29.0]] 9.1 (23) [49.2] [[58.8]] 15.2 (47.2) [149.2] [[31.2]] 12.7 (16.8) [108.2] [[42.5]]
4 14.5 (15.7) 52.0 (4.6) 20.7 (19.1) [42.8] [[60.2]] 22.3 (15.6) [53.8] [[57.1]] 22.9 (7.1) [57.9] [[56.0]] 25.2 (19.2) [73.8] [[51.5]] 24.7 (13.5) [70.3] [[52.5]]
6 27.6 (21.2) 77.9 (4.6) 35.7 (9.6) [29.3] [[54.2]] 33.5 (2.6) [21.4] [[57.0]] 34.1 (7.1) [23.6] [[56.2]] 36.2 (20.5) [31.2] [[53.5]] 34.8 (14.6) [26.1] [[55.3]]
8 45.7 (23.6) 96.8 (2.9) 53.0 (9.9) [16.0] [[45.2]] 47.4 (3.7) [3.7] [[51.0]] 46.8 (6) [2.4] [[51.7]] 47.8 (18.6) [4.6] [[50.6]] 46.4 (8.9) [1.5] [[52.1]]
12 89.7 (15.6) 112.3 (1.6) 100.0 (4.8) [11.5] [[11.0]] 78.9 (8.1) [12.0] [[29.7]] 76.9 (5.7) [14.3] [[31.5]] 74.1 (17.3) [17.4] [[34.0]] 78.8 (5.3) [12.2] [[29.8]]
Tests were conducted to compare the dissolution of Formulation 1 after storage at 25°C and 60% relative humidity for 0 to 12 months. The results are summarized in the table below. Dissolves after storage at 25 °C /60% relative humidity
Dissolution time (hours) T=0 ppseudo T=0 ffresh 1 month (%CV) [% change from T=0 p ] [[% change from T=0 f ]] 3 months (%CV) [% change from T=0 p ] [[% change from T=0 f ]] 6 months (%CV) [% change from T=0 p ] [[% change from T=0 f ]] 9 months (%CV) [% change from T=0 p ] [[% change from T=0 f ]] 12 months (%CV) [% change from T=0 p ] [[% change from T=0 f ]]
2 6.1 (29.6) 22.1 (17.2) 7.6 (7.7) [24.6] [[65.6]] 10.8 (15.7) [77.0] [[51.1]] 8.5 (19.2) [39.3] [[61.5]] 10.8 (15.8) [77.0] [[51.1]] 13.5 (24.7) [121.3] [[38.9]]
4 14.5 (15.7) 52.0 (4.6) 18.7 (18.6) [29.0] [[64.0]] 22.8 (23.7) [57.2] [[56.2]] 17.9 (11.9) [23.4] [[65.6]] 21.4 (5.5) [47.6] [[58.8]] 24.5 (17.4) [69.0] [[52.9]]
6 27.6 (21.2) 77.9 (4.6) 27.1 (22.7) [1.8] [[65.2]] 30.7 (29.6) [11.2] [[60.6]] 23.8 (11.6) [13.8] [[69.4]] 27.0 (7.3) [2.2] [[65.3]] 30.0 (15.7) [8.7] [[61.5]]
8 45.7 (23.6) 96.8 (2.9) 37.1 (18.1) [18/8] [[61.7]] 40.6 (29.9) [11.2] [[58.1]] 28.5 (13.2) [37.6] [[70.6]] 32.3 (6.4) [29.3] [[66.6]] 35.6 (14.7) [22.1] [[63.2]]
12 89.7 (15.6) 112.3 (1.6) 61.6 (16.6) [31.3] [[45.1]] 53.0 (32.2) [40.9] [[52.8]] 38.5 (12.2) [57.1] [[65.7]] 38.9 (6) [56.6] [[65.4]] 44.2 (12.2) [50.7] [[60.6]]
Tests were conducted to compare the dissolution of Formulation 1 after storage at 40°C and 75% relative humidity for 0, 1, 3 and 6 months. The results are summarized in the table below. Dissolves after storage at 40 °C /75% relative humidity
Dissolution time (hours) T=0 ppseudo T=0 ffresh 1 month (%CV) [% change from T=0 p ] [[% change from T=0 f ]] 3 months (%CV) [% change from T=0 p ] [[% change from T=0 f ]] 6 months (%CV) [% change from T=0 p ] [[% change from T=0 f ]]
2 6.1 (29.6) 22.1 (17.2) 11.7 (50) [91.8] [[47.1]] 16.9 (36.3) [177.0] [[23.5]] 1.8 (75) [70.5] [[91.9]]
4 14.5 (15.7) 52.0 (4.6) 52.0 (45.1) [258.6] [[0]] 59.8 (31.3) [312.4] [[15.0]] 36.2 (21.8) [149.7] [[30.4]]
6 27.6 (21.2) 77.9 (4.6) 87.0 (21.5) [215.2] [[11.7]] 97.8 (24) [254.3] [[25.5]] 76.7 (12.3) [177.9] [[1.5]]
8 45.7 (23.6) 96.8 (2.9) 107.3 (8.1) [134.8] [[10.8]] 110.9 (13) [142.7] [[14.6]] 101.2 (6.1) [121.4] [[4.5]]
12 89.7 (15.6) 112.3 (1.6) 118.7 (1.7) [32.3] [[5.7]] 115.1 (3.7) [28.3] [[2.5]] 112.6 (2.1) [25.5] [[0.3]]
Without intending to be bound by any particular theory, the increase in solubility after storage at 40°C compared to pseudo T = 0 values is believed to be due to the aging effects described above on the pseudo T = 0 samples tested when compared to A combination of temperature-dependent phase transitions in formulations when stored at 40°C.
The aged product of Comparative Formulation 1 was thermally cured and subsequently subjected to dissolution testing. Curing consists of applying a heat treatment and has been shown to stabilize pharmaceutical formulations (see, eg, US Pat. No. 6,645,527). Comparative Formulation 1 (aged sample) was heated at 40°C for 72 hours to cure and then stored at room temperature for 8 weeks. Testing of 25-hydroxyvitamin D after 0, 2, 4 and 8 weeks of storage at room temperature3
Release of self-curing formulations. The results are summarized in the table below. Dissolves after curing for 72 hours at 40 °C
Dissolution time (hours) T=0 2 weeks % LC [% change] 4 weeks % LC [% change] 8 weeks % LC [% change]
2 17.4 12.4 [28.7] 11.4 [34.5] 8.2 [52.9]
4 53.3 46.4 [12.9] 40.1 [24.8] 26.6 [50.1]
6 86.2 76.2 [11.6] 69.0 [20.0] 44.8 [48.0]
8 103.8 102.0 [1.7] 95.8 [7.7] 66.6 [35.8]
12 115.7 110.5 [4.5] 119.8 [3.5] 103.3 [10.7]
Example 2-25- Hydroxyvitamins D In vitro dissolution of stabilized controlled release formulations
Tested after storage at room temperature for 0 to 11 weeks, containing 90 µg of 25-hydroxyvitamin D3
, 19.88 wt% hard paraffin, 15.29 wt% hydroxypropyl methylcellulose, 22.55 wt% GMS, 9.76 wt% GELUCIRE 44/14, 2.36 wt% absolute ethanol, 29.88 wt% liquid paraffin and 0.02 wt% BHT (example preparation Dissolution of the sustained release formulation of substance A). The results are summarized in the table below. Dissolves after storage at room temperature / ambient humidity
Dissolution time (hours) T=0 3 weeks % LC [% change] 11 weeks % LC [% change]
2 15.45 14.20 [8.1%] 12.08 [21.8%]
4 36.3 38.80 [6.9%] 37.13 [2.3%]
6 56.9 62.70 [10.2%] 59.51 [4.6%]
8 71.1 71.90 [1.1%] 69.76 [1.9%]
12 89.4 91.20 [2.0%] 89.90 [0.6%]
Tested after storage at room temperature for 0 to 26 weeks, containing 90 µg of 25-hydroxyvitamin D3
, 19.88 wt% hard paraffin, 10.00 wt% hydroxypropyl methylcellulose, 22.55 wt% GMS, 9.76 wt% GELUCIRE 44/14, 2.36 wt% absolute ethanol, 35.17 wt% liquid paraffin and 0.02 wt% BHT (example preparation Dissolution of the sustained release formulation of substance B )). The results are summarized in the table below. Dissolves after storage at room temperature / ambient humidity
Dissolution time (hours) T=0 6 weeks % LC [% change] 13 weeks % LC [% change] 26 weeks % LC [% change]
2 30.15 25.40 [15.8%] 25.20 [16.4%] 21.10 [30.0%]
4 58.55 51.90 [11.4%] 51.80 [11.5%] 45.20 [22.8%]
6 72.1 74.40 [3.2%] 73.00 [1.2%] 67.63 [6.2%]
8 80.55 84.30 [4.7%] 84.50 [4.9%] 77.30 [4.0%]
12 91.8 94.10 [2.5%] 94.40 [2.8%] 91.16 [0.7%]
Example Formulation B exhibits substantially stable dissolution characteristics after storage at room temperature for at least 26 weeks.
Tested using storage conditions of 25°C and 60% relative humidity and 40°C and 75% relative humidity Contains 30 µg of 25-hydroxyvitamin D3
(Example Formulation C), 60 µg 25-hydroxyvitamin D3
(Example Formulation D) or 90 µg 25-hydroxyvitamin D3
Stability of the stabilized formulation of (Example Formulation E). The compositions of example formulations C to E are summarized in the table below: Components quantity
25-Hydroxyvitamin D 3 30 µg, 60 µg or 90 µg
solid paraffin 20.00wt%
mineral oil 35.36wt%
Hydroxypropyl methylcellulose K100M CR (METHOCEL) 10.00wt%
Glyceryl monostearate 22.55wt%
Dodecyl polyethylene glycol glyceride and polyoxyglyceride (GELUCIRE 44/14) 9.75wt%
Anhydrous ethanol 2.32wt%
BHT 0.02wt%
Soft capsule shell (VEGICAPS)
The formulation exhibited substantially stable dissolution characteristics after storage at 25°C and 60% relative humidity for at least 24 months (Figure 1). Dissolution results (%LC and %CV) are summarized in the table below. Dissolves after storage at 25 °C /60% relative humidity
time( hour) T=0 %LC (% CV) 1 month %LC (% CV) 3 months %LC (% CV) 6 months %LC (% CV) 9 months %LC (% CV) 12 month %LC (% CV) 18 months %LC (% CV) 24 months %LC (% CV)
30 µg 25-Hydroxyvitamin D 3 (Example Formulation C)
2 10.1 (16.1) 12.9 (25.2) 14.0 (48.5) 9.6 (38.3) 10.5 (18.2) 13.5 (35.8) 10.6 (26.5) 7.0 (47.8)
4 43.6 (12.7) 48.8 (10.9) 45.9 (29.9) 36.8 (25) 37.2 (11.1) 50.2 (14.8) 39.3 (22.9) 39.6 (32.3)
6 83.1 (5.7) 73.4 (9.2) 72.4 (7.5) 71.4 (6.8) 66.7 (10.6) 70.6 (11.5) 70.1 (7.2) 69.3 (12.6)
8 96.4 (6.5) 89.6 (4.4) 88.4 (4.7) 88.4 (5.7) 85.2 (4.9) 85.4 (9) 84 (5.1) 85.7 (8.2)
12 115.8 (4.5) 104.2 (1.9) 105.6 (1.4) 106.1 (1.6) 101.5 (1.5) 100.8 (3.9) 100.2 (4.5) 103 (2.6)
60 µg 25-Hydroxyvitamin D 3 (Example Formulation D)
2 17.5 (20) 16.3 (27.4) 16.1 (25.3) 17.7 (34.7) 11.2 (20.2) 14.3 (29.1) 16.1 (25.8) 12.4 (52.3)
4 53.6 (19.6) 55.1 (18.8) 53.8 (12.8) 55.3 (17.9) 43.7 (14) 51 (22.5) 52.9 (16.7) 41 (36.6)
6 83.9 (7.5) 78.7 (8.3) 79.9 (6.6) 78.4 (4.7) 72.2 (7.1) 75 (13) 72 (9.9) 64.7 (29.6)
8 99.2 (3.9) 94.3 (5.2) 97.2 (4.8) 92.5 (3.3) 87 (5.5) 88.9 (6.3) 84.9 (12.3)* 81.3 (21.7)
12 104.8 (3.3) 108.7 (1.8) 111.9 (1.1) 104.5 (0.5) 103.1 (0.8) 104.7 (1.4) 99.8 (4.6)* 101.7 (8)
90 µg 25-Hydroxyvitamin D 3 (Example Formulation E)
2 14.9 (19.9) 14.9 (8.6) 13.3 (41.2) 13.5 (23.4) 14.3 (30.4) 15 (35.1) 9.5 (37.1) 8.5 (53.2)
4 49.9 (16.4) 46.9 (10.2) 52.4 (18.5) 49.7 (16.4) 45.9 (25.6) 51.8 (14) 36.8 (34.5) 34.4 (24.9)
6 89.4 (7.2) 71.4 (4.1) 81.1 (5.6) 74.2 (11.1) 71.6 (17.6) 77 (4.9) 64.4 (10.3) 64.5 (15.1)
8 101.7 (2.5) 84.9 (2.8) 96.1 (2.3) 90.8 (6.4) 89 (9.4) 91.6 (3.3) 77.4 (15.7) 83.6 (11.2)
12 103 (2.1) 99.3 (2.4) 110 (1.3) 104.4 (1.1) 100.5 (2.4) 104.6 (0.3) 96.8 (5) 102.8 (3.4)
* 4 reps instead of 6 reps
25-hydroxyvitamin D released after aging3
The percentage change from the initial release amount is summarized in the table below. Time(h) 1 month % change 3 month change % 6 month change % 9 month change % 12 month change % 18 month change % 24 month change %
30 µg 25-Hydroxyvitamin D 3 (Example Formulation C)
2 27.7% 38.6% 5.0% 4.0% 33.7% 5.0% 30.7%
4 11.9% 5.3% 15.6% 14.7% 15.1% 9.9% 9.2%
6 11.7% 12.9% 14.1% 19.7% 15.0% 15.6% 16.6%
8 7.1% 8.3% 8.3% 11.6% 11.4% 12.9% 11.1%
12 10.0% 8.8% 8.4% 12.3% 13.0% 13.5% 11.1%
60 µg 25-Hydroxyvitamin D 3 (Example Formulation D)
2 6.9% 8.0% 1.1% 36.0% 18.3% 8.0% 29.1%
4 2.8% 0.4% 3.2% 18.5% 4.9% 1.3% 23.5%
6 6.2% 4.8% 6.6% 13.9% 10.6% 14.2% 22.9%
8 4.9% 2.0% 6.8% 12.3% 10.4% 14.4% 18.0%
12 3.7% 6.8% 0.3% 1.6% 0.1% 4.8% 3.0%
90 µg 25-Hydroxyvitamin D 3 (Example Formulation E)
2 0.0% 10.7% 9.4% 4.0% 0.7% 36.2% 43.0%
4 6.0% 5.0% 0.4% 8.0% 3.8% 26.3% 31.1%
6 20.1% 9.3% 17.0% 19.9% 13.9% 28.0% 27.9%
8 16.5% 5.5% 10.7% 12.5% 9.9% 23.9% 17.8%
12 3.6% 6.8% 1.4% 2.4% 1.6% 6.0% 0.2%
Example formulations C to E also exhibited substantially stable dissolution characteristics after storage at 40°C and 75% RH for at least 6 months (Figure 2). The dissolution results are summarized in the table below. Dissolves after storage at 40 °C /75% relative humidity
time( hour) Initial %LC (%CV) 1 month % LC (%CV) 3 months % LC (%CV) 6 months % LC (%CV)
30 µg 25-Hydroxyvitamin D 3 (Example Formulation C)
2 10.1 (16.1) 11.3 (54.3) 13.5 (53.8) 11.1 (14.8)
4 43.6 (12.7) 46 (27.1) 44.4 (23.9) 40.9 (13.9)
6 83.1 (5.7) 72.7 (9.7) 62.8 (20.4) 68.7 (7.3)
8 96.4 (6.5) 88.7 (5) 76.5 (12.5) 82.5 (4.1)
12 115.8 (4.5) 103.1 (0.9) 93.4 (7.6) 96.4 (2.8)
60 µg 25-Hydroxyvitamin D 3 (Example Formulation D)
2 17.5 (20) 12.9 (40.7) 15.5 (37) 13.9 (40)
4 53.6 (19.6) 50.7 (18.5) 54.4 (12) 49.8 (16.3)
6 83.9 (7.5) 75.8 (9.7) 78.3 (10.6) 74.7 (8.1)
8 99.2 (3.9) 91.2 (7.9) 91.6 (9.1) 88.5 (6.5)
12 104.8 (3.3) 100.7 (5.1) 104.1 (6.5) 101.5 (2.3)
90 µg 25-Hydroxyvitamin D 3 (Example Formulation E)
2 14.9 (19.9) 18.5 (32.5) 10.2 (44.6) 8.3 (34.7)
4 49.9 (16.4) 50.7 (12..8) 47 (14.6) 44.8 (10.6)
6 89.4 (7.2) 74.7 (8) 72.9 (5.2) 73 (3.4)
8 101.7 (2.5) 90.5 (5) 86.6 (4.8) 87.9 (3)
12 103 (2.1) 100.1 (1.4) 102.5 (1.6) 101.0 (1.9)
25-Hydroxyvitamin D released after exposure to storage conditions3
The percentage change from the initial release amount is summarized in the table below. time(hour) 1 month change % 3 month change % 6 month change %
30 µg 25-Hydroxyvitamin D 3 (Example Formulation C)
2 11.9% 33.7% 9.9%
4 5.5% 1.8% 6.2%
6 12.5% 24.4% 17.3%
8 8.0% 20.6% 14.4%
12 11.0% 19.3% 16.8%
60 µg 25-Hydroxyvitamin D 3 (Example Formulation D)
2 26.3% 11.4% 20.6%
4 5.4% 1.5% 7.1%
6 9.7% 6.7% 11.0%
8 8.1% 7.7% 10.8%
12 3.9% 0.7% 3.1%
90 µg 25-Hydroxyvitamin D 3 (Example Formulation E)
2 24.2% 31.5% 44.3%
4 1.6% 5.8% 10.2%
6 16.4% 18.5% 18.3%
8 11.0% 14.8% 13.6%
12 2.8% 0.5% 1.9%
The stability of Comparative Formulation 1, which does not contain cellulose compounds, and Example Formulation E, which contains hydroxypropyl methylcellulose, was evaluated after 12 months of storage at 25°C and 60% relative humidity (Figure 3). T dissolution results are summarized in the table below. Dissolves after storage at 25 °C /60% relative humidity
Dissolution time ( hours) Compare formulation 1 Example formulation E
Initial %LC 12 months % LC Initial %LC 12 months % LC
2 22.1 13.5 14.9 15.0
4 52.2 24.5 49.9 51.8
6 77.9 30.0 89.4 77.0
8 96.8 35.6 101.7 91.6
12 112.3 44.2 103.0 104.6
25-Hydroxyvitamin D released after exposure to storage conditions3
The percentage change from the initial release amount is summarized in the table below. Dissolution time ( hours) Compare Formulation 1 % change from initial Example formulation E % change from initial
2 38.9% 0.7%
4 53.1% 3.8%
6 61.5% 13.9%
8 63.2% 9.9%
12 60.6% 1.6%
Example 3 : In vivo results of unstabilized and stabilized controlled-release formulations
Conducting in vivo studies to evaluate 25-hydroxyvitamin D in human subjects3
Clinical pharmacokinetics of unstabilized and stabilized controlled release formulations. In Study A, 28 patients had stage 3 or 4 CKD, secondary parathyroid hyperactivity (stage 3: 70-1000 pg/mL iPTH; stage 4: 110-1000 pg/mL iPTH), and vitamin D insufficiency Subjects with total baseline 25-hydroxyvitamin D in serum of 15 ng/mL to 29 ng/mL received a single oral dose of controlled-release capsules or 448 µg of 25-hydroxyvitamin D in ethanol solution3
As a single intravenous dose, this capsule contains 450 µg or 900 µg of 25-hydroxyvitamin D3
, 20.00 wt% hard paraffin, 37.85 wt% GMS, 9.75 wt% GELUCIRE 44/14, 2.32 wt% absolute ethanol, 30.06 wt% mineral oil, and 0.02 wt% BHT (Comparative Formulation 3). None of the formulations contained cellulosic compounds.
25-Hydroxyvitamin D3
Serum concentrations gradually increase after administration of oral doses. 25-Hydroxyvitamin D3
The increase was dose proportional and reached 32 ng/mL (the approximate mean maximum value observed for serum concentrations (Cmax)) after administration of 900 µg capsules. The time to onset of Cmax (Tmax) is approximately 13 hours after dosing. In contrast, 25-hydroxyvitamin D3
Concentrations increase rapidly after intravenous administration. Maximum serum levels were achieved immediately following intravenous administration (Tmax = 0.5 hours) and an approximate mean Cmax of 134 ng/mL was achieved. The bioavailability of oral doses is approximately 6 to 11%. Following oral administration of 25-hydroxyvitamin D3
The terminal half-life (t1/2
) is about 12 to 22 days. No adverse effects on serum calcium or phosphorus or urinary calcium were observed in any treatment group.
Mean serum total 1,25-dihydroxyvitamin D levels increased rapidly following intravenous administration, increasing by approximately 13 pg/mL from pretreatment baseline 6 hours post-dose. In comparison, mean serum total 1,25-dihydroxyvitamin D following administration of 900 µg capsules increased proportionately and gradually by approximately 7 pg/mL over 48 hours post-dose.
Serum iPTH showed no meaningful changes over the first 96 hours after intravenous administration. In contrast, serum PTH gradually declined after dosing, reaching a maximum suppression of approximately 20% from pretreatment baseline for individuals receiving 900 µg capsules. The pharmacokinetic parameters observed for all treatment groups are summarized in the table below. parameters 450 μg orally (N=9) 900 μg orally (N=9) 448 μg intravenously (N=9)
naverage _ (SD) naverage _ (SD) naverage _ (SD)
median range median range median range
PK/PD group observed for 25-hydroxyvitamin D 3
AUC 0-42 days (ng*h/mL) 9 13353.12 (10606.47) 12196.45 888.39, 32885.95 9 21563.95 (9165.53) 17940.11 9292,88,38631.91 9 43463.51 (12589.57) 47115.66 23340.59, 63006.78
AUC 0- last (ng*h/mL) 9 13353.12 (10606.47) 12196.45 888.39,32885.95 9 21563,95 (9165.53) 17940.11 9292.88, 38631.91 9 43463.51 (12589.57) 47115.66 23340.59,63006.78
AUC 0-inf (ng*h/mL) 9 81511.71 (103037,08) 54967.57 4927.95, 333366.90 9 122901.73 (114168.13) 79902.04 25729.84, 378935.59 9 137955.58 (66746.71) 123580.87 39282.49, 243322.76
C max (ng/mL) 9 25.18(10.134) 20.52 15.35,42.24 9 31.54(15.765) 30.12 12.21, 67.01 9 133.99(19.311) 133.68 91.71, 160.91
C last (ng/mL) 9 18.11 (7.846) 15.84 10.30,29.80 9 19.08(7.611) 21.37 7.30, 27.93 9 35.07(12.330) 36.9.1 12.68,53.39
t max (h) 9 13.11 (9.597) 10.00 6.00,36.00 9 13.56 (9.989) 10.00 2.00, 30.00 9 0.49 (0.638) 0.25 0.083, 2.00
λ 2 (h -1 ) 9 0.0015 (0.0028) 0.0003 0.0001,0.0087 9 0.0003 (0.0002) 0.0004 0.0001,0.0005 9 0.0005 (0.0002) 0.0004 0.0002,0.0008
R 2 9 0.89(0.130) 0.96 0.662, 1.000 9 0.90(0.169) 0.99 0.523,0.998 9 0.91 (0.090) 0.93 0.730,1.000
t 1/2 (h) 9 2477.72 (2581.24) 2483.61 79.24, 8615.11 9 3228.63 (2734.74) 1937.32 1300.13,9646.71 9 1775.86(779.13) 1694.69 871.46, 3297.78
V d (L/ng) 9 49.42(18.30) 50.93 23.20, 72.76 9 45.06(1938) 40.080 20.77, 87.51 9 20.35(7.42) 19.550 13.04,32.68
CL (L/ng*h) 9 0.0499(0.0155) 0.0182 0.0030, 0.2029 9 0.0155(0.0119) 0.0125 0.0026,0.0389 9 0.0095 (0.0065) 0.0081 0.0041,0.0255
F Not applicable 0.306 (not applicable) not applicable not applicable Not applicable 0.247 (not applicable) not applicable not applicable Not applicable 1.000 (not applicable) not applicable not applicable
Baseline-adjusted pharmacokinetic parameters for all treatment groups are summarized in the table below. parameters 450 μg orally (N=9) 900 μg orally (N=9) 448 μg intravenously (N=9)
naverage _ (SD) naverage _ (SD) naverage _ (SD)
median range median range median range
AUC 0-42 days (ng*h/mL) 9 1394.89 (1911.41) 605.42 48.87, 4956.68 8 4525.43 (3123.29) 4801.54 148.07, 8843.74 9 19609.07 (5319.01) 18764.48 11066.02,28611.05
AUC 0-last (ng*h/mL) 9 1257.30 (2047.74) 48.87 -325.43, 4956.68 8 4274.27 (3488.40) 4801.54 -877.99, 8843.74 9 19609.07 (5319.01) 18764.48 11066.02,28611.05
AUC 0-inf (ng*h/mL) 6 3318.90 (4606.89) 547.25 8 6791.49 (5224.54) 6872.86 9 34543.75 (22103.97) 26962.25
C max (ng/mL) 9 50.78, 9878.03 6.90 (4.266) 5.70 2.93, 14.87 8 285.04,14979.17 14.17(9.884) 12.30 2.55,35.59 9 16868.97, 89126.53 110.33(14.536) 111.08 76.63, 127.40
C last (ng/mL) 9 2.36 (2.257) 2.05 0.16, 5.49 8 2.64(1.784) 3.01 0.42, 5.40 9 11.40(5.648) 9.01 5.84, 22.86
t max (h) 9 13.11(9.597) 10.00 6.00, 36.00 8 15.00(9.621) 10.00 8.00, 30.00 9 0.49 (0.638) 0.25 0.083,2.00
λ 2 (h -1 ) 6 0.018 (0.359) 0.0042 0.0008, 0.0910 7 0.0020 (0.0013) 0.0016 0.0008,0.0037 9 0.0011 (0.0005) 0.0010 0.0004, 0.0021
R 2 6 0.92(0.101) 0.96 0.743, 0.999 6 0.99 (0.020) 0.99 0.948, 1.000 9 0.92 (0.086) 0.95 0.720,0.999
t 1/2 (h) 6 307.86(336.42) 165.72 7.61,914.23 6 522.96(320.80) 530.00 189.84,879.31 9 745.86 (437.65) 663.43 337.37, 1834.71
V d (L/ng) 6 340.42(269.11) 249.77 80.51,771.79 6 82.92 (29.70) 77.11 39.96, 127.06 9 32.94 (11.00) 29.70 24.28, 58.95
CL (L/ng*h) 6 4.588 (7.525) 2.119 0.101,19.692 6 0.141 (0.080) 0.1200 0.0668, 0.2860 9 0.036 (0.014) 0.037 0.011,0.059
F Not applicable 0.064 (not applicable) not applicable not applicable Not applicable 0.109 (not applicable) not applicable not applicable Not applicable 1.000 (not applicable) not applicable not applicable
In Study B, 20 healthy individuals with mean baseline serum 25-hydroxyvitamin D of approximately 24 ng/mL (range 11 ng/mL to 45 ng/mL) received a single oral dose of a stabilized controlled-release capsule or 448 µg 25-hydroxyvitamin D in ethanol solution3
As a single intravenous dose, this capsule contains 900 µg of 25-hydroxyvitamin D3
, 20.00 wt% hard paraffin, 10.00 wt% HPMC, 22.55 wt% GMS, 9.75 wt% GELUCIRE 44/14, 2.32 wt% absolute ethanol, 35.36 wt% mineral oil, and 0.02 wt% BHT (example formulation F).
25-Hydroxyvitamin D following administration of stable oral formulations compared to intravenous administration3
A gradual increase in content is shown by a prolonged Tmax. Pharmacokinetic profile of 25-hydroxyvitamin D following administration of stable oral formulation3
The concentration increases gradually, with an average Tmax of 28 hours, while avoiding rapid increases in blood content in most individuals. Administration via intravenous administration results in 25-hydroxyvitamin D in all individuals3
Concentration increases rapidly. By the observed C between treatment groupsmax
Significant differences highlighted in avoiding 25-hydroxyvitamin D3
The content increases rapidly. The Cmax after oral administration was 58 ng/mL compared to the Cmax of 153 ng/mL after intravenous administration.
After administration of controlled-release capsules 25-hydroxyvitamin D3
The exposure is approximately two times less than after intravenous administration, although it is approximately twice as high after oral administration, resulting in approximately 25% bioavailability. t1/2
, elimination rate (CL) and volume distribution (Vd) appeared to be similar between treatment groups. t1/2
and CL values are consistent with reported 25-hydroxyvitamin D3
The extension is eliminated. In addition, the Vd value indicates that 25-hydroxyvitamin D3
Remains in systemic circulation and may be highly bound to DBP. The pharmacokinetic parameters observed for all treatment groups are summarized in the table below. parameters 900 μg CTAP101 capsule (N=10) 448 μg CTAP101 injection (N=10)
AUC 0-t (ng.h/mL)
Average (SD) 21545.20(7054.02) 25274.44(7206.93)
median 19904.00 25810.85
minimum value, maximum value 10176.40, 35885.02 8434.02, 35382.55
AUC 0-inf (ng.h/mL)
Average (SD) 77945.13(55896.15) 55234.52(27268.64)
median 58974.22 51247.29
minimum value, maximum value 19504.43,194796.33 22979.18, 119865.38
C max (ng/mL)
Average (SD) 57.657(39.3810) 153.029(20.8620)
median 37.925 152.890
minimum value, maximum value 24.43,146.86 125.94, 185.33
t max (h)
Average (SD) 28.100(27.4000) 0.272(0.2910)
median 21.000 0.161
minimum value, maximum value 4.00, 96.00 0.05, 1.00
t 1/2 (h)
Average (SD) 1389.40(1144.48) 660.23(415.82)
median 1042.60 607.65
minimum value, maximum value 557.32, 4173.67 238.46, 1733.68
λ 2 (h -1 )
Average (SD) 0.00072(0,00036) 0.00136(0.00071)
median 0.00067 0.00115
minimum value, maximum value 0.00017,0.00124 0.00040,0.00291
CL(L/h)
Average (SD) 0.0064(0.0027) 0.0098 (0.0046)
median 0.0066 0.0087
minimum value, maximum value 0.0018, 0.0098 0.0037, 0.0195
Vd(L)
Average(SD) 9.27(0.97) 7.50(1.19)
median 9.39 7.24
minimum value, maximum value 7.93, 10.49 6.02, 9.77
R 2
Average(SD) 0.80(0.24) 0.92 (0.075)
median 0.88 0.94
minimum value, maximum value 0.25, 0.99 0.74, 1.0
F
average 0.42(0.14) Not applicable
median 0.39 Not applicable
minimum value, maximum value 0.20, 0.71 Not applicable
Abbreviation for average individual bioavailability: N/A, not applicable
Baseline-adjusted pharmacokinetic parameters for all treatment groups are summarized in the table below. parameters 900 μg CTAP101 capsule (N=10) 448 μg CTAP101 injection (N=10)
AUC 0-t (ng.h/mL)
Average (SD) 6891.81 (6678.97) 13583.95 (3908.42)
median 4360.23 14853.46
minimum value, maximum value 1017.88, 20340.68 5302.50, 17194.59
AUC 0-inf (ng.h/mL)
Average (SD) 9418.00(9410.58) 17735.09(5249.38)
median 5420.04 18229.25
minimum value, maximum value 1179.07,28031.64 9820.16, 25534.45
C max (ng/mL)
Average (SD) 35.867 (39.3886) 133.653(20.7925)
median 14.910 133.785
minimum value, maximum value 6.50, 120.52 103.88, 166.34
t max (h)
Average (SD) 28.100(27.4001) 0.272(0.2914)
median 21.000 0.167
minimum value, maximum value 4.00, 96.00 0.05, 1.00
t 1/2 (h)
Average (SD) 270.61 (215.00) 264.08(82.23)
median 194.00 269.57
minimum value, maximum value 107.90, 832.70 132.46, 382.99
λ 2 (h -1 )
Average(SD) 0.00362(0.00182) 0.00292(0.00112)
median 0.00363 0.00257
minimum value, maximum value 0.00083, 0.00624 0.00181, 0.00523
CL(L/h)
Average (SD) 0.027 (0.0063) 0.028 (0.0093)
median 0.028 0.025
minimum value, maximum value 0.012, 0.033 0.018, 0.046
Vd(L)
Average (SD) 8.78 (3.08) 9.74(2.02)
median 8.08 9.47
minimum value, maximum value 5.06, 14.17 6.54, 13.27
R 2
Average (SD) 0.83 (0.22) 0.92 (0.072)
median 0.88 0.94
minimum value, maximum value 0.25, 1.0 0.74, 1.0
F
Average (SD) 0.25 (0.24) Not applicable
median 0.16 Not applicable
minimum value, maximum value 0.037, 0.75 Not applicable
Abbreviation for average individual bioavailability: N/A, not applicable
Study shows improved 25-hydroxyvitamin D with stable controlled-release formulation3
rate of absorption, resulting in serum 25-hydroxyvitamin D3
Produces a more gradual increase in content while maintaining distribution and elimination characteristics. In Study A, the stabilized formulation showed improved pharmacokinetic parameters (such as increased Tmax, AUC, and bioavailability) compared to the same administration of the non-stabilized formulation.
In Study C, 78 patients with stage 3 CKD (eGFR 25-70 mL/min/1.73 m2
), SHPT (>70 pg/mL plasma iPTH), and vitamin D insufficient (total baseline 25-hydroxyvitamin D in serum 10 ng/mL to 29 ng/mL) receiving a stabilized controlled-release formulation daily Oral doses or placebo for 6 weeks in formulations containing 30 µg, 60 µg, or 90 µg of 25-hydroxyvitamin D3
, 20.00 wt% hard paraffin, 10.00 wt% HPMC, 22.55 wt% GMS, 9.75 wt% GELUCIRE 44/14, 2.32 wt% absolute ethanol, 35.36 wt% mineral oil, and 0.02 wt% BHT (Example Formulation C from Example 2 , D and E).
Comparison of mean baseline serum 25-hydroxyvitamin D across all treatment groups3
concentration, and ranges from approximately 16 to 20 ng/mL. via 25-hydroxyvitamin D3
After treatment, serum 25-hydroxyvitamin D3
The average content gradually increased with repeated daily administration of 25-hydroxyvitamin D3
It then increased in a dose-proportional manner and began to approach steady state after 6 weeks (Figure 4). For administration of 30 µg, 60 µg and 90 µg 25-hydroxyvitamin D3
For the groups, the mean baseline-adjusted Cmax values were approximately 28, 60, and 86 ng/mL, respectively. As background-adjusted AUC in all dose groups0-6
Evaluated by Zhou, 25-hydroxyvitamin D3
The average exposure is proportional to the dose. Mean serum 25-hydroxyvitamin D at final dose3
Levels declined slowly but remained above baseline in all groups at the end of the study. average t1/2
It has been measured to be between 25 and 50 days. 25-Hydroxyvitamin D3
The baseline adjusted pharmacokinetic parameters are summarized in the table below. placebo 30 µg 60 µg 90 µg
Baseline(ng/mL)
Average (SD) 16.4 (8.2) 16.2 (7.3) 19.8 (8.7) 18.4 (9.8)
median 12.9 17.2 21.2 16.7
minimum value, maximum value 4.4, 30.4 5.0, 25.8 5.8, 32.5 6.7, 38.9
C max (ng/mL)
Average (SD) 4.1 (3.5) 27.8 (8.2) 60.3 (19.0) 85.7 (26.9)
median 3.1 28.1 60.8 76.0
minimum value, maximum value 0.6, 13.8 10.8, 43.4 30.3, 89.5 55.4, 146.4
AUC 0-6 Weeks (ng ·d/mL)
Average (SD) 45.9 (60.0) 709.2 (246.3) 1531.4 (374.8) 2134.3 (584.3)
median 32.1 6843.0 1573.0 1963.8
minimum value, maximum value -60.1, 222.3 307.8, 1249.0 712.7, 2221.8 1377.5, 3207.3
t max (d)
Average(SD) Not applicable 37.8 (10.4) 41.1 (5.2) 42.6 (5.3)
median Not applicable 42.50 43.0 43.0
minimum value, maximum value Not applicable 8.0, 44.0 29.0, 45.0 35.0, 57.0
t 1/2 (d)
Average(SD) Not applicable 25.8 (16.3) 33.1 (9.3) 50.1 (51.0)
median Not applicable 24.1 31.6 37.7
minimum value, maximum value Not applicable 5.2, 52.6 17.4, 52.3 23.2, 224.0
Mean baseline serum 1,25-dihydroxyvitamin D concentrations were compared across all treatment groups and concentrations gradually increased, similar to those seen in serum 25-hydroxyvitamin D3
effects on concentration. The mean ±SD baseline adjusted Cmax values of the 60 µg and 90 µg groups were higher (18.4±6.24 and 19.9±, respectively) compared with the placebo and 30 µg groups (5.7±6.35 and 6.4±7.66 ng/mL, respectively). 14.30 ng/mL). In 25-hydroxyvitamin D3
Baseline-adjusted AUC in dose groups0-6
Zhou assessed that the average exposure to 1,25-dihydroxyvitamin D was proportional to the dose. Baseline-adjusted pharmacokinetic parameters for 1,25-dihydroxyvitamin D are summarized in the table below. PlaceboN =23 30 µg N=12 60 µg N=16 90 µg N=14
Baseline (pg/mL)
Average (SD) 20.8 (10.11) 18.3 (7.53) 20.6 (7.62) 20.6 (7.29)
median 17.0 17.0 18.0 21.0
minimum value, maximum value 7.0, 41.4 5.1, 30.7 8.2, 33.6 9.3, 34.5
C max (pg/mL)
Average(SD) 7.6 (5.71) 6.4 (7.66) 18.4 (6.24) 19.9 (14.30)
median 4.9 5.0 18.4 18.9
minimum value, maximum value 1.9, 22.6 -6.3, 21.0 7.3, 29.9 -11.6, 48.3
AUC 0-6 Weeks (g ·d/mL)
Average (SD) 11.5 (112.97) 100.6 (185.38) 249.9 (198.83) 371.1 (290.81)
median 16.2 23.0 298.7 352.2
minimum value, maximum value -267.1, 219.8 -145.4, 452.3 -191.7, 563.6 -5.8, 1235.8
t max (d)
Average (SD) 24.4 (15.55) 16.8 (16.09) 26.4 (11.52) 25.5 (13.88)
median 23.0 12.0 23.0 23.00
minimum value, maximum value 2.0, 45.0 1.0, 44.0 8.0, 44.0 1.0, 44.0
Compared with placebo, 25-hydroxyvitamin D3
The stabilized controlled-release formulation increased serum total 25-hydroxyvitamin D levels to ≥ 30 ng/mL. Similarly, the stabilized formulation resulted in a significant reduction in mean plasma iPTH from baseline compared to placebo in all dose groups.
Daily administration of 25-hydroxyvitamin D in a stabilized controlled-release formulation3
Increases mean serum total 25-hydroxyvitamin D in an amount proportional to the dose administered. The lowest administered dose (30 µg) increased serum total 25-hydroxyvitamin D by 15.6±1.7 (SE) ng/mL at the end of treatment from pretreatment baseline (21.7±1.8 ng/mL), and the highest dose (90 µg) The serum total 25-hydroxyvitamin D increased from 21.8±1.2 ng/mL to 61.1±6.1 ng/mL. In contrast, in the combined placebo group, a decrease was observed at the end of treatment at 1.2 ± 0.7 ng/mL. The differences between the treatment and placebo groups were significant (p<0.0001) for all three doses studied. At the end of treatment, the mean serum 25-hydroxyvitamin D content in the 30 µg dose group was 37.3 ± 1.8 ng/mL (slightly higher than the minimum appropriate level of 30 ng mL specified by the K/DOQI), indicating that 30 µg is the minimum effective dosage.
The percentage of treated individuals achieving a serum total 25-hydroxyvitamin D level of ≥30 ng/mL at the end of treatment in the 30 µg, 60 µg, and 90 µg dose groups compared to 0% in the placebo group was 92.3%, 100.0% and 100.0%. These differences in response rates between active and placebo treatments were all significant (p<0.001).
Mean plasma iPTH at end of treatment versus administered 25-hydroxyvitamin D3
The dose is reduced proportionally. The lowest dose administered (30 µg) reduced iPTH by 20.2±5.8(SE)% from pretreatment baseline, and the highest dose (90 µg) reduced iPTH by 35.9±4.2%. In the combined placebo group, an increase of 17.2±7.8% was observed at the end of treatment. For all three doses studied, receiving 25-hydroxyvitamin D3
The difference between the group receiving placebo and the group receiving placebo was significant (p<0.005) and was favorably associated with the use of more effective and calciemic oral vitamin D hormone replacement therapies such as docalcidol, paricalcitol, and calcitriol) compared with the differences observed with longer treatments in placebo-controlled studies.
Patients receiving 25-hydroxyvitamin D who confirmed a decrease in iPTH from pretreatment baseline (i.e., two consecutive measurements) of at least 20% or 30% at EOT3
The percentage of individuals increased at doses ending at 60 µg. Similar response rates were observed in the 60 and 90 µg treatment groups, indicating that no additional benefit in iPTH reduction was seen with the 90 µg dose in this study. Response rates confirming a 20% reduction in iPTH were 38.5%, 70.6%, and 76.5% for the 30 µg, 60 µg, and 90 µg dose groups, respectively, compared with 9.7% in the combined placebo group. The difference in response rates observed for the 20% reduction was significant only for the 60 µg and 90 µg dose groups (p<0.005) and for the 30% reduction in all three dose groups (p<0.05). Data support 30 µg per day of 25-hydroxyvitamin D in a stabilized controlled-release formulation3
is the minimum effective dose.
25-Hydroxyvitamin D3
The stabilized formulations had no clinically significant effects on albumin-corrected serum calcium, serum phosphorus, and urinary calcium excretion. There were no adverse effects on serum calcium or serum phosphorus or urinary calcium during the 6-week treatment period.
Pharmacokinetic analysis revealed that in all three dose groups, 25-hydroxyvitamin D3
Stabilized formulation increases 25-hydroxyvitamin D in a dose-proportional manner over 6 weeks3
Exposure (AUC and Cmax
), t1/2
There is no difference. After 6 weeks of administration, the three treatment groups had not yet fully reached steady state. However, steady-state models indicate that steady state should have been reached by 7-9 weeks in all dose groups.
Data from this study clearly shows that 25-hydroxyvitamin D3
The stabilized controlled release formulation was effective in increasing serum total 25-hydroxyvitamin D to the minimum adequate level of 30 ng/mL and reducing plasma iPTH. The study also showed that the doses of 25-hydroxyvitamin D studied3
The stabilized formulation had no clinically relevant effects on serum calcium or phosphorus. Example 4 : In patients with secondary parathyroid hyperactivity and vitamin D Insufficient CKD Pharmacokinetic and pharmacodynamic characteristics of modified-release calcifediol in individuals
Menstruation-stabilizing 25-hydroxyvitamin D in both groups of individuals3
(Calcidiol, 25D3
) capsules were subjected to a multicenter, randomized, double-blind, placebo-controlled, repeated dose, safety, efficacy and PK/PD study. For this study enroll patients with stage 3 CKD (eGFR 25-70 mL/min/1.73 m2
), vitamin D deficiency (serum 25-hydroxyvitamin D ≥ 10 and ≤ 29 ng/mL), SHPT (plasma iPTH > 70 pg/mL), and men and women aged 18 to 85 years who do not require regular hemodialysis individual. Eligible individuals in the first group were randomly divided into 3 treatment groups in a 1:1:1 ratio: two groups received capsules at a daily oral dose of 60 or 90 μg, and one group received matching placebo capsules. Individuals in the second group were randomly divided into two treatment groups in a 1:1 ratio: one group received 30 μg capsules daily and the other group received placebo. Individuals in each group completed 6 weeks of treatment and entered a 6-week follow-up period, during which PK and PD samples were collected weekly. Serum calcium (Ca), phosphorus (P), and 25D were monitored weekly during 6 weeks of treatment and 6 weeks of follow-up.3
, total 1,25-dihydroxyvitamin D (1,25D) and plasma iPTH. ANCOVA model detection 25D3
Association of exposure with change from baseline in 1,25D and iPTH. Covariates included were baseline eGFR, weight and height, gender, age, race, diabetes status, and baseline concentrations of 1,25D or iPTH.
Figure 4 shows the mean baseline adjusted calcifediol concentration by treatment group (PK group). The average serum calcifediol level gradually increased in a dose-proportional manner and began to approach a steady state after 6 weeks. After 6 weeks of follow-up, levels decreased but remained above baseline in all active agent-treated groups.
Figure 5 shows a summary of baseline-adjusted PK parameters for calcifediol concentration by treatment group (PK population).
Figure 6 shows the mean baseline-adjusted serum 1,25-dihydroxyvitamin D levels obtained during the 6-week treatment period (PK population). Mean baseline-adjusted serum total 1,25-dihydroxyvitamin D levels increased over time in those individuals who were administered the active capsules compared to those who were administered placebo.
Figure 7 shows a summary of baseline-adjusted repeated dose PK parameters for serum 1,25-dihydroxyvitamin D by treatment group (PK population).
Figure 8 shows the mean percentage of baseline obtained in plasma iPTH content during 6 weeks of treatment (PK population). Active capsules significantly reduced mean plasma iPTH from baseline by 21%, 33% and 39% in all dose groups (30, 60 and 90 µg), respectively, compared to a 17% increase in the combined placebo group.
Figure 9 shows a summary of baseline adjusted repeated dose PK parameters for plasma iPTH by treatment group (PK population).
Figures 10 and 11 show plasma iPTH versus baseline adjusted calcifediol and 1,25-dihydroxyvitamin D exposure (AUC) at EOT in the PK population.0-6 weeks
) as a percentage change from baseline. Percent reduction in plasma iPTH from baseline to EOT as a function of serum calcifediol and total 1,25-dihydroxyvitamin D exposure during treatment (expressed as baseline-adjusted AUC0-6 weeks
) increases with increasing.
Stabilized, sustained-release 25-hydroxyvitamin D3
Capsules normalized 25D levels in most individuals and significantly reduced iPTH in all dose groups (30, 60 and 90 µg). Stabilized, sustained-release 25-hydroxyvitamin D3
Capsules Gradually Increase Serum 25D3
and serum 1,25D levels, with exposure increasing in a dose-dependent manner. 25D3
and total 1,25D exposure were both significant and inversely associated with changes in plasma iPTH from baseline. Only eGFR was a significant covariate in both models. These results demonstrate the stable, sustained release of 25-hydroxyvitamin D3
The capsules reliably normalized 25D levels, increased serum 1,25D levels, and inhibited increases in plasma iPTH without clinically meaningful effects on serum Ca and P during dose studies.***
The above description has been given for clarity of understanding only and is not to be construed as unnecessarily limiting, as modifications within the scope of the invention may be apparent to those skilled in the art.
Throughout this specification and the claims that follow, the word "comprise" and variations such as "comprises/comprising" will be understood to imply the inclusion of stated integers or steps unless otherwise specified herein. or an integer or a group of steps without excluding any other integer or step or group of steps or integers or steps.
Throughout this specification, unless otherwise described, a composition is described as including components or materials, and it is intended that the composition may also consist essentially of or consist of any combination of said components or materials. Likewise, unless otherwise described, a method is described as including particular steps, and it is intended that the method may also consist essentially of or consist of any combination of said steps. The invention illustratively disclosed herein may be suitably practiced in the absence of any element or step not specifically disclosed herein.
The practice of the methods disclosed herein and their individual steps can be performed manually and/or by means of electronic equipment. Although processes have been described with reference to specific embodiments, those of ordinary skill will readily appreciate that actions may be performed in other ways associated with these methods. For example, unless otherwise described, the order of various steps may be changed without departing from the scope or spirit of the method. Additionally, some of the individual steps may be combined, omitted, or further subdivided into other steps.
All patents, publications, and references cited herein are hereby incorporated by reference in their entirety. In the event of a conflict between this invention and incorporated patents, publications, and references, this invention shall control.
In view of the above description, contemplated embodiments include those described in the following numbered paragraphs.
1. A controlled-release formulation of a vitamin D compound containing 25-hydroxyvitamin D2
and 25-hydroxyvitamin D3
Either or both, the formulation includes a matrix that releases the bound and controlled release vitamin D compound, the matrix including a cellulose derivative.
2. A stabilized formulation for the controlled release of a vitamin D compound in the gastrointestinal tract of an individual who ingests the formulation, the formulation comprising a mixture of:
25-Hydroxyvitamin D2
and 25-hydroxyvitamin D3
one or both;
and an effective amount of a stabilizer, optionally a cellulosic compound, to cause dissolution in vitro at any given time point after four hours during two months of exposure to storage conditions of 25°C and 60% relative humidity. The difference between the amount of vitamin D compound released and the amount released at the same dissolution time point during in vitro dissolution prior to exposure of the formulation to storage conditions remains less than 30%.
3. A stabilized formulation for the controlled release of a vitamin D compound, the formulation comprising a mixture of:
25-Hydroxyvitamin D2
and 25-hydroxyvitamin D3
one or both;
wax matrix; and
Stabilizer, which optionally is a cellulose compound.
4. A stabilized formulation for the controlled release of a vitamin D compound in the gastrointestinal tract of an individual who ingests the formulation, the formulation comprising a mixture of:
25-Hydroxyvitamin D2
and 25-hydroxyvitamin D3
one or both;
wax matrix; and
Stabilizer, which optionally is a cellulose stabilizer.
5. A stabilized formulation for the controlled release of vitamin D, the formulation comprising a mixture of:
25-Hydroxyvitamin D2
and 25-hydroxyvitamin D3
one or both;
wax matrix; and
An effective amount of a stabilizer, optionally a cellulosic compound, such that at any given time point after four hours during an in vitro dissolution test after two months of exposure to storage conditions of 25°C and 60% relative humidity The difference between the amount of vitamin D compound released and the amount released at the same dissolution time point during in vitro dissolution prior to exposure of the formulation to storage conditions remains less than 30%.
6. A stabilized formulation for the controlled release of a vitamin D compound in the gastrointestinal tract of an individual who ingests the formulation, the formulation comprising a mixture of:
Active loaded wax base containing 25-hydroxy vitamin D2
and 25-hydroxyvitamin D3
one or both; and
cellulose stabilizer;
The formulation releases a certain amount of 25-hydroxyvitamin D during in vitro dissolution after storage at 25°C and 60% relative humidity for two months. In the absence of a cellulose stabilizer, the amount of 25-hydroxyvitamin D released is equivalent to that in the absence of a cellulose stabilizer. A change of 30% or less at any given dissolution time point compared to the amount released at the same dissolution time point during in vitro dissolution performed prior to exposure of the formulation to storage conditions.
7. In a formulation for controlled release of a vitamin D compound in the gastrointestinal tract of an individual who ingests the formulation, the improvement includes incorporating a cellulose stabilizer into the formulation.
8. In a formulation for the controlled release of a vitamin D compound in the gastrointestinal tract of an individual who ingests the formulation, the modification includes admixing the cellulosic compound into the formulation such that upon exposure to 25°C and 60% relative humidity The amount of 25-hydroxyvitamin D released at any given dissolution time point after four hours during in vitro dissolution after storage conditions for at least one month compared to in vitro dissolution performed prior to exposure of the formulation to storage conditions Compared with the release amount at the same dissolution time point during the period, the change is less than 30%.
9. The formulation of any of the preceding paragraphs, wherein the cellulose compound or cellulose stabilizer includes cellulose ether.
10. The formulation of paragraph 9, wherein the cellulose ether is selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose group.
11. Such as the formulation of paragraph 9, wherein the cellulose compound or cellulose stabilizer is hydroxypropyl methylcellulose.
12. A formulation as in any of the preceding paragraphs, wherein the formulation releases an amount of 25-hydroxyvitamin D during in vitro dissolution after exposure to storage conditions of 25°C and 60% relative humidity for two months, and The amount of release at any given dissolution time point after four hours changes by 30% or less compared to the amount released at the same dissolution time point during in vitro dissolution performed prior to exposure of the formulation to storage conditions.
13. A formulation as in any of the preceding paragraphs, wherein the formulation releases an amount of 25-hydroxyvitamin D during in vitro dissolution after being exposed to storage conditions of 40°C and 75% relative humidity for one month, and the formulation is The amount of release at any given dissolution time point after four hours changes by 30% or less than the amount released at the same dissolution time point during in vitro dissolution performed prior to exposure of the formulation to storage conditions.
14. The formulation of any of the preceding paragraphs, wherein the base includes a wax base that includes a controlled release agent, an emulsifier, and an absorption enhancer.
15. The formulation of paragraph 14, wherein the controlled release agent includes paraffin.
16. The formulation of paragraph 14 or 15, wherein the emulsifier has an HLB value of less than 7.
17. The formulation of paragraph 16, wherein the emulsifier includes glyceryl monostearate.
18. The formulation of any of paragraphs 14 to 17, wherein the absorption enhancer has an HLB value in the range of about 13 to about 18.
19. The formulation of paragraph 18, wherein the absorption enhancer is a mixture of dodecyl polyethylene glycol glyceride and dodecyl polyoxyglyceride.
20. The formulation of any of the preceding paragraphs, wherein the vitamin D compound includes 25-hydroxyvitamin D3
.
21. The formulation of any of the preceding paragraphs, further comprising an oily vehicle.
22. The formulation of paragraph 21, wherein the oily vehicle includes mineral oil.
23. The formulation of paragraph 22, wherein the formulation includes about 20 wt% paraffin, about 20 wt% to about 25 wt% glyceryl monostearate, about 10 wt% dodecyl polyethylene glycol glyceride, and A mixture of dodecyl polyoxyglycerides, about 30 wt% to about 35 wt% mineral oil, and about 10 wt% to about 15 wt% hydroxypropyl methylcellulose.
24. The formulation of any of the preceding paragraphs, wherein the formulation includes glyceryl monostearate.
25. The formulation of any of the preceding paragraphs, wherein the formulation includes one or more polyglycolated glycerides.
26. Sustained-release dosage forms in the form of capsules, tablets, sachets, dragees or suppositories include formulations of any of the preceding paragraphs.
27. For example, the dosage form in paragraph 26 includes capsules or tablets.
28. A dosage form as described in paragraph 27, which contains a capsule.
29. For example, the dosage forms in paragraph 26 include oral capsules, tablets, sachets, and sugar-coated pills.
30. A stabilized dosage form as set forth in any of the preceding paragraphs, characterized by dissolution characteristics that provide the following release of a vitamin D compound:
Less than 30% at 2 hours;
Greater than 45% at 6 hours; and
Greater than 80% at 12 hours.
31. For example, in the stabilized dosage form of paragraph 26, the release of vitamin D compound at 6 hours is less than 60%.
32. A stabilized sustained-release oral dosage form containing a vitamin D compound, characterized by providing in vitro dissolution characteristics for the following release of the vitamin D compound
Less than 30% at 100 to 140 minutes;
Greater than 45% at 5 to 7 hours; and
Greater than 80% at 11 to 13 hours.
33. The dosage form of paragraph 32, wherein the release of the vitamin D compound is
Less than 30% at 2 hours;
Greater than 45% at 6 hours; and
Greater than 80% at 12 hours.
34. For example, the dosage form of paragraph 32 or 33, wherein the release of vitamin D compound is less than 60% at 5 to 7 hours.
35. As in the dosage form of paragraph 34, the release of vitamin D compound at 6 hours is less than 60%.
36. A stabilized sustained-release oral dosage form containing a vitamin D compound, characterized by providing in vitro dissolution characteristics for the following release of the vitamin D compound
About 20% to about 40% at 2 hours;
At least 35% at 6 hours; and
At least 70% at 12 hours.
37. The dosage form of paragraph 36, in which the vitamin D compound
The release at 2 hours is about 25% to about 35%;
At least 40% at 6 hours; and
At least 75% at 12 hours.
38. The dosage form of paragraph 36 or 37, wherein the release of the vitamin D compound at 6 hours is 75% or less.
39. The dosage form of paragraph 38, wherein the release of the vitamin D compound at 6 hours is 65% or less.
40. The dosage form of paragraph 39, wherein the release of the vitamin D compound at 6 hours is 60% or less.
41. A stabilized sustained release dosage form comprising a vitamin D compound, characterized in that upon administration of the dosage form to a human patient, tmax
At least 4 hours.
42. Dosage form of paragraph 41, where tmax
At least 8 hours.
43. Dosage form of paragraph 42, where tmax
At least 12 hours.
44. Dosage form of paragraph 43, where tmax
At least 18 hours.
45. Dosage forms of paragraph 44, where tmax
At least 20 hours.
46. Dosage form of paragraph 45, where tmax
At least 24 hours.
47. Dosage form of paragraph 46, where tmax
At least 28 hours.
48. Dosage forms of paragraph 41, where tmax
In the range of 4 to 96 hours.
49. Dosage form of paragraph 48, where tmax
In the range of 18 to 30 hours.
50. Dosage form of paragraph 49, where tmax
In the range of 13 to 28 hours.
51. Dosage form of paragraph 50, where tmax
for approximately 28 hours.
52. A stabilized sustained-release dosage form comprising a 25-hydroxyvitamin D compound, the dosage form being characterized by providing a baseline-adjusted C per microgram of 25-hydroxyvitamin Dmax
, when administered to adults, the Cmax
In the range of about 0.0133 ng/mL to about 0.04 ng/mL.
53. A method of administering to a human patient a stabilized sustained release dosage form comprising a 25-hydroxyvitamin D compound, comprising administering to the patient an effective amount of the dosage form to provide at least about 0.2 ng/mL and less than 110 ng/mL Baseline adjusted Cmax
.
54. The method of paragraph 53, comprising administering an effective amount of the dosage form to provide a baseline-adjusted C in the range of about 0.2 to about 24 ng/mLmax
.
55. A method of administering to a human patient a stabilized sustained release dosage form comprising a 25-hydroxyvitamin D compound, comprising administering to the patient an effective amount of the dosage form to provide at least 52 ng*h/mL and less than 34,500 Baseline-adjusted AUC at ng*h/mL0-inf
.
56. The method of paragraph 55, comprising administering to the patient an effective amount of the dosage form to provide a baseline-adjusted AUC in the range of about 52 ng*h/mL to about 12,000 ng*h/mL.0-inf
.
57. A method of vitamin D supplementation comprising administering to an individual in need a formulation or dosage form of any of the preceding paragraphs.
58. A method of treating or preventing vitamin D-responsive disease in an individual, comprising administering to the individual a formulation or dosage form of any of the preceding paragraphs.
59. The method of paragraph 58, wherein the disease is selected from the group consisting of cancer (e.g., breast, lung, skin, melanoma, colon, colorectal, rectal, prostate, and bone cancer), autoimmune disease (e.g., type 1 diabetes, multiplex Sclerosis, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma, fibrosis, Grave's disease, Hashimoto's disease, acute or chronic transplant rejection, acute or chronic graft resistance Host diseases, inflammatory bowel disease, Crohn's disease, systemic lupus erythematosus, Sugarhren's syndrome, eczema and psoriasis, dermatitis (including atopic dermatitis, contact dermatitis, allergic dermatitis and /or chronic dermatitis), inflammatory diseases (such as asthma, chronic obstructive pulmonary disease, polycystic kidney disease, polycystic ovary syndrome, pancreatitis, nephritis, hepatitis and/or infection), hypertension, cardiovascular disease (individual Have atherosclerosis, arteriosclerosis, coronary artery disease, cerebrovascular disease, peripheral vascular disease, myocardial infarction, myocardial ischemia, cerebral ischemia, stroke, congestive heart failure, cardiomyopathy), obesity or other weight disorders , lipid disorders (such as hyperlipidemia, dyslipidemia including related diabetic dyslipidemia and mixed dyslipidemia, hypoalpha-lipoproteinemia, hypertriglyceridemia, hypercholesterolemia and low HDL (high-density lipoprotein) protein)), metabolic disorders (such as metabolic syndrome, type II diabetes, type I diabetes, hyperinsulinemia, abnormal glucose tolerance, insulin resistance, diabetic complications (including neuropathy, nephropathy, osteoporosis, retinopathy, Diabetic foot ulcers and cataracts)) and/or blood clots.
60. The method of paragraph 59, wherein the disease is selected from the group consisting of (i) in the form of parathyroid-hypoparathyroidism, pseudohypoparathyroidism, secondary hyperparathyroidism; (ii) in the form of pancreatic diabetes; (iii) In the form of medullary thyroid carcinoma; (iv) in the form of cutaneous psoriasis; wound healing form; (v) in the form of pulmonary sarcoidosis and tuberculosis; (vi) in the form of renal chronic kidney disease, hypophosphate VDRR, vitamin D-dependent rickets form; (vii) in the form of skeletal anticonvulsant therapy, osteofibrogenesis dysgenesis, cystic osteitis fibrosus, rickets, osteoporosis, osteopenia, osteosclerosis, renal osteodystrophy, rickets; (viii) in the form of Intestinal glucocorticoid antagonism, spontaneous hypercalcemia of infancy, malabsorption syndromes, steatorrhea, tropical sprue forms of diarrhea; and (ix) autoimmune disorders.
61. The method of paragraph 60, wherein the disease is selected from the group consisting of cancer, skin disorders (e.g., psoriasis), parathyroid disorders (e.g., hyperparathyroidism and secondary parathyroid hyperactivity), bone disorders (e.g., osteoporosis) and autoimmune disorders.
62. The method of paragraph 61, wherein the disease is secondary parathyroid hyperactivity.
63. The method of paragraph 62, wherein the individual has chronic kidney disease (CKD).
64. The method of paragraph 63, in which CKD is 3 or 4 periods.
65. The method of paragraph 64, wherein the patient is vitamin D deficient.
66. The method of any of the preceding paragraphs, wherein the patient is a human being.
67. The method of paragraph 66, in which the human being is an adult.
68. A composition substantially as described herein.