TWI743426B - Stabilized modified release vitamin d formulation and method of administering same - Google Patents

Abstract

A stabilized formulation for controlled release of a vitamin D compound is disclosed. The formulation comprises one or both of 25-hydroxyvitamin D₂ and 25-hydroxyvitamin D₃ and a cellulosic compound. The stabilized formulations exhibit a stable dissolution profile following exposure to storage conditions and demonstrate improved pharmacokinetic parameters compared to unstabilized formulations.

Description

Stable modified release vitamin D formulation and its administration method

The present invention generally relates to controlled release pharmaceutical compositions. More specifically, the present invention relates to controlled release formulations for the delivery of vitamin D compounds for intestinal absorption, such as 25-hydroxyvitamin D compounds, which can be stored stably over time.

Vitamin D metabolites called 25-hydroxyvitamin D ₂ and 25-hydroxyvitamin D ₃ (collectively called “25-hydroxyvitamin D”) are fat-soluble pro-steroid prohormones that help maintain normal levels of calcium and phosphorus in the bloodstream . Prohormone 25-hydroxyvitamin D _{2 is} produced from vitamin D ₂ (ergocalciferol) and 25-hydroxyvitamin D _{3 is} produced from vitamin D ₃ (cholecalciferol), mainly produced by one or more enzymes located in the liver . The two prohormones can also be _{produced from vitamin D 2} and vitamin D ₃ (collectively called "vitamin D") in certain cells outside the liver, such as intestinal epithelial cells, which contain the same or similar enzymes found in the liver Enzyme. The 25-hydroxyvitamin D pro-hormone is further metabolized in the kidneys into effective vitamin D hormones. The prohormone 25-hydroxyvitamin D _{2 is} metabolized into 1α,25-dihydroxyvitamin D ₂ ; similarly, 25-hydroxyvitamin D _{3 is} metabolized into 1α,25-dihydroxyvitamin D ₃ (calcitriol). The production of these active hormones from the pre-hormone of 25-hydroxyvitamin D can also occur in cells outside the kidney that contain the required enzymes (classes). Controlled release formulations of 25-hydroxyvitamin D ₂ and/or 25-hydroxyvitamin D ₃ can be administered for the treatment of 25-hydroxyvitamin D deficiency and deficiency without the presence of 25 in the lumen, cells and blood. -The super-physiological surge in the content of hydroxyvitamin D and its consequences; substantially does not cause an increase in the metabolism of the administered 25-hydroxyvitamin D; and does not cause serious side effects related to vitamin D supplementation, namely vitamin D toxicity. The controlled release formulation effectively reduces the amount of PTH without causing an undesirable increase in serum calcium and serum phosphorus and is therefore suitable for the treatment of secondary hyperparathyroidism in patients with CKD, for example. See International Patent Application Nos. PCT/US2007/061521 and PCT/US2008/061579 and U.S. Patent Application No. 12/109,983, which are incorporated herein by reference. The controlled release composition substantially increases the absorption of 25-hydroxyvitamin D via transport on DBP and decreases the absorption of 25-hydroxyvitamin D via transport in chylomicrons. The composition also provides for maintaining the blood content of 25-hydroxyvitamin D substantially constant during the 24-hour post-administration period. By providing the gradual, continuous and direct release of 25-hydroxyvitamin D ₂ /25-hydroxyvitamin D ₃ , and preferential absorption through DBP in the circulation (rather than chylomicrons), 25 in the blood, in the lumen and in the cells -A sharp increase in the concentration of hydroxyvitamin D can also reduce or eliminate the super-physiological amount and related undesired metabolism. In addition, by providing gradual and sustained release, compared with the administration of immediate release formulations, the serum content of 25-hydroxyvitamin D can be increased and maintained more predictably, thereby allowing consistent dosage and reducing or eliminating the need for frequent patient monitoring . In order to deliver the benefits of the 25-hydroxyvitamin D controlled release formulation to patients, a stable pharmaceutical composition that maintains the desired solubility properties of the formulation for an extended period of time (for example, after shipping and storage) is required.

The present invention includes a controlled-release vitamin D formulation containing a vitamin D compound and a cellulose compound. The present invention also encompasses storage-stable formulations for the controlled release of vitamin D compounds in the gastrointestinal tract of an individual ingesting the formulation. In one aspect, the stabilized formulation includes 25-hydroxyvitamin D ₂ and 25-hydroxyvitamin D ₃ and one or both of a stabilizer or a stabilizing compound (such as a cellulose compound). When compared with the disclosed formulations that do not contain these agents, the stabilized formulations and the stabilizers of the present invention may have improved or relatively improved "storage stability" or stability after aging , And one or more other characteristics including improved physical, chemical, and biological properties. Compared with aging, unstable formulations, the claimed formulation is therefore suitable as a therapy with a longer shelf life and improved bioavailability. In one embodiment, the stabilized formulation includes one or both of 25-hydroxyvitamin D ₂ and 25-hydroxyvitamin D ₃ , lipophilic base (e.g. wax base) and stabilizer (e.g. cellulose compound) . In one aspect, the stabilized formulation includes _{one or both of 25-hydroxyvitamin D 2} and 25-hydroxyvitamin D ₃ , a wax base, and a cellulose stabilizer. In another aspect, the formulation includes _{one or both of 25-hydroxyvitamin D 2} and 25-hydroxyvitamin D ₃ , a wax base, and an effective amount of cellulose compound to maintain the stabilization described herein. Degree. In one embodiment, the stabilized formulation comprises a mixture of active loaded wax matrices comprising one or both of _{25-hydroxyvitamin D 2} and 25-hydroxyvitamin D _{3 and a cellulose stabilizer, wherein} During in vitro dissolution after storage at 25°C and 60% relative humidity for at least one month, the formulation releases a certain amount of 25-hydroxyvitamin D, which is the same dissolution time during in vitro dissolution on fresh products Compared with the release amount at one point, the release amount varies by 30% or less than 30% at all dissolution test time points. In one embodiment, the formulation is an improved formulation for the controlled release of vitamin D compounds. In one aspect, the improvement comprises the incorporation of stabilizers into the formulation for the controlled release of the vitamin D compound in the gastrointestinal tract of the individual ingesting the formulation. In another aspect, the improvement comprises mixing an effective amount of a cellulosic compound into the formulation for the controlled release of the vitamin D compound in the gastrointestinal tract of an individual ingesting the formulation. This provides the favorable stability described herein. In one embodiment, the present invention comprises a _{stable sustained-release vitamin D formulation comprising 25-hydroxyvitamin D 2} or 25-hydroxyvitamin D ₃ or a combination thereof and a sustained-release excipient, wherein the formulation has a T ₀ According to the formula X = T ₀ +/-30%, the dissolution characteristic X is maintained under storage conditions selected from room temperature and ambient humidity, or 25°C and 60%RH, or 40°C and 75%RH. From the summary of the following [Embodiment Mode] adopted in conjunction with the schema, other aspects and advantages will be obvious to those skilled in the art. Although the compositions and methods are susceptible to different forms of embodiments, the following description includes specific embodiments, in which it is understood that the disclosure is illustrative and is not intended to limit the invention to the specific embodiments described herein. For the compositions and methods described herein including (but not limited to) components, their composition ranges, substitutions, conditions, and steps (features as appropriate), it is expected to be selected from the various aspects, embodiments, and examples provided herein.

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t_max 表徵，該t_max 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C_max ，當投與成人時，該C_max 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C_max ，該C_max 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AUC_0-inf ，該AUC_0-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AUC_0-inf 或AUC_0-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，C_max (例如絕對C_max 或相比於基線之C_max )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 = 0_p (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 = 0_f 以指示新鮮樣品。亦報告變異係數(%CV)。自藉由T = 0_p 及T = 0_f 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。

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。

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。

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。

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。

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。

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：

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。

* 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。

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。

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。

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。

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。

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(t_1/2 )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。

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。

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C_max 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。t_1/2 、消除率(CL)及體積分佈(Vd)在處理組之間顯示為類似的。t_1/2 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。

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。

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AUC_0-6 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t_1/2 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。

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AUC_0-6 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。

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C_max )，t_1/2 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(AUC_0-6wk )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AUC_0-6wk )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t_max 至少為4小時。 42. 段落41之劑型，其中t_max 至少為8小時。 43. 段落42之劑型，其中t_max 至少為12小時。 44. 段落43之劑型，其中t_max 至少為18小時。 45. 段落44之劑型，其中t_max 至少為20小時。 46. 段落45之劑型，其中t_max 至少為24小時。 47. 段落46之劑型，其中t_max 至少為28小時。 48. 段落41之劑型，其中t_max 在4至96小時範圍內。 49. 段落48之劑型，其中t_max 在18至30小時範圍內。 50. 段落49之劑型，其中t_max 在13至28小時範圍內。 51. 段落50之劑型，其中t_max 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C_max ，當投與成人時，該C_max 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C_max 。 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C_max 。 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AUC_0-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AUC_0-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-REFERENCE TO RELATED APPLICATIONS This document claims the rights and interests of 35 USC §119(e) of U.S. Provisional Patent Application No. 61/801,896 filed on March 15, 2013, and its 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 the administered vitamin D compound in a manner other than immediate release. As used herein, the terms "sustained release" and "extended release" are used interchangeably and refer to the release of the administered vitamin D compound over a longer period of time than comparable immediate release formulations, resulting in a comparable Compared with the immediate release formulation, the serum concentration of the vitamin D compound remained elevated at baseline for a longer period of time. The foregoing terms optionally include delayed release features. For example, delayed release type of controlled release formulations at a time by the C _max was greater than the C _max of the immediate release formulation characterization. As another example, the release of the 25-hydroxyvitamin D compound will preferably be such that the total serum or blood content of the 25-hydroxyvitamin D is maintained or increased for an extended period of time (for example, 4 to 24 hours or even longer) Such rate exceeding the pre-dosed amount. As used herein, unless otherwise specified, the term "cellulose compound" may include cellulose (C ₆ H ₁₀ O ₅ ) _n or cellulose derivatives. "Cellulose ethers" are cellulose derivatives that have been chemically modified to cause partial or complete etherification of hydroxyl groups in cellulose molecules. Examples of cellulose derivatives that can be used as stabilizing agents include (but are not limited to) celluronic acid, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl Methyl cellulose, methyl cellulose, polyanionic cellulose and combinations thereof. The term also encompasses each cellulosic compound or stabilizer corresponding to different levels of variables such as molecular weight, viscosity, and solubility. Any vitamin D compounds and combinations thereof suitable for prophylactic and/or therapeutic use are expected 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 D ₃ (cholecalciferol), vitamin D ₂ (ergocalciferol), 25-hydroxyvitamin D ₃ , 25-hydroxyvitamin D ₂ , 25-hydroxyvitamin D ₄ , 25- Hydroxyvitamin D ₅ , 25-hydroxyvitamin D ₇ , 1α,25-dihydroxyvitamin D ₃ , 1α,25-dihydroxyvitamin D ₂ , 1α,25-dihydroxyvitamin D ₄ and vitamin D analogs (including all hydroxy And dihydroxy form), the vitamin D analogs include 1,25-dihydroxy-19-nor-vitamin D ₂ and 1α-hydroxyvitamin D ₃ . In one embodiment, the vitamin D compound includes one or more hydroxy forms, such as a combination of 25-hydroxyvitamin D ₃ and 25-hydroxyvitamin D ₂ . In particular, the types of vitamin D compounds expected to be used in the formulations disclosed herein may include 25-hydroxyvitamin D ₂ , 25-hydroxyvitamin D ₃ or a combination thereof. Especially consider 25-hydroxyvitamin D ₃ . As used herein, the term 25-hydroxyvitamin D refers to one of 25-hydroxyvitamin D ₃ , 25-hydroxyvitamin D ₂ , 25-hydroxyvitamin D ₄ , 25-hydroxyvitamin D ₅ or 25-hydroxyvitamin D ₇ or _{More than one, and intended to be one or more of 25-hydroxyvitamin D 3} and 25-hydroxyvitamin D ₂ in any of the non-preferred embodiments, preferably 25-hydroxyvitamin D ₃ . Accordingly, any and all of the formulations described herein, the active agents may include the particular intended 25-hydroxy-25-hydroxy vitamin D ₂ and vitamin D _3, 25-hydroxy vitamin D ₃ in particular, one of or both. In the present invention, the vitamin D compound (or a combination thereof) is also referred to as the "active" part of the formulation (or "active" agent) to distinguish it from the controlled release matrix, stabilizer, and other excipients. In the pharmacokinetic test of the sample using 25-hydroxyvitamin D ₃ as the active agent reported in this article, the reference to 25-hydroxyvitamin D should be interpreted as meaning 25-hydroxyvitamin D ₃ and everything related to it The pharmacokinetic (PK) results (e.g. t _max , C _max , AUC) should be understood to be based on 25-hydroxyvitamin D ₃ . As used herein, a "stabilized" formulation refers to a formulation that exhibits stable in vitro dissolution characteristics (according to any of the parameters described further herein) and after initial manufacturing (e.g., storage on actual shelves or accelerated stable storage conditions) After a period of time, a controlled release (e.g. sustained release) formulation of vitamin D compounds in vivo. The release of the active ingredient can be measured using a suitable in vitro dissolution method, such as one of the methods known in the art. In principle, if the formulation is stable, it can be measured using any of the following dissolution studies, which are described in the United States Pharmacopoeia, USP 29-NF 24, Dissolution <711> Physical Test and Measurement, United States Pharmacopoeia Convention Corporation, Rockville, MD, 2006, pages 2673-2682; European Pharmacopoeia 2.9.3 solid dosage form dissolution test or Japanese Pharmacopoeia 6.10 dissolution test. For the purpose of the present invention, the in vitro dissolution method is the United States Pharmacopeia, USP 29-NF 24, dissolution <711> physical test and measurement, United States Pharmacopeia Convention Corporation, Rockville, MD, 2006, pages 2673-2682, using the following examples As described in Equipment 2 (Stirring Paddle Method). As used herein, _tmax (or Tmax) is defined as the time at which the plasma concentration of the active compound reaches its maximum at a dose interval after administration of the formulation of the present invention. When a single 25-hydroxyvitamin D compound (such as 25-hydroxyvitamin D ₃ ) is administered, unless otherwise specified, t _{max is} defined as the plasma concentration of _{25-hydroxyvitamin D 3 in} the serum after administration of the formulation. The time at which the interval reaches its maximum value. In line with the NKF K/DOQI guidelines, as used in this article, vitamin D sufficient is defined as the serum 25-hydroxyvitamin D content ≥ 30 ng/mL, and vitamin D deficiency is defined as the serum 25-hydroxyvitamin D content of 16-30 ng/mL, A mild vitamin D deficiency is defined as a serum 25-hydroxyvitamin D content of 5-15 ng/mL, and a severe vitamin D deficiency is defined as a 25-hydroxyvitamin D content of less than 5 ng/mL. In the jurisdiction that prohibits the granting of patent rights for methods practiced on the human body, the meaning of “taking” the composition for a human individual should be limited to prescribing (drug) the human individual will use any technique (such as oral, inhalation, surface coating) , Injection, insertion, etc.) Self-administered controlled substances. It is expected to adopt the broadest reasonable interpretation consistent with the laws or regulations that define the patentable subject matter. In the authority that does not prohibit the granting of patent rights for methods that are practiced on the human body, "taking" the composition includes the two methods of practice on the human body and the aforementioned activities. It is specifically understood that any numerical value described 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 listed are to be regarded as expressly stated in this application. For example, if the concentration range or the favorable effect range is stated as 1% to 50%, it is desirable to clearly enumerate values such as 2% to 40%, 10% to 30%, or 1% to 3% in this specification. . As another example, the concentration of about 20% is intended to include values of 19.5% up to 20.5%. These examples are only examples of specific expectations. The formulation disclosed herein is a formulation for the controlled release of vitamin D compounds in the gastrointestinal tract of an individual ingesting the formulation. The formulation will include a vitamin D compound as described herein, a matrix component (such as a lipophilic matrix) that releasably binds the vitamin D compound and a controlled release of the vitamin D compound, and a stabilizer (such as a cellulosic compound). The stabilized formulation of the present invention releases a certain amount of 25-hydroxyvitamin D in in vitro dissolution after storage for a period of time, which is not substantially different from the dissolution of the same formulation only after manufacture and before storage . For example, in one embodiment, the formulation releases a certain amount of 25-hydroxyvitamin D during in vitro dissolution after being exposed to storage conditions of 25°C and 60% relative humidity for two months. During the in vitro dissolution before exposure to storage conditions (that is, the freshly prepared product), compared to the release amount at the same dissolution time point, the release amount changes at any given dissolution time point after four hours 30 % Or less than 30%. The following table provides the expected storage stability of the embodiments of the present invention after initial manufacturing at 25°C and 60%RH and or after multiple storage at 40°C and 75%RH, and at different times during the dissolution test Examples of the degree of sexual favorability. The degree of storage stability is expressed by the maximum deviation from the nominal activity performance, that is, the maximum% change from the LC. An alternative embodiment of the maximum deviation is also provided.

In one embodiment, the formulation will have an advantageous degree of stability immediately following the stability described in the above table at multiple time points throughout the dissolution test, for example, at least at two time points of 2 and 4 hours, as the case may be. 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 characteristics after storage follow the dissolution characteristics of the fresh product. Alternatively, the formulation will have an advantageous degree of stability immediately following the stability described in the table above at least at the time points of 2, 6, and 12 hours. Alternatively, the formulation will have an advantageous degree of stability immediately following the above-mentioned table at least at 4, 8 and 12 hour time points. Alternatively, the formulation will have an advantageous degree of stability next to the stability described in the table above at least at the time points of 2, 4, and 6 hours. Alternatively, the formulation will have an advantageous degree of stability immediately following the stability described in the table above at least at 4, 6, 8, and 12 hours or all of 4 hours and thereafter. In any and all of the examples described in the table immediately above, the deviation intention can be positive (more release) or negative (less release) in terms of fresh product. In one embodiment, the deviation is intended to be in a negative direction (less release) at multiple points in time. Furthermore, in one embodiment, if the stabilizer is not present in the formulation, the deviation in the dissolution release is intended to be negative (less release) at multiple time points. In any embodiment encompassed herein, the dissolution release profile of the formulation may have the characteristics of 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, greater than 80% at 12 hours, and further as appropriate at 6 hours Less than 60% of the release of vitamin D compounds. In another embodiment, the formulation can provide a living body that releases less than 30% of the vitamin D compound 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 providing in vitro dissolution characteristics of less than 30% 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 less than 60% at 5 to 7 hours or less than 60% at 6 hours as appropriate. In another embodiment, the formulation can be provided by providing a living body with about 20% to about 40% at 2 hours, at least 35% at 6 hours, and at least 70% of the release of vitamin D compounds at 12 hours Characterization of external dissolution characteristics. In another embodiment, the formulation can be provided by providing about 25% to about 35% at 2 hours, at least 40% at 6 hours, and at least 75% of the release of the vitamin D compound at 12 hours. Characterization of in vitro dissolution characteristics. In these types of embodiments, depending on the circumstances, the release of the vitamin D compound is, for example, 75% or less than 75% at 6 hours, or 65% or less than 65% at 6 hours, or 60% at 6 hours. Or less than 60%. In any of the embodiments described herein, the stabilized formulation can be _{characterized by a tmax} after administration to a human patient dosage form, which _tmax is 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, for example in the range of 4 to 96 hours, or in the range of 18 to 30 hours, or in the range of 13 to 28 hours, or for example 28 hours. In any of the embodiments contemplated herein, comprising a formulation of 25-hydroxyvitamin D, characterized by providing per microgram of 25-hydroxyvitamin D baseline-adjusted C _max was, when administered to an adult, the C _max of about 0.0133 ng/mL to about 0.04 ng/mL. In any of the methods covered 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 adjusting the C _max, the C _max of at least about 0.2 ng / mL, and optionally less than 110 ng / mL, and further optionally to 24 ng / mL or less than 24 ng / mL, for example from about 0.2 to about 24 ng / Within the mL range. In any of the methods covered 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 AUC _0-inf , the AUC _{0-inf is} at least 52 ng*h/mL, and optionally less than 34,500 ng*h/mL, and further as appropriate, about 12,000 ng*h/mL or less than 12,000 ng*h /mL, for example, in the range of about 52 ng*h/mL to about 12,000 ng*h/mL. In any of the embodiments described herein, the stabilized formulation is intended to be bioequivalent to the freshly prepared product after storage. Thus, for example, a stable formulation can provide the area under the curve of the active agent (or the total 25-hydroxyvitamin D in the serum) after storage, and the AUC (such as AUC _0-inf or AUC _0-t ) is within the 90% confidence interval Within, or within 80% to 125% of the average value of fresh products, or within 80% to 120% of the average value. Additionally or in the alternative, the stabilized formulations of the active agent may be provided (or serum total 25-hydroxy vitamin D) after storage of the maximum serum concentration, C _max (e.g. absolute or C _max C _max as compared to the baseline) Within the 90% confidence interval, or within 80% to 125% of the average value of fresh products, or within 80% to 120% of the average value. In one embodiment, the stabilized formulation includes _{one or both of 25-hydroxyvitamin D 2} and 25-hydroxyvitamin D ₃ , a wax matrix, and a cellulosic compound. In one aspect, the stabilized formulation includes _{one or both of 25-hydroxyvitamin D 2} and 25-hydroxyvitamin D ₃ , a wax base, and a cellulose stabilizer. In another aspect, the formulation includes _{one or both of 25-hydroxyvitamin D 2} and 25-hydroxyvitamin D ₃ , a wax base, and an effective amount of a cellulose compound to provide advantageous stability as described herein The degree, for example, according to any one of the following table or examples in accordance with the following. For example, the amount can effectively provide the amount of active agent released at the time of dissolution during the in vitro dissolution period after exposure to storage conditions of 25°C and 60% relative humidity for at least one month. During the in vitro dissolution before storage conditions, there is a 30% or less than 30% difference between the amount released at the same dissolution time point, and the lack of stabilizers in the comparative formulation will result in the dissolution release after the same storage conditions A bigger difference. In one aspect, the formulation is a modified formulation that is used for the controlled release of vitamin D compounds in the gastrointestinal tract of an individual ingesting the formulation. In one embodiment, the improvement comprises the incorporation of a cellulose stabilizer into the formulation for the controlled release of the vitamin D compound in the gastrointestinal tract of the individual ingesting the formulation. In another embodiment, the improvement comprises mixing an effective amount of a cellulosic compound into the formulation for the controlled release of the vitamin D compound in the gastrointestinal tract of the individual ingesting the formulation, thereby providing the advantageous benefits described herein The degree of stability is, for example, according to any one of the following table or the following examples. For example, the amount can effectively provide the amount of active agent released at the time of dissolution during the in vitro dissolution period after exposure to storage conditions of 25°C and 60% relative humidity for at least one month. During the in vitro dissolution before storage conditions, there is a 30% or less than 30% difference between the amount released at the same dissolution time point, and the lack of stabilizers in the comparative formulation will result in the dissolution release after the same storage conditions A bigger difference. The stabilizer may include a cellulosic compound. Examples of cellulosic compounds and stabilizers used in the stabilized formulation of the present invention may include, but are not limited to, cellulosic acid, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl Base cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyanionic cellulose, and combinations thereof. It also covers poloxamer (e.g. polaxamer 407), poly(ethylene oxide) polymers (e.g. Dow's POLYOX polymers), povidones and fumed silica (e.g. AEROSIL 200, Evonik Industries AG, Essen, Germany) one or more of them. The stabilizer (e.g., cellulose compound) is preferably present in an amount (wt%) of at least about 5% of the formulation based on the total weight of the formulation excluding any other coatings or shells. For example, the cellulose 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 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 should be understood that the stabilizers mentioned in this article are intended to stabilize the dissolution release profile (and therefore the in vivo release profile) against the substantial changes that occur over time during storage conditions (such as typical shelf storage conditions). Reagents. Other agents known in the art as preservatives used to prevent 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 expected to be used 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, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and combinations thereof. Especially consider hydroxypropyl methylcellulose (HPMC). HPMC can be characterized by one or more of the following characteristics, which are individually and in combination to specify expectations. The methoxy component% in HPMC can be in the range of 19-24. The hydroxypropyl component% can be in the range of 7-12. The apparent viscosity (2% aqueous solution at 20°C) can be at least 50,000 cps, or at least 80,000 cps, or about 80 to 120,000 cps, or 3000 to 120,000 cps, or 11,000 to 120,000 cps, or 80,000 to Within the range of 120,000 centipoise. Specifically, the apparent viscosity (2% aqueous solution at 20°C) can be in the range of 80,000 to 120,000 centipoise. The pH value (1% aqueous solution) can be in the range of 5.5 to 8.0. For example, a suitable hydroxypropyl methylcellulose with all 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 main component of the matrix (e.g., at 65°C or in the range of 60°C to 75°C). In one embodiment, the cellulosic compound will be hydrophilic. The pharmaceutical formulation of the present invention comprising one or more of 25-hydroxyvitamin D ₂ and 25-hydroxyvitamin D _{3 and a cellulose compound unexpectedly has the effect of} Improved stability. In one embodiment, the stabilized formulation of the present invention comprises a mixture of active loaded lipophilic bases comprising one or both of _{25-hydroxyvitamin D 2} and 25-hydroxyvitamin D _{3 and a cellulose stabilizer} , Wherein the formulation releases a certain amount of 25-hydroxyvitamin D during the in vitro dissolution period after being exposed to storage conditions of 25°C and 60% relative humidity for at least one month, and the live body is performed on the freshly prepared product Compared with the release amount at the same dissolution time point during the external dissolution, the release amount changes by 30% or less than 30% at any given dissolution time point. The unstabilized formulation exhibits a change 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 a certain amount of 25-hydroxyvitamin D after exposure to storage conditions, which can vary at a given dissolution time point, such as in vitro dissolution on freshly prepared products Compared with the release amount at the same dissolution time point during the period, the change exceeded 30%. The change at a given point in time can be an increase or decrease in the rate of dissolution, and these changes produce a dissolution characteristic whose profile is different from the shape of the initial dissolution characteristic. Compared with the stabilized formulation of the present invention, the unstabilized formulation also exhibits different characteristics after storage as described herein (for example, after storage at 25° C. and 60% RH for 3 months or more) In vivo effects. Compared with unstabilized formulations, stabilized formulations exhibit different clinical pharmacokinetics after storage as described herein (for example, after storage at 25°C and 60% RH for 3 months or more) Parameters such as improved bioavailability. The stabilized formulation of the present invention may have a base formulation that is not stable in storage and a stabilizer that stabilizes the formulation in storage as described herein. The matrices that releasably bind and controllably release the active ingredient can be, for example, lipophilic matrices, including wax matrices. The wax matrix can provide a solid or semi-solid formulation at room temperature and a solid, semi-solid or liquid formulation at body temperature, preferably a semi-solid or liquid formulation 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 wax, microcrystalline wax, paraffin wax, carnauba wax, and beeswax); polyethoxylated castor oil derivatives, hydrogenated Of 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. It is preferably a non-digestible waxy substance (such as hard 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 the form of 50 wt% or less than 50 wt%, 40 wt% or less than 40 wt%, 35 wt% or less than 35 wt% or 30 wt% or less than 30 wt%. 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 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 polyglycerides; including glycerol monooleate, glycerol dioleate, glycerol monostearate, glycerol distearate, glycerol monopalmitate and glycerol dipalmitate; fatty acid glycerol Lactate; propylene glycol ester including propylene glycol monopalmitate, propylene glycol monostearate and propylene glycol monooleate; sorbitan including sorbitan monostearate, sorbitan sesquioleate Sugar alcohol esters; fatty acids and soaps including stearic acid, palmitic acid and oleic acid; and mixtures thereof; glycerol monooleate, glycerol dioleate, glycerol monostearate, glycerol distearate , Glycerol monopalmitate, and glycerol dipalmitate; fatty acid glycerol lactate; including propylene glycol monopalmitate, propylene glycol monostearate and propylene glycol monooleate; including sorbitan monostearate Fatty acid esters, sorbitan esters of sorbitan sesquioleate; fatty acids and soaps including stearic acid, palmitic acid and oleic acid; and mixtures thereof. Preferably the lipophilic agent is selected from glycerides and their derivatives. The preferred glycerides are selected from the group consisting of medium-chain or long-chain glycerides, caprylic hexyl 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, caprylic/capric glycerides Ester, glyceryl monocaprylate, glyceryl monocaprylate, caprylic/capric linoleic acid triglyceride, and caprylic/capric acid/succinic acid triglyceride. Monoglycerides with low melting points are preferably used for preparing formulations. Preferred monoglycerides include, but are not limited to, glycerol monostearate, glycerol monopalmitate, glycerol monooleate, glycerol monocaprylate, glycerol monocaprate, glycerol monolaurate, etc., preferably It is glyceryl monostearate (GMS). GMS is a natural emulsifier. It is oil-soluble but hardly soluble in water. The HLB value of GMS is 3.8. The lipophilic emulsifier may be present, for example, in an amount of about 10 wt% to about 40 wt% or 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) such as polyvinyl glycosylated glycerides such as caprylyl hexyl polyglycerol glycerides, also known as polyglycolized glycerides or pegylated glycerides. (PEGylated) glycerides. The PEGylated glycerides that can be used in the composition include (but are not limited to) monoglycerides, diglycerides and triglycerides, and mixtures of mono- and di-esters of polyethylene glycol, polyvinyl glycosylated almonds Glycerides, polyvinyl glycosylated corn glycerides and polyvinyl glycosylated caprylic/capric triglycerides. The HLB value of the absorption enhancer can be 13-18 or 13-15. A preferred absorption enhancer is known under the trade name 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 different applications (including the preparation of sustained-release pharmaceutical compositions). GELUCIRE compounds are inert, semi-solid waxy materials that are amphoteric and can obtain varying physical characteristics (such as melting point, HLB, and solubility) in different solvents. It is actually a surfactant and is dispersed or dissolved in an aqueous medium to form micelles, microspheres or liposomes. It is identified by its melting point/HLB value. The 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 polyethylene glycol dodecanoate and polyoxyglycerol dodecanoate), which has a melting point of 44°C and an HLB of 14. The absorption enhancer may be present, for example, in an amount of about 5 wt% to about 20 wt% or 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 base provides a combination of pharmaceutically active ingredients (for example, vitamin D compounds _{such as 25-D 2} , 25-D ₃ or both) at a temperature of about 0°C to about 50°C higher than the melting point of the wax base, And then the method of filling the melt (solution and/or dispersion) into a suitable capsule. The capsule can be of any variety compatible with the temperature at which the melt is filled, including soft or hard gelatin capsules and animal or vegetable gelatin capsules. The melt solidifies in the capsule when cooled to room temperature. In one aspect, the stabilized formulation may further include an oily vehicle _{for 25-hydroxyvitamin D 2} and/or 25-hydroxyvitamin D _3. Any pharmaceutically acceptable oil can be used. Examples include animals (e.g. fish), plants (e.g. soybeans) and mineral oil. The oil will preferably easily dissolve the 25-hydroxyvitamin D compound used. Preferred oily vehicles include non-digestible oils such as mineral oil, in particular, liquid paraffin and squalene. The oily vehicle can be, for example, about 10 wt% to about 50 wt%, or about 15 wt% to about 45 wt%, or about 20 wt% to about 40 wt%, or about 30 wt% to about 40 wt% of the formulation. It exists in the form of a concentration within the range of %. 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 the wax base and the oily 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 small 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 such that, for example, each unit dose contains 1 to 1000 μg of 25-hydroxyvitamin D ₂ and/or 25-hydroxyvitamin D ₃ at a concentration, and is prepared in this way In order to achieve the _{controlled or substantially constant release of 25-hydroxyvitamin D 2} /25-hydroxyvitamin D ₃ , it will be released into the ileum of the gastrointestinal tract of humans or animals over an extended period of time as the case may be. Examples of doses 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% of the vitamin D compound within the first 24 hours after administration, more preferably at least 80%. _{Advantageously, 25-hydroxyvitamin D 2} , 25-hydroxyvitamin D ₃ or a combination thereof together with other therapeutic agents can be administered, for example, orally, according to the above-mentioned embodiments, for example, at a dose of 1 to 100 μg per day. In one embodiment, the dose will be selected to provide an average increase in _{serum 25-hydroxyvitamin D 3 of about 1 to 3 ng/ml during the dose interval.} In an embodiment, the formulations described herein can be administered to increase and preferably also maintain the 1,25-dihydroxyvitamin D content in the blood at 25 pg/mL, 30 pg/mL or higher (e.g. 25 pg/mL, 30 pg/mL or higher). -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, the formulations described herein can be administered to patients to reduce or maintain reduced serum parathyroid hormone levels, preferably by an amount that reduces PTH levels by at least 30%, or reduces PTH serum levels to CKD The target range of phase (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 4 and The period is 150-300 pg/mL (equivalent to 16.5-33.0 pmol/L) (defined in K/DOQI Guide No. 1)). In another aspect, the formulation of the present invention can be administered to patients suffering from secondary hyperthyroidism of chronic kidney disease (such as stage 3 or 4, or stage 3, 4 or 5) to reduce serum PTH content. The dosages described herein are intended to be used in any of the methods of treatment described herein. It should be understood that the actual preferred amount of vitamin D compound under specific circumstances will vary according to the specific composition formulated, the mode of application, and the specific site being treated. The dosage can be determined using conventional considerations, for example, by comparing the different activities of conventional hormones and known agents, for example, by means of appropriate conventional pharmacological protocols. The specific dosage for each specific patient may be determined by various factors, such as age, weight, general health, gender, diet, timing and mode of administration, excretion rate, combined use of drugs and the severity of the specific disease for which the therapy is administered . Patients requiring vitamin D supplementation include healthy individuals and individuals at risk of vitamin D deficiency 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 allergy, vegetarians who do not consume milk, and breastfed infants); individuals with rickets; individuals with dark skin (e.g. in the United States, 42% are between 15 and 49 years old) African American women are vitamin D deficient compared with 4% of white women); elderly (decreased ability to synthesize vitamin D and more likely to stay indoors); institutionalized adults (adults who may stay indoors, including those with Individuals with Alzheimer's disease or mental illness); individuals covering all bare skin (such as people of certain religions or cultures); individuals who always use sunscreen (for example, coated with a sun protection factor (SPF) value 8 sunscreens reduce the production of vitamin D by 95%, and a higher SPF value can further reduce vitamin D); suffering from fat absorption syndrome (including (but not limited to) cystic fibrosis, cholestatic liver disease, etc.) Individuals suffering from liver disease, gallbladder disease, pancreatin deficiency, Crohn's disease, inflammatory bowel disease, stomatitis, diarrhea or celiac disease, or surgical removal of part or all of the stomach and/or intestine); Individuals with inflammatory bowel disease; individuals with Crohn's disease; individuals with small intestine removed; individuals with gum disease; taking drugs that increase vitamin D metabolism (including phenytoin, phosphorus) Individuals with fosphenytoin, phenobarbital, carbamazepine, and rifampin; taking drugs that reduce the absorption of vitamin D (including cholestyramine, colestyramine) (colestipol, orlistat, mineral oil, and fat substitutes); individuals taking drugs that inhibit the activation of vitamin D (including ketoconazole); individuals taking drugs that reduce calcium absorption (including corticosteroids) Individuals with obesity (vitamin D deposited in body fat storage is less bioavailable); individuals with osteoporosis; patients with low bone mineral density and osteoporosis; and / Or women after menopause. According to the Medical Association report on the dietary reference intake of vitamin D, food consumption data indicate that the median vitamin D intake of young and elderly women is lower than the current recommended intake; the data shows that more than 50% of young and old women Older women did 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 cystic fibrous osteitis). In other aspects, the composition and method of the present invention are suitable for the prevention or treatment of vitamin D-responsive diseases, that is, vitamin D, 25-hydroxyvitamin D or active vitamin D (such as 1,25-dihydroxyvitamin D) ) A disease that prevents the onset or development of a disease or reduces the signs or symptoms of the disease. Such vitamin D-responsive diseases include cancer (such as breast, lung, skin, melanoma, colon, colorectal, rectum, prostate, and bone cancer). It has been observed that 1,25-dihydroxyvitamin D induces cell differentiation of multiple cells and/or inhibits cell proliferation in vitro. Vitamin D-responsive diseases also include autoimmune diseases, such as type I diabetes, multiple sclerosis, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma, fibrosis, and Grave 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, Hugherian syndrome, Eczema and 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 have also been reported including hypertension and cardiovascular disease. Thus, the present invention covers the prevention or treatment of individuals who are at risk of suffering from cardiovascular disease, such as atherosclerosis, arteriosclerosis, coronary artery disease, cerebrovascular disease, peripheral vascular disease, myocardial infarction, and 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, hypo-α-lipoproteinemia) Dyslipidemia, hypertriglyceridemia, hypercholesterolemia and low HDL (high density lipoprotein)), metabolic disorders (e.g. metabolic syndrome, type II diabetes, type I diabetes, hyperinsulinemia, glucose tolerance Individuals with abnormalities, insulin resistance, diabetic complications (including neuropathy, nephropathy, retinopathy, diabetic foot ulcers and cataracts) and/or blood clots. Diseases that can benefit from the adjustment of vitamin D compound levels include (but are not limited to): (i) in the form of parathyroid-parathyroidism, pseudoparathyroidism, secondary hyperparathyroidism; (ii) in the form of pancreas Diabetes; (iii) in the form of medullary thyroid carcinoma; (iv) in the form of skin psoriasis; wound healing; (v) in the form of pulmonary sarcoidosis and tuberculosis; (vi) in the form of renal chronic kidney disease, low phosphate VDRR , Vitamin D-dependent rickets; (vii) In the form of bone anticonvulsant treatment, bone fibrogenesis, cystic fibrous osteitis, rickets, osteoporosis, osteopenia, osteopetrosis, renal osteodystrophy, rickets Form; (viii) In the form of intestinal glucocorticoid antagonism, spontaneous hypercalcemia in infancy, malabsorption syndrome, steatorrhea, tropical stomatitis diarrhea; and (ix) autoimmune disorders. In the embodiment of the present invention, the diseases that benefit from the adjustment of the content of vitamin D compounds are selected from cancer, skin disorders (such as psoriasis), parathyroid disorders (such as hyperparathyroidism and secondary hyperparathyroidism) , Bone disorders (such as osteoporosis) and autoimmune disorders. The formulation can be prepared by a procedure that is just within the abilities of those skilled in the art. For example, if necessary, the components of the matrix (such as wax and oily vehicle) can be melted to provide a flowable liquid, thereby making it easier to obtain a homogeneous mixture. The active agent (for example, 25-hydroxyvitamin D ₂ and/or 25-hydroxyvitamin D ₃ ) 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 may be added after all matrix components (e.g., waxes and oils) have been blended and before being combined 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, part of the oily vehicle, controlled release agent, and emulsifier is heated to a relatively high temperature (for example, 65°C) and mixed before adding the absorption enhancer, then mixed until homogeneous, and then cooled to a moderately high temperature (For example, 50°C to 55°C). In a separate container, mix and heat the remaining parts of the anti-oxidant preservative and the oily vehicle to a medium high temperature (for example, 50° C.), and then combine and mix with the wax mixture until a homogeneous solution is obtained. Then, the stabilizer is added and mixed. Then, the vitamin D compound solution in ethanol is combined with a homogeneous waxy solution, mixed until a homogeneous solution is obtained, preferably filled into capsules, and then cooled to room temperature. In another preferred method, part of the oily vehicle, controlled release agent, and emulsifier is 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, mix and heat the antioxidant preservative, the remaining part of the oily vehicle, and the stabilizer to a temperature of 55°C to 60°C, and then combine and mix with the wax mixture until a homogeneous solution is obtained. Then, the vitamin D compound solution in ethanol is combined with a homogeneous waxy 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 before administration to a patient in need of treatment. The capsules can be hard or soft, and soft capsules are especially considered. A standard capsule filling machine can be used to fill the formulation into the gelatin capsule, such as by melting the formulation and injecting it into the soft capsule shell. Examples of soft capsule shells include VEGICAPS and OPTISHELL technologies (Catalent, Somerset, NJ, USA). In the alternative, the formulation can be made into a unit dosage form by any other suitable process, for example, to produce lozenges, sachets, dragees, suppositories, or the like. In one embodiment, the formulation is prepared for oral delivery and administered by oral delivery. In another embodiment, the formulation is prepared as a suppository and administered as a suppository, such as a rectal suppository. Unless otherwise specified, the formulations and methods of use and preparation are expected to include embodiments that include 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 ratio of each of the compounds in the combination administered will depend on the specific disease condition being treated. For example, we can choose to interact with one or more calcium salts (expected as calcium supplements or dietary phosphate binders), bisphosphonates, calcimimetics, nicotinic acid, iron, phosphate binders , Cholecalciferol, Ergocalciferol, Active Vitamin D Sterols, Blood Sugar and Hypertension Control Agents, CYP24 of Degradable Vitamin D Agents, and Different Anti-neoplastic Agents and Inhibitors of other Cytochrome P450 Enzymes Administer together 25 -Hydroxyvitamin D ₂ and/or 25-hydroxyvitamin D ₃ (for example, oral). In addition, we can choose different anti-neoplastic agents and inhibitors from cholecalciferol, ergocalciferol, active vitamin D sterol, blood sugar and hypertension control agents, degradable vitamin D agents CYP24, and other cytochrome P450 enzymes. The drug is administered intravenously with 25-hydroxyvitamin D ₂ and/or 25-hydroxyvitamin D ₃ . In fact, when the treatment of a disease condition is the desired endpoint, a higher dose of the compound of the present invention is used, while a lower dose is usually used for preventive purposes, that is, in any given situation, a specific dose is administered It will be adjusted according to the specific compound administered, the disease to be treated, individual conditions and other relevant medical facts that can change the activity of the drug or individual response, as those familiar with the art know. As mentioned above, the formulation is preferably filled into gelatin capsules, but it can also be administered in pure form or in one or more outer coatings (such as enteric coatings). It is also contemplated that the formulation can be compressed into tablets, and in this case can 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 can be selected from various specific examples provided herein. For example, a preferred formulation includes 25-hydroxyvitamin D (for example, about 30 μg, about 60 μg, or about 90 μg 25-hydroxyvitamin D ₃ ), about 2 wt% (for example, 2.32 wt%) absolute ethanol, about 10 wt% (e.g. 9.75 wt%) GELUCIRE 44/14, about 20 wt% (e.g. 20.00 wt.%) hard paraffin, about 23 wt% (e.g. 22.55 wt%) GMS, about 35 wt% (e.g. 35.36 wt%) liquid Paraffin or mineral oil, about 10 wt% HPMC, and a small amount of preservatives (such as 0.02 wt% BHT) as appropriate. A variation of this formulation would include about 15% (eg 15.29 wt%) HPMC and about 30 wt% (eg 29.88 wt%) liquid paraffin or mineral oil. Examples The following examples illustrate specific formulations and methods of preparation. Examples are provided for illustration and are not intended to limit the scope of the present invention. In the example, the USP equipment 2 (stirring paddle method) described in USP 29-NF 24, general rule <711> dissolution is used, and the dissolution test in vitro is performed using the dissolving medium described below. Generally speaking, the method is carried out according to the following steps. Put the volume of the dissolving medium (±1%) in the container of the designated equipment, assemble the equipment, equilibrate the dissolving medium to 37±0.5°C and remove the thermometer. Place the dose unit in the device, take care to remove air bubbles from the surface of the dose unit, and then operate the device at the specified rate. At each point in the time period, a specimen was taken from the middle area (not less than 1 cm from the container wall) between the surface of the dissolving medium and the top of the rotating blade. Replace the aliquot drawn for analysis with the same volume of fresh dissolving medium at 37°C. Keep the container covered during the test duration and verify the temperature of the tested mixture at the appropriate time. In this case, use a suitable analytical method (Ultra Performance Liquid Chromatography (UPLC)) for analysis. Six capsules of each formulation were tested at each time point. The dissolution medium is a 0.05 M pH 6.8 phosphate buffer solution/1% sodium lauryl sulfate dissolution medium at 37±0.5°C and the equipment is operated at 100 revolutions per minute. Samples were taken out at 2, 4, 6, 8 and 12 hours and the 25-hydroxyvitamin D content of each sample was measured using UPLC. In vitro sustained release of Examples 1-25- unstabilized hydroxyvitamin D of the test formulations dissolved 90 μg 25- hydroxy vitamin D _3, 19.98 wt% hard paraffin, 37.85 wt% GMS, 9.76 wt % GELUCIRE 44/14 , 2.36 wt% anhydrous ethanol, 29.88 wt% liquid paraffin and 0.02 wt% BHT (comparative formulation 1) mixture made of the dissolution of the formulation. The formulation does not contain cellulose compounds. The average amount of 25-hydroxyvitamin D ₃ released is summarized in the table below. The average amount is calculated at T = 0 and after controlled storage of the formulation at 5°C and ambient humidity for up to 12 months. Calculate the average percentage of the nominal drug loading of the dosage form (average% of the labeled amount, %LC). Before the test, make sure that the samples are stored at a temperature within the range of 15°C to 30°C and ambient humidity for a period of about 3 months. Therefore, the samples that should indicate the time zero point are marked as T = 0 _p (pseudo time zero point), and it should be understood that the samples that have been aged for 1 month, 3 months, 6 months, 9 months, and 12 months are also Go through the aging period of about 3 months just described. In order to provide a more accurate baseline, prepare and test fresh batches of the same type of samples without any aging. This data is marked as T = 0 _f to indicate fresh samples. The coefficient of variation (%CV) is also reported. The percentage change from the initial amount of 25-hydroxyvitamin D ₃ released by batches of T = 0 _p and T = 0 _f are provided in brackets and double brackets, respectively.

The test compares 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.

The test compares 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.

Without intending to be bound by any particular theory, the increase in the degree of dissolution after storage at 40°C compared to the pseudo T = 0 value is considered to be due to the above-mentioned aging effect of the tested pseudo T = 0 sample and when A combination of temperature-dependent phase changes in the formulation when stored at 40°C. The aged product of Comparative Formulation 1 was thermally cured, and then subjected to a dissolution test. Curing consists of applying heat treatment and has been shown to be stable pharmaceutical formulations (see, for example, U.S. Patent No. 6,645,527). Comparative formulation 1 (aged sample) was heated at 40°C for 72 hours for curing, and then stored at room temperature for 8 weeks. _{The release of 25-hydroxyvitamin D 3} from the curing formulation was tested after storage at room temperature for 0, 2, 4, and 8 weeks. The results are summarized in the table below.

Examples 2-25- vitro controlled release of the stabilized hydroxyvitamin D of the formulation after storage at room temperature the dissolution test 0-11 weeks, containing 90 μg 25- hydroxy vitamin D _3, 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 formulation A) sustained release formulation Dissolve. The results are summarized in the table below.

After the test is stored at room temperature for 0 to 26 weeks, it contains 90 µg 25-hydroxyvitamin D ₃ , 19.88 wt% hard paraffin, 10.00 wt% hydroxypropyl methylcellulose, 22.55 wt% GMS, 9.76 wt% GELUCIRE 44/ 14. Dissolution of a sustained release formulation of 2.36 wt% absolute ethanol, 35.17 wt% liquid paraffin and 0.02 wt% BHT (example formulation B)). The results are summarized in the table below.

Example Formulation B showed substantially stable dissolution characteristics after storage at room temperature for at least 26 weeks. Use 25 ℃ and 60% relative humidity and 40 ℃ and 75% relative humidity to test storage conditions including 30 µg 25-hydroxyvitamin D ₃ (example formulation C), 60 µg 25-hydroxyvitamin D ₃ (example formulation D) Or the stability of the stabilized formulation of 90 µg 25-hydroxyvitamin D _{3 (example formulation E).} The compositions of the example formulations C to E are summarized in the following table:

The formulation exhibited substantially stable dissolution characteristics after storage at 25°C and 60% relative humidity for at least 24 months (Figure 1). The dissolution results (%LC and %CV) are summarized in the table below.

_{* The percentage change between the amount of 25-hydroxyvitamin D 3} released after 4 repetitions and 6 times of aging compared to the initial release is summarized in the table below.

Example formulations C to E also exhibit 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.

_{The percentage change between the amount of 25-hydroxyvitamin D 3} released after exposure to storage conditions compared to the initial release amount is summarized in the table below.

The stability of Comparative Formulation 1 containing no cellulose compound and Example Formulation E containing hydroxypropyl methylcellulose was evaluated after storage at 25° C. and 60% relative humidity for 12 months (Figure 3). The T dissolution results are summarized in the table below.

_{The percentage change between the amount of 25-hydroxyvitamin D 3} released after exposure to storage conditions compared to the initial release amount is summarized in the table below.

Example 3 : In vivo results of unstabilized and stabilized controlled release formulations. In vivo studies were conducted to evaluate the clinical drugs of unstabilized and stabilized controlled release formulations _{of 25-hydroxyvitamin D 3 in humans.}代dynamics. In Study A, 28 patients had stage 3 or 4 CKD, secondary hyperparathyroidism (stage 3: 70-1000 pg/mL iPTH; stage 4: 110-1000 pg/mL iPTH) and vitamin D deficiency (Total baseline 25-hydroxyvitamin D in serum is 15 ng/mL to 29 ng/mL) Individuals receiving a single oral dose of controlled release capsules or a single intravenous _{dose of 448 µg 25-hydroxyvitamin D 3 in ethanol solution} Inner dose, the capsule contains 450 µg or 900 µg 25-hydroxyvitamin D ₃ , 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 (compare formulation 3). None of the formulations contain cellulose compounds. The serum concentration of 25-hydroxyvitamin D ₃ gradually increased after the oral dose was administered. The increase in 25-hydroxyvitamin D ₃ was dose-proportional and reached 32 ng/mL (approximate average maximum value (Cmax) observed in serum concentration) after administration of 900 µg capsules. The time to Cmax (Tmax) is approximately 13 hours after administration. In contrast, the concentration of 25-hydroxyvitamin D ₃ increased rapidly after intravenous administration. Immediately after intravenous administration (Tmax = 0.5 hours), the maximum serum content was reached and reached an approximate average Cmax of 134 ng/mL. The bioavailability of the oral dose is about 6 to 11%. The terminal half-life (t _1/2 ) of 25-hydroxyvitamin D ₃ after oral administration is about 12 to 22 days. No adverse effects on serum calcium or phosphorus or urine calcium were observed in any treatment group. The average serum total 1,25-dihydroxyvitamin D amount increased rapidly after intravenous injection and increased by about 13 pg/mL from the pretreatment baseline 6 hours after administration. In contrast, the average serum total 1,25-dihydroxyvitamin D amount increased by approximately 7 pg/mL after the administration of 900 µg capsules and 48 hours after administration. Serum iPTH showed no meaningful change in the first 96 hours after intravenous administration. In contrast, serum PTH gradually decreased after administration, reaching a maximum inhibition of approximately 20% from the pretreatment baseline for individuals receiving 900 µg capsules. The pharmacokinetic parameters observed for all treatment groups are summarized in the table below.

The baseline adjusted pharmacokinetic parameters of all treatment groups are summarized in the table below.

In Study B, 20 healthy individuals with a 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 stabilized controlled release capsules Or a single intravenous dose of 448 µg 25-hydroxyvitamin D _{3 in} ethanol solution, the capsule contains 900 µg 25-hydroxyvitamin D ₃ , 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). _{Compared with intravenous administration, the gradual increase in 25-hydroxyvitamin D 3} content after administration of the stabilized oral formulation is shown by the prolonged Tmax. The pharmacokinetic profile after administration of the stabilized oral formulation showed a _{gradual increase in the concentration of 25-hydroxyvitamin D 3} , with an average Tmax of 28 hours, while avoiding a rapid increase in blood content in most individuals. Administration by intravenous administration resulted in a rapid increase in the concentration _{of 25-hydroxyvitamin D 3 in all individuals. The significant difference in C max} observed between the treatment groups highlights the avoidance of the rapid increase in _{25-hydroxyvitamin D 3 content.} Compared with the Cmax of 153 ng/mL after intravenous administration, the Cmax after oral administration was 58 ng/mL. _{The exposure of 25-hydroxyvitamin D 3} after administration of the controlled release capsule is about two times smaller than that after intravenous administration, although oral administration is about twice as high, resulting in about 25% bioavailability. t _1/2 , elimination rate (CL) and volume distribution (Vd) showed similarity between treatment groups. The values of t _1/2 and CL are in line with the reported extended elimination _{of 25-hydroxyvitamin D 3.} In addition, the Vd value indicates that 25-hydroxyvitamin D _{3 is} maintained in the systemic circulation and may be highly bound to DBP. The pharmacokinetic parameters observed for all treatment groups are summarized in the table below.

The baseline adjusted pharmacokinetic parameters of all treatment groups are summarized in the table below.

Modified release formulations studies have shown that 25-hydroxy vitamin D ₃ The rate of absorption of the stabilized control, resulting in a more gradual increase in the serum 25-hydroxy vitamin D ₃ content while maintaining the 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 unstabilized formulation. In Study C, 78 patients had stage 3 CKD (eGFR 25-70 mL/min/1.73 m ² ), SHPT (> 70 pg/mL plasma iPTH) and vitamin D deficiency (total baseline 25-hydroxyvitamin D in serum) Individuals from 10 ng/mL to 29 ng/mL) receive daily oral doses of stabilized controlled release formulations or receive a placebo for 6 weeks, these formulations containing 30 µg, 60 µg, or 90 µg 25-hydroxy Vitamin D ₃ , 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 (from the example of Example 2 Formulations C, D and E). The average baseline serum 25-hydroxyvitamin D ₃ concentration of all treatment groups was compared, and it was in the range of about 16 to 20 ng/mL. By 25-hydroxyvitamin D ₃ after treatment, the mean serum 25-hydroxy vitamin D ₃ content of the gradual increase in the daily and repeated after ₃ to increase the administered dose-proportional manner of 25-hydroxyvitamin D, and 6 weeks after Close to steady state (Figure 4). For the 30 µg, 60 µg, and 90 µg 25-hydroxyvitamin D ₃ groups, the average baseline adjusted Cmax values were approximately 28, 60, and 86 ng/mL, respectively. In all dose groups, as _{assessed by background adjusted AUC 0-6} weeks, the average exposure of 25-hydroxyvitamin D ₃ is proportional to the dose. According to the final dose, the average serum 25-hydroxyvitamin D ₃ content decreased slowly, but at the end of the study all groups remained above baseline. The average t _{1/2 has} been determined to be approximately between 25 and 50 days. The baseline adjusted pharmacokinetic parameters of 25-hydroxyvitamin D ₃ are summarized in the table below.

The average baseline serum 1,25-dihydroxyvitamin D concentration of all treatment groups was compared and the concentration gradually increased, similar to the effect produced _{on the serum 25-hydroxyvitamin D 3 concentration.} The mean ±SD baseline-adjusted Cmax values of the 60 µg and 90 µg groups were higher than those of the placebo and 30 µg groups (5.7±6.35 and 6.4±7.66 ng/mL, respectively) (18.4±6.24 and 19.9± 14.30 ng/mL). In the 25-hydroxyvitamin D ₃ dose group, as assessed by baseline-adjusted AUC _0-6 weeks, the average exposure of 1,25-dihydroxyvitamin D is proportional to the dose. The baseline-adjusted pharmacokinetic parameters of 1,25-dihydroxyvitamin D are summarized in the table below.

Compared with placebo, in significantly more individuals in all active groups, _{the stabilized controlled release formulation of 25-hydroxyvitamin D 3} increased the total serum 25-hydroxyvitamin D content to ≥ 30 ng/mL. Similarly, the stabilized formulation in all dose groups resulted in a significant reduction in mean plasma iPTH from baseline compared to placebo. _{The 25-hydroxyvitamin D 3} administered daily in the stabilized controlled release formulation increases the average serum total 25-hydroxyvitamin D, and the increase is proportional to the dose. The lowest dose (30 µg) increases the total serum 25-hydroxyvitamin D from the pretreatment baseline (21.7±1.8 ng/mL) by 15.6±1.7(SE) ng/mL at the end of treatment, and the highest dose (90 µg) Increase the total serum 25-hydroxyvitamin D from 21.8±1.2 ng/mL by 61.1±6.1 ng/mL. In contrast, in the combined placebo group, a decrease was observed at the end of the 1.2±0.7 ng/mL treatment. For all three doses studied, the difference between the treatment group and the placebo group was significant (p<0.0001). At the end of the treatment, the average serum 25-hydroxyvitamin D content in the 30 µg dose group was 37.3±1.8 ng/mL (slightly higher than the minimum appropriate content of 30 ng mL prescribed by K/DOQI), indicating that 30 µg is the minimum effective dose. Compared with 0% in the placebo group, in the 30 µg, 60 µg, and 90 µg dose groups, the percentage of treated individuals who achieved a total serum 25-hydroxyvitamin D content of ≥30 ng/mL at the end of treatment was 92.3%, 100.0% and 100.0%. The difference in these response rates between the active and placebo treatments was significant (p<0.001). The average plasma iPTH at the end of the treatment decreased in proportion to the dose of _{25-hydroxyvitamin D 3 administered.} The lowest dose (30 µg) reduced iPTH from the pretreatment baseline by 20.2±5.8(SE)%, 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 the treatment. For all three doses studied, _{the difference between the 25-hydroxyvitamin D 3} group and the placebo group was significant (p<0.005), and it was beneficially compared with the use of more effective and blood calcium oral vitamin D hormone replacement Therapies (such as docalcitol, paricalcitol, and calcitriol) compared to the differences observed with longer treatments in placebo-controlled studies. _{The percentage of individuals receiving 25-hydroxyvitamin D 3} who confirmed that iPTH had decreased from the baseline of pretreatment (ie, two consecutive measurements) by at least 20% or 30% at the EOT increased after the end of the dose of 60 µg. Similar response rates were observed in the 60 and 90 µg treatment groups, indicating that no other benefit in reducing iPTH was observed for the 90 µg dose in this study. Compared with 9.7% in the combined placebo group, for the 30 µg, 60 µg, and 90 µg dose groups, the response rates for confirming a 20% reduction in iPTH were 38.5%, 70.6%, and 76.5%, respectively. The difference in response rate observed for a 20% reduction was only significant for the 60 µg and 90 µg dose groups (p<0.005) and was significant for a 30% reduction in all three dose groups (p<0.05). The data supports the conclusion that 30 µg per day of 25-hydroxyvitamin D ₃ in a stabilized controlled release formulation is the minimum effective dose. The stabilized formulation of 25-hydroxyvitamin D ₃ has no clinically significant effect on corrected albumin-corrected serum calcium, serum phosphorus and urinary calcium excretion. There is no adverse effect on serum calcium or serum phosphorus or urine calcium during the 6-week treatment period. Pharmacokinetic analysis revealed in all three dose groups, 25-hydroxy Vitamin D ₃ by the stability of formulations over 6 weeks to increase the 25-hydroxyvitamin D and ₃ dose-proportional mode of exposure (AUC and C _max), There is no difference in t _1/2. After 6 weeks of administration, the three treatment groups have not yet fully reached a steady state. However, the steady state model showed that steady state should have been reached by 7-9 weeks in all dose groups. The data from this study clearly show that _{the stabilized controlled release formulation of 25-hydroxyvitamin D 3} is effective in increasing the total serum 25-hydroxyvitamin D to the minimum appropriate level of 30 ng/mL and reducing plasma iPTH. The study also showed that _{the stabilized formulation of 25-hydroxyvitamin D 3 at} the studied dose has no clinically practical effect on serum calcium or phosphorus. Example 4 : Modification of the pharmacokinetic and pharmacodynamic characteristics of calcifediol release in CKD individuals with secondary hyperparathyroidism and vitamin D deficiency ₃ (Calcifediol, 25D ₃ ) capsules are multi-center, randomized, double-blind, placebo-controlled, repeated dose, safety, efficacy, and PK/PD studies. For this study, recruit patients with stage 3 CKD (eGFR 25-70 mL/min/1.73 m ² ), vitamin D deficiency (serum 25-hydroxyvitamin D ≥ 10 and ≤ 29 ng/mL), SHPT (plasma iPTH ＞ 70 pg/mL) and male and female individuals aged 18 to 85 who do not require regular hemodialysis. Eligible individuals in the first group were randomly divided into 3 treatment groups at a ratio of 1:1:1: the two groups received capsules at a daily oral dose of 60 or 90 μg, and one group received matched placebo capsules. Individuals in the second group were randomly divided into two treatment groups at a 1:1 ratio: one group received 30 μg capsules per day and the other group received placebo. Individuals in each group completed the 6-week treatment and entered the 6-week follow-up period, during which PK and PD samples were collected every week. _{Serum calcium (Ca), phosphorus (P), 25D 3} , total 1,25-dihydroxyvitamin D (1,25D) and plasma iPTH were monitored weekly during the 6-week treatment and 6-week follow-up period. The ANCOVA model examines the association between 25D ₃ exposure and baseline changes from 1, 25D and iPTH. The covariates included are baseline eGFR, weight and height, gender, age, race, diabetes status, and baseline concentration of 1,25D or iPTH. Figure 4 shows the average baseline-adjusted calcifediol concentration obtained by the treatment group (PK group). The average content of serum calcifediol gradually increased in proportion to the dose and began to approach steady state after 6 weeks. After 6 weeks of follow-up, the content decreased in all active agent treatment groups but remained above baseline. Figure 5 shows a summary of baseline-adjusted PK parameters of the calcifediol concentration obtained by the treatment group (PK group). Figure 6 shows the average baseline-adjusted serum 1,25-dihydroxyvitamin D content obtained during the 6-week treatment period (PK group). Compared with those individuals who were administered a placebo, in those individuals who were administered the active agent capsules, the average baseline-adjusted serum total 1,25 dihydroxyvitamin D content increased over time. Figure 7 shows a summary of baseline-adjusted repeated dose PK parameters of serum 1,25-dihydroxyvitamin D obtained by the treatment group (PK group). Figure 8 shows the baseline mean percentage of plasma iPTH levels obtained during the 6-week treatment (PK cohort). Compared with the 17% increase in the combined placebo group, the active agent capsules in all dose groups (30, 60, and 90 µg) significantly reduced mean plasma iPTH from baseline by 21%, 33%, and 39%, respectively. Figure 9 shows a summary of the baseline-adjusted repeated dose PK parameters of plasma iPTH obtained by the treatment group (PK group). Figures 10 and 11 show the percentage of plasma iPTH in the PK group at EOT relative to the baseline-adjusted _calcifediol and 1,25-dihydroxyvitamin D exposure (AUC 0-6wk) from baseline. The percentage of plasma iPTH decrease from baseline to EOT increased with the increase in serum calcidiol and total 1,25 dihydroxyvitamin D exposure (expressed as baseline adjusted AUC _0-6wk ) during the treatment period. The stable and sustained release of 25-hydroxyvitamin D ₃ capsules normalized 25D content in most individuals and significantly reduced iPTH in all dose groups (30, 60 and 90 µg). After stable and sustained release of 25-hydroxyvitamin D ₃ capsules, the serum 25D ₃ and serum 1,25D content gradually increased, and the exposure increased in a dose-dependent manner. Both 25D ₃ and total 1,25D exposure were significant and negatively correlated with the change in plasma iPTH from baseline. Only eGFR is a significant covariate in the two models. These results show that the stable and sustained release 25-hydroxyvitamin D ₃ capsules can reliably normalize 25D content, increase serum 1,25D content, and inhibit the increase of plasma iPTH without producing serum Ca and P during the dose study. The effect of clinical significance. *** Given that the above description is only for clear understanding, and should not be interpreted as an unnecessary limitation, it is also obvious to those skilled in the art that modifications within the scope of the present invention can be made. Throughout this specification and subsequent patent applications, unless otherwise specified herein, the term "comprise" and variants (such as "comprises/comprising") should be understood as implying the inclusion of the whole or step Or a whole or a group of steps but does not exclude any other whole or a step or a step or a whole or a group of steps. Throughout this specification, unless otherwise described, the composition is described as including components or substances, and the composition is intended to also consist essentially of or consist of any combination of said components or substances. Likewise, unless described in other ways, the method is described as including specific steps, and it is intended that the method may also consist essentially of or consist of any combination of the steps. In the absence of any elements or steps that are not specifically disclosed herein, the present invention illustratively disclosed herein can be suitably practiced. The practice of the method disclosed herein and its individual steps can be performed manually and/or by means of electronic equipment. Although the manufacturing process has been described with reference to specific embodiments, it will be easy for those of ordinary skill to understand that other methods related to these methods can be used to perform actions. For example, unless described in other ways, the order of various steps can be changed without departing from the scope or spirit of the method. In addition, some of the individual steps can be combined, omitted or further subdivided into other steps. All patents, publications and references cited in this article are hereby incorporated by reference in their entirety. In the event of a conflict between the present invention and the incorporated patents, publications and references, the present invention shall be controlled. In view of the foregoing description, the covered embodiments include those described in the numbered paragraphs below. 1. A controlled-release formulation of vitamin D compounds comprising _{one or both of 25-hydroxyvitamin D 2} and 25-hydroxyvitamin D ₃ , the formulation comprising a matrix capable of releasable binding and controlled release of vitamin D compounds, The matrix contains cellulose derivatives. 2. A stabilized formulation for the controlled release of vitamin D compounds in the gastrointestinal tract of an individual ingesting the formulation, the formulation comprising a mixture of: one of 25-hydroxyvitamin D ₂ and 25-hydroxyvitamin D ₃ One or both; and an effective amount of stabilizer, which is a cellulosic compound as the case may be, so that the in vitro dissolution period after exposure to storage conditions of 25°C and 60% relative humidity for two months, after four hours The difference between the amount of vitamin D compound released at any given time point and the amount released during the in vitro dissolution before exposing the formulation to storage conditions at the same dissolution time point remains less than 30%. 3. A stabilized formulation for the controlled release of vitamin D compounds, the formulation comprising a mixture of: one or both of _{25-hydroxyvitamin D 2} and 25-hydroxyvitamin D _{3; wax base;} And stabilizers, which are optionally cellulose compounds. 4. A stabilized formulation for the controlled release of vitamin D compounds in the gastrointestinal tract of an individual ingesting the formulation, the formulation comprising a mixture of: one of 25-hydroxyvitamin D ₂ and 25-hydroxyvitamin D ₃ 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: _{one or both of 25-hydroxyvitamin D 2} and 25-hydroxyvitamin D ₃ ; wax base; and An effective amount of stabilizer, which is a cellulosic compound as the case may be, so that during the in vitro dissolution test after two months of exposure to storage conditions of 25°C and 60% relative humidity, at any given time point after four hours The difference between the amount of vitamin D compound released and the amount released at the same dissolution time point during the in vitro dissolution performed before exposing the formulation to storage conditions is maintained to be less than 30%. 6. A stabilized formulation for the controlled release of vitamin D compounds in the gastrointestinal tract of an individual ingesting the formulation, the formulation comprising a mixture of the following: an active loaded wax matrix containing 25-hydroxyvitamin D ₂ and 25 -One or both of hydroxyvitamin D ₃ ; and cellulose stabilizer; wherein the formulation releases a certain amount of 25-hydroxy during in vitro dissolution after being stored at 25°C and 60% relative humidity for two months Vitamin D, in the absence of a cellulose stabilizer, the release amount is compared with the release amount at the same dissolution time point during in vitro dissolution before exposing the formulation to storage conditions, at any given The time of dissolution changes by 30% or less than 30%. 7. In formulations for the controlled release of vitamin D compounds in the gastrointestinal tract of an individual ingesting the formulation, the improvement includes the incorporation of a cellulose stabilizer into the formulation. 8. In formulations for the controlled release of vitamin D compounds in the gastrointestinal tract of individuals ingesting the formulation, the improvement includes mixing a cellulosic compound into the formulation so that it is exposed to 25°C and 60% relative humidity. During the in vitro dissolution period after storage conditions for at least one month, the amount of 25-hydroxyvitamin D released at any given dissolution time point after four hours, and the amount of 25-hydroxyvitamin D released before exposing the formulation to the 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 comprises cellulose ether. 10. The formulation of paragraph 9, wherein the cellulose ether is selected from the group consisting of methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose The group. 11. The formulation of paragraph 9, wherein the cellulose compound or cellulose stabilizer is hydroxypropyl methylcellulose. 12. The formulation of any of the preceding paragraphs, wherein the formulation releases a certain amount of 25-hydroxyvitamin D during in vitro dissolution after being exposed to storage conditions of 25°C and 60% relative humidity for two months. Comparing the release amount at the same dissolution time point during the in vitro dissolution performed before exposing the formulation to storage conditions, the release amount changes by 30% or less than 30% at any given dissolution time point after four hours. 13. The formulation of any of the preceding paragraphs, wherein the formulation releases a certain 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. Compared to the release amount at the same dissolution time point during the in vitro dissolution of the formulation before being exposed to storage conditions, the release amount changes by 30% or less than 30% at any given dissolution time point after four hours. 14. The formulation of any of the preceding paragraphs, wherein the matrix comprises a wax matrix, and the wax matrix comprises a controlled release agent, an emulsifier, and an absorption enhancer. 15. The formulation of paragraph 14, wherein the controlled release agent comprises paraffin. 16. The formulation of paragraph 14 or 15, wherein the emulsifier has an HLB value less than 7. 17. The formulation of paragraph 16, wherein the emulsifier comprises 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 polyglycerol dodecanoate and polyoxyglycerol dodecanoate. 20. The formulation of any one of the preceding paragraphs, wherein the vitamin D compound comprises 25-hydroxyvitamin D ₃ . 21. The formulation of any one of the preceding paragraphs, which further comprises an oily vehicle. 22. The formulation of paragraph 21, wherein the oily vehicle comprises mineral oil. 23. The formulation of paragraph 22, wherein the formulation comprises about 20 wt% paraffin wax, about 20 wt% to about 25 wt% glyceryl monostearate, about 10 wt% lauryl polyethylene glycol glyceride, and A mixture of polyoxyglycerides of dodecanoic acid, about 30 wt% to about 35 wt% of mineral oil, and about 10 wt% to about 15 wt% of hydroxypropyl methylcellulose. 24. The formulation of any of the preceding paragraphs, wherein the formulation comprises glyceryl monostearate. 25. The formulation of any of the preceding paragraphs, wherein the formulation comprises one or more PEGylated glycerides. 26. Sustained release dosage forms in the form of capsules, lozenges, sachets, dragees or suppositories comprise the formulation of any of the preceding paragraphs. 27. The dosage form of paragraph 26, which comprises a capsule or a lozenge. 28. The dosage form of paragraph 27, which comprises a capsule. 29. The dosage form of paragraph 26, which comprises oral capsules, lozenges, sachets, and dragees. 30. A stabilized dosage form as in any of the preceding paragraphs, characterized in that it provides the following release of vitamin D compound with a dissolution profile of less than 30% at 2 hours; greater than 45% at 6 hours; and greater than at 12 hours 80%. 31. The stabilized dosage form of paragraph 26, wherein the release of the vitamin D compound at 6 hours is less than 60%. 32. A stabilized sustained-release oral dosage form containing a vitamin D compound, characterized in that it provides the following release of the vitamin D compound in vitro dissolution characteristics of less than 30% at 100 to 140 minutes; greater than 45% at 5 to 7 hours ; And greater than 80% from 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. The dosage form of paragraph 32 or 33, wherein the release of the vitamin D compound is less than 60% in 5 to 7 hours. 35. The dosage form of paragraph 34, wherein the release of the 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 the following release of the vitamin D compound in vitro dissolution profile of 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, wherein the release of the vitamin D compound is about 25% to about 35% at 2 hours; 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 containing a vitamin D compound, characterized in that t _{max is} at least 4 hours after the dosage form is administered to a human patient. 42. The dosage form of paragraph 41, wherein t _{max is} at least 8 hours. 43. The dosage form of paragraph 42, wherein t _{max is} at least 12 hours. 44. The dosage form of paragraph 43, wherein t _{max is} at least 18 hours. 45. The dosage form of paragraph 44, wherein t _{max is} at least 20 hours. 46. The dosage form of paragraph 45, wherein t _{max is} at least 24 hours. 47. The dosage form of paragraph 46, wherein t _{max is} at least 28 hours. 48. The dosage form of paragraph 41, wherein t _{max is} in the range of 4 to 96 hours. 49. The dosage form of paragraph 48, wherein t _{max is} in the range of 18 to 30 hours. 50. The dosage form of paragraph 49, wherein t _{max is} in the range of 13 to 28 hours. 51. The dosage form of paragraph 50, wherein _tmax is about 28 hours. 52. A stabilized comprising a compound of the 25-hydroxy vitamin D sustained release dosage form characterized by providing per microgram of 25-hydroxyvitamin D baseline-adjusted C _max was, when administered to an adult, the C _max of about 0.0133 ng/mL to about 0.04 ng/mL. 53. A method for administering to a human patient a stabilized sustained-release dosage form comprising a 25-hydroxyvitamin D compound, which comprises 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 _{C max} after baseline adjustment. 54. The method of paragraph 53, which comprises administering an effective amount of the dosage form to provide a baseline adjusted _{Cmax in the} range of about 0.2 to about 24 ng/mL. 55. A method of administering to a human patient a stabilized sustained-release dosage form comprising a 25-hydroxyvitamin D compound, which comprises 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 0-inf of} ng*h/mL. 56. The method of paragraph 55, which comprises administering to the patient an effective amount of the dosage form to provide a baseline adjusted AUC _{0-inf in the} range of about 52 ng*h/mL to about 12,000 ng*h/mL. 57. A method of vitamin D supplementation, which comprises administering to an individual who needs the formulation or dosage form of any one of the preceding paragraphs. 58. A method of treating or preventing a vitamin D-responsive disease in an individual, which comprises administering to the individual the formulation or dosage form of any one of the preceding paragraphs. 59. The method of paragraph 58, wherein the disease is selected from cancer (such as breast, lung, skin, melanoma, colon, colorectal, rectal, prostate, and bone cancer), autoimmune diseases (such as type I diabetes, multiple Sclerosis, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma, fibrosis, Grave's disease, Hashimoto's disease, acute or chronic transplant rejection, acute or chronic graft resistance Host disease, inflammatory bowel disease, Crohn's disease, systemic lupus erythematosus, Schuglen's syndrome, eczema and psoriasis, dermatitis (including atopic dermatitis, contact dermatitis, allergic dermatitis and / Or chronic dermatitis), inflammatory diseases (e.g. asthma, chronic obstructive pulmonary disease, polycystic kidney disease, polycystic ovary syndrome, pancreatitis, nephritis, hepatitis and/or infection), hypertension, cardiovascular disease (individual Suffering from 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, dyslipidemia of hypo-α-lipoproteinemia, hypertriglyceridemia, hypercholesterolemia, and low HDL (high density lipid) Protein)), metabolic disorders (e.g. metabolic syndrome, type II diabetes, type I diabetes, hyperinsulinemia, impaired 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 (i) parathyroid-parathyroid hypothyroidism, pseudoparathyroid hypothyroidism, secondary parathyroid hyperenergy (Ii) in the form of pancreatic diabetes; (iii) in the form of medullary thyroid carcinoma; (iv) in the form of skin psoriasis; wound healing; (v) in the form of pulmonary sarcoidosis and tuberculosis; (vi) in the form of Renal chronic kidney disease, low phosphate VDRR, vitamin D-dependent rickets; (vii) in the form of bone anticonvulsant therapy, bone fibrogenesis, cystic fibrous osteitis, rickets, osteoporosis, osteopenia, osteosclerosis , Renal osteodystrophy, rickets; (viii) in the form of intestinal glucocorticoid antagonism, spontaneous hypercalcemia in infancy, malabsorption syndrome, steatorrhea, tropical stomatitis; and (ix) autoimmune Disease 61. The method of paragraph 60, wherein the disease is selected from cancer, skin disorders (such as psoriasis), parathyroid disorders (such as hyperparathyroidism and secondary hyperparathyroidism), bone disorders (such as osteoporosis) 62. The method of paragraph 61, wherein the disease is secondary hyperparathyroidism. 63. The method of paragraph 62, wherein the individual has chronic kidney disease (CKD). 64. The method of paragraph 63, The CKD is stage 3 or 4. 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. 67. The method of paragraph 66, in which humans are adults. 68. A composition substantially as described herein.

Figure 1 shows the dissolution characteristics of the formulation of the present invention after storage at 25°C and 60% relative humidity for 0 to 24 months. The dissolution time in hours is plotted on the X axis, and the average percentage _{of 25-hydroxyvitamin D 3 dissolved on the Y axis is shown.} Figures 1A, 1B, and 1C show the dissolution characteristics of formulations containing 30 µg, 60 µg, and 90 µg 25-hydroxyvitamin D _{3, respectively.} Figure 2 shows the dissolution characteristics of the formulation of the present invention after storage at 40°C and 75% relative humidity for 0 to 6 months. The dissolution time in hours is plotted on the X axis, and the average percentage _{of 25-hydroxyvitamin D 3 dissolved on the Y axis is shown.} Figures 2A, 2B, and 2C show the dissolution characteristics of formulations containing 30 µg, 60 µg, and 90 µg 25-hydroxyvitamin D _{3, respectively.} Figure 3 shows the dissolution characteristics of the formulation of the present invention after storage at 25°C and 60% relative humidity for 0 to 12 months. The dissolution time in hours is plotted on the X axis, and the average labeled amount _{of 25-hydroxyvitamin D 3 released is displayed on the Y axis.} Figure 3A shows the dissolution characteristics of a comparative formulation that does not contain a cellulose compound. Figure 3B shows the dissolution characteristics of the stabilized formulation of the present invention. Figure 4 shows the average baseline adjusted calcifediol concentration obtained by the treatment group (PK group) of the patients described in Example 4 who were treated with the formulation of the present invention. Figure 5 shows the summary baseline adjusted PK parameters of the calcifediol concentration obtained by the treatment group (PK group) of the patients described in Example 4 who were treated with the formulation of the present invention. Figure 6 shows the average baseline adjusted serum 1,25-dihydroxyvitamin D levels obtained during 6 weeks of treatment (PK group) of the patients described in Example 4 who were treated with the formulation of the present invention. Figure 7 shows a summary of the PK parameters of the baseline-adjusted repeated doses of serum 1,25-dihydroxyvitamin D in the treatment group (PK group) of the patients described in Example 4, these patients undergoing the formulation of the present invention deal with. Figure 8 shows the average baseline percentage of plasma iPTH obtained during 6 weeks of treatment (PK group) of the patients described in Example 4 who were treated with the formulation of the present invention. Figure 9 shows a summary of the baseline-adjusted PK parameters of the resulting baseline-adjusted repeated doses of plasma iPTH by the treatment group (PK group) of patients described in Example 4 who were treated with the formulation of the present invention. Figures 10 and 11 show the exposure of plasma iPTH to baseline-adjusted calcifediol and 1,25-dihydroxyvitamin D in the PK group of patients treated with the formulation of the present invention described in Example 4 at EOT (AUC _0-6wk ) The percentage change from baseline.

Claims (23)

A stabilized formulation for sustained release of vitamin D compounds, the formulation comprising a mixture of: _{one or both of 25-hydroxyvitamin D 2} and 25-hydroxyvitamin D ₃ ; and a stabilizer, which Contains materials selected from the group consisting of cellulose compounds, poloxamers, poly(ethylene oxide) polymers, povidones, aerosol silica and combinations thereof, wherein the The stabilizer is present in an amount of at least about 5% to 30% (wt%) of the formulation based on the total weight of the formulation excluding any other coatings or shells, which is effective when exposed to 25°C and 60% relative humidity The amount of vitamin D compound released at any given time during the in vitro dissolution period after two months after two months is the same as the amount of vitamin D compound released during the in vitro dissolution period before exposing the formulation to the storage conditions The difference between the release amounts at the time of dissolution is maintained to be less than 30%. Such as the formulation of claim 1, which comprises a matrix capable of releasably binding and controlling the release of one or both of _{the 25-hydroxyvitamin D 2} and 25-hydroxyvitamin D _3. The formulation of claim 1 or 2, which comprises a lipophilic base containing one or both of _{the 25-hydroxyvitamin D 2} and 25-hydroxyvitamin D _3. The formulation of claim 3, wherein the lipophilic base comprises wax. Such as the formulation of claim 1 or 2, wherein the formulation is used for ingesting the formulation Oral formulations for sustained release of vitamin D compounds in the body’s gastrointestinal tract. The formulation of claim 1 or 2, wherein the stabilizer comprises a cellulose compound. The formulation of claim 6, wherein the cellulose compound comprises cellulose ether. The formulation of claim 7, wherein the cellulose ether comprises one of methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose Or more. The formulation of claim 8, wherein the cellulose ether comprises hydroxypropyl methylcellulose. The formulation of claim 1 or 2, wherein the vitamin D contains 25-hydroxyvitamin D ₃ . A stabilized formulation for sustained release of vitamin D compounds, the formulation comprising a mixture of: _{one or both of 25-hydroxyvitamin D 2} and 25-hydroxyvitamin D ₃ ; a non-wax base; and A stabilizer, which includes a material selected from the group consisting of: cellulose compound, poloxamer, poly(ethylene oxide) polymer, povidones, aerosol silica and its combination. A sustained-release dosage form in the form of capsules, tablets, sachets, sugar-coated pills or suppositories Formula, the dosage form contains the formulation according to any one of claims 1 to 11. The sustained-release dosage form of claim 12, wherein the dosage form contains 5 to 80 μg of 25-hydroxyvitamin D ₃ . The sustained-release dosage form of claim 13, wherein the dosage form contains 30 μg or 60 μg of 25-hydroxyvitamin D ₃ . A use of the formulation according to any one of claims 1 to 11, which is used for the preparation of medicines for the treatment of vitamin D-responsive diseases in patients. A use of the sustained-release dosage form according to any one of claims 12 to 14, which is used to prepare medicines for the treatment of vitamin D-responsive diseases in patients. The use of claim 15 or 16, wherein the vitamin D-responsive disease: (a) is selected from cancer, skin disease, parathyroid disease, skeletal disease, and autoimmune disease; or (b) is selected from psoriasis , Hyperparathyroidism, secondary hyperparathyroidism and osteoporosis; or (c) secondary hyperparathyroidism. Such as the use of claim 15 or 16, wherein the patient: (a) suffers from chronic kidney disease (CKD); or (b) have chronic kidney disease stage 3 or 4; or (c) have chronic kidney disease stage 3 or 4 and vitamin D deficiency; or (d) have chronic kidney disease stage 3 or 4 and vitamin D deficiency. Such as the use of claim 15 or 16, wherein the vitamin D-responsive disease is secondary hyperthyroidism of chronic kidney disease. Such as the use of claim 19, wherein the vitamin D-responsive disease is secondary hyperthyroidism of stage 3 or 4 chronic kidney disease. Such as the use of claim 15 or 16, wherein the patient is: (a) human; or (b) adult. Such as the use of claim 15 or 16, wherein the medicine contains 25-hydroxyvitamin D _{3 in} a daily dose of 5 to 80 μg. Such as the use of claim 22, wherein the medicine contains 25-hydroxyvitamin D _{3 in} a daily dose of 30 μg or 60 μg.

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