TW201934117A - 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 method of taking the same

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

Vitamin D metabolites called 25-hydroxyvitamin D ₂ and 25-hydroxyvitamin D ₃ (collectively "25-hydroxyvitamin D") are fat-soluble 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 (cholcalciferol), which is produced mainly by one or more enzymes located in the liver . Two prohormones can also be produced from vitamin D ₂ and vitamin D ₃ (collectively referred to as "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. 25-hydroxyvitamin D pre-hormones are further metabolized in the kidneys into effective vitamin D hormones. The pro-hormone 25-hydroxyvitamin D _{2 is} metabolized to 1α, 25-dihydroxyvitamin D ₂ ; likewise, 25-hydroxyvitamin D _{3 is} metabolized to 1α, 25-dihydroxyvitamin D ₃ (calcitriol). The production of these active hormones from the 25-hydroxyvitamin D prohormone can also occur in cells containing the desired enzyme (class) outside the kidney. 25-hydroxyvitamin D ₂ and / or 25-hydroxyvitamin D ₃ controlled release formulations can be administered for the treatment of 25-hydroxyvitamin D deficiency and deficiency without the presence of 25 in the lumen, cells and blood -A hyperphysiological surge in hydroxyvitamin D content and its consequences; does not substantially cause an increase in the metabolism of the 25-hydroxyvitamin D administered; and does not cause serious side effects related to vitamin D supplementation, namely vitamin D toxicity. Controlled release formulations effectively reduce the amount of PTH without causing unwanted increases in serum calcium and serum phosphorus and are therefore suitable for use in the treatment of, for example, recurrent paraparathyroidism in patients with CKD. See International Patent Application Nos. PCT / US2007 / 061521 and PCT / US2008 / 061579 and US 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 that the blood level of 25-hydroxyvitamin D is maintained substantially constant during the 24-hour period of administration. By providing a gradual, sustained, and direct release of 25-hydroxyvitamin D ₂ / 25-hydroxyvitamin D ₃ , and preferentially absorbed by circulating DBP (not chylomicrons), 25 in blood, intraluminal and intracellular -A sharp increase in the concentration of hydroxyvitamin D can also reduce or eliminate paraphysiological amounts and related undesired metabolism. In addition, by providing gradual and sustained release, the serum content of 25-hydroxyvitamin D can be more predictably increased and maintained compared to the administration of immediate release formulations, thereby allowing for consistent dosage and reducing or eliminating the need for frequent patient monitoring . In order to deliver the benefits of a 25-hydroxyvitamin D controlled release formulation to a patient, a stable pharmaceutical composition is needed that maintains the desired dissolving properties of the formulation for an extended period of time, such as after shipping and storage.

The present invention includes a controlled release vitamin D formulation comprising a vitamin D compound and a cellulose compound. The invention also includes 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 comprises one or both of 25-hydroxyvitamin D ₂ and 25-hydroxyvitamin D ₃ and a stabilizer or a stabilizing compound (such as a cellulose compound). When compared to the disclosed formulations that do not contain such agents, the stabilized formulations of the present invention and the stabilizers may have improved or relatively improved "storage stability" or post-aging stability , And one or more other characteristics including improved physical, chemical, and biological properties. Compared to aging, unstable formulations, the claimed formulations are 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 , a lipophilic matrix (such as a wax matrix), and a stabilizer (such as a cellulose compound). . In one aspect, the stabilized formulation includes one or both of 25-hydroxyvitamin D ₂ and 25-hydroxyvitamin D ₃ , a wax matrix, 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 matrix, and an effective amount of a cellulose compound to maintain the stabilization benefits described herein. Degree. In one embodiment, the stabilized formulation comprises an active-loaded wax matrix mixture comprising one or both of 25-hydroxyvitamin D ₂ and 25-hydroxyvitamin D ₃ and a cellulose stabilizer, wherein During in vitro dissolution during storage conditions of at least one month at 25 ° C and 60% relative humidity, the formulation releases a certain amount of 25-hydroxyvitamin D, the same dissolution time as in vitro dissolution performed on fresh products Compared with the release amount at the point, the release amount changed by 30% or less at all the dissolution test time points. In one embodiment, the formulation is an improved formulation for controlled release of a vitamin D compound. In one aspect, the improvement comprises incorporating a stabilizer into the formulation for controlled release of the vitamin D compound in the gastrointestinal tract of an individual ingesting the formulation. In another aspect, the improvement comprises mixing an effective amount of a cellulose 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 advantageous stability described herein. In one embodiment, the present invention comprises 25 comprising _2-hydroxy vitamin D or a combination _{thereof. 3} and sustained release of the sustained release excipient stabilization of vitamin D 25-hydroxy vitamin D formulation, wherein the formulation has at T ₀ The dissolution characteristic X, which is maintained according to the formula X = T ₀ +/- 30% through storage conditions selected from, for example, room temperature and ambient humidity, or 25 ° C and 60% RH, or 40 ° C and 75% RH. The following summary of the [embodiment] adopted by the self-combination scheme will be apparent to other skilled persons in other aspects and advantages. Although the compositions and methods are susceptible to different forms of examples, the following description includes specific examples, with the understanding that the disclosure is illustrative and is not intended to limit the invention to the specific examples described herein. The compositions and methods (optional features) described herein including, but not limited to, the components, their composition ranges, substitutions, conditions, and steps are expected to be selected from various aspects, embodiments, and examples provided herein.

Cross-reference to related applications This article claims the benefit of 35 U.S.C. § 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 that departs from 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 compared to comparable immediate release formulations, resulting in a comparable to The serum concentration of the vitamin D compound remained elevated above baseline for a longer period than the immediate release formulation. The foregoing terms optionally include delayed release characteristics. For example, a delayed release type of controlled release formulation will_max Greater than C for immediate release formulation_max Characterization. As another example, the release of a 25-hydroxyvitamin D compound will preferably be such that the total serum or blood content of 25-hydroxyvitamin D is maintained or increased for an extended period of time (e.g., 4 to 24 hours or even longer) Such rates exceed pre-dosed amounts. As used herein, unless otherwise specified, the term "cellulose compound" may include cellulose (C₆ H₁₀ O₅ )_n Or cellulose derivatives. A "cellulose ether" is a cellulose derivative that has been chemically modified to cause local 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, cellulonic acid, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl Methyl cellulose, methyl cellulose, polyanionic cellulose, and combinations thereof. The cellulose compounds or stabilizers of different levels corresponding to variables such as molecular weight, viscosity, solubility are also encompassed by the term. Any vitamin D compound and combination thereof suitable for preventive and / or therapeutic use is intended to be included in the formulations described herein. Vitamin D, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and other metabolites and vitamin D analogs are also used as active compounds in pharmaceutical compositions. Specific examples include (but are not limited to) Vitamin D₃ (Cholecalciferol), Vitamin D₂ (Ergocalciferol), 25-hydroxyvitamin D₃ 25-hydroxyvitamin D₂ 25-hydroxyvitamin D₄ 25-hydroxyvitamin D₅ 25-hydroxyvitamin D₇ , 1α, 25-dihydroxyvitamin D₃ , 1α, 25-dihydroxyvitamin D₂ , 1α, 25-dihydroxyvitamin D₄ And vitamin D analogs (including all hydroxyl and dihydroxy forms), such vitamin D analogs include 1,25-dihydroxy-19-nor-vitamin D₂ And 1α-hydroxyvitamin D₃ . In one embodiment, the vitamin D compound includes one or more hydroxyl forms, such as 25-hydroxyvitamin D₃ And 25-hydroxyvitamin D₂ Of combination. Types of vitamin D compounds specifically contemplated for use in the formulations disclosed herein may include 25-hydroxyvitamin D₂ 25-hydroxyvitamin D₃ Or a combination. Especially considering 25-hydroxyvitamin D₃ . As used herein, the term 25-hydroxyvitamin D refers to 25-hydroxyvitamin D₃ 25-hydroxyvitamin D₂ 25-hydroxyvitamin D₄ 25-hydroxyvitamin D₅ Or 25-hydroxyvitamin D₇ One or more of them, and is intended to be 25-hydroxyvitamin D in any reference to yet preferred embodiments₃ And 25-hydroxyvitamin D₂ One or more of these, preferably 25-hydroxyvitamin D₃ . Thus, in any and all formulations described herein, a particular intended active agent may include 25-hydroxyvitamin D₂ And 25-hydroxyvitamin D₃ Especially 25-hydroxyvitamin D₃ Either or both. In the present invention, a vitamin D compound (or a combination thereof) is also referred to as the "active" portion of a formulation (or "active" agent) to distinguish it from a controlled release matrix, stabilizer, and other excipients. Reported on the use of 25-hydroxyvitamin D₃ In the pharmacokinetic test of a sample of active agent, the reference of 25-hydroxyvitamin D should be interpreted as meaning 25-hydroxyvitamin D₃ And all pharmacokinetic (PK) results related to it (such as t_max , C_max , AUC) should be understood as based on 25-hydroxyvitamin D₃ . As used herein, a "stabilized" formulation is one that exhibits stable in vitro dissolution characteristics (according to any of the parameters further described herein) and after initial manufacturing (e.g., actual shelf storage or accelerated stable storage conditions) After a period of time, a controlled release (e.g., sustained release) formulation of a vitamin D compound 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 Tests and Measurements, United States Pharmacopoeia Convention company, Rockville, MD, 2006, pages 2673-2682; European Pharmacopoeia 2.9.3 dissolution test of solid dosage form or Japanese Pharmacopoeia 6.10 dissolution test. For the purposes of the present invention, the in vitro dissolution method is the United States Pharmacopoeia, USP 29-NF 24, physical testing and determination of dissolution <711>, United States Pharmacopeia Convention, Rockville, MD, 2006, pages 2673-2682, using the following examples Device 2 as described in (Stirring Paddle Method). As used herein, t_max (Or Tmax) is defined as the time after which the plasma concentration of the active compound reaches its maximum at dose intervals after administration of a formulation of the invention. When administered with a single 25-hydroxyvitamin D compound (e.g. 25-hydroxyvitamin D₃ ), Unless otherwise specified, t_max Defined as serum 25-hydroxyvitamin D after administration of the formulation₃ The time at which the plasma concentration reaches its maximum at dose intervals. In accordance with NKF K / DOQI guidelines, as used herein, adequate vitamin D is defined as serum 25-hydroxyvitamin D content ≥ 30 ng / mL, and insufficient vitamin D is defined as serum 25-hydroxyvitamin D content is 16-30 ng / mL, Mild vitamin D deficiency was defined as serum 25-hydroxyvitamin D content of 5-15 ng / mL, and severe vitamin D deficiency was defined as 25-hydroxyvitamin D content of less than 5 ng / mL. In the ban on granting patent rights for methods practiced on the human body, the meaning of "taking" a composition to a human individual should be limited to prescribing (medicating) the human individual by any technique (such as oral, inhalation, surface coating , Injections, insertions, etc.) controlled substances for self-administration. It is expected to adopt the broadest reasonable interpretation consistent with laws or regulations that define patentable subject matter. Among the rights that do not prohibit granting patents on methods practiced on the human body, "taking" the composition includes both methods practiced 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 value to the upper limit value, that is, all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered as explicitly stated in this application. For example, if the concentration range or beneficial effect range is stated as 1% to 50%, it is desirable to explicitly list 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 a value of 19.5% up to 20.5%. These examples are specific examples only. Disclosed herein are formulations for the controlled release of a vitamin D compound in the gastrointestinal tract of an individual ingesting the formulation. The formulation will include a vitamin D compound as described herein, a matrix component (e.g., a lipophilic matrix) and a stabilizer (e.g., a cellulose compound) that releasably bind to the vitamin D compound and controllably release the vitamin D 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 dissolution is not substantially different from 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 two months of exposure to storage conditions at 25 ° C and 60% relative humidity, and when the formulation is During in-vitro dissolution before exposure to storage conditions (i.e., freshly made product), the amount of release at the same dissolution time point changes at any given dissolution time point 30 hours after 30 hours. % Or less than 30%. The following table provides the storage stability expected for the examples of the present invention after initial storage at 25 ° C and 60% RH and after multiple storage at 40 ° C and 75% RH, and at different times during the dissolution test An example of the degree of sexual favorability. The degree of storage stability is expressed as the maximum deviation from the nominal activity potency, which is the maximum% change from LC. Alternative embodiments of maximum deviation are also provided. In one embodiment, the formulation will have a favorable degree of stability immediately following the above-mentioned stability at multiple time points throughout the dissolution test, such as at least two time points of 2 and 4 hours, as appropriate At the 6 hour time point, further optionally at the 8 hour time point and further at the 12 hour time point, so that the dissolution profile after storage follows the dissolution profile of the fresh product. Alternatively, the formulation will have a favorable degree of stability immediately after the time points of at least 2, 6, and 12 hours. Alternatively, the formulation will have a favorable degree of stability immediately at least at 4, 8, and 12 hour time points as described in the table above. Alternatively, the formulation will have a favorable degree of stability immediately at least at the time points of 2, 4 and 6 hours. Alternatively, the formulation will have a favorable degree of stability at least at 4, 6, 8 and 12 hours, or at all times of 4 hours, and immediately thereafter, as described in the table above. In any and all of the examples described immediately below in the table above, the deviation from the fresh product may be positive (more released) or negative (less released). In one embodiment, the deviation is intended to be in a negative direction (less released) at multiple points in time. Furthermore, in one embodiment, if no stabilizer is present in the formulation, the deviation in dissolution release is intended to be negative (less released) at multiple time points. In any of the embodiments covered herein, the dissolution release profile of a formulation may be characterized by any of the examples provided below. For example, a formulation can be characterized by a dissolution release curve that provides less than 30% at 2 hours, greater than 45% at 6 hours, and greater than 80% at 12 hours, and further optionally at 6 hours Less than 60% of vitamin D compounds are released. In another embodiment, the formulation may be provided by a living body that provides less than 30% of vitamin D compounds at 100 to 140 minutes, more than 45% at 5 to 7 hours, and more than 80% at 11 to 13 hours. Characterization of external dissolution. In another embodiment, the formulation can be characterized by providing in vitro dissolution characteristics that release less than 30% of vitamin D compounds at 2 hours, greater than 45% at 6 hours, and greater than 80% at 12 hours. In these types of examples, the release of the vitamin D compound is optionally less than 60% at 5 to 7 hours or less than 60% at 6 hours. In another embodiment, the formulation may be by providing a living body that releases about 20% to about 40% at 2 hours, at least 35% at 6 hours, and at least 70% of the vitamin D compound at 12 hours. Characterization of external dissolution. In another embodiment, the formulation may be provided by providing a release of the vitamin D compound from about 25% to about 35% at 2 hours, at least 40% at 6 hours, and at least 75% at 12 hours. Characterization of in vitro dissolution characteristics. In these types of examples, the release of the vitamin D compound is, for example, 75% or less at 6 hours, or 65% or less at 65 hours, or 60% at 6 hours Or less than 60%. In any of the embodiments described herein, the stabilized formulation can be obtained by t_max Characterization, the t_max 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, such as in the range of 4 to 96 hours, or 18 to 30 hours Within the range, or within the range of 13 to 28 hours, or, for example, 28 hours. In any of the embodiments covered herein, a formulation comprising 25-hydroxyvitamin D is characterized by providing a baseline-adjusted C per microgram of 25-hydroxyvitamin D_max , When administered to an adult, the C_max In the range of about 0.0133 ng / mL to about 0.04 ng / mL. In any of the methods encompassed herein, the method may include administering to a human patient a stabilized sustained release dosage form comprising a 25-hydroxyvitamin D compound, including administering to the patient an effective amount of a formulation to provide a baseline Adjustment C_max , The C_max At least about 0.2 ng / mL, and optionally less than 110 ng / mL, and further optionally 24 ng / mL or less, such as in the range of about 0.2 to about 24 ng / mL. In any of the methods encompassed herein, the method may include administering to a human patient a stabilized sustained release dosage form comprising a 25-hydroxyvitamin D compound, including administering to the patient an effective amount of a formulation to provide a baseline Adjusted AUC_0-inf , The AUC_0-inf At least 52 ng * h / mL, and optionally less than 34,500 ng * h / mL, and further optionally about 12,000 ng * h / mL or less than 12,000 ng * h / mL, such as at 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 a freshly made product after storage. Thus, for example, a stabilized formulation can provide the area under the curve of the active agent (or total 25-hydroxyvitamin D in serum) after storage, AUC (eg, AUC_0-inf Or AUC_0-t ) Within the 90% confidence interval, or within 80% to 125% of the average of fresh produce, or within 80% to 120% of its average. Additionally or in the alternative, the stabilized formulation may provide a maximum serum concentration of the active agent (or total serum 25-hydroxyvitamin D) after storage, C_max (E.g. absolute C_max Or C compared to baseline_max ) Within the 90% confidence interval, or within 80% to 125% of the average of fresh produce, or within 80% to 120% of its average. In one embodiment, the stabilized formulation comprises 25-hydroxyvitamin D₂ And 25-hydroxyvitamin D₃ One or both of the wax matrix and the cellulose compound. In one aspect, the stabilized formulation comprises 25-hydroxyvitamin D₂ And 25-hydroxyvitamin D₃ One or both of wax base and cellulose stabilizer. In another aspect, the formulation comprises 25-hydroxyvitamin D₂ And 25-hydroxyvitamin D₃ One or both of a wax base and an effective amount of a cellulose compound to provide advantageous stability as described herein, for example, according to any of the examples immediately following the above table or meeting the examples described below. For example, this amount is effective to provide the amount of active agent released at the time of dissolution during in vitro dissolution at least one month after storage conditions exposed to 25 ° C and 60% relative humidity and exposure of the formulation to During in vitro dissolution performed before storage conditions, there is a difference of 30% or less between the amounts released at the same dissolution time point, while the lack of stabilizers for comparative formulations will result in dissolution release after the same storage conditions Bigger difference. In one aspect, the formulation is a modified formulation for controlled release of a vitamin D compound in the gastrointestinal tract of an individual ingesting the formulation. In one embodiment, the modification comprises incorporating a cellulose stabilizer into the formulation for controlled release of the vitamin D compound in the gastrointestinal tract of an individual ingesting the formulation. In another embodiment, the improvement comprises blending an effective amount of a cellulose compound into the formulation for the controlled release of the vitamin D compound in the gastrointestinal tract of an individual who ingests the formulation, thereby providing advantageous as described herein Stability, for example according to any of the examples immediately following the above table or conforming to the following. For example, this amount is effective to provide the amount of active agent released at the time of dissolution during in vitro dissolution at least one month after storage conditions exposed to 25 ° C and 60% relative humidity and exposure of the formulation to During in vitro dissolution performed before storage conditions, there is a difference of 30% or less between the amounts released at the same dissolution time point, while the lack of stabilizers for comparative formulations will result in dissolution release after the same storage conditions Bigger difference. The stabilizer may include a cellulose compound. Examples of cellulose compounds and stabilizers used in the stabilized formulations of the present invention may include, but are not limited to, cellulonic acid, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl 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). The stabilizer (e.g., a cellulose compound) is preferably present in an amount of at least about 5% (wt%) of the formulation based on the total weight of the formulation other than any other coating or shell. 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 In the form of%, or an amount greater than 15 wt% of the formulation. Suitable ranges include 5 wt% to 30 wt%, 10 wt% to 20 wt%, 10 wt% to 15 wt%, 5 wt% to 15 wt%, and 7.5 wt% to 12.5 wt.%. Examples include about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, and about 14 wt % And about 15 wt%. It should be understood that the stabilizers mentioned herein are intended to stabilize the dissolution release curve (and hence the in vivo release curve) against substantial changes that occur over time during storage conditions (e.g., typical shelf storage conditions). Reagent. Other agents known in the art as preservatives to prevent degradation of the active ingredients themselves are not intended to be encompassed by the terms `` stabilizing agent '' and `` stabilizer '', although such preservatives Agents are also contemplated for use in the formulations of the invention. In a class of embodiments, 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 considered is hydroxypropyl methylcellulose (HPMC). HPMC can be characterized by one or more of the following characteristics, which are individually and individually anticipated in combination. The methoxy component% in HPMC can be in the range of 19 to 24. The hydroxypropyl component% may be in the range of 7 to 12. Apparent viscosity (2% aqueous solution at 20 ° C) can be at least 50,000 centipoise, or at least 80,000 centipoise, or about 80 to 120,000 centipoise, or 3000 to 120,000 centipoise, or 11,000 to 120,000 centipoise, or 80,000 to Within 120,000 centipoise. In particular, the apparent viscosity (2% aqueous solution at 20 ° C) can be in the range of 80,000 to 120,000 centipoise. The pH (1% aqueous solution) can range from 5.5 to 8.0. For example, a suitable hydroxypropyl methylcellulose having all of the above properties, including 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 cellulose compound will be insoluble in the matrix formulation at the melting point of the major components of the matrix (eg, at 65 ° C or in the range of 60 ° C to 75 ° C). In one embodiment, the cellulose compound will be hydrophilic. Contains 25-hydroxyvitamin D₂ And 25-hydroxyvitamin D₃ The pharmaceutical formulations of the present invention, one or more of which are cellulose compounds, have unexpectedly improved stability compared to formulations lacking cellulose compounds. In one embodiment, the stabilized formulation of the invention comprises 25-hydroxyvitamin D₂ And 25-hydroxyvitamin D₃ And a cellulose-stabilized active-loaded lipophilic matrix mixture in which the formulation is released during in vitro dissolution after exposure to storage conditions at 25 ° C and 60% relative humidity for at least one month A certain amount of 25-hydroxyvitamin D, which changes by 30% at any given dissolution time point compared to the release amount at the same dissolution time point during in vitro dissolution performed on a freshly prepared product Or less than 30%. Unstabilized formulations exhibit variations in the amount of active ingredient released after the composition has been stored for a period of time, as shown in the examples below. Unstabilized formulations release a certain amount of 25-hydroxyvitamin D after exposure to storage conditions, which release amount can vary at a given point in time of dissolution, such as in vitro dissolution with freshly prepared products Compared with the release amount at the same dissolution time point, the change was more than 30%. The change at a given point in time may be an increase or decrease in the dissolution rate, and the changes produce a dissolution profile whose dissolution profile is different from the shape of the original dissolution profile. Compared to the stabilized formulations of the present invention, the unstabilized formulations also exhibit different characteristics after storage as described herein (e.g., after storage at 25 ° C and 60% RH for 3 months or more). In vivo effects. Compared to unstabilized formulations, stabilized formulations exhibit different clinical pharmacokinetics after storage as described herein (e.g., after storage at 25 ° C and 60% RH for 3 months or more). Parameters such as improved bioavailability. The stabilized formulations of the present invention may have a base formulation that is not storage stable and a stabilizer that stabilizes the formulation storage as described herein. Matrices that releasably bind and controllably release the active ingredient can be, for example, lipophilic matrices, including wax matrices. The wax matrix can provide formulations that are solid or semi-solid at room temperature and formulations that are solid, semi-solid, or liquid at body temperature, preferably formulations that are semi-solid or liquid at body temperature. In one aspect, the wax matrix comprises a controlled release agent, an emulsifier, and an absorption enhancer. Examples of controlled release agents suitable for this purpose include, but are not limited to, waxes (including synthetic waxes, microcrystalline waxes, solid paraffin wax, carnauba wax, and beeswax); polyethoxylated castor oil derivatives, hydrogenated Vegetable oils, glycerol mono-, bis-, or melanoate; long-chain alcohols (such as stearyl alcohol, cetyl alcohol, and polyethylene glycol); and mixtures of any of the foregoing. Non-digestible waxy substances (such as hard paraffin) are preferred. Controlled release agents may be present in an amount of at least 5 wt% or greater than about 5 wt% of the formulation. For example, depending on the controlled release agent used, the controlled release agent may include 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 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 the formulation. The controlled release agent may be present in an amount 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%, and about 24 wt % And about 25 wt%. Examples of emulsifiers suitable for use in the formulation include, but are not limited to, lipophilic agents (such as mixed fatty acid monoglycerides; mixed fatty acid diglycerides; mixtures of fatty acid mono and diglycerides) having an HLB of less than 7; Lipophilic polyglyceryl esters; including glycerol monooleate, glyceryl dioleate, glyceryl monostearate, glyceryl distearate, glyceryl monopalmitate, and glyceryl dipalmitate; fatty acid glycerol Lactate; propylene glycol esters including propylene glycol monopalmitate, propylene glycol monostearate, and propylene glycol monooleate; sorbitans including sorbitan monostearate, sorbitan sesquioleate Sugar alcohol esters; fatty acids and their soaps including stearic acid, palmitic acid and oleic acid; and mixtures thereof; glycerol monooleate, glyceryl dioleate, glyceryl monostearate, glyceryl distearate , Glyceryl monopalmitate, and glyceryl dipalmitate; fatty acid glycerol lactate; propylene glycol monopalmitate, propylene glycol monostearate, and propylene glycol monooleate; including sorbitan monohard Esters, sorbitan esters sorbitan sesquioleate of alcohol; include stearic acid, palmitic acid, and fatty acids and oleic acid soaps; and mixtures thereof. Preferred lipophilic agents are selected from glycerides and derivatives thereof. Preferred glycerides are selected from the group consisting of medium- or long-chain glycerides, caprylyl 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 glycerol Esters, glyceryl monocaprylate, glyceryl monodicaprylate, triglyceryl caprylate / capric linoleate and triglyceryl caprylate / caprate / succinate. Monoglycerides having a low melting point are preferably used in the preparation of formulations. Preferred monoglycerides include, but are not limited to, glyceryl monostearate, glyceryl monopalmitate, glyceryl monooleate, glyceryl monocaprylate, glyceryl monodecanoate, glyceryl monolaurate, and the like. It is glyceryl monostearate (GMS). GMS is a natural emulsifier. It is oil-soluble but hardly soluble in water. GMS has an HLB value of 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, octylhexyl polyethylene glycol glycerides such as polyvinyl glycosylated glycerides, also known as polyglycolized glycerides or pegylated (PEGylated) glyceride. PEGylated glycerides that can be used in the composition include, but are not limited to, monoglycerides, diglycerides and triglycerides, and mixtures of mono and diesters of polyethylene glycol, polyethylene glycosylated almonds Glyceryl esters, polyvinyl glycosylated corn glycerides, and polyvinyl glycosylated caprylic / capric triglycerides. The HLB value of the absorption enhancer may be 13 to 18 or 13 to 15. A preferred absorption enhancer is known under the brand 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 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 cells, microspheres, or lipid particles. It is identified by its melting point / HLB value. Melting points are 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 twelve fluorene polyethylene glycol glyceride and twelve fluorene polyoxyglyceride), which has a melting point of 44 ° C and an HLB of 14. The absorption enhancer may be present, for example, in an amount 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 matrix provides a temperature that is above the melting point of the wax matrix at about 0 ° C to about 50 ° C in combination with a pharmaceutically active ingredient (such as, for example, 25-D₂ , 25-D₃ Or both vitamin D compounds), and subsequently filling the melt (solution and / or dispersion) into a suitable capsule. Capsules can be any variety that is compatible with the temperature at which the melt is filled, including soft or hard gelatin capsules and animal or plant gelatin capsules. The melt solidified in the capsule when cooled to room temperature. In one aspect, the stabilized formulation may further comprise 25-hydroxyvitamin D₂ And / or 25-hydroxyvitamin D₃ Oily vehicle. Any pharmaceutically acceptable oil can be used. Examples include animals (such as fish), plants (such as soybeans), and mineral oil. The oil will preferably readily dissolve the 25-hydroxyvitamin D compound used. Preferred oily vehicles include non-digestible oils, such as mineral oils, and particularly liquid paraffin and squalene. The oily vehicle may be, for example, from about 10 wt% to about 50 wt%, or from about 15 wt% to about 45 wt%, or from about 20 wt% to about 40 wt%, or from about 30 wt% to about 40 wt. Concentrations in the range of% exist. 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 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 large wax base can be used. The stabilized controlled-release composition of the present invention is preferably designed to contain, for example, 1 to 1000 μg of 25-hydroxyvitamin D per unit dose.₂ And / or 25-hydroxyvitamin D₃ Concentration and prepared in this way to achieve 25-hydroxyvitamin D₂ / 25-hydroxyvitamin D₃ The effect is controlled or substantially constant release, and optionally released into the ileum of the gastrointestinal tract of a human or animal over an extended period of time. Examples of dosages include 1 μg to 1000 μg, 1 μg to 600 μg, 1 μg to 400 μg, 1 μg to 200 μg, 1 μg to 100 μg, 5 μg to 90 μg, 30 μg to 80 μg, 20 per unit dose 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, and more preferably at least 80%, within the first 24 hours after administration. Advantageously, 25-hydroxyvitamin D can be administered, for example, orally, according to the above embodiments, for example, at a dose of 1 to 100 μg per day₂ 25-hydroxyvitamin D₃ Or a combination thereof along with other therapeutic agents. In one embodiment, the dose will be selected to provide serum 25-hydroxyvitamin D at a dose interval of about 1 to 3 ng / ml₃ The average rise. In embodiments, the formulations described herein can be administered elevated and preferably also maintains 1,25-dihydroxyvitamin D content in blood at 25 pg / mL, 30 pg / mL or higher (e.g. 25 -65 pg / mL) for an extended period of time, such as at least one month, at least three months, at least six months, or longer. In one aspect, the formulations described herein can be administered to a patient to reduce or maintain a reduced serum parathyroid hormone content, preferably an amount that reduces the PTH content by at least 30%, or to reduce the serum content of PTH to CKD Target range for phases (e.g. 35-70 pg / mL for phase 3 (equivalent to 3.85-7.7 pmol / L), 70-110 pg / mL for phase 4 (equivalent to 7.7-12.1 pmol / L), and for phase 5 The required amount is 150-300 pg / mL (equivalent to 16.5-33.0 pmol / L) (as defined in K / DOQI Guide No. 1). In another aspect, a formulation of the present invention can be administered to a patient suffering from secondary thyroid high energy disorder (eg, stage 3 or 4 or stage 3, 4 or 5) of chronic kidney disease to reduce serum PTH content. The dosages described herein are intended for use in any of the methods of treatment described herein. It should be understood that the actual preferred amount of a vitamin D compound in a particular situation will vary depending on the particular composition being formulated, the mode of application, and the particular site being treated. Dosages can be determined using conventional considerations, such as by comparing the different activities of hormones and known agents, for example by means of appropriate conventional pharmacological protocols. The specific dosage to be used for each specific patient may depend on various factors such as age, weight, general health, gender, diet, timing and pattern of administration, excretion rate, severity of the particular condition of the combination agent and application therapy . Patients in need of 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 consume vitamin D fortified milk Adults (e.g., lactose intolerant individuals, milk allergies, vegetarians who do not consume milk, and breastfed infants); individuals with rickets; dark-skinned individuals (e.g., in the United States, 42% are between 15 and 49 African American women have a vitamin D deficiency compared to 4% of white women); the elderly (reduced ability to synthesize vitamin D and are more likely to stay indoors); institutionalized adults (adults who may stay indoors, including those with Individuals with Alzheimer's disease or psychosis); individuals who cover all exposed skin (such as people of certain religions or cultures); individuals who always use sunscreen (e.g., a sun protection factor (SPF) value 8 sunscreens reduce the production of vitamin D by 95%, and higher SPF values can further reduce vitamin D); patients with lipoabsorption syndrome (including (but not limited to) cystic fibrosis, bile stagnation liver disease, other Individuals with liver disease, gallbladder disease, pancreatin deficiency, Crohn's disease, inflammatory bowel disease, oral inflammatory 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 bowel resection; individuals with gum disease; taking drugs that increase vitamin D metabolism (including phenytoin, phosphorus Individuals with phenytoin, phenobarbital, carbamazepine, and rifampin; taking drugs that reduce vitamin D absorption (including cholestyramine, colestipol (colestipol), orlistat, mineral oil and fat substitutes; individuals taking drugs that inhibit vitamin D activation (including ketoconazole); taking drugs that reduce calcium absorption (including corticosteroids) Individuals; 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 After women. According to the Medical Association report on dietary reference intakes of vitamin D, food consumption data indicates that the median intake of vitamin D in young and older women is lower than the currently recommended intake; data indicates that more than 50% of young and older Older women do not consume the recommended amount of vitamin D. Optionally excluded from the methods of the invention described herein is the treatment of individuals suffering from renal osteodystrophy, including chondropathy and cystic fibrous osteitis. In other aspects, the compositions and methods of the present invention are suitable for preventing or treating vitamin D-responsive diseases, that is, where vitamin D, 25-hydroxyvitamin D, or active vitamin D (eg, 1,25-dihydroxyvitamin D) ) A disease that prevents the onset or development or reduction of signs or symptoms of the disease. Such vitamin D-responsive diseases include cancer (eg, breast, lung, skin, melanoma, colon, colorectal, rectum, prostate, and bone cancer). 1,25-dihydroxyvitamin D has been observed to induce cell differentiation and / or inhibit cell proliferation of multiple cells 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's disease , Hashimoto's disease, acute or chronic transplant rejection, acute or chronic graft-versus-host disease, inflammatory bowel disease, Crohn's disease, systemic lupus erythematosus, Hughlian's 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 infections. Vitamin D-responsive diseases have also been reported including hypertension and cardiovascular disease. Thus, the present invention encompasses the prevention or treatment of individuals at risk for cardiovascular disease, such as 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 (e.g. hyperlipidemia, including related diabetic dyslipidemia, and mixed hypolipidemia and low alpha-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 content adjustments of vitamin D compounds include (but are not limited to): (i) in the form of parathyroid-parathyroidism, pseudoparathyroidism, secondary parathyroidism; (ii) in the pancreas Forms of diabetes; (iii) Forms of medullary thyroid carcinoma; (iv) Forms of psoriasis of the skin; Forms of wound healing; (v) Forms of pulmonary sarcomatosis and tuberculosis; (vi) Forms of chronic kidney disease of the kidney, hypophosphatemic VDRR , Vitamin D-dependent form of rickets; (vii) skeletal anticonvulsant therapy, poor bone fibrogenesis, cystic fibrosing osteitis, chondropathy, osteoporosis, osteopenia, osteosclerosis, renal osteodystrophy, rickets Forms; (viii) in the form of intestinal glucocorticoid antagonism, spontaneous hypercalcemia in infancy, malabsorption syndrome, fatty dysentery, tropical oral inflammatory diarrhea; and (ix) autoimmune disorders. In the embodiment of the present invention, the disease benefiting from the content adjustment of the vitamin D compound is selected from cancer, skin disorders (such as psoriasis), and parathyroid disorders (such as parathyroid and secondary parathyroid) , Skeletal disorders (such as osteoporosis), and autoimmune disorders. Formulations can be prepared by procedures well within the capabilities of those skilled in the art. For example, the components of the matrix, such as waxes and oily vehicles, can be melted as needed to provide a flowable liquid thereby making it easier to obtain a homogeneous mixture. Mix an active agent (e.g. 25-hydroxyvitamin D₂ And / or 25-hydroxyvitamin D₃ ) Is added to a liquid vehicle, 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 (such as waxes and oils) are 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, a portion of the oily vehicle, controlled release agent, and emulsifier is heated to a relatively high temperature (e.g., 65 ° C) and mixed before the absorption enhancer is added, and then mixed until homogeneous, and then cooled to a moderate high temperature (For example, 50 ° C to 55 ° C). In a separate container, the remaining portions of the antioxidant preservative and the oily vehicle are mixed and heated to a medium high temperature (for example, 50 ° C), and then combined with the wax mixture and mixed until a homogeneous solution is obtained. Then, a 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 a capsule, and then cooled to room temperature. In another preferred method, a part of the oily vehicle, the controlled release agent and the emulsifier is heated at a temperature of 55 ° C to 60 ° C and mixed before the absorption enhancer is added, and then mixed until homogeneous. In a separate container, the antioxidant preservative, the remainder of the oily vehicle and the stabilizer are mixed and heated to a temperature of 55 ° C to 60 ° C, and then combined and mixed 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 a capsule, and then cooled to room temperature. The formulation is preferably placed in a capsule before administration to a patient in need of treatment. Such capsules may be hard or soft, and soft capsules are especially contemplated. Gelatin capsules can be filled with the formulation using a standard capsule filling machine, such as by filling the formulation and injecting it into a soft capsule shell. Examples of soft capsule shells include VEGICAPS and OPTISHELL technology (Catalent, Somerset, NJ, USA). In the alternative, the formulation may be made into unit dosage forms by any other suitable process, such as 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 formulations are prepared for suppositories and administered as suppositories, such as rectal suppositories. Unless otherwise stated, formulations and methods used and prepared are intended 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, a vitamin D compound is administered in combination with one or more other therapeutic agents. If a vitamin D compound is administered in combination with one or more other therapeutic agents, the proportion of each of the compounds in the combination administered will depend on the particular disease condition being treated. For example, I can choose one or more calcium salts (expected as a calcium supplement or dietary phosphate binder), bisphosphonates, calcimimetics, nicotinic acid, iron, phosphate binders Different anti-neoplastic agents and inhibitors of calciferol, ergocalciferol, active vitamin D sterols, blood glucose and hypertension control agents, CYP24 which can degrade vitamin D agents and other cytochrome P450 enzymes 25 -Hydroxyvitamin D₂ And / or 25-hydroxyvitamin D₃ (E.g. orally). In addition, I can choose different anti-neoplastic agents and inhibitors from cholecalciferol, ergocalciferol, active vitamin D sterols, blood glucose and hypertension control agents, CYP24 and other cytochrome P450 enzymes that can degrade vitamin D agents 25-hydroxyvitamin D₂ And / or 25-hydroxyvitamin D₃ . In fact, when the therapeutic treatment of a disease condition is the desired endpoint, a higher dose of a compound of the invention is used, while a lower dose is generally used for preventive purposes, i.e. the specific dose administered in any given situation It will be adjusted according to the specific compound administered, the disease to be treated, the individual's condition, and other relevant medical facts that can alter the drug activity or individual response, as is well known to those skilled in the art. 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 coating films, such as enteric coating films. It is also contemplated that the formulations may be compressed into lozenges, and in this case may include one or more lozenge compression excipients. In the compositions and methods described herein, the above-mentioned preferred steps, preferred components, their preferred composition ranges, and preferred combinations can be selected from various specific examples provided herein. For example, preferred formulations include 25-hydroxyvitamin D (e.g., about 30 μg, about 60 μg, or about 90 μg 25-hydroxyvitamin D₃ ), About 2 wt% (e.g. 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% (eg 35.36 wt%) liquid paraffin or mineral oil, about 10 wt% HPMC and optionally a small amount of preservative (eg 0.02 wt% BHT). Variations of this formulation would include about 15% (eg, 15.29 wt%) HPMC and about 30% (eg, 29.88 wt%) liquid paraffin or mineral oil.Examples The following examples illustrate specific formulations and methods of making them. The examples are provided for illustration and are not intended to limit the scope of the invention. In the examples, USP equipment 2 (stirring paddle method) as described in USP 29-NF 24, General <711> Dissolution was used, and in vitro dissolution tests were performed using the dissolution medium described below. Generally, the method is performed according to the following steps. Place the volume of the dissolving medium (± 1%) in the container of the specified equipment, assemble the equipment, equilibrate the dissolving medium to 37 ± 0.5 ° C and remove the thermometer. Place the dosage unit in the device, taking care to remove air bubbles from the surface of the dosage unit and then operate the device at the specified rate. At each of the times, specimens were taken from the intermediate area (not less than 1 cm from the container wall) between the surface of the dissolution medium and the top of the rotating blade. Replace the aliquots taken for analysis with the same volume of fresh dissolution medium at 37 ° C. Keep the container covered for the duration of the test and verify the temperature of the test mixture at the appropriate time. In this case the analysis is performed using a suitable analytical method (Ultra High Performance Liquid Chromatography (UPLC)). Six capsules of each formulation were tested at each time point. The dissolution medium was 0.05 M phosphate buffer solution / 1% sodium lauryl sulfate at 37 ± 0.5 ° C, pH 6.8, and the equipment was operated at 100 revolutions per minute. Samples were taken at 2, 4, 6, 8 and 12 hours and the 25-hydroxyvitamin D content of each sample was determined using UPLC.Examples 1-25- Hydroxyvitamin D In vitro dissolution of unstable sustained release formulations Tested by 90 µg of 25-hydroxyvitamin D₃ , 19.98 wt% hard paraffin, 37.85 wt% GMS, 9.76 wt% GELUCIRE 44/14, 2.36 wt% absolute ethanol, 29.88 wt% liquid paraffin, and 0.02 wt% BHT (comparative formulation 1) Dissolve. The formulation does not contain cellulose compounds. 25-hydroxyvitamin D released₃ The average amounts are summarized in the table below. These average amounts are based on the average percentage of the nominal drug loading of each dosage form at T = 0 and after the formulation has been stored for up to 12 months at 5 ° C and ambient humidity. (Average% of marked amount,% LC). Prior to testing, it was determined that the samples were stored at a temperature in the range of 15 ° C to 30 ° C and ambient humidity for a period of about 3 months. Therefore, mark the sample that should represent time zero as T = 0_p (Pseudo-zero time) and it should be understood that samples that have been aged for 1 month, 3 months, 6 months, 9 months, and 12 months have also undergone the aging period of about 3 months just described. To provide more accurate baselines, fresh batches of the same type of samples are prepared and tested without any aging. This data is labeled T = 0_f To indicate a fresh sample. The coefficient of variation (% CV) is also reported. By T = 0_p And T = 0_f 25-hydroxyvitamin D released in batches₃ The percentage change in the initial amount is provided in parentheses and double brackets, respectively. Tests for 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 dissolution of Formulation 1 was tested after storage at 40 ° C and 75% relative humidity for 0, 1, 3 and 6 months. The results are summarized in the table below. It is not intended to be bound by any particular theory, and the increase in solubility after storage at 40 ° C compared to the pseudo T = 0 value is believed to be due to the aging effects and current conditions described above for the pseudo T = 0 sample tested Combination of temperature-dependent phase transitions in the formulation when stored at 40 ° C. The aged product of Comparative Formulation 1 was thermally cured and subsequently subjected to a dissolution test. Curing consists of applying a heat treatment and has been shown to stabilize pharmaceutical formulations (see, for example, US 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. Tested for 25-hydroxyvitamin D after 0, 2, 4 and 8 weeks of storage at room temperature₃ Release of self-curing formulations. The results are summarized in the table below. Examples 2-25- Hydroxyvitamin D In vitro dissolution of stable controlled release formulations Tested after storage at room temperature for 0 to 11 weeks, containing 90 µg of 25-hydroxyvitamin D₃ , 19.88 wt% hard paraffin, 15.29 wt% hydroxypropyl methylcellulose, 22.55 wt% GMS, 9.76 wt% GELUCIRE 44/14, 2.36 wt% absolute ethanol, 29.88 wt% liquid paraffin, and 0.02 wt% BHT (example formulation Dissolution of the sustained release formulation of item A). The results are summarized in the table below. Tested after storage at room temperature for 0 to 26 weeks, containing 90 µg of 25-hydroxyvitamin D₃ , 19.88 wt% hard paraffin, 10.00 wt% hydroxypropyl methyl cellulose, 22.55 wt% GMS, 9.76 wt% GELUCIRE 44/14, 2.36 wt% absolute ethanol, 35.17 wt% liquid paraffin, and 0.02 wt% BHT (example formulation Dissolution of sustained release formulations of substance B)). The results are summarized in the table below. Example Formulation B showed a substantially stable dissolution profile after storage at room temperature for at least 26 weeks. Storage conditions tested at 25 ° C and 60% relative humidity and 40 ° C and 75% relative humidity include 30 µg of 25-hydroxyvitamin D₃ (Example formulation C), 60 µg 25-hydroxyvitamin D₃ (Example Formulation D) or 90 µg 25-hydroxyvitamin D₃ (Example formulation E) Stability of stabilized formulations. 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. * 4 repetitions instead of 6 times 25-hydroxyvitamin D released after aging₃ The percentage change between the amount compared to the initial release is summarized in the table below. The example formulations C to E also substantially exhibited stable dissolution characteristics after storage at 40 ° C. and 75% RH for at least 6 months (FIG. 2). The dissolution results are summarized in the table below. 25-hydroxyvitamin D released after exposure to storage conditions₃ The percentage change between the amount compared to the initial release is summarized in the table below. The stability of Comparative Formulation 1 without cellulose compounds and Example Formulation E containing hydroxypropyl methylcellulose was evaluated after storage at 25 ° C. and 60% relative humidity for 12 months (FIG. 3). The T dissolution results are summarized in the table below. 25-hydroxyvitamin D released after exposure to storage conditions₃ The percentage change between the amount compared to the initial release is summarized in the table below. Examples 3 : In vivo results of unstabilized and stabilized controlled release formulations Conduct in vivo studies to evaluate 25-hydroxyvitamin D in human individuals₃ Clinical pharmacokinetics of unstabilized and stabilized controlled release formulations. In Study A, 28 patients had Stage 3 or Stage 4 CKD, secondary parathyroidism (Phase 3: 70-1000 pg / mL iPTH; Stage 4: 110-1000 pg / mL iPTH), and vitamin D deficiency Individuals (total baseline 25-hydroxyvitamin D in serum between 15 ng / mL and 29 ng / mL) received a single oral dose of a controlled release capsule or 448 µg of 25-hydroxyvitamin D in an ethanol solution₃ Single intravenous dose, this capsule contains 450 µg or 900 µg 25-hydroxyvitamin D₃ , 20.00 wt% hard paraffin, 37.85 wt% GMS, 9.75 wt% GELUCIRE 44/14, 2.32 wt% absolute ethanol, 30.06 wt% mineral oil, and 0.02 wt% BHT (comparative formulation 3). None of the formulations contained cellulose compounds. 25-hydroxyvitamin D₃ The serum concentration gradually increased after the oral dose was administered. 25-hydroxyvitamin D₃ The increase was proportional to the dose and reached 32 ng / mL after administration of 900 µg capsules (approximate average mean (Cmax) observed for serum concentration). The time to Cmax (Tmax) was approximately 13 hours after administration. In contrast, 25-hydroxyvitamin D₃ The concentration increased rapidly after intravenous administration. Immediately after intravenous administration (Tmax = 0.5 hours), the maximum serum content was reached and an approximate average Cmax of 134 ng / mL was reached. The bioavailability of an oral dose is about 6 to 11%. 25-hydroxyvitamin D after oral administration₃ Final half-life (t_1/2 ) 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 content increased rapidly after intravenous injection, and increased approximately 13 pg / mL from the pretreatment baseline 6 hours after administration. In contrast, the average serum total 1,25-dihydroxyvitamin D amount was gradually increased by about 7 pg / mL 48 hours after the administration of 900 µg capsules after the administration. Serum iPTH showed no meaningful change in the first 96 hours after intravenous administration. In contrast, serum PTH gradually decreased after dosing, achieving a maximum inhibition of approximately 20% from the baseline of individuals receiving 900 µg capsules. The pharmacokinetic parameters observed for all treatment groups are summarized in the table below. Baseline adjusted pharmacokinetic parameters for all treatment groups are summarized in the table below. In Study B, 20 healthy individuals with an average baseline serum of about 24 ng / mL (ranging from 11 ng / mL to 45 ng / mL) 25-hydroxyvitamin D received a single oral dose of a stable controlled release capsule Or 448 µg of 25-hydroxyvitamin D in ethanol solution₃ Single intravenous dose, this capsule contains 900 µg of 25-hydroxyvitamin D₃ , 20.00 wt% hard paraffin, 10.00 wt% HPMC, 22.55 wt% GMS, 9.75 wt% GELUCIRE 44/14, 2.32 wt% absolute ethanol, 35.36 wt% mineral oil, and 0.02 wt% BHT (example formulation F). 25-hydroxyvitamin D after administration of stabilized oral formulations compared to intravenous administration₃ The gradual increase in content is shown by an extended Tmax. Pharmacokinetic profile after administration of stabilized oral formulations shows 25-hydroxyvitamin D₃ The concentration gradually increased, with an average Tmax of 28 hours, while avoiding a rapid increase in blood content in most individuals. Administration by intravenous administration results in 25-hydroxyvitamin D in all individuals₃ The concentration increases rapidly. With the observed C between treatment groups_max Significant differences in highlighting avoidance of 25-hydroxyvitamin D₃ The content increases rapidly. Compared to a Cmax of 153 ng / mL after intravenous administration, the Cmax after oral administration was 58 ng / mL. 25-hydroxyvitamin D after administration of controlled release capsules₃ The exposure is about two times smaller than after intravenous administration, although oral administration is about twice as high, resulting in about 25% bioavailability. t_1/2 The elimination rate (CL) and volume distribution (Vd) were similar between treatment groups. t_1/2 And CL values correspond to the reported 25-hydroxyvitamin D₃ The extension is eliminated. In addition, the Vd value indicates 25-hydroxyvitamin D₃ Maintained in the systemic circulation, may be highly bound to DBP. The pharmacokinetic parameters observed for all treatment groups are summarized in the table below. Baseline adjusted pharmacokinetic parameters for all treatment groups are summarized in the table below. Studies show improved 25-hydroxyvitamin D with stable controlled release formulation₃ 25-hydroxyvitamin D₃ A more gradual increase in content occurs while maintaining distribution and elimination characteristics. Compared to the same administration of the unstabilized formulation in Study A, the stabilized formulation showed improved pharmacokinetic parameters (such as increased Tmax, AUC, and bioavailability). In Study C, 78 patients with stage 3 CKD (eGFR 25-70 mL / min / 1.73 m² ), SHPT (> 70 pg / mL plasma iPTH) and vitamin D deficiency (total baseline 25-hydroxyvitamin D in serum from 10 ng / mL to 29 ng / mL) Individuals receiving stable controlled release formulations daily Oral dose or placebo for 6 weeks, these formulations contain 30 µg, 60 µg or 90 µg 25-hydroxyvitamin D₃ , 20.00 wt% hard paraffin, 10.00 wt% HPMC, 22.55 wt% GMS, 9.75 wt% GELUCIRE 44/14, 2.32 wt% absolute ethanol, 35.36 wt% mineral oil, and 0.02 wt% BHT (Example Formulation C from Example 2 , D and E). Compare mean baseline serum 25-hydroxyvitamin D across all treatment groups₃ Concentration, and in the range of about 16 to 20 ng / mL. 25-hydroxyvitamin D₃ After treatment, serum 25-hydroxyvitamin D₃ The average content gradually increases and 25-hydroxyvitamin D is administered repeatedly every day₃ It then increased in proportion to the dose and began to approach steady state after 6 weeks (Figure 4). For administration of 30 µg, 60 µg and 90 µg 25-hydroxyvitamin D₃ In groups, the average baseline adjusted Cmax values were about 28, 60, and 86 ng / mL, respectively. Background adjusted AUC in all dose groups_0-6 Assessed by Zhou, 25-hydroxyvitamin D₃ The average exposure is proportional to the dose. According to the final dose, the average serum 25-hydroxyvitamin D₃ Levels decreased slowly, but all groups remained above baseline at the end of the study. Mean t_1/2 It was determined to be between about 25 and 50 days. 25-hydroxyvitamin D₃ The baseline adjusted pharmacokinetic parameters are summarized in the table below. Compare the mean baseline serum 1,25-dihydroxyvitamin D concentrations of all treatment groups with increasing concentrations similar to 25-hydroxyvitamin D₃ Effect on concentration. The mean ± SD baseline adjusted Cmax values for the 60 µg and 90 µg groups were higher compared to 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). 25-hydroxyvitamin D₃ Baseline adjusted AUC_0-6 Assessed by Zhou, 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. 25-hydroxyvitamin D in significantly more individuals in all active agent groups compared to placebo₃ The stabilized controlled release formulation increased total serum 25-hydroxyvitamin D content to ≥ 30 ng / mL. Similarly, stable formulations in all dose groups compared to placebo resulted in a significant reduction in mean plasma iPTH from baseline. 25-Hydroxyvitamin D is administered daily in a stable controlled release formulation₃ The average serum total 25-hydroxyvitamin D was increased in an amount proportional to the administered dose. The lowest dose (30 µg) increased total serum 25-hydroxyvitamin D by 15.6 ± 1.7 (SE) ng / mL from the pretreatment baseline (21.7 ± 1.8 ng / mL) at the end of the treatment, and the highest dose (90 µg) Increased 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 studied doses, the difference between the treatment group and the placebo group was significant (p <0.0001). At the end of 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 specified by K / DOQI), indicating that 30 µg was the smallest effective dose. Compared to 0% in the placebo group, the percentage of treated individuals achieving a total 25-hydroxyvitamin D content of ≥30 ng / mL serum at the end of treatment in the 30 µg, 60 µg, and 90 µg dose groups was 92.3%, 100.0% and 100.0%. These differences in response rates between active and placebo treatments were all significant (p <0.001). Mean plasma iPTH and 25-hydroxyvitamin D administered at end of treatment₃ The dose is proportionally reduced. The lowest dose (30 µg) reduced iPTH from the pretreated 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. Received 25-hydroxyvitamin D for all three studied doses₃ The difference between the group and the placebo group was significant (p <0.005), and it was beneficially compared with the use of more effective and calcium calcium oral vitamin D hormone replacement therapies (e.g., docalciferol, paricalcitol, and Calcitriol) compared the differences observed in longer treatments in placebo-controlled studies. Confirmed at EOT that iPTH has decreased from pretreatment baseline (i.e., two consecutive measurements) by at least 20% or 30% of 25-hydroxyvitamin D₃ The percentage of individuals increased at the end of the dose to 60 µg. Similar response rates were observed in the 60 and 90 µg treatment groups, suggesting that no other benefits in iPTH reduction were observed for the 90 µg dose in this study. Compared to 9.7% in the combined placebo group, the response rates for confirming a 20% reduction in iPTH for the 30 µg, 60 µg, and 90 µg dose groups were 38.5%, 70.6%, and 76.5%, respectively. The difference in response rate observed for a 20% reduction was significant only for the 60 μg and 90 μg dose groups (p <0.005) and for all 30 dose groups was a significant 30% reduction (p <0.05). Data support 30 µg of 25-hydroxyvitamin D per day in stabilized controlled release formulations₃ The conclusion is the minimum effective dose. 25-hydroxyvitamin D₃ The stabilized formulation has no clinically significant effect on albumin-corrected serum calcium, serum phosphorus, and urine calcium excretion. There were no adverse effects on serum calcium or serum phosphorus or urine calcium during the 6-week treatment period. Pharmacokinetic analysis revealed 25-hydroxyvitamin D in all three dose groups₃ Stable formulation increases 25-hydroxyvitamin D in a dose-proportional manner over 6 weeks₃ Exposure (AUC and C_max ), T_1/2 no difference. After 6 weeks of administration, the three treatment groups have not yet fully reached steady state. However, the steady-state model shows that steady-state should be reached by 7-9 weeks in all dose groups. Data from this study clearly show 25-hydroxyvitamin D₃ The stabilized controlled release formulation is effective in increasing total serum 25-hydroxyvitamin D to a minimum appropriate level of 30 ng / mL and reducing plasma iPTH. Study also shows 25-hydroxyvitamin D at study dose₃ Stable formulations have no clinically meaningful impact on serum calcium or phosphorus. Examples 4 : In patients with secondary parathyroid high energy and vitamins D Inadequate CKD Pharmacokinetics and pharmacodynamic characteristics of modified release of calcidiol in individuals Stable 25-hydroxyvitamin D in two groups of individuals₃ (Calcifediol, 25D₃ ) Capsules were studied in a multicenter, randomized, double-blind, placebo-controlled, repeated dose, safety, efficacy, and PK / PD study. For this study recruited patients with stage 3 CKD (eGFR 25-70 mL / min / 1.73 m² ), Vitamin D deficiency (serum 25-hydroxyvitamin D ≥ 10 and ≤ 29 ng / mL), SHPT (plasma iPTH> 70 pg / mL), and men and women aged 18 to 85 who do not need to undergo regular hemodialysis individual. Eligible individuals in the first group were randomly divided into three treatment groups at a ratio of 1: 1: 1: two groups received capsules at a daily oral dose of 60 or 90 μg and one group received matching placebo capsules. Individuals in the second group were randomly divided into two treatment groups at a 1: 1 ratio: one group received 30 μg capsules daily and the other received a placebo. Individuals in each group completed 6 weeks of treatment and entered a 6-week follow-up period during which PK and PD samples were collected weekly. Monitor serum calcium (Ca), phosphorus (P), 25D weekly during 6-week treatment and 6-week follow-up₃ , Total 1,25-dihydroxyvitamin D (1,25D) and plasma iPTH. ANCOVA model detection 25D₃ Correlation of exposure with baseline changes from 1,25D and iPTH. The covariates included were baseline eGFR, weight and height, gender, age, ethnicity, diabetes status, and baseline concentrations of 1,25D or iPTH. Figure 4 shows the average baseline-adjusted calcifediol concentration obtained by the treatment group (PK group). The average serum calcifediol content gradually increased in a proportional manner to the dose and began to approach steady state after 6 weeks. After 6 weeks of follow-up, the levels were reduced but remained above baseline in all active agent-treated groups. Figure 5 shows a summary of the baseline-adjusted PK parameters of the calcifediol concentration obtained by the treatment group (PK group). Figure 6 shows the mean baseline adjusted serum 1,25-dihydroxyvitamin D content obtained during the 6-week treatment period (PK group). The mean baseline-adjusted serum total 1,25 dihydroxyvitamin D content increased over time in those individuals administered the active agent capsules compared to those administered placebo. Figure 7 shows a summary of the baseline adjusted adjusted dose PK parameters for serum 1,25-dihydroxyvitamin D obtained by the treatment group (PK group). Figure 8 shows the baseline mean percentages obtained in the plasma iPTH content during the 6-week treatment (PK group). Compared to the 17% increase in the combined placebo group, active agent capsules significantly reduced mean plasma iPTH from baseline by 21%, 33%, and 39% in all dose groups (30, 60, and 90 µg), respectively. Figure 9 shows a summary of the baseline adjusted adjusted dose PK parameters of plasma iPTH obtained by the treatment group (PK group). Figures 10 and 11 show plasma iPTH at baseline during EOT in the PK population relative to baseline adjusted calcifediol and 1,25-dihydroxyvitamin D exposure (AUC_0-6wk ) Percent change from baseline. Percent reduction in plasma iPTH from baseline to EOT with serum calcifediol and total 1,25 dihydroxyvitamin D exposure during treatment (expressed as baseline-adjusted AUC_0-6wk ) Increase and increase. Stable, sustained release of 25-hydroxyvitamin D₃ Capsules normalize 25D content in most individuals and significantly reduce iPTH in all dose groups (30, 60, and 90 µg). Stable, sustained release of 25-hydroxyvitamin D₃ Capsules gradually increase serum 25D₃ And serum 1,25D content in which exposure increased in a dose-dependent manner. 25D₃ And total 1,25D exposure were both significant and negatively correlated with changes in plasma iPTH from baseline. Only eGFR was a significant covariate in both models. These results show stable, sustained release of 25-hydroxyvitamin D₃ Capsules reliably normalize the 25D content, increase serum 1,25D content, and suppress the increase in plasma iPTH, and have no clinically meaningful effects on serum Ca and P during dose studies.*** The above description is given only for clear understanding, and should not be interpreted as an unnecessary limitation. It may also be obvious to those skilled in the art that modifications within the scope of the present invention may be made. Throughout this specification and the scope of subsequent patent applications, unless otherwise specified herein, the term "comprise" and variations (such as "comprises / comprising") shall be understood to imply the inclusion of the stated whole or step Or groups or steps but not excluding any other whole or step or step or group of steps. Throughout this specification, unless otherwise described, a composition is described as including a component or substance, and the composition is intended to also consist essentially of, or consist of, any combination of the components or substances. Also, unless described otherwise, a method is described as including a particular step, and the method is intended to also consist essentially of or from any combination of the steps. In the absence of any element or step that is not specifically disclosed herein, the invention illustratively disclosed herein may be appropriately practiced. The practice of the methods disclosed herein and their individual steps can be performed manually and / or by means of electronic equipment. Although the process has been described with reference to specific embodiments, one of ordinary skill will readily understand that actions may be performed in other ways related to these methods. For example, unless described otherwise, the order of various steps may be changed without departing from the scope or spirit of the method. In addition, some of the individual steps may be combined, omitted, or further subdivided into other steps. All patents, publications, and references cited herein are hereby incorporated by reference in their entirety. In the event of conflict between the invention and incorporated patents, publications, and references, the invention should be controlled. In light of the above description, the embodiments covered include those described in the following numbered paragraphs. 1. A controlled release formulation of a vitamin D compound comprising 25-hydroxyvitamin D₂ And 25-hydroxyvitamin D₃ Either or both, the formulation comprises a matrix of releasably bound and controlled release vitamin D compounds, the matrix comprising a cellulose derivative. 2. A stabilized formulation for the controlled release of a vitamin D compound in the gastrointestinal tract of an individual ingesting the formulation, the formulation comprising a mixture of: 25-hydroxyvitamin D₂ And 25-hydroxyvitamin D₃ Either one or both; and an effective amount of a stabilizer, optionally a cellulose compound, such that during in vitro dissolution after two months of exposure to storage conditions at 25 ° C and 60% relative humidity, The difference between the amount of vitamin D compound released at any given time point after the hour and the amount of release at the same dissolution time point during in vitro dissolution performed prior to exposing the formulation to storage conditions remains less than 30 %. 3. A stabilized formulation for the controlled release of a vitamin D compound, the formulation comprising a mixture of: 25-hydroxyvitamin D₂ And 25-hydroxyvitamin D₃ Either or both; a wax matrix; and a stabilizer, optionally a cellulose compound. 4. A stabilized formulation for the controlled release of a vitamin D compound in the gastrointestinal tract of an individual who ingests the formulation, the formulation comprising a mixture of: 25-hydroxyvitamin D₂ And 25-hydroxyvitamin D₃ Either or both; a wax matrix; and a stabilizer, optionally a cellulose stabilizer. 5. A stabilized formulation for controlled release of vitamin D, the formulation comprising a mixture of: 25-hydroxyvitamin D₂ And 25-hydroxyvitamin D₃ Either or both; a wax matrix; and an effective amount of a stabilizer, optionally a cellulose compound, to allow in vitro dissolution testing after two months of exposure to storage conditions at 25 ° C and 60% relative humidity Period between the amount of vitamin D compound released at any given time point after four hours and the amount released at the same dissolution time point during in vitro dissolution performed prior to exposing the formulation to storage conditions The difference remains less than 30%. 6. A stabilized formulation for the controlled release of a vitamin D compound in the gastrointestinal tract of an individual ingesting the formulation, the formulation comprising a mixture of: an active loading wax matrix comprising 25-hydroxyvitamin D₂ And 25-hydroxyvitamin D₃ One or both of them; and a cellulose stabilizer; wherein the formulation releases a certain amount of 25-hydroxyvitamin D during in vitro dissolution after two months of storage exposed to 25 ° C and 60% relative humidity, In the presence of a cellulose stabilizer, this amount of release varies at any given time of dissolution compared to that at the same dissolution time point during in vitro dissolution performed prior to exposing the formulation to storage conditions. 30% or less. 7. In a formulation for the controlled release of a vitamin D compound in the gastrointestinal tract of an individual ingesting the formulation, the improvement comprises incorporating a cellulose stabilizer into the formulation. 8. In a formulation for the controlled release of a vitamin D compound in the gastrointestinal tract of an individual who ingests the formulation, the modification includes blending a cellulose compound into the formulation to expose it to 25 ° C and 60% relative humidity. During in vitro dissolution at least one month after storage conditions, the amount of 25-hydroxyvitamin D released at any given dissolution time point after four hours and the in vitro dissolution performed before exposing the formulation to storage conditions Compared with the release amount at the same dissolution time point, the change is less than 30%. 9. The formulation of any of the preceding paragraphs, wherein the cellulose compound or cellulose stabilizer comprises a 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 Group. 11. The formulation of paragraph 9, wherein the cellulose compound or cellulose stabilizer is hydroxypropylmethyl cellulose. 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 two months of exposure to storage conditions at 25 ° C and 60% relative humidity, and Comparing the release amount at the same dissolution time point during in vitro dissolution performed prior to exposure of the formulation to storage conditions, the release amount varies by 30% or less at any given dissolution time point after four hours. 13. The formulation as in any of the preceding paragraphs, wherein the formulation releases a certain amount of 25-hydroxyvitamin D during in vitro dissolution after one month of storage conditions exposed to 40 ° C and 75% relative humidity, and The release amount varies by 30% or less at any given dissolution time point after four hours compared to the release amount at the same dissolution time point during in vitro dissolution performed prior to the storage conditions being exposed to the formulation. 14. The formulation of any of the preceding paragraphs, wherein the matrix comprises a wax matrix, the wax matrix comprising 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 paragraphs 14 or 15, wherein the emulsifier has an HLB value of 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 according to paragraph 18, wherein the absorption enhancer is a mixture of dodecafluoropolyethylene glycol glyceride and dodecafluoropolyoxyglyceride. 20. The formulation of any of the preceding paragraphs, wherein the vitamin D compound comprises 25-hydroxyvitamin D₃ . 21. The formulation of any of the preceding paragraphs, further comprising an oily vehicle. 22. The formulation of paragraph 21, wherein the oily vehicle comprises a mineral oil. 23. The formulation of paragraph 22, wherein the formulation comprises about 20 wt% paraffin, about 20 wt% to about 25 wt% glyceryl monostearate, about 10 wt% dodecadiol polyethylene glycol glyceride, and A mixture of dodecafluoropolyoxyglyceride, about 30 wt% to about 35 wt% mineral oil, and about 10 wt% to about 15 wt% hydroxypropyl methylcellulose. 24. The formulation of any of the preceding paragraphs, wherein the formulation 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 include the formulation of any of the preceding paragraphs. 27. The dosage form of paragraph 26, comprising a capsule or lozenge. 28. The dosage form of paragraph 27, comprising a capsule. 29. The dosage form of paragraph 26, which comprises oral capsules, lozenges, sachets, sugar-coated pills. 30. A stabilized dosage form as in any of the preceding paragraphs, characterized in that it provides a dissolution profile of the following release of the vitamin D compound of less than 30% at 2 hours; greater than 45% at 6 hours; and greater than 12 hours 80%. 31. The stabilized dosage form of paragraph 26, wherein the vitamin D compound releases less than 60% at 6 hours. 32. A stabilized sustained release oral dosage form comprising a vitamin D compound, characterized by providing in vitro dissolution characteristics of the following release of the vitamin D compound, less than 30% at 100 to 140 minutes; greater than 45% at 5 to 7 hours ; And greater than 80% at 11 to 13 hours. 33. The dosage form of paragraph 32, wherein the release of the vitamin D compound is less than 30% at 2 hours; greater than 45% at 6 hours; and greater than 80% at 12 hours. 34. The dosage form of paragraphs 32 or 33, wherein the release of the vitamin D compound is less than 60% at 5 to 7 hours. 35. The dosage form of paragraph 34, wherein the vitamin D compound releases less than 60% at 6 hours. 36. A stabilized sustained release oral dosage form comprising a vitamin D compound, characterized by providing an in vitro dissolution profile of the vitamin D compound below about 2% 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 vitamin D compound releases from 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 comprising a vitamin D compound, characterized in that after the dosage form is administered to a human patient t_max At least 4 hours. 42. The dosage form of paragraph 41, wherein t_max At least 8 hours. 43. The dosage form of paragraph 42, wherein t_max At least 12 hours. 44. The dosage form of paragraph 43, wherein t_max At least 18 hours. 45. The dosage form of paragraph 44, wherein t_max At least 20 hours. 46. The dosage form of paragraph 45, wherein t_max At least 24 hours. 47. The dosage form of paragraph 46, wherein t_max At least 28 hours. 48. The dosage form of paragraph 41, wherein t_max In the range of 4 to 96 hours. 49. The dosage form of paragraph 48, wherein t_max In the range of 18 to 30 hours. 50. The dosage form of paragraph 49, wherein t_max In the range of 13 to 28 hours. 51. The dosage form of paragraph 50, wherein t_max For about 28 hours. 52. A stabilized sustained release dosage form comprising a 25-hydroxyvitamin D compound, the dosage form characterized by providing a baseline-adjusted C per microgram of 25-hydroxyvitamin D_max , When administered to an adult, the C_max In the range of about 0.0133 ng / mL to about 0.04 ng / mL. 53. A method of administering a stabilized sustained release dosage form comprising a 25-hydroxyvitamin D compound to a human patient, comprising administering to the patient an effective amount of the dosage form to provide at least about 0.2 ng / mL and less than 110 ng / mL Baseline adjusted C_max . 54. The method of paragraph 53, comprising administering an effective amount of the dosage form to provide a baseline adjusted C in the range of about 0.2 to about 24 ng / mL_max . 55. A method of administering a stabilized sustained release dosage form comprising a 25-hydroxyvitamin D compound to a human patient, comprising administering to the patient an effective amount of the dosage form to provide at least 52 ng * h / mL and less than 34500 ng * h / mL Baseline Adjusted AUC_0-inf . 56. The method of paragraph 55, comprising administering to the patient an effective amount of the dosage form to provide a baseline-adjusted AUC in the range of about 52 ng * h / mL to about 12,000 ng * h / mL_0-inf . 57. A method of vitamin D supplementation comprising administering to an individual in need of a formulation or dosage form as in any of the preceding paragraphs. 58. A method of treating or preventing a vitamin D-responsive disease in an individual, comprising administering to the individual a formulation or dosage form as in any of the preceding paragraphs. 59. The method of paragraph 58, wherein the disease is selected from the group consisting of cancer (e.g. breast, lung, skin, melanoma, colon, colorectal, rectum, prostate and bone cancer), autoimmune disease (e.g. type I diabetes, multiple Sclerosis, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma, fibrosis, Graves' 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, Sjogren'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 infections), hypertension, cardiovascular disease (individuals) Have atherosclerosis, atherosclerosis, 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 (e.g. hyperlipidemia, dyslipidemia including related diabetic dyslipidemia and mixed hypolipidemia, hypolipoproteinemia, hypertriglyceridemia, hypercholesterolemia, and low HDL (high Density lipoprotein)), metabolic disorders (e.g., metabolic syndrome, type 2 diabetes, type 1 diabetes, hyperinsulinemia, glucose intolerance, insulin resistance, diabetic complications (including neuropathy, nephropathy, osteoporosis, retina Disease, diabetic foot ulcers and cataracts)) and / or blood clots. 60. The method of paragraph 59, wherein the disease is selected from the group consisting of (i) parathyroid-parathyroid low energy, pseudoparathyroid low energy, secondary parathyroid Forms of thyroid high energy; (ii) in the form of pancreatic diabetes; (iii) in the form of medullary thyroid carcinoma; (iv) in skin psoriasis; in the form of wound healing; (v) in the form of pulmonary sarcoma and tuberculosis; (vi) ) In the form of renal chronic kidney disease, hypophosphatemic VDRR, vitamin D-dependent rickets; (vii) in skeletal anticonvulsant therapy, poor bone fibrogenesis, cystic fibrous osteitis, chondropathy, osteoporosis, Osteopenia, osteosclerosis, renal osteodystrophy, rickets; (viii) forms of intestinal glucocorticoid antagonism, spontaneous hypercalcemia in infancy, malabsorption syndrome, fatty rash, tropical mouth inflammatory diarrhea; and (ix) an autoimmune disorder. 61. The method of paragraph 60, wherein the disease is selected from the group consisting of cancer, skin disorders (such as psoriasis), parathyroid disorders (such as parathyroid high energy and secondary parathyroid high energy), Bone disorders (such as osteoporosis) and autoimmune disorders. 62. The method of paragraph 61, wherein the disease is secondary parathyroid high energy disease. 63. The method of paragraph 62, wherein the individual has chronic kidney disease (CKD). 64 . The method of paragraph 63, wherein the CKD is stage 3 or 4. 65. The method of paragraph 64, wherein the patient is a vitamin D deficiency. 66. The method of any of the preceding paragraphs, wherein the patient is a human. 67. The method of paragraph 66, wherein the human being is an adult. 68. A composition as substantially described herein.

Figure 1 shows the dissolution characteristics of the formulations of the 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 is displayed on the Y-axis. Figures 1A, 1B, and 1C show the dissolution characteristics of formulations containing 30 µg, 60 µg, and 90 µg of 25-hydroxyvitamin D ₃ , respectively. Figure 2 shows the dissolution characteristics of the formulations of the 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 is displayed on the Y-axis. Figures 2A, 2B, and 2C show the dissolution characteristics of formulations containing 30 µg, 60 µg, and 90 µg of 25-hydroxyvitamin D ₃ , respectively. Figure 3 shows the dissolution characteristics of the formulations of the 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 without cellulose compounds. Figure 3B shows the dissolution characteristics of the stabilized formulations 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 invention. FIG. 5 shows a summary baseline adjusted PK parameter of the calcidiol concentration obtained by the treatment group (PK group) of the patients described in Example 4, which were treated with the formulation of the present invention. Figure 6 shows the mean baseline-adjusted serum 1,25-dihydroxyvitamin D content obtained during a 6-week treatment (PK cohort) of patients described in Example 4 who were treated with a formulation of the invention. Figure 7 shows a summary of the PK parameters of the baseline-adjusted repeated doses of the serum 1,25-dihydroxyvitamin D obtained by the treatment group (PK group) of the patients described in Example 4, which patients received the formulation of the invention deal with. Figure 8 shows the mean percentage of the baseline iPTH in plasma obtained during the 6-week treatment (PK cohort) of the patients described in Example 4 who were treated with the formulation of the invention. Figure 9 shows a summary of the PK parameters of the baseline adjusted repeated doses of plasma iPTH obtained by the treatment group (PK group) of the patients described in Example 4 who were treated with the formulation of the invention. Figures 10 and 11 show the plasma iPTH at EOT versus baseline-adjusted calcifediol and 1,25-dihydroxyvitamin D in the PK population of patients treated with the formulations of the invention described in Example 4 (AUC _0-6wk ) Percent change from baseline.

Claims (10)

A controlled release formulation of a vitamin D compound, comprising one or both of 25-hydroxyvitamin D ₂ and 25-hydroxyvitamin D ₃ , the formulation comprising a matrix capable of releasing binding and controlling the release of the vitamin D compound The matrix contains a cellulose derivative. A stabilized formulation for the controlled release of a vitamin D compound, the formulation comprising one or both of 25-hydroxyvitamin D ₂ and 25-hydroxyvitamin D ₃ ; a mixture of a wax matrix and a stabilizer, the The stabilizer is optionally a cellulose compound. A stabilized formulation of 25-hydroxyvitamin D ₂ and / or 25-hydroxyvitamin D ₃ comprising about 20 wt% paraffin, about 20 wt% to about 25 wt% glyceryl monostearate, about 10 wt % Dodecafluoropolyethylene glycol glyceride and dodecapolypolyoxyglyceride, about 30 wt% to about 35 wt% mineral oil, and about 10 wt% to about 15 wt% hydroxypropyl methylcellulose. The formulation according to any one of claims 1 to 3, which is used to increase the serum 25-hydroxyvitamin D content in a patient. The formulation of any one of claims 1 to 3, which is used to increase the serum 1,25-dihydroxyvitamin D content in a patient. The formulation according to any one of claims 1 to 3, which is used to reduce the serum intact parathyroid hormone content in a patient. A formulation as claimed in any one of claims 1 to 3 for use in the treatment of 25-hydroxyvitamin D deficiency or deficiency. The formulation of any one of claims 1 to 3, for use in the treatment of secondary parathyroidism. The formulation of any one of claims 1 to 3, for use in treating a patient with chronic kidney disease. Use of a formulation as claimed in any one of claims 1 to 3 for the manufacture of a medicament for the treatment of secondary parathyroidism.