TWI645864B - Stabilized modified release vitamin d formulation and method of administering same - Google Patents

Abstract

The present invention discloses a stabilized formulation for controlled release of a vitamin D compound. The formulation comprises one or both of 25-hydroxyvitamin D ₂ and 25-hydroxyvitamin D ₃ and a cellulose compound. Stabilized formulations exhibit stable dissolution characteristics upon exposure to storage conditions and exhibit improved pharmacokinetic parameters compared to unstabilized formulations.

Description

Stable modified release of vitamin D formulation and method of administration thereof Cross-reference to related applications

The benefit of 35 U.S.C. § 119(e) of U.S. Provisional Patent Application Serial No. 61/801,896, filed on Jan.

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

The vitamin D metabolites known as 25-hydroxyvitamin D ₂ and 25-hydroxyvitamin D ₃ (collectively referred to as "25-hydroxyvitamin D") are fat-soluble steroid pro-hormones that help maintain normal levels of calcium and phosphorus in the bloodstream. . The prohormone 25-hydroxyvitamin D _{2 is} produced from vitamin D ₂ (ergocalciferol) and 25-hydroxyvitamin D _{3 is} produced from vitamin D ₃ (cholecalciferol), mainly produced by one or more enzymes located in the liver. . The two prohormones can also be produced from vitamin D ₂ and vitamin D ₃ (collectively 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.

The 25-hydroxyvitamin D pre-hormone is further metabolized in the kidney to an effective vitamin D hormone. The prohormone 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 (calcitrienol). The production of such active hormones from the 25-hydroxyvitamin D pre-hormone can also occur in cells outside the kidney containing the desired enzyme (class).

A controlled release formulation that can be administered with 25-hydroxyvitamin D ₂ and/or 25-hydroxyvitamin D ₃ for the treatment of 25-hydroxyvitamin D deficiency and deficiency without the presence of intraluminal, intracellular and intravascular 25 - Super-physiological surge of hydroxyvitamin D content and its consequences; does not substantially cause an increase in the metabolism of the administered 25-hydroxyvitamin D; and does not cause serious side effects associated with vitamin D supplementation, namely vitamin D toxicity. Controlled release formulations effectively reduce the amount of PTH without causing undesirable increases in serum calcium and serum phosphorus and are therefore useful for treating, for example, CKD patients with secondary parathyroid gland hyperactivity. See International Patent Application No. PCT/US2007/061521 and PCT/US2008/061579, and U.S. Patent Application Serial No. 12/109,983, the disclosure of which is incorporated herein by reference.

The controlled release composition substantially increases the absorption of 25-hydroxyvitamin D via transport on the DBP and reduces the absorption of 25-hydroxyvitamin D via transport in the chylomicrons. The composition also provides that the amount of 25-hydroxyvitamin D in the blood is maintained substantially constant during the 24 hour post-dose period. By providing gradual, sustained, and direct release of 25-hydroxyvitamin D ₂ /25-hydroxyvitamin D ₃ , and preferentially absorbing DBP (rather than chylomicrons) in the circulation, in the blood, intraluminal, and intracellular 25 - The concentration of hydroxyvitamin D is dramatically increased, and the super-physiological amount and related undesired metabolism can be alleviated or eliminated. In addition, by providing a gradual and sustained release, the serum levels of 25-hydroxyvitamin D can be more predictably increased and maintained as compared to the immediate release formulation, thereby allowing for consistent doses and reducing or eliminating the need for frequent monitoring of patients. .

In order to deliver to a patient the benefit of a controlled release formulation of 25-hydroxyvitamin D, it is desirable to maintain a stable pharmaceutical composition for a period of time (e.g., after shipping and storage) that maintains the desired solubility properties of the formulation for extended periods of time.

The present invention comprises a controlled release vitamin D formulation comprising a vitamin D compound and a cellulosic compound.

The invention also encompasses a storage stable formulation for the controlled release of a vitamin D compound in the gastrointestinal tract of an individual ingesting a formulation. In one aspect, the stabilized formulation comprises 25-hydroxy and 25-hydroxy vitamin D ₂ and vitamin D ₃ compound stabilizer or stabilizer (e.g. a cellulose compound) in one or both. The stabilized formulations of the present invention and the stabilizers may have improved or relatively improved "storage stability" or post-aging stability when compared to the disclosed formulations without such agents. And one or more other features including improved physical, chemical, and biological properties. The claimed formulations are thus suitable as a therapy with a longer shelf life and improved bioavailability compared to aging, unstable formulations.

In one embodiment, the stabilized formulation comprises one or both of 25-hydroxyvitamin D ₂ and 25-hydroxyvitamin D ₃ , a lipophilic matrix (eg, a wax matrix), and a stabilizer (eg, a cellulose compound) . In one aspect, the stabilized formulation comprises 25-hydroxy-25-hydroxy vitamin D ₂ and vitamin D _3, waxes and cellulose matrix one stabilizer or both. In another aspect, the formulation comprises one or both of 25-hydroxyvitamin D ₂ and 25-hydroxyvitamin D ₃ , a wax base, and an effective amount of a cellulose compound to maintain the stability described herein. Degree.

In one embodiment, the stabilized formulation comprises a mixture of active loaded wax matrices comprising one or both of 25-hydroxyvitamin D ₂ and 25-hydroxyvitamin D ₃ and a cellulose stabilizer, wherein The formulation releases a certain amount of 25-hydroxyvitamin D during in vitro dissolution at 25 ° C and storage conditions at 60% relative humidity for at least one month, the same dissolution time as during in vitro dissolution on fresh products The amount of release was 30% or less than 30% at all dissolution test time points compared to the amount of release at the point.

In one embodiment, the formulation is a modified release control for a vitamin D compound. Good formulation. In one aspect, the ameliorating comprises incorporating a stabilizer into the formulation for controlled release of the vitamin D compound in the gastrointestinal tract of the individual ingesting the formulation. In another aspect, the improvement comprises controlled release of a vitamin D compound in the gastrointestinal tract of an individual in which an effective amount of the cellulosic compound is admixed to the formulation for ingestion of the formulation. Thereby providing an advantageous degree of stability as described herein.

In one embodiment, the invention comprises a stable sustained release vitamin D formulation comprising 25-hydroxyvitamin D ₂ or 25-hydroxyvitamin D ₃ or a combination thereof and a sustained release excipient, wherein the formulation has a T ₀ lower The dissolution profile X, which is maintained according to the formula X = T ₀ +/- 30%, is stored under storage conditions selected, for example, from room temperature and ambient humidity, or 25 ° C and 60% RH, or 40 ° C and 75% RH.

Other aspects and advantages of the general practitioner will be apparent from the following review of the embodiments taken in conjunction with the drawings. Although the compositions and methods are susceptible to various forms of the embodiments, the following description includes specific embodiments, and the disclosure is intended to be illustrative and not intended to limit the invention to the particular embodiments described herein.

The compositions and methods (as appropriate) of the compositions described herein, including but not limited to, components, ranges of compositions, substitutions, conditions, and procedures, are contemplated to be selected from the various aspects, examples, and examples provided herein.

Figure 1 shows the dissolution characteristics of the formulations of the present invention after storage for 0 to 24 months at 25 ° C and 60% relative humidity. X-axis depicts the dissolution time in hours, and the average percentage of dissolved Y axis shows the 25-hydroxy vitamin D _3. 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 for 0 to 6 months at 40 ° C and 75% relative humidity. X-axis depicts the dissolution time in hours, and the average percentage of dissolved Y axis shows the 25-hydroxy vitamin D _3. 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 for 0 to 12 months at 25 ° C and 60% relative humidity. X-axis depicts the dissolution time in hours, and the average amount of label released in the Y-axis shows the 25-hydroxy vitamin D _3. Figure 3A shows the dissolution profile of a comparative formulation that does not contain a cellulosic compound. Figure 3B shows the dissolution characteristics of the stabilized formulations of the present invention.

Figure 4 shows the average baseline adjusted ossification diol concentration obtained by the treatment group (PK population) of the patients described in Example 4, which patients were treated with the formulations of the present invention.

Figure 5 shows a summary baseline adjusted PK parameter of the resulting calcifediol concentration by the treatment group (PK population) of the patient described in Example 4, which patients were treated with the formulation of the present invention.

Figure 6 shows the mean baseline adjusted serum 1,25-dihydroxyvitamin D content obtained during the 6 week treatment (PK population) of the patients described in Example 4, which patients were treated with the formulations of the present invention.

Figure 7 shows a summary of the PK parameters of the baseline adjusted repeated doses of serum 1,25-dihydroxyvitamin D by the treatment group (PK group) of the patients described in Example 4, the formulations of the patients according to the invention deal with.

Figure 8 shows the average percentage of baseline obtained as a plasma iPTH amount during the 6 week treatment (PK population) of the patients described in Example 4, which patients were treated with the formulations of the present invention.

Figure 9 shows a summary of the PK parameters of the resulting baseline adjusted repeated doses of plasma iPTH by the treatment group (PK population) of the patients described in Example 4, which patients were treated with the formulations of the present invention.

Figures 10 and 11 show plasma iPTH versus baseline adjusted calcifediol and 1,25-dihydroxyvitamin D exposure at EOT in the PK population of patients treated with the formulation of the invention described in Example 4. (AUC _0-6wk ) Percentage change from baseline.

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 is free of immediate release. As used herein, the terms "sustained release" and "extended release" are used interchangeably and refer to the release of the administered vitamin D compound over a longer period of time than comparable immediate release formulations, resulting in comparable The serum concentration of the vitamin D compound remained elevated for a longer period of time compared to the immediate release of the formulation. The foregoing terminology includes, as appropriate, a delayed release profile. For example, delayed release type of controlled release formulations at a time by the C _max was greater than the C _max of the immediate release formulation characterization. As another example, the release of the 25-hydroxyvitamin D compound will preferably be such that the total serum or blood content of 25-hydroxyvitamin D is maintained or increased over an extended period of time (eg, 4 to 24 hours or even longer). Such rates exceed the pre-dosage amount.

As used herein, unless otherwise specified, the term "cellulose compound" may include cellulose _{(C 6 H 10 O 5)} n , or a cellulose derivative. "Cellulose ether" is a cellulose derivative that has been chemically modified to cause partial or complete etherification of hydroxyl groups in the cellulose molecule. Examples of cellulose derivatives useful as stabilizing agents include, but are not limited to, cellulosic acid, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl Methylcellulose, methylcellulose, polyanionic cellulose, and combinations thereof. The term also encompasses individual cellulose compounds or stabilizers corresponding to different grades of variables such as molecular weight, viscosity, solubility.

Any vitamin D compound and combinations thereof suitable for prophylactic and/or therapeutic use are contemplated to be included in the formulations described herein. Vitamin D, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and other metabolites and vitamin D analogs are also useful as active compounds in pharmaceutical compositions. Specific examples include, but are not limited to, vitamin D ₃ (cholecalciferol), vitamin D ₂ (ergocalciferol), 25-hydroxyvitamin D ₃ , 25-hydroxyvitamin D ₂ , 25-hydroxyvitamin D ₄ , 25- Hydroxyvitamin D ₅ , 25-hydroxyvitamin D ₇ , 1α,25-dihydroxyvitamin D ₃ , 1α,25-dihydroxyvitamin D ₂ , 1α,25-dihydroxyvitamin D ₄ and vitamin D analogues (including all hydroxyl groups) and dihydroxy form), such vitamin D analogs include 19-nor-1,25-dihydroxy - 1α- hydroxy-vitamin D ₂ and vitamin D _3. In one embodiment, the vitamin D compound comprises one or more hydroxyl forms, such as 25-hydroxy vitamin _{D. 3} and 25-hydroxyvitamin D ₂ of the composition.

Vitamins contemplated for particular types of formulations disclosed herein, the D 25-hydroxy compound may include vitamin D _2, 25- hydroxy Vitamin D or a combination _{thereof. 3.} Especially consider 25-hydroxyvitamin D ₃ . As used herein, the term 25-hydroxyvitamin D refers to one of 25-hydroxyvitamin D ₃ , 25-hydroxyvitamin D ₂ , 25-hydroxyvitamin D ₄ , 25-hydroxyvitamin D ₅ or 25-hydroxyvitamin D ₇ or and more, and are intended to refer to any yet preferred _{embodiment. 3} as 25-hydroxyvitamin D and 25-hydroxyvitamin D in one or more of _2, preferably 25-hydroxy vitamin D _3. Accordingly, any and all of the formulations described herein, the active agents may include the particular intended 25-hydroxy-25-hydroxy vitamin D ₂ and vitamin D _3, 25-hydroxy vitamin D ₃ in particular, one of or both. In the present invention, the vitamin D compound (or a combination thereof) is also referred to as the "active" portion of the formulation (or "active" agent) to distinguish it from a controlled release matrix, stabilizer, and other excipients. In the pharmacokinetic test reported herein for a sample using 25-hydroxyvitamin D ₃ as the active agent, the reference to 25-hydroxyvitamin D should be interpreted to mean 25-hydroxyvitamin D ₃ and all related thereto pharmacokinetic (PK) result (e.g. t _max, C _max, AUC) is understood to be based on the 25-hydroxy vitamin D _3.

As used herein, "stable" formulation refers to exhibiting stable in vitro dissolution characteristics (according to any of the parameters further described herein) and after initial manufacture (eg, in actual shelf storage or accelerated stable storage conditions) After a period of time, a controlled release (e.g., sustained release) formulation of the 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 assayed using any of the following dissolution studies described in the US Pharmacopoeia, USP 29-NF 24, Dissolution <711> Physical Testing and Determination, US Pharmacopoeia Convention Corporation, Rockville, MD, 2006, pp. 2673 2682 pages; European Pharmacopoeia 2.9.3 solid dosage form dissolution test 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, Dissolution <711> Physical Test and Determination, US Pharmacopoeia Convention Corporation, Rockville, MD, 2006, pages 2673-2682, using the following examples Equipment 2 (stirring paddle method) as described.

As used herein, _tmax (or Tmax) is defined as the time after which the plasma concentration of the active compound reaches its maximum at the dose interval after administration of the formulation of the invention. When administered with a single 25-hydroxy vitamin D compound (e.g. 25-hydroxy vitamin D _3), unless otherwise specified, t _max is defined as the formulation after administration, serum 25-hydroxyvitamin D concentrations in plasma at a dose of ₃ The time the interval reaches its maximum value.

Comply with NKF K/DOQI guidelines, as defined herein, vitamin D is adequately defined as serum 25-hydroxyvitamin D 30ng/mL, defined as vitamin D deficiency as serum 25-hydroxyvitamin D content of 16-30ng/mL, and mild vitamin D deficiency as serum 25-hydroxyvitamin D content of 5-15ng/mL, and will be severe Vitamin D deficiency is defined as a 25-hydroxyvitamin D content of less than 5 ng/mL.

In the privilege of granting a patent for a method of practice on the human body, the meaning of "taking" the composition for a human individual should be limited by the opening of the human individual by any technique (eg, oral, inhalation, surface coating). , injection, insertion, etc.) Self-administered controlled substances. It is expected that the broadest and most reasonable interpretation consistent with the laws or regulations defining the patentable subject matter will be used. In the privilege of not granting a patent for a method of practice on the human body, the "administration" composition includes two methods of practice on the human body as well as the aforementioned activities.

It is to be understood that all of the values recited herein, including all values of the lower and the For example, if the concentration range or favorable effect range is stated as 1% to 50%, it is desirable to explicitly recite values such as 2% to 40%, 10% to 30%, or 1% to 3% in the present specification. . As another example, about 20% of the stated concentration is intended to include a value from 19.5% up to 20.5%. These examples are only examples of specific expectations.

Disclosed herein are formulations for the controlled release of a vitamin D compound in the gastrointestinal tract of an individual ingesting a formulation. Formulations will include a vitamin D compound as described herein, a matrix component that releasably binds to a vitamin D compound and a controllably releasing a vitamin D compound (e.g., a lipophilic matrix), and a stabilizer (e.g., a cellulosic compound).

The stabilized formulation of the present invention releases a certain amount of 25-hydroxyvitamin D in in vitro dissolution after storage for a period of time which is not substantially different from dissolution of the same formulation only after manufacture and prior to storage. . For example, in one embodiment, the formulation releases a quantity of 25-hydroxyvitamin D during in vitro dissolution after exposure to storage conditions at 25 ° C and 60% relative humidity for two months, with the formulation being formulated The amount of release at the same dissolution time point during the in vitro dissolution period prior to exposure to storage conditions (ie, the freshly produced product) was changed at any given dissolution time point after four hours. % or less than 30%.

The following table provides the storage stability expected of the examples of the present invention after initial production at 25 ° C and 60% RH and or after multiple storages at 40 ° C and 75% RH, and at different times during the dissolution test. An example of the degree of sexual advantage. The degree of storage stability is expressed as the maximum deviation from the nominal activity, i.e., 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 as described in the above table at various time points throughout the dissolution test, for example at least at 2 and 4 hours, as appropriate At 6 hours, further depending on the situation, 8 hours The point and further conditions are also at the 12 hour time point so that the dissolution characteristics after storage follow the solubility characteristics of the fresh product. Alternatively, the formulation will have an advantageous degree of stability as described in the above table at least at the 2, 6 and 12 hour time points. Alternatively, the formulation will have an advantageous degree of stability as described in the above table at least at the 4, 8 and 12 hour time points. Alternatively, the formulation will have an advantageous degree of stability as described in the above table at least at the 2, 4 and 6 hour time points. Alternatively, the formulation will have an advantageous degree of stability immediately following the above table, at least at the 4, 6, 8 and 12 hour time points or all of the 4 hours time and thereafter.

In any and all of the examples described immediately in the above table, the deviation from the fresh product may be positive (more release) or negative (less release). In one embodiment, the deviation is intended to be in a negative direction (less release) at multiple points in time. Further, in one embodiment, if no stabilizer is present in the formulation, the deviation in dissolution release is intended to be negative (less release) at multiple points in time.

In any of the embodiments encompassed herein, the dissolution release profile of the formulation can have the characteristics of any of the examples provided herein below. For example, the formulation can be characterized by a dissolution release profile that provides less than 30% at 2 hours, greater than 45% at 6 hours, and greater than 80% at 12 hours and further conditions at 6 hours. Less than 60% release of the vitamin D compound.

In another embodiment, the formulation can be provided by providing a living body that is less than 30% at 100 to 140 minutes, greater than 45% at 5 to 7 hours, and greater than 80% of the release of a vitamin D compound at 11 to 13 hours. Characterization of external dissolution characteristics. In another embodiment, the formulation can be characterized by providing an in vitro dissolution profile of less than 30% at 2 hours, greater than 45% at 6 hours, and greater than 80% release of the vitamin D compound at 12 hours. In these types of embodiments, the release of the vitamin D compound is less than 60% at 5 to 7 hours or less than 60% at 6 hours, as appropriate.

In another embodiment, the formulation can be provided by about 20% to about 2 hours. In vitro dissolution profile of 40%, at least 35% at 6 hours and at least 70% release of vitamin D compound at 12 hours. In another embodiment, the formulation can be provided by providing a release of at least 45% to about 35% at 2 hours, at least 40% at 6 hours, and at least 75% at 12 hours. In vitro dissolution characterization. In these types of embodiments, the release of the vitamin D compound, as appropriate, is, for example, 75% or less at 6 hours, or 65% or less at 6 hours, or 60% at 6 hours. Or less than 60%.

In any of the embodiments described herein, the stabilized formulation can be characterized by _tmax after administration to a human patient dosage form, the _tmax being at least 4 hours, or at least 8 hours, or at least 12 hours, or at least 18 Hour, or at least 20 hours, or at least 24 hours, or at least 28 hours, such as in the range of 4 to 96 hours, or in the range of 18 to 30 hours, or in the range of 13 to 28 hours, or, for example, 28 hours.

In any of the embodiments contemplated herein, comprising a formulation of 25-hydroxyvitamin D, characterized by providing per microgram of 25-hydroxyvitamin D baseline-adjusted C _max was, when administered to an adult, the C _max of about 0.0133 From ng/mL to about 0.04 ng/mL.

In any of the methods encompassed herein, the method can comprise administering to a human patient a stabilized sustained release dosage form comprising a 25-hydroxyvitamin D compound, comprising administering to the patient an effective amount of the formulation to provide a baseline adjustments C _max, C _max which is at least about 0.2ng / mL, and optionally less than 110ng / mL, and further optionally a 24ng / mL or less than 24ng / mL, such as in the 24ng / mL range from about 0.2 to about.

In any of the methods encompassed herein, the method can comprise administering to a human patient a stabilized sustained release dosage form comprising a 25-hydroxyvitamin D compound, comprising administering to the patient an effective amount of the formulation to provide a baseline adjusting the AUC _0-inf, AUC _0-inf which is at least 52ng ^{* h} / mL, and optionally less than 34,500ng ^{* h} / mL, and further optionally from about 12,000ng ^{* h} / mL or less 12,000ng ^{* h} / mL, for example from about 52ng ^{* h} / mL to about 12,000ng ^{* h} / mL range.

In any of the embodiments described herein, the stabilized formulation is intended to be bioequivalent to the freshly prepared product after storage. Thus, for example, a stabilized formulation can provide an area under the curve of the active agent (or total 25-hydroxyvitamin D in serum) after storage, and the AUC (eg, AUC0 _-inf or AUC0 _-t ) is in the 90% confidence interval. Within, or within 80% to 125% of the average of fresh products, or within 80% to 120% of the average. Additionally or in the alternative, the stabilized formulations of the active agent may be provided (or serum total 25-hydroxy vitamin D) after storage of the maximum serum concentration, C _max (e.g. absolute or C _max C _max as compared to the baseline) Within the 90% confidence interval, or within 80% to 125% of the average of fresh products, or within 80% to 120% of the average.

In one embodiment, the stabilized formulation comprises 25-hydroxy-25-hydroxy vitamin D ₂ and vitamin D _3, waxes and cellulose matrix, one or both of the compounds. In one aspect, the stabilized formulation comprises 25-hydroxy-25-hydroxy vitamin D ₂ and vitamin D _3, waxes and cellulose matrix one stabilizer or both. In another aspect, the formulation comprises one or both of 25-hydroxyvitamin D ₂ and 25-hydroxyvitamin D ₃ , a wax base, and an effective amount of a cellulose compound to provide advantageous stability as described herein. Degrees, for example, according to any of the examples immediately following the above table or meeting the following. For example, the amount is effective to provide an amount of active agent that is released at a dissolution time point during in vitro dissolution after exposure to storage conditions of 25 ° C and 60% relative humidity for at least one month. A difference of 30% or less between the amounts released at the same dissolution time point during in vitro dissolution performed prior to storage conditions, whereas the comparative formulation lacking stabilizer 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 ameliorating comprises incorporating a cellulosic stabilizer into the formulation for controlled release of the vitamin D compound in the gastrointestinal tract of the individual ingesting the formulation. In another embodiment, the improvement comprises mixing an effective amount of the cellulosic compound into the formulation for ingesting the formulation Controlled release of a vitamin D compound in the gastrointestinal tract of an individual to provide advantageous stability as described herein, for example, according to any of the examples immediately following the above table or consistent with the following. For example, the amount is effective to provide an amount of active agent that is released at a dissolution time point during in vitro dissolution after exposure to storage conditions of 25 ° C and 60% relative humidity for at least one month. A difference of 30% or less between the amounts released at the same dissolution time point during in vitro dissolution performed prior to storage conditions, whereas the comparative formulation lacking stabilizer will result in dissolution release after the same storage conditions. Bigger difference.

The stabilizer may include a cellulose compound. Examples of cellulosic compounds and stabilizers for use in the stabilized formulations of the present invention may include, but are not limited to, cellulosic acid, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl Cellulose, hydroxypropyl methylcellulose, methylcellulose, polyanionic cellulose, and combinations thereof. Also encompasses poloxamers (eg polaxamer 407), poly(ethylene oxide) polymers (eg Dow's POLYOX polymers), povidones and aerosolized cerium oxide (eg AEROSIL 200, Evonik Industries) One or more of AG, Essen, Germany). The stabilizing agent (e.g., cellulosic compound) is preferably present in an amount of at least about 5% by weight (wt%) of the formulation based on the total weight of the formulation other than any other coating or outer shell. For example, the cellulosic compound can be at least 5% by weight of the formulation, or at least 10% by weight of the formulation, or at least 15% by weight of the formulation, or greater than 5% by weight of the formulation, or greater than 10% by weight of the formulation, or greater than the formulation. The amount of 15 wt% of the substance is present. Suitable ranges include 5 wt% to 30 wt%, 10 wt% to 20 wt%, 10 wt% to 15 wt%, 5 wt% to 15 wt%, and 7.5 wt% to 12.5 wt.%. Examples include about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, and about 15 wt%. It will be appreciated that the stabilizers referred to herein are those which are stable over time during storage conditions (e.g., typical shelf storage conditions) to stabilize the dissolution profile (and thus the in vivo release profile). Reagents. Used for Other agents known in the art as preservatives which prevent degradation of the active ingredient itself are not intended to be encompassed by the terms "stabilizing agent" and "stabilizer", although such preservatives are also Formulations contemplated for use in the present invention.

In one class of embodiments, the cellulosic compound is a cellulose ether. Examples of cellulose ethers include, but are not limited to, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and combinations thereof.

In particular, hydroxypropyl methylcellulose (HPMC) is considered. The HPMC can be characterized by one or more of the following features, which are specifically and individually expected in combination. The methoxy component % in HPMC can range from 19 to 24. The hydroxypropyl component % can range from 7 to 12. Viscosity (2% aqueous solution at 20 ° C) may be at least 50,000 centipoise, or at least 80,000 centipoise, or at 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 range from 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 an apparent viscosity in the range of 80,000 to 120,000 centipoise (2% aqueous solution at 20 ° C) is METHOCEL K100M CR (Dow Wolff Cellulosics, Midland, Michigan).

In one embodiment, the cellulosic compound will be insoluble in the matrix formulation at the melting point of the major component of the matrix (e.g., at 65 ° C or in the range of 60 ° C to 75 ° C).

In one embodiment, the cellulosic compound will be hydrophilic.

The pharmaceutical formulation of the present invention comprising one or more of 25-hydroxyvitamin D ₂ and 25-hydroxyvitamin D ₃ and a cellulose compound unexpectedly has a warp compared to a formulation lacking a cellulosic compound Improved stability. In one embodiment, the stabilized formulations of the present invention comprises a mixture comprising 25-hydroxy vitamin D ₂ and 25-hydroxyvitamin D ₃ and lipophilic base cellulose stabilizers one or both of the active loading of Where the formulation releases a quantity of 25-hydroxyvitamin D during in vitro dissolution after exposure to storage conditions at 25 ° C and 60% relative humidity for at least one month, and living with the freshly prepared product The amount of release varies by 30% or less at any given dissolution time point compared to the amount of release at the same dissolution time point during the external dissolution.

The unstabilized formulation exhibits a change in the amount of active ingredient released after the composition has been stored for a period of time, as shown in the examples below. An unstabilized formulation releases a quantity of 25-hydroxyvitamin D upon exposure to storage conditions, which can be varied at a given point in time, for example, in vitro dissolution on freshly prepared products. The change was more than 30% compared to the release amount at the same dissolution time point during the period. The change at a given point in time may be an increase or decrease in the rate of dissolution, and such changes result in a dissolution profile having a different solubility profile than the shape of the initial dissolution profile. The unstabilized formulation also exhibits a different appearance after storage as described herein (eg, after storage for 3 months or longer at 25 ° C and 60% RH) compared to the stabilized formulations of the present invention. In vivo effect. Stabilized formulations exhibit different clinical pharmacokinetics after storage as described herein (eg, after storage for 3 months or longer at 25 ° C and 60% RH) compared to unstabilized formulations Parameters such as improved bioavailability. The stabilized formulations of the present invention may have a base formulation that is unstable to storage and a stabilizer that stabilizes the storage of the formulation as described herein.

The matrix that releasably binds and controllably releases the active component can be, for example, a lipophilic matrix, including a wax matrix. The wax base can provide a solid or semi-solid formulation at room temperature and provides a solid, semi-solid or liquid formulation at body temperature, preferably a semi-solid or liquid formulation at body temperature. In one aspect, the wax matrix comprises a controlled release agent, an emulsifier, and an absorption enhancer.

Examples of controlled release agents suitable for this use 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 oil, glycerol mono-, di- or tri-allate; long-chain alcohols (such as stearyl alcohol, cetyl alcohol and polyethylene glycol); and mixtures of any of the above. Better not Digestive waxy material (such as hard paraffin).

The controlled release agent may be present in an amount of at least 5% by weight of the formulation or greater than about 5% by weight of the formulation. For example, depending on the controlled release agent used, the controlled release agent may comprise at least 5% by weight of the formulation or at least 10% by weight of the formulation, or at least 15% by weight of the formulation, or at least 20% by weight of the formulation, or At least 25% by weight of the formulation, or greater than 5% by weight of the formulation, or greater than 10% by weight of the formulation, or greater than 15% by weight of the formulation, or greater than 20% by weight of the formulation and or greater than 25% by weight of the formulation. The controlled release agent may be present in an amount of 50 wt% or less, 40 wt% or less than 40 wt%, 35 wt% or less than 35 wt% or 30 wt% or less than 30 wt%. Suitable ranges include 5 wt% to 40 wt%, 10 wt% to 30 wt%, and 15 wt% to 25 wt%. Examples include about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, and about 25 wt%.

Examples of emulsifiers suitable for use in the formulation include, but are not limited to, lipophilic agents having an HLB of less than 7, such as a mixed fatty acid monoglyceride; a mixed fatty acid diglyceride; a mixture of fatty acid mono- and diglycerides; a lipophilic polyglycerol; glycerol monooleate, glycerol dioleate, glyceryl monostearate, glyceryl distearate, glycerol monopalmitate and glyceryl dipalmitate; fatty acid glycerol Lactic acid ester; propylene glycol monoglyceride including propylene glycol monopalmitate, propylene glycol monostearate and propylene glycol monooleate; dehydrated sorbitol including sorbitan monostearate and sorbitan sesquioleate Sugar alcohol esters; fatty acids including stearic acid, palmitic acid and oleic acid and soaps thereof; and mixtures thereof; glycerol monooleate, glycerol dioleate, glyceryl monostearate, glyceryl distearate , glycerol monopalmitate, and glyceryl dipalmitate; fatty acid glycerol lactate; including propylene glycol monopalmitate, propylene glycol monostearate and propylene glycol monooleate propylene glycol ester; 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 the group consisting of glycerides and derivatives thereof. Preferred glyceride is selected from A group consisting of medium or long chain glycerides, octadecyl polyglycol glycerides, and mixtures thereof.

Preferred medium chain glycerides include, but are not limited to, medium chain monoglycerides, medium chain diglycerides, caprylic/capric triglycerides, glycerol monolaurate, glyceryl monostearate, caprylic/capric glycerol Ester, monocaprylin, mono-caprylic acid glyceride, caprylic/capric acid linoleic acid triglyceride and caprylic/capric acid/succinic acid triglyceride.

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 monocaprate, glycerol monolaurate, and the like, preferably It is glyceryl monostearate (GMS). GMS is a natural emulsifier. It is oil soluble but poorly soluble in water. The HLB value of GMS is 3.8. The lipophilic emulsifier can be present, for example, in an amount from about 10% to about 40% by weight or from about 20% to about 25% by weight. 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, octyl hexanoyl polyethylene glycol glyceride such as polyvinyl glycosylated glycerides, also known as polyglycolized glycerides or PEGylated (PEGylated) glyceride. The PEGylated glycerides which may be employed in the compositions include, but are not limited to, monoglycerides, diglycerides and triglycerides, and mixtures of monoesters and diesters of polyethylene glycol, polyvinyl glycosylated almonds. Glycerides, polyvinyl glycosylated corn glycerides and polyvinyl glycosylated caprylic/capric triglycerides. The absorption enhancer may have an HLB value of from 13 to 18 or from 13 to 15.

One preferred absorption enhancer known is under the trade name GELUCIRE (Gattefossé Corporation, Paramus, New Jersey, USA). GELUCIRE is a well-known excipient which is a family of fatty acid esters of glycerol and PEG esters, also known as pegylated glycerides. GELUCIRE is used in a variety of applications including the preparation of sustained release pharmaceutical compositions. GELUCIRE compounds are inert, semi-solid waxy materials that are amphoteric and that exhibit varying physical characteristics (such as melting point, HLB, and solubility) in different solvents. It is actually The surfactant is dispersed or dissolved in an aqueous medium to form micelles, microspheres or vesicles. It is identified by its melting point / HLB value. The melting point is expressed in degrees Celsius. One or a mixture of different grades of GELUCIRE excipients can be selected to achieve the desired characteristics of the melting point and/or HLB value. Preferably, the GELUCIRE composition is GELUCIRE 44/14 (a mixture of twelve oxime polyethylene glycol glycerides and twelve oxime polyoxyglycerides) having a melting point of 44 ° C and an HLB of 14. The absorption enhancer can be present, for example, in an amount from about 5 wt% to about 20 wt% or from about 8 wt% to about 15 wt%. Other examples include about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, and about 15 wt%.

The low melting point of the wax matrix provides a combination of a pharmaceutically active ingredient (eg, a vitamin D compound such as 25-D ₂ , 25-D ₃ or both) at a temperature of from about 0 ° C to about 50 ° C above the melting point of the wax matrix. And then the method of filling the melt (solution and/or dispersion) into a suitable capsule. The capsules can be of any variety compatible with the temperature at which the melt is filled, including soft or hard gelatin capsules and animal or vegetable gelatin capsules. The melt solidifies in the capsule upon cooling to room temperature.

In one aspect, the stabilized formulation may further comprise a 25-hydroxy vitamin D ₂ and / or 25-hydroxyvitamin D ₃ of the oil vehicle. Any pharmaceutically acceptable oil can be used. Examples include animals (eg, fish), plants (eg, soybeans), and mineral oils. The oil will preferably dissolve the 25-hydroxyvitamin D compound used. Preferred oily vehicles include non-digestible oils such as mineral oils, in particular, liquid paraffin and squalene. The oily vehicle can be present, for example, in a concentration ranging from about 10% to about 50%, or from about 15% to about 45%, or from about 20% to about 40%, or from about 30% to about 40% by weight of the formulation. . In one embodiment, suitable liquid paraffin may be characterized by one or more of the following parameters: specific gravity of from about 0.88 to 0.89; kinematic viscosity (40 ° C) of from about 64 cSt to about 70 cSt; molecular weight of 424; paraffinic percent It 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 amount of wax matrix can be used, and if a lighter oil component is used, a relatively large amount of wax matrix can be used.

The stabilized controlled release compositions of the present invention are preferably designed, for example, to have a concentration of from 1 to 1000 μg of 25-hydroxyvitamin D ₂ and/or 25-hydroxyvitamin D ₃ per unit dose, and are prepared in this manner. A controlled or substantially constant release of the effect of 25-hydroxyvitamin D ₂ /25-hydroxyvitamin D ₃ is achieved, which is optionally released into the ileum of the gastrointestinal tract of a human or animal over an extended period of time. Examples of the dose include 1 μg to 1000 μg, 1 μg to 600 μg, 1 μg to 400 μg, 1 μg to 200 μg, 1 μg to 100 μg, 5 μg to 90 μg, 30 μg to 80 μg, 20 μg to 60 μg, 30 μg to 60 μg, 35 μg to 50 μg, 5 μg to 50 μg per unit dose. And 10 μg to 25 μg, for example, 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, more preferably at least 80%, during the first 24 hours after administration.

It is advantageous, for example orally, according to the above embodiment, for example, 1 to 100μg per day dose administered and 25-hydroxy vitamin D _2, 25- hydroxy Vitamin D ₃ or combinations thereof together with other therapeutic agents. In one embodiment, the dosage will be selected to provide a dosage interval of about 1 to 3ng / ml of serum 25-hydroxyvitamin D ₃ were elevated.

In embodiments, the formulations described herein can be administered elevatedly and preferably also maintain a 1,25-dihydroxyvitamin D content in the blood at 25 pg/mL, 30 pg/mL or higher (eg, 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 formulation described herein can be administered to a patient to reduce or maintain a reduced serum parathyroid hormone content, preferably at least a 30% reduction in PTH content, or to reduce the serum levels of PTH to CKD. Target range (for example, 35-70pg/mL for phase 3 (equivalent to 3.85-7.7pmol/L), 70-110pg/mL for phase 4 (equivalent to 7.7-12.1pmol/L), and for phase 5 The amount required is 150-300 pg/mL (equivalent to 16.5-33.0 pmol/L) (as defined in K/DOQI Guide No. 1).

In another aspect, it can be secondary to hyperthyroidism with chronic kidney disease (eg 3 Patients in stage 4, or stage 3, 4 or 5) are administered a formulation of the invention to reduce serum PTH levels.

The dosages described herein are contemplated for use in any of the methods of treatment described herein. It will be appreciated that the actual preferred amount of the vitamin D compound will vary depending upon 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 customary comparison of hormones and different activities of known agents, for example by means of appropriate conventional pharmacological protocols.

The particular dose for each particular patient may depend on a variety of factors, such as age, weight, general health, sex, diet, timing and mode of administration, rate of excretion, combination of agents, and severity of the particular condition in which the therapy is administered. .

Patients requiring vitamin D supplementation include healthy individuals and individuals at risk of deficiency or deficiency of vitamin D, such as individuals with 1, 2, 3, 4 or 5 CKD; infants who do not drink vitamin D fortified milk, children and Adults (eg lactose intolerant individuals, milk allergic individuals, vegetarians who do not consume milk, and breastfed babies); individuals with rickets; dark-skinned individuals (eg in the United States, 42% between the ages of 15 and 49) The difference between African American women and 4% of white women is vitamin D deficiency); the elderly (reduced vitamin D ability and more likely to stay indoors); institutionalized adults (possibly indoors, including adults) Individuals with Alzheimer's disease or mental illness; individuals covering all bare skin (such as people of certain religions or cultures); individuals who always use sunscreens (eg, coated sun protection factor (SPF) values) 8 sunscreens reduce 95% of vitamin D production, and higher SPF values can further reduce vitamin D); suffer from fat malabsorption syndrome (including but not limited to cystic fibrosis, biliary stagnation liver disease, An individual with liver disease, gallbladder disease, pancreatic enzyme deficiency, Crohn's disease, inflammatory bowel disease, stomatitis diarrhea or celiac disease or surgical removal of some or all of the stomach and/or intestines; Individuals with inflammatory bowel disease; individuals with Crohn's disease; individuals who have had their small intestine removed; individuals with gingivitis; taking drugs that increase vitamin D metabolism (including phenytoin) Individuals (phenytoin), fosphenytoin, phenobarbital, carbamazepine, and rifampin; taking drugs that reduce vitamin D absorption (including cholestyramine) Individuals with colestipol, orlistat, mineral oil and fat substitutes; individuals taking drugs that inhibit the activation of vitamin D (including ketoconazole); taking drugs that reduce calcium absorption Individuals (including corticosteroids); individuals with obesity (vitamin D deposited in body fat stores are less bioavailable); individuals with osteoporosis; low bone mineral density and osteoporosis Patients with symptoms; and/or women after menopause. According to the Medical Society report on the dietary reference intake of vitamin D, the food consumption data indicates that the median intake of vitamin D for young and older women is lower than the current recommended intake; the data indicates that more than 50% of the young and Older women do not consume the recommended amount of vitamin D.

Excluding from the methods of the invention described herein is the treatment of individuals suffering from renal osteodystrophy (including rickets and cystic fibrosis).

In other aspects, the compositions and methods of the present invention are useful for the prevention or treatment of a vitamin D-reactive disease, wherein vitamin D, 25-hydroxyvitamin D or active vitamin D (eg 1,25-dihydroxyvitamin D) A disease that prevents the onset of disease or develops or reduces signs or symptoms of the disease. Such vitamin D reactive diseases include cancer (eg, breast, lung, skin, melanoma, colon, colorectal, rectal, prostate, and bone cancer). It has been observed that 1,25-dihydroxyvitamin D induces cell differentiation and/or inhibits cell proliferation of a plurality of cells in vitro. Vitamin D-reactive diseases also include autoimmune diseases such as type I diabetes, multiple sclerosis, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma, fibrosis, Grave's disease , Hashimoto's disease, acute or chronic graft rejection, acute or chronic graft-versus-host disease, inflammatory bowel disease, Crohn's disease, systemic lupus erythematosus, Hugh's syndrome, Eczema and psoriasis, dermatitis (including atopic dermatitis, contact dermatitis, atopic dermatitis and/or chronic dermatitis). Vitamin D-reactive diseases also include other inflammatory diseases such as asthma and chronic Obstructive pulmonary disease, polycystic kidney disease, polycystic ovarian syndrome, pancreatitis, nephritis, hepatitis and/or infection. Vitamin D-reactive diseases including hypertension and cardiovascular disease have also been reported. Thus, the present invention encompasses the prevention or treatment of individuals at risk of developing cardiovascular disease, such as atherosclerosis, arteriosclerosis, coronary artery disease, cerebrovascular disease, peripheral vascular disease, myocardial infarction, myocardial ischemia , cerebral ischemia, stroke, congestive heart failure, cardiomyopathy, obesity or other body weight disorders, lipid disorders (eg hyperlipidemia, including associated diabetic dyslipidemia and mixed dyslipidemia, low alpha-lipoproteinemia) Dyslipidemia, hypertriglyceridemia, hypercholesterolemia and low HDL (high density lipoprotein), metabolic disorders (eg metabolic syndrome, type 2 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 bloodshots.

Diseases that can benefit from the adjustment of vitamin D compounds include (but are not limited to): (i) in the form of parathyroid-parathyroid hypoxia, pseudo parathyroid hypoenergy, secondary parathyroid gland; (ii) pancreas Form of diabetes; (iii) in the form of medullary thyroid carcinoma; (iv) in the form of psoriasis of the skin; form of wound healing; (v) in the form of pulmonary sarcoma and tuberculosis; (vi) renal chronic kidney disease, low phosphate VDRR , vitamin D-dependent rickets; (vii) skeletal anticonvulsive therapy, poor bone fiber formation, cystic fibrosis, rickets, osteoporosis, osteopenia, osteopetrosis, renal osteodystrophy, rickets Form; (viii) in the form of intestinal glucocorticoid antagonism, spontaneous hypercalcemia in infancy, malabsorption syndrome, fatty sputum, tropical inflammatory diarrhea; and (ix) autoimmune disorder.

In an embodiment of the invention, the disease benefiting from the adjustment of the vitamin D compound is selected from the group consisting of cancer, skin disorders (eg, psoriasis), parathyroid disorders (eg, parathyroid gland hyperthyroidism, and secondary parathyroid dysfunction). , 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, components of the matrix (eg, waxes and oily vehicles) can be melted as needed to provide a flowable liquid thereby making it easier to obtain a homogeneous mixture. The active agent (eg, 25-hydroxyvitamin D ₂ and/or 25-hydroxyvitamin D ₃ ) is added to the liquid carrier, for example, dissolved in an alcohol such as absolute ethanol, and the ingredients are combined to provide a homogeneous mixture. In one embodiment, the stabilizer can be added after all matrix components (eg, waxes and oils) are blended and prior to combination 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 oil vehicle, controlled release agent, and emulsifier is heated to a relatively high temperature (eg, 65 ° C) and mixed prior to the addition of the absorption enhancer, followed by mixing until homogenization, followed by cooling to moderately high temperatures. (eg 50 ° C to 55 ° C). In a separate container, the remainder of the antioxidant preservative and the oil vehicle are mixed and heated to a moderately high temperature (e.g., 50 ° C), then combined and mixed with the wax mixture until a homogeneous solution is obtained. Then, stabilizers and mixing are added. The solution of the vitamin D compound in ethanol is then combined with a homogeneous waxy solution and mixed until a homogeneous solution is obtained, preferably filled into a capsule, and then cooled to room temperature. In another preferred method, one portion of the oil vehicle, controlled release agent, and emulsifier is heated at a temperature of from 55 ° C to 60 ° C and mixed prior to the addition of the absorption enhancer, followed by mixing until homogenization. In a separate container, the antioxidant preservative, the remainder of the oil vehicle, and the stabilizer are mixed and heated to a temperature between 55 ° C and 60 ° C, and then combined and mixed with the wax mixture until a homogeneous solution is obtained. The solution of the vitamin D compound in ethanol is then combined with a homogeneous waxy solution and 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 prior to administration to a patient in need of treatment. The capsules may be hard or soft, and in particular soft capsules are contemplated. The formulation can be filled into a gelatin capsule using a standard capsule filling machine, such as by melting the formulation and injecting it into the soft capsule shell. Examples of soft capsule shells include VEGICAPS and OPTISHELL technology (Catalent, Somerset, NJ, USA). In the alternative, any other suitable The formulations are formulated in unit dosage form, for example, to produce lozenges, sachets, dragees, suppositories, or the like.

In one embodiment, a formulation is prepared for oral delivery and administered by oral delivery. In another embodiment, the formulation is prepared for suppository and administered as a suppository, such as a rectal suppository.

The formulations and methods of use and preparation are intended to include embodiments including any combination of one or more of the optional elements, features and steps described further below, unless otherwise stated.

Thus, in one embodiment, the formulation further includes a preservative such as an antioxidant. Butylated hydroxytoluene (BHT) is preferred.

In another embodiment, the vitamin D compound is administered in combination with one or more other therapeutic agents.

If a vitamin D compound is administered in combination with one or more other therapeutic agents, the ratio of each of the compounds in the combination administered will depend on the particular disease condition being treated. For example, we may choose one or more calcium salts (expected as calcium supplements or dietary phosphate binders), bisphosphonates, calciimetics, niacin, iron, phosphate binders , cholecalciferol, ergocalciferol, active vitamin D sterol, blood sugar and hypertension control agents, CYP24 degradable vitamin D agents and other anti-neoplastic agents and inhibitors of other cytochrome P450 enzymes 25 - Hydroxyvitamin D ₂ and / or 25-hydroxyvitamin D ₃ (for example, oral). In addition, we can choose different anti-neoplastic agents and inhibitions from cholecalciferol, ergocalciferol, active vitamin D sterol, blood sugar and hypertension control agents, CYP24 and other cytochrome P450 enzymes of degradable vitamin D. The agents are administered intravenously with 25-hydroxyvitamin D ₂ and/or 25-hydroxyvitamin D ₃ . In practice, a higher dose of a compound of the invention is used when the therapeutic treatment of the disease condition is the desired endpoint, while the lower dose is usually used for prophylactic purposes, i.e., in any given case, the particular dose administered Modulations will be made based on the particular compound being administered, the condition being treated, the individual condition, and other medical facts that may alter the activity of the drug or the individual's response, as is well known to those skilled in the art.

As noted above, the formulation is preferably filled into a gelatin capsule, but it can also be administered in neat form or in one or more overcoat films, such as enteric coatings. It is also contemplated that the formulation may be compressed into a troche, and in this case may comprise one or more lozenge compressed excipients.

In the compositions and methods described herein, the preferred steps, preferred components, preferred ranges of compositions, and preferred combinations may be selected from the various specific examples provided herein. For example, preferred formulations include 25-hydroxyvitamin D (eg, about 30 μg, about 60 μg, or about 90 μg of 25-hydroxyvitamin D ₃ ), about 2 wt% (eg, 2.32 wt%) of absolute ethanol, about 10 wt% (eg, 9.75) Gt%) GELUCIRE 44/14, about 20 wt% (eg 20.00 wt.%) hard paraffin, about 23 wt% (eg 22.55 wt%) GMS, about 35 wt% (eg 35.36 wt%) liquid paraffin or mineral oil, about 10 wt% HPMC and, if appropriate, a small amount of preservative (eg 0.02 wt% BHT). A variation of this formulation will include about 15% (e.g., 15.29 wt%) HPMC and about 30 wt% (e.g., 29.88 wt%) liquid paraffin or mineral oil.

Instance

The following examples illustrate specific formulations and methods for their preparation. The examples are provided for illustration and are not intended to limit the scope of the invention.

The in vitro dissolution test was carried out in the examples using USP Apparatus 2 (stirring paddle method) as described in USP 29-NF 24, General <711> Dissolution, using the dissolution medium described below. In general, the method is carried out according to the following steps. The volume of dissolution medium (±1%) was placed in a container of the designated equipment, the equipment was assembled, the dissolution medium was equilibrated to 37 ± 0.5 °C and the thermometer was removed. Place the dose single position 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, the specimen was taken from the intermediate region between the surface of the dissolving medium and the top of the rotating blade (not less than 1 cm from the wall of the vessel). The extracted aliquots were replaced with the same volume of fresh dissolution medium at 37 °C. Maintain container coverage for the duration of the test and verify that the test is mixed at the appropriate time The temperature of the object. In this case, the analysis is carried out 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/1% sodium dodecyl sulfate dissolution medium at 37 ± 0.5 ° C and operated at 100 rpm. Samples were taken at 2, 4, 6, 8 and 12 hours and the 25-hydroxyvitamin D content of each sample was determined using UPLC.

Example 1-25 - In vitro dissolution of an unstabilized sustained release formulation of hydroxyvitamin D

Test consisted of 90 μg 25-hydroxyvitamin D ₃ , 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 The dissolution of the formulation made from the mixture. The formulation does not contain a cellulose compound. The average amount of the 25-hydroxy vitamin D ₃ released are summarized in the following table, in such amounts, the average at T = 0, and stored at 5 ℃ controlled humidity in the formulation and up to 12 months after each The average percentage of the nominal drug loading of the dosage form (average % of the labeled amount, % LC) was calculated. The sample was determined to be stored at a temperature ranging from 15 ° C to 30 ° C and ambient humidity for a period of about 3 months prior to testing. Therefore, the sample indicating the time zero should be marked as T=0 _p (pseudo-time zero) and the samples aged after 1 month, 3 months, 6 months, 9 months and 12 months should be known. Experience the approximately 3 month aging period just described. To provide more accurate baselines, samples of the same type of fresh batch were prepared and tested without any aging, and this data was labeled T=0 _f to indicate fresh samples. The coefficient of variation (%CV) is also reported. The percentage change from the initial amount of 25-hydroxyvitamin D ₃ released by the batches of T=0 _p and T=0 _f is provided in parentheses and double brackets, respectively.

The dissolution of Formulation 1 was compared after storage for 0 to 12 months at 25 ° C and 60% relative humidity. The results are summarized in the table below.

The dissolution of Formulation 1 was compared after storage at 40 ° C and 75% relative humidity for 0, 1, 3 and 6 months. The results are summarized in the table below.

Without intending to be bound by any particular theory, the increase in solubility after storage at 40 °C compared to the pseudo T=0 value is believed to be due to the aging effect described above and the A combination of temperature dependent phase changes in the formulation at 40 ° C.

The aged product of Comparative Formulation 1 was heat cured and subsequently subjected to a dissolution test. Curing consists of applying a heat treatment and has shown a stable pharmaceutical formulation (see, e.g., U.S. Patent No. 6,645,527). Comparative formulation 1 (aged sample) was heated at 40 ° C for 72 hours for curing and then stored at room temperature for 8 weeks. 0,2,4 tested after storage at room temperature for 8 weeks and 25-hydroxy vitamin D ₃ from the cured release formulations. The results are summarized in the table below.

Example 2-25 - In vitro dissolution of a stable controlled release formulation of hydroxyvitamin D

The test contained 90 μg of 25-hydroxyvitamin D ₃ , 19.88 wt% hard paraffin, 15.29 wt% hydroxypropyl methylcellulose, 22.55 wt% GMS, 9.76 wt% GELUCIRE 44/14 after storage for 0 to 11 weeks at room temperature. The dissolution of the sustained release formulation of 2.36 wt% absolute ethanol, 29.88 wt% liquid paraffin, and 0.02 wt% BHT (Example Formulation A). The results are summarized in the table below.

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

Example Formulation B shows a substantially stable dissolution profile after storage for at least 26 weeks at room temperature.

Test containing 30 μg of 25-hydroxyvitamin D ₃ (Example Formulation C), 60 μg of 25-hydroxyvitamin D ₃ (Example Formulation D) or 90 μg using storage conditions of 25 ° C and 60% relative humidity and 40 ° C and 75% relative humidity. 25-hydroxy vitamin D ₃ (examples of formulation E) the stability of the stabilized formulations. The compositions of the example formulations C to E are summarized in the table below:

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

^* 4 repetitions instead of 6 times

The percentage change between the initial release as compared to the amount of 25-hydroxy vitamin D ₃ of the released after aging are summarized in the table.

The example formulations C to E also exhibited substantially stable dissolution characteristics after storage for at least 6 months at 40 ° C and 75% RH (Figure 2). The dissolution results are summarized in the table below.

Percentage change compared to the initial release between the released after exposure to storage conditions of 25-hydroxy vitamin D ₃ in the amounts outlined in the table below.

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

Percentage change compared to the initial release between the released after exposure to storage conditions of 25-hydroxy vitamin D ₃ in the amounts outlined in the table below.

Example 3: In vivo results of unstabilized and stabilized controlled release formulations

Vivo studies performed to evaluate the clinical human subject in a controlled release 25-hydroxyvitamin D ₃ without the stability of the product of the stabilized formulations of pharmacokinetics. In Study A, 28 patients with stage 3 or 4 CKD, secondary parathyroid dysfunction (stage 3: 70-1000 pg/mL iPTH; stage 4: 110-1000 pg/mL iPTH) and vitamin D deficiency (serum) Individuals with a total baseline 25-hydroxyvitamin D of 15 ng/mL to 29 ng/mL receive a single oral dose of controlled release capsules or a single intravenous dose of 448 μg 25-hydroxyvitamin D ₃ in ethanol solution. Contains 450 μg or 900 μg of 25-hydroxyvitamin D ₃ , 20.00 wt% hard paraffin, 37.85 wt% GMS, 9.75 wt% GELUCIRE 44/14, 2.32 wt% absolute ethanol, 30.06 wt% mineral oil, and 0.02 wt% BHT (comparative formulation) 3). None of the formulations contained a cellulose compound.

The serum concentration of 25-hydroxyvitamin D ₃ gradually increases after administration of the oral dose. 25-hydroxy Vitamin D ₃ increases and the proportion of the dose to achieve 32ng / mL (approximate average maximum serum concentration observed (a Cmax)) after administration of 900μg capsule. The time to occurrence of Cmax (Tmax) is approximately 13 hours after administration. In contrast, the concentration of 25-hydroxy vitamin D ₃ after the administration of the rapid increase in administered intravenously. Immediately after administration by intravenous administration (Tmax = 0.5 hours), the maximum serum content was reached and an approximate mean Cmax of 134 ng/mL was reached. The bioavailability of oral doses is about 6 to 11%. The terminal half-life (t _1/2 ) of 25-hydroxyvitamin D ₃ after oral administration is about 12 to 22 days. No adverse effects on serum calcium or phosphorus or urine calcium were observed in any of the treatment groups.

The mean serum total 1,25-dihydroxyvitamin D amount increased rapidly after administration by intravenous injection, and increased by about 13 pg/mL from the pretreatment baseline 6 hours after administration. In contrast, the average serum total 1,25-dihydroxyvitamin D amount was administered at a dose ratio of about 7 pg/mL 48 hours after administration after administration of 900 μg of the capsule.

Serum iPTH display showed no practical change in the first 96 hours after administration via intravenous administration. In contrast, serum PTH gradually decreased after administration, reaching a maximum inhibition of about 20% from the pretreatment baseline for individuals receiving 900 [mu]g capsules. Observed The pharmacokinetic parameters of the treated groups are summarized in the table below.

The 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 25-hydroxyvitamin D of about 24 ng/mL (ranging from 11 ng/mL to 45 ng/mL) received a single oral dose or ethanol solution in a stabilized controlled release capsule. A single intravenous dose of 448 μg of 25-hydroxyvitamin D ₃ containing 900 μg of 25-hydroxyvitamin D ₃ , 20.00 wt% hard paraffin, 10.00 wt% HPMC, 22.55 wt% GMS, 9.75 wt% GELUCIRE 44/14 2.32 wt% absolute ethanol, 35.36 wt% mineral oil and 0.02 wt% BHT (example formulation F).

As compared with intravenous administration, by increasing the extension of the ₃ content of 25-hydroxyvitamin D after oral administration of the stabilized formulations show Tmax. After oral administration of the stabilized formulations show pharmacokinetic profiles 25-hydroxy vitamin D ₃ concentration gradually increased, wherein an average Tmax of 28 hours, most individuals while avoiding a rapid increase in blood content. Administered intravenously administered to the subject results in a rapid increase in all 25-hydroxy vitamin D ₃ concentration. Significant difference between the treatment groups by C _max observed in the highlight 25-hydroxy vitamin D ₃ to avoid a rapid increase in the content. The Cmax after oral administration was 58 ng/mL compared to Cmax of 153 ng/mL after intravenous administration.

After administration of the controlled release capsules of 25-hydroxy vitamin D ₃ smaller than twice the exposure after intravenously administered about, although oral administration is about twice as high, resulting in about 25% of the bioavailability. t _1/2 , elimination rate (CL), and volume distribution (Vd) are shown to be similar between treatment groups. The values of t _1/2 and CL are consistent with the prolonged elimination of the reported 25-hydroxyvitamin D ₃ . In addition, the Vd value indicates that 25-hydroxyvitamin D _{3 is} maintained in the systemic circulation and may be highly bound to DBP. The pharmacokinetic parameters of all treatment groups observed are summarized in the table below.

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

Modified release formulations studies have shown that 25-hydroxy vitamin D ₃ The rate of absorption of the stabilized control, resulting in a more gradual increase in the serum 25-hydroxy vitamin D ₃ content while maintaining the distribution and elimination characteristics. Stabilized formulations showed improved pharmacokinetic parameters (such as increased Tmax, AUC, and bioavailability) in Study A compared to the same administration of the unstabilized formulation.

In study C, 78 patients with stage 3 CKD (eGFR 25-70 mL/min/1.73 m ² ), SHPT (>70 pg/mL plasma iPTH), and vitamin D deficiency (total baseline 25-hydroxyvitamin D in serum was 10 ng) Individuals from /mL to 29 ng / mL) received a daily oral dose of a stable controlled release formulation or received a placebo for 6 weeks, the formulations containing 30 μg, 60 μg or 90 μg of 25-hydroxyvitamin D ₃ , 20.00 wt% Hard paraffin, 10.00 wt% HPMC, 22.55 wt% GMS, 9.75 wt% GELUCIRE 44/14, 2.32 wt% absolute ethanol, 35.36 wt% mineral oil, and 0.02 wt% BHT (example formulations C, D, and E from Example 2) ).

Comparison of all treatment groups at baseline mean serum concentration of 25- ₃ hydroxy vitamin D, and the range from about 16 to 20ng / mL range. By 25-hydroxyvitamin D ₃ after treatment, the mean serum 25-hydroxy vitamin D ₃ content of the gradual increase in the daily and repeated after ₃ to increase the administered dose-proportional manner of 25-hydroxyvitamin D, and 6 weeks after Near steady state (Figure 4). For the group administered with 30 μg, 60 μg, and 90 μg of 25-hydroxyvitamin D ₃ , the mean baseline adjusted Cmax values were about 28, 60, and 86 ng/mL, respectively. The background adjustments AUC _0-6 weeks assessed in all dose groups, based dose proportional average of 25-hydroxyvitamin D ₃ of the exposure. In accordance with the last dose, the mean serum 25-hydroxy vitamin D ₃ content decreased gradually, but the end of the study remains above the baseline for all groups. The average t _{1/2 was} determined to be between about 25 and 50 days. The baseline-adjusted pharmacokinetic parameters for 25-hydroxyvitamin D ₃ by the outlined in Table.

Comparing the average of all treatment groups at baseline serum concentration of 1,25-dihydroxy vitamin D and with increasing concentrations, similar to the effect produced on the ₃ serum 25-hydroxy vitamin D concentrations. The mean ± SD baseline adjusted Cmax values for the 60 μg and 90 μg groups were higher than those for 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 / respectively). mL). As assessed _0-6 weeks of baseline-adjusted AUC in the 25-hydroxyvitamin D ₃ dose groups of the Department dose proportional 1,25-hydroxyvitamin D of the average exposure. Baseline adjusted pharmacokinetic parameters for 1,25-dihydroxyvitamin D are summarized in the table below.

Compared with placebo in significantly more of all individuals in the active group, 25-hydroxy Vitamin D ₃ was stabilized controlled release formulations of the total 25-hydroxyvitamin D in serum increased to 30 ng/mL. Similarly, stable formulations in all dose groups resulted in a significant reduction in mean plasma iPTH from baseline compared to placebo.

Administered daily to the stabilized controlled release formulations of the 25-hydroxy Vitamin D ₃ increases in mean serum total 25-hydroxy vitamin D, and increasing the amount of administered dose proportional. The lowest dose (30 μg) at the end of the treatment increased serum total 25-hydroxyvitamin D from the pretreatment baseline (21.7 ± 1.8 ng/mL) by 15.6 ± 1.7 (SE) ng / mL, and the highest dose (90 μg) serum Total 25-hydroxyvitamin D increased by 61.1 ± 6.1 ng/mL from 21.8 ± 1.2 ng/mL. In contrast, in the combined placebo group, a decrease at the end of the 1.2 ± 0.7 ng/mL treatment was observed. The difference between the treatment group and the placebo group was significant (p < 0.0001) for all three doses studied. At the end of the treatment, the mean serum 25-hydroxyvitamin D content in the 30 μg dose group was 37.3 ± 1.8 ng/mL (slightly above the minimum appropriate level of 30 ng mL as specified by K/DOQI), indicating 30 μg as the minimum effective dose.

Achieved at the end of treatment in the 30 μg, 60 μg, and 90 μg dose groups compared to 0% in the placebo group The percentage of treated individuals with a total 25-hydroxyvitamin D content of 30 ng/mL serum was 92.3%, 100.0%, and 100.0%. The difference in response rates between the active agent and placebo treatment was significant (p < 0.001).

The mean plasma iPTH at the end of the treatment decreased in proportion to the dose of 25-hydroxyvitamin D ₃ administered. The lowest dose (30 μg) reduced iPTH by 20.2 ± 5.8 (SE)% from the pretreatment baseline, and the highest dose (90 μg) reduced iPTH by 35.9 ± 4.2%. In the combined placebo group, an increase of 17.2 ± 7.8% was observed at the end of the treatment. The difference between the 25-hydroxyvitamin D ₃ group and the placebo group was significant (p < 0.005) for all three doses studied, and it was advantageously replaced with a more effective and blood calcium oral vitamin D hormone replacement. Comparisons of the differences observed in longer treatments in the placebo-controlled study (eg, calcitriol, paricalcitol, and calcitriol).

Confirmed EOT iPTH reduction from pretreatment baseline (i.e., two successive measurements) of at least 20% or 30% of individuals receiving a percentage of 25-hydroxy vitamin D ₃ in the case where the dose is increased to 60μg end. A similar response rate was observed in the 60 and 90 [mu]g treatment groups, indicating that no other benefit in terms of iPTH reduction was observed for the 90 [mu]g dose in this study. The response rates for a 20% reduction in iPTH were confirmed to be 38.5%, 70.6%, and 76.5%, respectively, for the 30 μg, 60 μg, and 90 μg dose groups compared to 9.7% in the combined placebo group. The difference in response rates observed for a 20% reduction was significant only for the 60 μg and 90 μg dose groups (p < 0.005) and was significant (p < 0.05) for all 30 dose reductions. Information support 30μg daily release formulation in the 25-hydroxyvitamin D ₃ in the stabilized control of the minimum effective dose of conclusions.

25-hydroxy Vitamin D ₃ of the stabilized formulations of the albumin-corrected by the corrected serum calcium, urinary calcium excretion and serum phosphorus does not have a significant clinical effect. There was no adverse effect on serum calcium or serum phosphorus or urinary calcium during the 6-week treatment period.

Pharmacokinetic analysis revealed in all three dose groups, 25-hydroxy Vitamin D ₃ by the stability of formulations over 6 weeks to increase the 25-hydroxyvitamin D and ₃ dose-proportional mode of exposure (AUC and C _max), There is no difference in t _1/2 . After 6 weeks of administration, the three treatment groups had not fully reached steady state. However, the steady state model showed that steady state should have been reached by 7-9 weeks in all dose groups.

Data from this study clearly show controlled release of 25-hydroxyvitamin D ₃ by the stability of the formulations in serum total 25-hydroxyvitamin D was increased to the appropriate minimum content 30ng / mL of plasma and reducing iPTH aspect valid. The study also shows the Dose of 25-hydroxyvitamin D ₃ by the stability of the formulation have no effect on a clinically meaningful on serum calcium or phosphorus.

Example 4: Pharmacokinetics and pharmacodynamics of modified release of calcifediol in CKD individuals with secondary parathyroid gland hyperactivity and vitamin D deficiency

Multicenter, randomized, double-blind, placebo-controlled, repeated dose, safety, efficacy, and PK/PD of stabilized 25-hydroxyvitamin D ₃ (calciferated glycol, 25D ₃ ) capsules in two groups of individuals the study. For this study, patients with stage 3 CKD (eGFR 25-70 mL/min/1.73 m ² ) and vitamin D deficiency (serum 25-hydroxyvitamin D) were enrolled. 10 and 29 ng/mL), SHPT (plasma iPTH > 70 pg/mL) and male and female individuals aged 18 to 85 years without regular hemodialysis. Individuals in the first group were randomly divided into 3 treatment groups at a 1:1:1 ratio: the two groups received capsules at an oral dose of 60 or 90 μg per day and one group received matching placebo capsules. Individuals in the second group were randomized into two treatment groups at a 1:1 ratio: one group received 30 μg capsules daily and the other group 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. Serum calcium (Ca), phosphorus (P), 25D ₃ , total 1,25-dihydroxyvitamin D (1,25D) and plasma iPTH were monitored weekly during 6 weeks of treatment and 6 weeks of follow-up. The ANCOVA model detects the association of 25D ₃ exposure with baseline changes from 1,25D and iPTH. Covariates included were baseline eGFR, body weight and height, gender, age, race, 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 population). The average level of serum calcifediol was gradually increased in proportion to the dose and approached steady state at 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 baseline adjusted PK parameter summary of ossogenic diol concentration obtained by treatment group (PK population).

Figure 6 shows the mean baseline adjusted serum 1,25-dihydroxyvitamin D content obtained during the 6 week treatment period (PK population). The mean baseline adjusted serum total 1,25 dihydroxyvitamin D content increased over time in those individuals who were administered the active agent capsules compared to those who administered the placebo.

Figure 7 shows a summary of baseline adjusted dose PK parameters of serum 1,25-dihydroxyvitamin D obtained by treatment group (PK population).

Figure 8 shows the mean percentage of baseline obtained in plasma iPTH content during 6 week treatment (PK population). The active capsules significantly reduced mean plasma iPTH from baseline by 21%, 33%, and 39%, respectively, in all dose groups (30, 60, and 90 μg) compared to the 17% increase in the combined placebo group.

Figure 9 shows a summary of baseline adjusted adjusted dose PK parameters of plasma iPTH obtained by treatment group (PK population).

Figures 10 and 11 show the percentage of plasma iPTH versus baseline adjusted _calcifediol and 1,25-dihydroxyvitamin D exposure (AUC _0-6wk ) from baseline in the PK population. The percentage of plasma iPTH decreased from baseline to EOT increased with increasing _{serum calcifediol} and total 1,25 dihydroxyvitamin D exposure (expressed as baseline adjusted AUC _{0-6 wk} ) during _treatment .

The stabilized sustained-release 25-hydroxy vitamin D ₃ capsules so that the content of most individuals of normalization and 25D iPTH decreased in all dose groups (30, 60 and 90 ug) in. Stable, sustained release of 25-hydroxyvitamin D ₃ capsules gradually increased serum 25D ₃ and serum 1,25D levels, with exposure increasing in a dose-dependent manner. Both 25D ₃ and total 1,25D exposure were significant and negatively correlated with plasma iPTH from baseline changes. Only eGFR was a significant covariate in both models. These results show that the stable, sustained release of 25-hydroxyvitamin D ₃ capsules reliably normalizes the 25D content, increases serum 1,25D content, and inhibits plasma iPTH elevation without producing serum Ca and P during dose studies. The clinically meaningful effect.

***

The above description is given for the sake of clarity and is not to be construed as unnecessarily limiting, and modifications within the scope of the invention will be apparent to those skilled in the art.

Throughout this specification and the following claims, the word "comprise" and variations (such as "comprises/comprising") are to be understood to include the whole or the steps, unless otherwise specified herein. Or a group of the whole or a step, but does not exclude any other whole or steps or steps or groups of steps or steps.

Throughout the specification, unless otherwise stated, 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 otherwise described, the method is described as including a particular step, and the method is intended to be substantially any combination of the steps. Or consist of this combination. The invention disclosed herein is suitably practiced in the absence of any element or step that is not specifically disclosed herein.

The practice of the methods disclosed herein and the individual steps thereof can be performed manually and/or by electronic equipment. Although the process has been described with reference to a particular embodiment, one of ordinary skill in the art will readily appreciate that the action can be performed in other ways related to the methods. For example, the order of the various steps may be varied, without departing from the scope or spirit of the method, unless otherwise described. 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. The present invention should be controlled in the event of a conflict between the present invention and the incorporated patents, publications and references.

In view of the above description, the embodiments covered include the embodiments described in the following numbered paragraphs.

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 of releasable binding and controllably releasing a vitamin D compound, The matrix comprises a cellulose derivative.

2. A method for uptake in the gastrointestinal tract of an individual in a controlled release formulation of the vitamin D compounds of the stabilized formulations, the formulation comprises a mixture of the following: ₃ of 25-hydroxyvitamin D ₂ and 25-hydroxy vitamin D vitamin One or both; and an effective amount of a stabilizer, optionally as a cellulose compound, during in vitro dissolution after two months of exposure to storage conditions of 25 ° C and 60% relative humidity, after four hours The difference between the amount of vitamin D compound released at any given time point and the amount of release at the same dissolution time point during in vitro dissolution prior to exposure of the formulation to storage conditions was maintained to be less than 30%.

3. A stabilized formulation for controlling release of the vitamin D compound of the formulation comprising a mixture of: 25-hydroxy-25-hydroxy vitamin D ₂ and vitamin D in one or _{both. 3;} wax matrices; And a stabilizer, which is optionally a cellulose compound.

4. A method for uptake in the gastrointestinal tract of an individual in a controlled release formulation of the vitamin D compounds of the stabilized formulations, the formulation comprising a mixture of: 25-hydroxy-25-hydroxy vitamin D ₂ and vitamin D in _{the. 3} One or both; a wax base; and a stabilizer, optionally a cellulose stabilizer.

A formulation for stabilized control of the release of vitamin D, which formulation comprises a mixture of the following: 25-hydroxy-25-hydroxy vitamin D ₂ and vitamin D in one or _{both. 3;} wax matrices; and An effective amount of a stabilizer, optionally as a cellulose compound, during an in vitro dissolution test after two months of exposure to storage conditions of 25 ° C and 60% relative humidity, at any given time point after four hours The difference between the amount of released vitamin D compound and the amount of release at the same dissolution time point during in vitro dissolution performed prior to exposing the formulation to storage conditions was maintained to be less than 30%.

6. A method for uptake in the gastrointestinal tract of an individual in a controlled release formulation of the vitamin D compounds of the stabilized formulations, the formulation comprising a mixture of: active cargo wax matrix, comprising 25-hydroxy vitamin D ₂ and 25 release an amount of 25-hydroxyvitamin wherein during formulation is dissolved in vitro exposure to 25 deg.] C and 60% relative humidity after two months of storage; hydroxy vitamin D ₃ in one or both -; and cellulose stabilizers Vitamin D, in the absence of a cellulosic stabilizer, the release amount is compared to the release amount at the same dissolution time point during in vitro dissolution performed prior to exposing the formulation to storage conditions, at any given Change 30% or less than 30% at the time of dissolution.

7. In a formulation for controlled release of a vitamin D compound in the gastrointestinal tract of an individual ingesting a formulation, the improvement comprises incorporating a cellulosic stabilizer into the formulation.

8. In a formulation for controlled release of a vitamin D compound in the gastrointestinal tract of an individual ingesting a formulation, the improvement comprises mixing the cellulosic compound into the formulation such that upon exposure to 25 ° C and 60% relative humidity The amount of 25-hydroxyvitamin D released during any in vitro dissolution period after at least one month of storage, at any given dissolution time point after four hours, and in vitro dissolution prior to exposing the formulation to storage conditions The change in the period at the same dissolution time point was 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 methylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Group.

11. The formulation of paragraph 9, wherein the cellulosic compound or cellulosic stabilizer is hydroxypropyl methylcellulose.

12. The formulation of any of the preceding paragraphs, wherein the formulation releases a quantity of 25-hydroxyvitamin D during in vitro dissolution after exposure to storage conditions of 25 ° C and 60% relative humidity for two months, 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 exposure to the storage conditions.

13. The formulation of any of the preceding paragraphs, wherein the formulation releases a quantity of 25-hydroxyvitamin D during in vitro dissolution after exposure to storage conditions of 40 ° C and 75% relative humidity for one month, 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 exposure to the storage conditions.

The formulation of any of the preceding paragraphs, wherein the matrix comprises a wax matrix comprising a controlled release agent, an emulsifier, and an absorption enhancer.

15. The formulation of paragraph 14, wherein the controlled release reagent comprises paraffin wax.

16. The formulation of paragraph 14 or 15, wherein the emulsifier has an HLB value of less than 7.

17. The formulation of paragraph 16, wherein the emulsifier 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 from about 13 to about 18.

19. The formulation of paragraph 18, wherein the absorption enhancer is a mixture of twelve oxime polyethylene glycol glycerides and twelve oxime polyoxyglycerides.

20. A section of any of the preceding paragraphs of the formulation, wherein the vitamin D compound comprises 25-hydroxy Vitamin D _3.

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 mineral oil.

23. The formulation of paragraph 22, wherein the formulation comprises about 20% by weight paraffin wax, about 20% to about 25% by weight glyceryl monostearate, about 10% by weight of 12 醯 polyethylene glycol glyceride, and 12 醯 poly A mixture of oxyglycerides, from about 30% to about 35% by weight mineral oil and from about 10% to about 15% by weight hydroxypropyl methylcellulose.

The formulation of any of the preceding paragraphs, wherein the formulation comprises glyceryl monostearate.

The formulation of any of the preceding paragraphs, wherein the formulation comprises one or more pegylated glycerides.

26. A sustained release dosage form in the form of a capsule, lozenge, sachet, dragee or suppository comprising a formulation according to any of the preceding paragraphs.

27. The dosage form of paragraph 26, which comprises a capsule or lozenge.

28. The dosage form of paragraph 27, which comprises a capsule.

29. The dosage form of paragraph 26, which comprises an oral capsule, a lozenge, a sachet, a dragee.

30. A stabilized dosage form according to any of the preceding paragraphs, characterized in that the dissolution profile of the following release of the vitamin D compound is less than 30% at 2 hours; greater than 45% at 6 hours; and greater than at 12 hours 80%.

31. The stabilized dosage form of paragraph 26, wherein the release of the vitamin D compound is less than 60% at 6 hours.

32. A stabilized sustained release oral dosage form comprising a vitamin D compound, characterized in that the in vitro dissolution profile of the following release of the vitamin D compound is 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 paragraph 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 release of the vitamin D compound is less than 60% at 6 hours.

36. A stabilized sustained release oral dosage form comprising a vitamin D compound, characterized in that the in vitro dissolution profile of the following release of the vitamin D compound is provided from about 20% to about 40% at 2 hours; At least 35% at 6 hours; and at least 70% at 12 hours.

37. The dosage form of paragraph 36, wherein the release of the vitamin D compound at about 2 hours is from about 25% to about 35%; at least 40% at 6 hours; and at least 75% at 12 hours.

38. The dosage form of paragraph 36 or 37, wherein the release of the vitamin D compound at 7 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 than 65%.

40. The dosage form of paragraph 39, wherein the release of the vitamin D compound at 60 hours is 60% or less.

41. A stabilized sustained release dosage form comprising a vitamin D compound, characterized in that _{tmax is} at least 4 hours after administration of the dosage form to a human patient.

42. The dosage form of paragraph 41, wherein _{tmax is} at least 8 hours.

43. The dosage form of paragraph 42, wherein _{tmax is} at least 12 hours.

44. The dosage form of paragraph 43, wherein _{tmax is} at least 18 hours.

45. The dosage form of paragraph 44, wherein _{tmax is} at least 20 hours.

46. The dosage form of paragraph 45, wherein _{tmax is} at least 24 hours.

47. The dosage form of paragraph 46, wherein _{tmax is} at least 28 hours.

48. The dosage form of paragraph 41, wherein _{tmax is} in the range of 4 to 96 hours.

49. The dosage form of paragraph 48, wherein _{tmax is} in the range of 18 to 30 hours.

50. The dosage form of paragraph 49, wherein _{tmax is} in the range of 13 to 28 hours.

51. The dosage form of paragraph 50, wherein _tmax is about 28 hours.

52. A stabilized comprising a compound of the 25-hydroxy vitamin D sustained release dosage form characterized by providing per microgram of 25-hydroxyvitamin D baseline-adjusted C _max was, when administered to an adult, the C _max of about 0.0133 From ng/mL to about 0.04 ng/mL.

53. A method of administering to a human patient a stabilized sustained release dosage form comprising a 25-hydroxyvitamin D compound, comprising administering to the patient an effective amount of the dosage form to provide at least about 0.2 ng/mL and less than 110 ng/mL. _Cmax adjusted by baseline.

54. The method of paragraph 53, which comprises administering an effective amount of the dosage form to provide a baseline adjusted _{Cmax in the} range of from about 0.2 to about 24 ng/mL.

55. A method comprising sustained release dosage form 25-hydroxy vitamin D compound of the stabilized administering to a human patient, comprising administering an effective amount to the patient the dosage form to provide at least 52ng ^{* h} / mL and to less than 34500ng ^* Baseline adjusted AUC _{0-inf for} h/mL.

56. The method of paragraph 55, which comprises administering to a patient an effective amount of the dosage form to provide from about 52ng ^{* h} / mL to approximately baseline-adjusted by the 12,000ng ^{* h} / mL range AUC _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 reactive 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 (eg, breast, lung, skin, melanoma, colon, colorectal, rectal, prostate, and bone cancer), autoimmune disease (eg, type I diabetes, multiple Sclerosis, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma, fibrosis, Graves' disease, Hashimoto's disease, acute or chronic graft rejection, acute or chronic graft resistance Host disease, inflammatory bowel disease, Crohn's disease, systemic lupus erythematosus, Hugh's syndrome, eczema and psoriasis, dermatitis (including atopic dermatitis, contact dermatitis, atopic dermatitis and / or chronic dermatitis), inflammatory diseases (such as asthma, chronic obstructive pulmonary disease, polycystic kidney disease, polycystic ovarian syndrome, pancreatitis, nephritis, hepatitis and / or infection), hypertension, cardiovascular disease (individual Suffering from atherosclerosis, arteriosclerosis, coronary artery disease, cerebrovascular disease, week Vascular disease, myocardial infarction, myocardial ischemia, cerebral ischemia, stroke, congestive heart failure, cardiomyopathy, obesity or other body weight disorders, lipid disorders (eg hyperlipidemia, including associated diabetes dyslipidemia and mixing) Abnormal dyslipidemia, dyslipidemia, hypertriglyceridemia, hypercholesterolemia, and low HDL (high-density lipoprotein), metabolic disorders (eg, metabolic syndrome, type 2 diabetes, type I diabetes) Hyperinsulinemia, abnormal glucose tolerance, insulin resistance, diabetic complications (including neuropathy, nephropathy, osteoporosis, retinopathy, diabetic foot ulcers and cataracts) and/or bloodshots.

60. The method of paragraph 59, wherein the disease is selected from the group consisting of (i) a form of parathyroid-parathyroid hypoxia, pseudohypothyroid dysfunction, secondary parathyroid hyperactivity; (ii) a form of pancreatic diabetes; (iii) In the form of medullary thyroid carcinoma; (iv) skin psoriasis; wound healing; (v) pulmonary sarcoma and tuberculosis; (vi) renal chronic kidney disease, hypophosphate VDRR, vitamin D-dependent rickets Form; (vii) skeletal anticonvulsant therapy, poor bone fiber formation, cystic fibrosis, rickets, osteoporosis, osteopenia, osteopetrosis, renal osteodystrophy, rickets; (viii) Intestinal glucocorticoid antagonism, spontaneous hypercalcemia in infancy, malabsorption syndrome, fatty sputum, tropical inflammatory diarrhea; and (ix) autoimmune disorders.

61. The method of paragraph 60, wherein the disease is selected from the group consisting of cancer, a skin condition (eg, psoriasis), a parathyroid disorder (eg, parathyroid dysfunction and secondary parathyroid dysfunction), a skeletal disorder (eg, osteoporosis). And autoimmune disorders.

62. The method of paragraph 61, wherein the disease is secondary parathyroid hyperactivity.

63. The method of paragraph 62, wherein the individual has chronic kidney disease (CKD).

64. The method of paragraph 63, wherein the CKD is 3 or 4 stages.

65. The method of paragraph 64, wherein the patient is deficient in vitamin D.

The method of any of the preceding paragraphs, wherein the patient is a human.

67. The method of paragraph 66, wherein the human is an adult.

68. A composition as substantially described herein.

Claims (32)

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 releasable binding and controllably releasing the vitamin D compound a matrix comprising a cellulose derivative selected from the group consisting of: cellulosic acid, carboxymethylcellulose, ethylcellulose, polyanionic cellulose, cellulose ether, and combinations thereof; and wherein the formulation is for the vitamin D The change in the dissolution release of the compound is stable. A stabilized formulation for 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 stabilizer is a cellulosic compound; and wherein the formulation is stable to changes in the dissolution release of the vitamin D compound. The formulation of claim 1 or claim 2, wherein the cellulose compound or cellulose derivative comprises a cellulose ether. The formulation of claim 3, wherein the cellulose ether is selected from the group consisting of methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose or A group of combinations. The formulation of claim 4, wherein the cellulose ether is hydroxypropyl methylcellulose. The formulation of claim 1 or claim 2, wherein the formulation releases a certain amount of 25-hydroxyvitamin D during in vitro dissolution after exposure to storage conditions of 25 ° C and 60% relative humidity for two months, The release amount is 30% or less at any given dissolution time point after four hours as compared to the release amount at the same dissolution time point during in vitro dissolution of the formulation prior to exposure to the storage conditions. %. The formulation of claim 1 or claim 2, wherein the formulation releases a certain amount of 25-hydroxyvitamin D during in vitro dissolution after exposure to a storage condition of 40 ° C and 75% relative humidity for one month, The release amount is 30% or less at any given dissolution time point after four hours as compared to the release amount at the same dissolution time point during in vitro dissolution of the formulation prior to exposure to the storage conditions. . The formulation of claim 1 or claim 2, wherein the matrix comprises a wax matrix comprising a controlled release agent, an emulsifier, and an absorption enhancer. The formulation of claim 8, wherein the wax comprises paraffin wax. The formulation of claim 8, wherein the emulsifier has an HLB value of less than 7. The formulation of claim 8, wherein the emulsifier comprises glyceryl monostearate. The formulation of claim 8, wherein the absorption enhancer has an HLB value in the range of from about 13 to about 18. The formulation of claim 8, wherein the absorption enhancer is a mixture of twelve oxime polyethylene glycol glycerides and twelve oxime polyoxyglycerides. The requested item 1 or 2 formulation of requests, wherein the vitamin D compound comprises 25-hydroxy Vitamin D _3. The formulation of claim 1 or claim 2, further comprising an oily vehicle. The formulation of claim 15, wherein the oily vehicle comprises mineral oil. The formulation of claim 8, wherein the formulation comprises about 20% by weight paraffin wax, about 20% by weight to about 25% by weight glyceryl monostearate, about 10% by weight of dodecyl polyethylene glycol glyceride, and twelve oxime polyoxygen A mixture of glycerides, from about 30% to about 35% by weight mineral oil and from about 10% to about 15% by weight hydroxypropyl methylcellulose. The formulation of claim 1 or claim 2, wherein the dissolution profile provides less than 30% at 2 hours; greater than 45% at 6 hours and greater than 80% release of the vitamin D compound at 12 hours. A sustained release dosage form in the form of a capsule, lozenge, sachet, dragee or suppository comprising a formulation as claimed in claim 1 or claim 2. One kind of 25- hydroxy vitamin D ₂ and / or 25-hydroxy vitamin D ₃ of the stabilized formulations, comprising 25-hydroxy vitamin D ₂ and / or 25-hydroxy vitamin D _3, from about 20wt% paraffin, from about 20wt% to A mixture of about 25 wt% glyceryl monostearate, about 10 wt% of dodecyl polyethylene glycol glyceride and tweezane polyoxyglyceride, from about 30 wt% to about 35 wt% mineral oil, and from about 10 wt% to about 15 wt% Hydroxypropyl methylcellulose; and wherein the formulation is stable to changes in the dissolution release of the vitamin D compound. A formulation according to any one of claims 1, 2 or 20 for use in raising serum 25-hydroxyvitamin D levels in a patient. A formulation according to any one of claims 1, 2 or 20 for use in raising serum 1,25-dihydroxyvitamin D content in a patient. A formulation according to any one of claims 1, 2 or 20 for use in reducing serum complete parathyroid hormone levels in a patient. A formulation according to any one of claims 1, 2 or 20 for use in the treatment of deficiency or deficiency of vitamin D. A formulation according to any one of claims 1, 2 or 20 for use in the treatment of secondary parathyroid dysfunction. A formulation according to any one of claims 1, 2 or 20 for use in treating a patient suffering from chronic kidney disease. Use of a formulation according to any one of claims 1, 2 or 20 for the manufacture of a medicament for increasing serum 25-hydroxyvitamin D levels in a patient. Use of a formulation according to any one of claims 1, 2 or 20 for the manufacture of a medicament for increasing serum 1,25-dihydroxyvitamin D levels in a patient. Use of a formulation according to any one of claims 1, 2 or 20 for manufacture A drug used to reduce serum levels of complete parathyroid hormone in a patient. A use of a formulation according to any one of claims 1, 2 or 20 for the manufacture of a medicament for the treatment of deficiency or deficiency of vitamin D. A use of a formulation according to any one of claims 1, 2 or 20 for the manufacture of a medicament for the treatment of secondary parathyroid dysfunction. A use of a formulation according to any one of claims 1, 2 or 20 for the manufacture of a medicament for treating a patient suffering from chronic kidney disease.