NZ711924B2

NZ711924B2 - Stabilized modified release vitamin d formulation and method of administering same

Info

Publication number: NZ711924B2
Application number: NZ711924A
Authority: NZ
Inventors: Sammy A Agudoawu; Joel Z Melnick; Samir P Tabash; Jay A White
Original assignee: Opko Ireland Global Holdings Ltd
Priority date: 2013-03-15
Filing date: 2014-03-14
Publication date: 2021-04-30

Abstract

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

Description

STABILIZED MODIFIED E VITAMIN D FORMULATION AND METHOD OF ADMINISTERING SAME REFERENCE TO RELATED APPLICATION The beneﬁt under 35 U.S.C. §119(e) ofUS. Provisional Patent ation Serial No. 61/801,896 ﬁled March 15, 2013, is hereby claimed and the disclosure thereof is incorporated herein by reference.

BACKGROUND Field of the Disclosure The sure relates generally to controlled release pharmaceutical compositions.

More particularly, the invention relates to controlled-release formulations for delivery of a vitamin D nd for intestinal absorption, such as a 25-hydroxyvitamin D compound, which are shelf-stable over time.

Brief Description of Related Technology The Vitamin D metabolites known as 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 (collectively referred to as “25-hydroxyvitamin D”) are fat-soluble steroid prohormones that contribute to the maintenance of normal levels of calcium and phosphorus in the bloodstream.

The prohormone 25-hydroxyvitamin D2 is produced from Vitamin D2 (ergocalciferol) and 25- hydroxyvitamin D3 is produced from Vitamin D3 calciferol), primarily by one or more s located in the liver. The two prohormones also can be produced outside of the liver from Vitamin D2 and Vitamin D3 (collectively referred to as “Vitamin D”) in certain cells, such as enterocytes, which contain s cal or similar to those found in the liver.

The 25-hydroxyvitamin D prohormones are ﬁlrther metabolized in the kidneys into potent Vitamin D hormones. The prohormone 25-hydroxyvitamin D2 is lized into - dihydroxyvitamin D2; likewise, 25-hydroxyvitamin D3 is metabolized into lot,25- dihydroxyvitamin D3 (calcitriol). Production of these active hormones from the 25- hydroxyvitamin D prohormones also can occur outside of the kidney in cells which contain the required enzyme(s).

Controlled e formulations of 25-hydroxyvitamin D2 and/or 25-hydroxyvitamin D3 can be administered to treat 25-hydroxyvitamin D insufficiency and def1ciency without supraphysiological surges in intraluminal, intracellular and blood levels of 25-hydroxyvitamin D and their consequences; without causing substantially sed catabolism of the administered -hydroxyvitamin D; and, without causing serious side effects associated with Vitamin D mentation, namely Vitamin D toxicity. The controlled release formulations effectively lower PTH levels without undesirable increases in serum calcium and serum phosphorus and are therefore useful for ng secondary hyperparathyroidism, for e in CKD patients. See ational Patent Application Nos. PCT/U82007/061521 and PCT/U82008/061579 and US.

Patent Application No. 12/ 1 09,983, incorporated herein by reference.

The controlled released compositions provide substantially increased absorption of 25- hydroxyvitamin D via transport on DBP and decreased absorption via transport in icrons.

The compositions also provide maintenance of substantially constant blood levels of 25- hydroxyvitamin D during a 24-hour post-dosing period. By providing a gradual, sustained and direct release of 25-hydroxyvitamin hydroxyvitamin D3 and absorption preferentially to circulating DBP (rather than to chylomicrons), blood, intraluminal and intracellular 25- hydroxyvitamin D concentration spikes, i.e., supraphysiologic levels and related unwanted catabolism can be mitigated or eliminated. rmore, by providing a gradual and sustained release, serum levels of roxyvitamin D can be increased and ined more predictably than by administration of immediate release formulations, allowing for a consistent dosage and reducing or ating the need for frequent patient monitoring.

To deliver the beneﬁts of controlled release formulations of 25-hydroxyvitamin D to patients, there is a need for stabilized pharmaceutical compositions that retain the d dissolution properties of the formulation, for extended periods of time, e.g., after shipping and storage.

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

The present invention also comprises a storage-stabilized formulation for lled release of a vitamin D compound in the gastrointestinal tract of a subject which ingests the formulation. In one aspect, the stabilized formulation comprises one or both of 25- hydroxyvitamin D2 and 25-hydroxyvitamin D3 and a stabilizing agent or stabilizing compound, e.g. a cellulosic compound. The stabilized formulations of the invention with the recited stabilizing agent(s) can have improved or relatively improved “storage stability”, or stability following aging, as well as one or more additional characteristics including improved physical, al and biological properties when compared to the sed formulations that do not contain such agents. The claimed ations are thus suitable as therapeutics that possess a long shelf life as well as improved ilability compared to aged, unstable formulations.

In one embodiment, the stabilized formulation includes one or both of 25- hydroxyvitamin D2 and 25-hydroxyvitamin D3, a lipophilic matrix (e.g. a wax ), and a stabilizing agent (e. g., a cellulosic compound). In one aspect, a stabilized formulation includes one or both of roxyvitamin D2 and 25-hydroxyvitamin D3, a wax matrix, and a cellulosic stabilizing agent. In another aspect, the formulation includes one or both of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3, a wax matrix, and an ive amount of a cellulosic compound to maintain an advantageous degree of stabilization described herein.

In one type of embodiment, the ized formulation comprises a mixture of an -loaded wax matrix comprising one or both of 25-hydroxyvitamin D2 and 25- hydroxyvitamin D3 and a osic stabilizing agent, wherein the formulation releases an amount of 25-hydroxyvitamin D during in vitro dissolution after exposure to storage ions of at least one month at 25 0C and 60% relative humidity that varies at all dissolution g time points by 30% or less compared to the amount released at the same dissolution time points during in vitro dissolution conducted on fresh product.

In one type of embodiment, the formulation is an improvement formulation for controlled e of a vitamin D compound. In one aspect, the improvement comprises admixing a stabilizing agent into a formulation for controlled release of a vitamin D compound in the gastrointestinal tract of a subject which ingests the formulation. In another , the improvement comprises an effective amount of a cellulosic compound admixed into a formulation for controlled release of a vitamin D compound in the gastrointestinal tract of a subject which ingests the formulation to provide an advantageous degree of ity described herein.

In one embodiment, the invention comprises a stable sustained release vitamin D formulation comprising 25-hydroxyvitamin D2 or 25-hydroxyvitamin D3 or combinations thereof and sustained e excipients wherein said ation has a dissolution proﬁle X at To that retains this proﬁle according to the formula X=T0+/-30% over e conditions selected from room temperature and ambient humidity, or 25 0C and 60% RH, or 40 0C and 75% RH, for example.

Further s and advantages will be apparent to those of ordinary skill in the art from a review of the following detailed description, taken in conjunction with the gs.

While the compositions and methods are susceptible of embodiments in various forms, the description hereafter includes speciﬁc ments with the understanding that the disclosure is rative, and is not intended to limit the invention to the speciﬁc embodiments described herein.

For the itions and methods described herein, optional features, including but not limited to components, compositional ranges thereof, substituents, conditions, and steps, are contemplated to be selected from the various s, embodiments, and examples provided herein.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the dissolution proﬁle of formulations according to the disclosure after storage for 0 to 24 months at 25 0C and 60% relative humidity. The dissolution time in hours is depicted on the X-axis and the mean percent of 25-hydroxyvitamin D3 dissolved is shown on the y-aXis. Figures 1A, 1B, and 1C show the dissolution proﬁle of formulations comprising 30 ug, 60 ug, and 90 ug of 25-hydroxyvitamin D3, respectively.

Figure 2 shows the dissolution proﬁle of formulations according to the disclosure after storage for 0 to 6 months at 40 0C and 75% relative humidity. The dissolution time in hours is depicted on the X-axis and the mean percent of 25-hydroxyvitamin D3 dissolved is shown on the y-aXis. s 2A, 2B, and 2C show the dissolution proﬁle of formulations comprising 30 ug, 60 ug, and 90 ug of 25-hydroxyvitamin D3, respectively.

Figure 3 shows the dissolution proﬁle of formulations after storage for 0 to 12 months at 25 0C and 60% relative humidity. The ution time in hours is depicted on the X-axis and the mean % Label Claim of 25-hydroxyvitamin D3 released is shown on the y-aXis. Figure 3A shows the dissolution proﬁle of a comparative ation that does not contain a cellulosic compound. Figure 3B shows the dissolution proﬁle of a stabilized formulation according to the sure.

Figure 4 shows the resulting mean baseline-adjusted ediol concentrations by treatment group (PK tion) for the patients described in Example 4 treated with a formulation according to the disclosure.

Figure 5 shows the resulting summary baseline-adjusted PK ters for calcifediol concentrations by treatment group (PK population) for the patients described in Example 4 treated with a ation according to the disclosure.

Figure 6 shows the resulting mean baseline-adjusted serum l,25-dihydroxyvitamin D levels during the 6-week treatment (PK population) for the patients described in Example 4 treated with a formulation according to the disclosure.

Figure 7 shows a summary of the resulting baseline-adjusted repeat-dose PK parameters for serum l,25-dihydroxyvitamin D by treatment group (PK population) for the patients bed in Example 4 treated with a formulation according to the disclosure.

Figure 8 shows the resulting mean percent of baseline in plasma iPTH levels during the 6-week ent (PK population) for the patients described in Example 4 treated with a formulation according to the disclosure.

Figure 9 shows a y of the resulting ne-adjusted repeat-dose PK parameters for plasma iPTH by treatment group (PK population) for the ts described in Example 4 treated with a formulation according to the disclosure.

Figures 10 and ll show the percent change from baseline at EOT for plasma iPTH relative to baseline-adjusted calcifediol and l,25-dihydroxyvitamin D exposure (AUC0_6Wk) in the PK Population for the ts described in Example 4 treated with a formulation according to the disclosure.

ED DESCRIPTION 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 way that deviates from immediate e. 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 a comparable immediate e formulation, resulting in serum trations of the vitamin D compound that remain elevated over baseline for a longer period of time than for a comparable immediate release formulation. The foregoing terms ally include delayed release characteristics. For example, a delayed release type of controlled release formulation will be characterized by Cmax at a time greater than Cmax for an immediate release formulation. As another example, the release of a 25-hydroxyvitamin D nd will preferably be at such a rate that total serum or blood levels of 25-hydroxyvitamin D are maintained or ed above predosing levels for an extended period of time, e.g. 4 to 24 hours or even longer.

As used herein, the term “cellulosic compound” can include cellulose (C6H1005)Il or a derivative of cellulose, unless speciﬁed otherwise. A “cellulose ether” is a cellulose derivative that has been chemically modiﬁed to result in partial or complete etherif1cation of the hydroxyl groups in the cellulose molecule. es of cellulose derivatives which can be used as stabilizing agents include, but are not limited to, celluloronic acid, y methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, hydroxyl propyl methylcellulose, methyl cellulose, polyanionic cellulose, and combinations thereof, for example.

Different grades of each cellulosic compound or izing agent, corresponding to variations in, e.g., molecular weight, viscosity, solubility, and ion, are also encompassed by the terms.

Any vitamin D compound suitable for prophylactic and/or therapeutic use, and combinations thereof, are contemplated for inclusion in the formulation described herein.

Vitamin D, 25-hydroxyvitamin D, l,25-dihydroxyvitamin D, and other lites and analogs of Vitamin D are also useful as active compounds in pharmaceutical compositions. Speciﬁc examples include, but are not limited to, n D3 (cholecalciferol), Vitamin D2 (ergocalciferol), 25-hydroxyvitamin D3, 25-hydroxyvitamin D2, 25-hydroxyvitamin D4, 25- yvitamin D5, 25-hydroxyvitamin D7, lu,25-dihydroxyvitamin D3, lu,25- dihydroxyvitamin D2, lu,25-dihydroxyvitamin D4, and vitamin D analogs (including all hydroxy and dihydroxy forms), including l,25-dihydroxy-l9-nor-vitamin D2, and lu-hydroxyvitamin D3.

In one type of embodiment, the vitamin D compound includes one or more y forms, such as a ation of roxyvitamin D3 and 25-hydroxyvitamin D2.

A type of Vitamin D compound particularly contemplated for use in the ation sed herein can include 25-hydroxyVitamin D2, 25-hydroxyVitamin D3, or a combination thereof. 25-hydroxyVitamin D3, is particularly contemplated. As used herein, the term 25- hydroxyVitamin D refers to one or more of 25-hydroxyVitamin D3, 25-hydroxyVitamin D2, 25- hydroxyVitamin D4, 25-hydroxyVitamin D5, or 25-hydroxyVitamin D7, and it is contemplated that in any reference o a red embodiment is one or more of 25-hydroxyVitamin D3 and 25- hydroxyVitamin D2, preferably 25-hydroxyVitamin D3. Thus, in any and all formulations described herein, it is speciﬁcally contemplated that the active can include one or both of 25- hydroxyVitamin D2 and 25-hydroxyVitamin D3, particularly 25-hydroxyVitamin D3. In the disclosure herein, the Vitamin D compound (or combination thereof) is also referred to as the “active” part of the formulation (or “active” agents), as distinguished from the controlled release matrix, the stabilizing agent, and other excipients. In the pharmacokinetic testing reported herein with samples that used 25-hydroxyVitamin D3 as the active, references to roxyVitamin D should be interpreted to mean roxyVitamin D3, and all pharmacokinetic (PK) results associated with (e.g., tmax, Cmax, AUC) should be understood to be based on 25-hydroxyVitamin As used herein, a “stabilized” formulation refers to a formulation exhibiting a stable in vitro dissolution proﬁle (according to any of the parameters described further ) and controlled e (e. g., sustained release) of a Vitamin D compound in viva, for a time following initial manufacture, e. g. following actual shelf storage or accelerated stability storage conditions.

The release of the active ingredient can be measured using a suitable in vitro ution method, such as one of the methods already known in the art. In principle, any of the dissolution studies described in the United States Pharmacopeia, USP 29-NF 24, Dissolution <7l l> physical tests and determinations, United States Pharmacopeial tion, Inc., RockVille, MD, 2006, pp. 2673—2682.; an Pharmacopoeia 2.9.3 Dissolution Test for Solid Dosage Forms, or the Japanese copoeia 6.10 Dissolution Test, can be used to determine if a formulation is stable. For purposes of the present invention, the in vitro dissolution method is United States Pharmacopeia, USP 29-NF 24, Dissolution <7l l> al tests and determinations, United States Pharmacopeial tion, Inc., RockVille, MD, 2006, pp. 2673—2682, using Apparatus 2 (paddle method), as described in the Examples below.

As used herein, tmax (or Tmax) is deﬁned as the time for the plasma concentration of the active compound to reach its maximum in a dose al following administration of a formulation according to the invention. When administering a single 25-hydroxyvitamin D compound, for example 25-hydroxyvitamin D3, trnax is deﬁned as the time for the plasma concentration of serum 25-hydroxyvitamin D3 to reach its maximum in a dose interval following administration of the formulation, unless speciﬁed otherwise.

Consistent with the NKF K/DOQI ines, as used herein Vitamin D ency is deﬁned as serum 25-hydroxyvitamin D levels 2 30 ng/mL, Vitamin D ciency is deﬁned as serum 25-hydroxyvitamin D of 16-30 ng/mL, mild Vitamin D deﬁciency is deﬁned as serum 25- hydroxyvitamin D of 5-15 ng/mL, and severe Vitamin D deﬁciency is deﬁned as serum 25- hydroxyvitamin D below 5 ng/mL.

In jurisdictions that forbid the patenting of methods that are practiced on the human body, the meaning of “administering” of a composition to a human subject shall be restricted to prescribing a lled substance that a human subject will self-administer by any technique (e. g., orally, inhalation, topical application, injection, ion, etc.). The broadest reasonable interpretation that is consistent with laws or regulations deﬁning patentable subject matter is intended. In jurisdictions that do not forbid the patenting of methods that are practiced on the human body, the “administering” of compositions includes both methods practiced on the human body and also the foregoing activities.

It is speciﬁcally understood that any numerical value recited herein includes all values from the lower value to the upper value, i.e., all le combinations of cal values between the lowest value and the t value enumerated are to be ered to be expressly stated in this application. For example, if a concentration range or a beneﬁcial effect range is stated as 1% to 50%, it is intended that values such as 2% to 40%, 10% to 30%, or 1% to 3%, etc., are expressly enumerated in this speciﬁcation. As r example, a stated concentration of about 20% is intended to include values from 19.5% up to 20.5%. These are only examples of what is speciﬁcally intended.

Disclosed herein are formulations for controlled release of a Vitamin D compound in the gastrointestinal tract of a subject which ingests the formulation. The formulation will e a Vitamin D compound as described herein, a matrix component that releasably binds the Vitamin D compound and controllably releases the vitamin D nd (e.g., a ilic matrix), and a stabilizer (e. g. a cellulosic compound).

A stabilized formulation according to the disclosure herein, following storage for a period of time, releases an amount of 25-hydroxyvitamin D in in vitro ution that does not substantially differ from the ution of the same formulation just after manufacturing and prior to e. For example, in one embodiment, a ation releases an amount of 25- hydroxyvitamin D during in vitro dissolution after exposure to storage conditions of two months at 25 0C and 60% relative humidity that varies at any given ution time point after four hours by 30% or less compared to the amount released at the same dissolution time point during in vitro dissolution conducted prior to exposing the formulation to the storage conditions (i.e., freshly-produced product).

The table below provides examples of advantageous degrees of e stability contemplated for embodiments of the invention following storage at 25 0C and 60% RH, and alternatively at 40°C and 75% RH for various times following initial manufacturing, and at various times in during dissolution testing. The degrees of storage stability are expressed in terms of the maximum deviation from nominal active potency, i.e. maximum % change from LC.

Alternative embodiments ofmaximum deviation are also provided.

Time 1 month 3 mos. 6 mos. 9 mos. 12 mos. 18 mos. 24 mos. storage at 25 °C and 60% RH %, or 25%, or 20%, or %, or 10% %, or 25%, or 20%, or %, or 10% %, or 25%, or 20%, or %, or 10% %, or 25%, or 20%, or %, or 10% WO 43941 % 10% 10% 10% 10% 10% %, or 25%, or 20%, or %, or 10% storage at 40 °C and 75% RH %, or 25%, or 20%, or %, or 10% %, or 25%, or 20%, or %, or 10% %, or 25%, or 20%, or %, or 10% %, or 25%, or 20%, or %, or 10% %, or 25%, or 20%, or %, or 10% In one type of embodiment, the formulation will have advantageous degrees of stability described in the table immediately above at multiple time points throughout the ution testing, e.g. at least at both 2 and 4 hour time points, optionally also at the 6 hour time point, further optionally also at the 8 hour time point, and further optionally also at the 12 hour time point, such that the dissolution proﬁle after storage follows the dissolution proﬁle of fresh product. Alternatively, the formulation will have advantageous degrees of stability described in the table immediately above at least at the 2, 6, and 12 hour time points. Alternatively, the formulation will have advantageous degrees of stability described in the table immediately above at least at the 4, 8, and 12 hour time points. Alternatively, the formulation will have advantageous degrees of stability described in the table immediately above at least at the 2, 4, and 6, hour time points. Alternatively, the formulation will have advantageous degrees of stability described in the table ately above at least at the 4, 6, 8, and 12 hour time , or at all times of 4 hours and thereafter.

In any and all of the embodiments described in the table immediately above, it is contemplated that the deviation can be positive (more release) or negative (less release) with respect to the fresh product. In one type of embodiment, it is contemplated that the ion will be in the negative (less release) direction at multiple time points. Still ﬁlrther, in one type of embodiment it is contemplated that the deviation in dissolution release would have been negative (less release) at le time points but for the presence of the stabilizing agent in the formulation.

In any of the embodiments contemplated herein, the dissolution release proﬁle of the formulation can have the characteristics of any one of the examples provided herein below. For example, the formulation can be terized by a dissolution release proﬁle providing a release of vitamin D compound of less than 30% at 2 hours, r than 45% at 6 hours, and greater than 80% at 12 hours, and further optionally less than 60% at 6 hours.

In another type of embodiment, the ation can be characterized by an in vitro dissolution proﬁle providing release of vitamin D nd of less than 30% at 100 to 140 minutes, r than 45% at 5 to 7 hours, and greater than 80% at 11 to 13 hours. In another type of embodiment, the formulation can be characterized by an in vitro dissolution proﬁle providing release of vitamin D compound of less than 30% at 2 hours, greater than 45% at 6 hours, and greater than 80% at 12 hours. In these types of embodiments, optionally the release of vitamin D compound at 5 to 7 hours is less than 60%, or at 6 hours is less than 60%.

In another type of embodiment, the formulation can be characterized by an in vitro dissolution proﬁle providing release of vitamin D compound of about 20% to about 40% at 2 hours, at least 35% at 6 hours, and at least 70% at 12 hours. In another type of embodiment, the formulation can be characterized by an in vitro dissolution proﬁle providing release of vitamin D nd of about 25% to about 35% at 2 hours, at least 40% at 6 hours, and at least 75% at 12 hours. In these types of ments, optionally the release of vitamin D compound is 75% or less at 6 hours, or 65% or less at 6 hours, or 60% or less at 6 hours, for example.

In any of the embodiments described herein, the ized formulation can be characterized by a tmax following administration of the dosage form to a human patient, of at least 4 hours, or at least 8 hours, or at least 12 hours, or at least 18 hours, or at least 20 hours, or at WO 43941 least 24 hours, or at least 28 hours, for example in a range of 4 to 96 hours, or in a range of 18 to hours, or in a range of 13 to 28 hours, or is 28 hours, for example.

In any of the embodiments contemplated herein a formulation sing 25- hydroxyvitamin D can be characterized by providing a baseline-adjusted Cmax per microgram of -hydroxyvitamin D in a range of about 0.0133 ng/mL to about 0.04 ng/mL when administered to an adult human.

In any of the methods contemplated herein, the method can e administering a stabilized sustained release dosage form comprising a 25-hydroxyvitamin D compound to a human patient, comprising administering an effective amount of the formulation to the patient to provide a baseline-adjusted Cmax of at least about 0.2 ng/mL and optionally less than 110 ng/mL, and ﬁarther optionally 24 ng/mL or less, for example in a range of about 0.2 to about 24 ng/mL.

In any of the methods contemplated herein, the method can include administering a stabilized sustained release dosage form comprising a roxyvitamin D compound to a human t, comprising administering an effective amount of the formulation to the patient to provide a ne-adjusted AUCO_inf of at least 52 ng*h/mL, and optionally less than 34,500 ng*h/mL, and further optionally about 12,000 ng*h/mL or less, for example in a range of about 52 ng*h/mL to about 12,000 ng*h/mL.

In any of the embodiments bed herein, it is contemplated that the stabilized formulation, following storage, can be bioequivalent to the freshly-made product. Thus, for example, the stabilized formulation, following storage, can provide an area under the curve for the active (or serum total roxyvitamin D), AUC (e.g., AUCO_infor AUC0_t) within a 90% nce interval, or within 80% to 125% of the mean, or within 80% to 120% of the mean of the fresh product. In addition or in the ative, the stabilized formulation, following storage, can provide a maximum serum concentration of the active (or serum total 25-hydroxyvitamin D), Cmax (e.g., Cmax absolute, or Cmax compared to baseline) within a 90% conﬁdence al, or within 80% to 125% of the mean, or within 80% to 120% of the mean, of the fresh product.

In one embodiment, a stabilized formulation comprises one or both of 25- hydroxyvitamin D2 and 25-hydroxyvitamin D3, a wax matrix, and a cellulosic compound. In one aspect, a stabilized formulation comprises one or both of 25-hydroxyvitamin D2 and 25- hydroxyvitamin D3, a wax matrix, and a cellulosic stabilizing agent. In another aspect, the formulation comprises one or both of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3, a wax , and an effective amount of a cellulosic compound to provide an advantageous degree of stability as described herein, e.g. with respect to the table immediately above or consistent with any of the es described below. For example, the amount can be effective to provide a difference of 30% or less between the amount of active ed during in vitro dissolution after re to storage ions of at least one month at 25 0C and 60% ve humidity at a dissolution time point and the amount released at the same dissolution time point during in vitro dissolution conducted prior to exposing the formulation to the storage conditions, while a comparative formulation lacking the stabilizing agent would result in a greater difference in dissolution release following the same storage conditions.

In one , the formulation is an improved formulation for lled release of a vitamin D compound in the gastrointestinal tract of a subject which ingests the formulation. In one embodiment, the improvement comprises admixing a cellulosic izing agent into a formulation for controlled release of a vitamin D compound in the gastrointestinal tract of a subject which ingests the formulation. In another embodiment, the improvement comprises an ive amount of a cellulosic compound admixed into a formulation for controlled release of a vitamin D compound in the gastrointestinal tract of a subject which ingests the formulation to provide an advantageous degree of stability as described herein, e.g. with t to the table immediately above or consistent with any of the Examples bed below. For example, the amount can be effective to provide a difference of 30% or less between the amount of active released during in vitro dissolution after exposure to storage conditions of at least one month at 0C and 60% relative humidity at a ution time point and the amount released at the same dissolution time point during in vitro ution conducted prior to exposing the formulation to the storage conditions, while a comparative formulation lacking the stabilizing agent would result in a r difference in dissolution release following the same storage conditions.

The stabilizing agents can include cellulose compounds. Examples of cellulose compounds and stabilizing agents for use in the stabilized formulations of the disclosure can include, but are not limited to, celluloronic acid, y methyl cellulose, ethyl ose, hydroxyl ethyl cellulose, hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, methylcellulose, polyanionic cellulose, and combinations thereof Also contemplated are one or more of poloxamers (e. g., polaxamer 407), poly (ethylene oxide) polymers (e. g., Dow’s POLYOX polymers), nes, and ﬁlmed s (e. g., AEROSIL 200, Evonik Industries AG, Essen, Germany). The stabilizer, e. g. a cellulosic compound, preferably is present in an amount of at least about 5 % of the formulation, based on the total weight of the ation excluding any additional coatings or shells (wt%). For example, the cellulosic compound can be present in an amount of at least 5 wt% of the formulation, or at least 10 wt% of the ation, or at least wt% of the formulation, or r than 5 wt% of the formulation, or greater than 10 wt% of the formulation, or greater than 15 wt% of the formulation. Suitable ranges include 5 wt% to 30 wt%, 10 wt% to 20 wt%, 10 wt% to 15 wt%, 5 wt% to 15 wt%, and 7.5 wt% to 12.5 wt.%.

Examples include about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, and about 15 wt%. It will be understood that the stabilizing agent referred to herein is an agent that stabilizes the dissolution release proﬁle (and thus also the in viva release proﬁle) against ntial change over time during storage conditions, e.g. typical shelf storage conditions. Other agents which are known in the art as preservatives for preventing degradation of the active component itself are not intended to be encompassed within the terms “stabilizing agent” and “stabilizer” although such preservatives are also contemplated for use in the formulations of the present ion.

In one class of embodiment, the osic compound is a cellulose ether. Examples of cellulose ethers include, but are not limited to, methylcellulose, hydroxyl propyl methylcellulose, yl ethyl methylcellulose, hydroxyl ethyl cellulose, hydroxyl propyl cellulose, and combinations thereof. yl propyl cellulose (HPMC) is particularly contemplated. The HPMC can be characterized by one or more of the following features, which are speciﬁcally plated individually and in combinations. The % methyoxyl component in the HPMC can be in a range of 19 to 24. The % hydroxypropyl component can be in a range of 7 to 12. The apparent viscosity (2% solution in water at 20°C) can be at least 50,000 cP, or at least 80,000 cP, or in a range of about 80 to 120,000 cP, or 3000 to 120,000 cP, or 11,000 to 120,000 cP, or 80,000 to 120,000 cP. Particularly, the apparent viscosity (2% solution in water at 20°C) can be in a range of 80,000 to 120,000 CF. The pH (1% solution in water) can be in a range of5.5 to 8.0. For example, a suitable hydroxyl propyl methylcellulose having all of the foregoing properties, including an apparent viscosity (2% solution in water at 20°C) in a range of 80,000 to 120,000 CF, is METHOCEL K100M CR (Dow Wolff Cellulosics, Midland, Michigan).

In one type of embodiment, the osic compound will be insoluble in the matrix formulation at the melt point of the primary components of the matrix, e.g., at 65 0C or in a range of 60 0C to 75 0C.

In one type of embodiment, the cellulosic compound will be hydrophilic.

The pharmaceutical formulations according to the disclosure comprising one of more of roxyVitamin D2 and 25-hydroxyVitamin D3 and a cellulosic compound have unexpectedly improved stability compared to formulations lacking a cellulosic compound. In one embodiment, a stabilized formulation according to the disclosure comprises a mixture of an active-loaded lipophilic matrix comprising one or both of 25-hydroxyVitamin D2 and 25- hydroxyVitamin D3 and a cellulosic stabilizing agent, n the formulation releases an amount of roxyVitamin D during in vitro dissolution after exposure to e conditions of at least one month at 25 0C and 60% relative humidity that varies at any given dissolution time point by 30% or less compared to the amount released at the same dissolution time point during in vitro dissolution conducted on freshly-made product. [005 6] Formulations that are not stabilized exhibit changes in the amount of active ingredient released after the composition is stored for a period of time, as shown in the Examples below.

An unstabilized formulation releases an amount of 25-hydroxyVitamin D following exposure to e conditions that can vary at a given ution time point, for example by more than 30% compared to the amount released at the same dissolution time point during in vitro dissolution conducted on freshly-made t. The changes may be an increase or decrease in the dissolution rate at a given time point, and such s produce a dissolution profile whose curve is distinct from the shape of the initial ution profile. An unstabilized formulation also exhibits different in vivo effects compared to a stabilized formulation according to the sure, following storage as described herein, e. g. following 3 months or more of e at 0C and 60% RH. A stabilized formulation demonstrates ent clinical pharmacokinetic parameters, such as improved bioavailability, compared to an unstabilized formulation, following storage as described herein, e. g. following 3 months or more of storage at 25 0C and 60% RH. A stabilized formulation according to the disclosure can have a base formulation which is storage unstable, combined with a stabilizing agent which renders the formulation storage stable as described herein.

WO 43941 The matrix that releasably binds and llably releases the active component can be, for example, a lipophilic matrix, including a wax matrix. A wax matrix can provide a formulation which is solid or semi-solid at room temperature and solid, semi-solid, or liquid at body temperature, preferably semi-solid or liquid at body temperature. In one aspect, the wax matrix comprises a lled release agent, an emulsiﬁer, and an absorption enhancer.

Examples of controlled release agents suitable for use include, but are not limited to, waxes, including synthetic waxes, microcrystalline wax, parafﬁn wax, camauba wax, and beeswax; polyethoxylated castor oil tives, hydrogenated vegetable oils, glyceryl mono-, di- or tribehenates; long-chain alcohols, such as stearyl l, cetyl alcohol, and polyethylene glycol; and mixtures of any of the foregoing. Non-digestible waxy nces, such as hard parafﬁn wax, are red.

The controlled release agent can be present in an amount of at least 5 wt% of the ation, or greater than about 5 wt% of the formulation. For example, depending on the controlled release agent used, the controlled release agent can comprise at least 5 wt% of the formulation or at least 10 wt% of the formulation, or at least 15 wt% of the formulation, or at least 20 wt% of the formulation, or at least 25 wt% of the formulation, or greater than 5 wt% of the formulation, or greater than 10 wt% of the formulation, or greater than 15 wt% of the formulation, or greater than 20 wt% of the formulation, and or greater than 25 wt% of the formulation. The controlled release agent can be present in an amount 50 wt% or less, 40 wt% or less, 35 wt% or less, or 30 wt% or less. Suitable ranges include 5 wt% to 40 wt%, 10 wt% to 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 mixed fatty acid monoglycerides; mixed fatty acid diglycerides; es of fatty acid mono- and erides; lipophilic polyglycerol esters; glycerol esters including glyceryl monooleate, yl dioleate, glyceryl monostearate, glyceryl distearate, glyceryl lmitate, and glyceryl dipalmitate; glyceryl- lacto esters of fatty acids; propylene glycol esters including propylene glycol monopalmitate, ene glycol monostearate, and propylene glycol monooleate; sorbitan esters including WO 43941 sorbitan monostearate, sorbitan oleate; fatty acids and their soaps including stearic acid, palmitic acid, and oleic acid; and mixtures thereof glyceryl monooleate, glyceryl dioleate, glyceryl monostearate, glyceryl rate, glyceryl lmitate, and glyceryl dipalmitate; glyceryl-lacto esters of fatty acids; ene glycol esters including propylene glycol monopalmitate, propylene glycol monostearate, and propylene glycol monooleate; sorbitan esters including an monostearate, sorbitan sesquioleate; fatty acids and their soaps including stearic acid, palmitic acid, and oleic acid; and mixtures thereof A preferred lipoidic agent is selected from glycerides and derivatives thereof Preferred glycerides are selected from the group consisting of medium or long chain glycerides, ocaproyl macrogolglycerides, and es thereof red medium chain glycerides include, but are not limited to, medium chain monoglycerides, medium chain diglycerides, caprylic/capric triglyceride, glyceryl monolaurate, glyceryl monostearate, caprylic/capric glycerides, glycerylmonocaprylate, glyceryl monodicaprylate, caprylic/capric linoleic triglyceride, and caprylic/capric/succinic triglyceride.

Monoglycerides having a low melting point are preferred for making the formulation.

Preferred monoglycerides include but are not limited to, glyceryl monostearate, glyceryl monopalmitate, glyceryl eate, glyceryl monocaprylate, glyceryl monocaprate, glyceryl monolaurate, etc., preferably glycerol monostearate (GMS). GMS is a natural emulsifying agent.

It is oil soluble, but poorly soluble in water. GMS has an HLB value of 3.8. The lipophilic emulsifier can be present in an amount in a range of about 10 wt% to about 40 wt%, or about 20 wt% to about 25 wt%, for example. 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, caprylocaproyl macrogolglycerides such as polyethylene glycosylated ides, also known as polyglycolized ides or PEGylated glycerides. ted glycerides which may be employed in the composition include, but are not limited to, mixtures of monoglycerides, diglycerides, and triglycerides and monoesters and diesters of hylene glycol, polyethylene glycosylated almond glycerides, polyethylene glycosylated corn glycerides, and polyethylene glycosylated caprylic/capric triglyceride. The tion enhancer can have an HLB value from 13 to 18, or from 13 to 15.

One preferred absorption enhancer is known under the trade name GELUCIRE (Gattefosse 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 polyglycolized ides. GELUCIRE is used in various applications including preparing sustained release pharmaceutical itions. GELUCIRE compounds are inert, olid waxy materials which are amphiphilic and are available with varying physical characteristics such as melting point, HLB, and solubilities in various solvents. They are surface active in nature and disperse or solubilize in aqueous media forming micelles, microscopic globules or vesicles. They are identified by their melting point/HLB value. The melting point is expressed in degrees Celsius.

One or a mixture of different grades of GELUCIRE excipient may be chosen to achieve the desired teristics of melting point and/or HLB value. A preferred GELUCIRE composition is RE 44/14, a mixture of lauroyl macrogolglycerides and lauroyl polyoxylglycerides that has a melting point of 44 CC and a HLB of 14. The tion enhancer can be present in an amount of about 5 wt% to about 20 wt%, or about 8 wt% to about 15 wt%, for example. Other examples include about 8 wt%, about 9 wt%, about 10 wt%, about ll, wt% about 12 wt%, about 13 wt%, about 14 wt%, and about 15 wt%.

The low melting points of the wax matrix provide a means of orating the pharmaceutically active ingredients, e.g. the vitamin D compound such as 25-D2, 25-D3, or both, at temperatures from about 0 0C to about 50 OC above the melting point of the wax matrix and then filling the melt (solution and/or dispersion) in suitable capsules. The capsules can be of any variety that is compatible with the ature of the melt fill, including soft or hard gelatin capsules, and animal or ble gelatin capsules. The melt solidifies inside the capsules upon cooling to room temperature.

In one aspect, a stabilized formulation may further comprise an oily e for the 25- hydroxyvitamin D2 and/or roxyvitamin D3. Any pharmaceutically-acceptable oil can be used. Examples include animal (e. g., fish), vegetable (e. g., soybean), and mineral oils. The oil preferably will y dissolve the 25-hydroxyvitamin D compound used. Preferred oily vehicles include non-digestible oils, such as l oils, particularly liquid paraffins, and squalene. The oily vehicle can be present at a concentration in a range about 10 wt% to about 50 wt% of the formulation, or about 15 wt% to about 45 wt%, or about 20 wt% to about 40 wt%, or about 30 wt% to about 40 wt%, for example. In one type of embodiment, a suitable liquid parafﬁn can be characterized by one or more of the following parameters: speciﬁc gravity about 0.88 to 0.89; kinematic ity (40 0C) about 64 cSt to about 70 cSt; molecular weight 424; % parafﬁnic arbons about 59; and pour point -24 0C. The ratio between the wax matrix and the oily vehicle can be optimized in order to achieve the desired rate of release of the vitamin D compound. Thus, if a heavier oil component is used, relatively less of the wax matrix can be used, and if a lighter oil component is used, then vely more wax matrix can be used.

The ized controlled release compositions in accordance with the invention preferably are designed to contain concentrations of 25-hydroxyvitamin D2 and/or 25- hydroxyvitamin D3 of l to 1000 ug per unit dose, for example, and are prepared in such a manner as to effect controlled or substantially constant release of the 25-hydroxyvitamin D2/25- hydroxyvitamin D3, optionally into the ileum of the intestinal tract, of humans or animals over an extended period of time. Example dosages include 1 ug to 1000 ug per unit dose, 1 ug to 600 ug, 1 ug to 400 ug, 1 ug to 200 ug, 1 ug to 100 ug, 5 ug to 90 ug, 30 ug to 80 ug, 20 ug to 60 ug, 30 ug to 60 ug, 35 ug to 50 ug, 5 ug to 50 ug, and 10 ug to 25 ug, for example 20 ug, 25 Mg, 30 Mg, 40 Mg, 50 Mg, 60 Mg, 70 Mg, 80 Mg, 90 Mg, and 100 us- In one preferred class of embodiments, the controlled release formulation releases at least 70%, more preferably at least 80% of the vitamin D compound within the ﬁrst 24 hours after dosing.

Advantageously, 25-hydroxyvitamin D2, 25-hydroxyvitamin D3 or combinations f together with other eutic agents can be administered, e. g. orally, in accordance with the above described embodiments in dosage amounts of from 1 to 100 ug per day, for e. In one type of embodiment, the dose will be selected to provide an average rise in serum 25-hydroxyvitamin D3 of about I to 3 ng/ml in a dose interval.

In embodiments, the formulations described herein can be stered to raise and preferably also maintain blood ihydroxyvitamin D levels at 25 pg/mL, 30 pg/mL, or higher, e. g. 25-65 pg/mL for an extended period, for example at least one month, at least three months, at least six months, or longer.

In one aspect, the formulations described herein can be administered to patients to lower or maintain lowered serum parathyroid hormone levels, preferably an amount that lowers PTH levels by at least 30%, or alternatively the amount needed to reduce serum levels of PTH to the target range for the CKD stage (e. g., for Stage 3 is 35-70 pg/mL (equivalent to 3.85-7.7 ), for Stage 4 is 70-110 pg/mL (equivalent to .l ), and for Stage 5 is 150- 300 pg/mL (equivalent to 16.5-33.0 pmol/L) (deﬁned in K/DOQI Guideline No. l)).

In another aspect, the formulations according to the disclosure herein can be administered to a patient suffering from hyperparathyroidism secondary to chronic kidney e (e. g., Stage 3 or 4, or Stage 3, 4 or 5) to lower the serum PTH level.

The dosages described herein are contemplated for any of the therapeutic methods described herein. It will be appreciated that the actual preferred amount of a vitamin D compound in a speciﬁc case will vary according the particular compositions formulated, the mode of application, and the particular situs being treated. Dosages can be determined using conventional considerations, e.g., by customary comparison of the differential activity of the hormone and of a known agent, e. g. by means of an appropriate conventional pharmacological protocol.

The speciﬁc doses for each particular patient can depend on a wide variety of factors, for example, on the age, body weight, l state of health, sex, on the diet, on the timing and mode of administration, on the rate of excretion, and on medicaments used in combination and the severity of the particular disorder to which the therapy is applied.

Patients in need of vitamin D supplementation include healthy subjects and subjects at risk for vitamin D insufﬁciency or deﬁciency, for example, subjects with Stage 1, 2, 3, 4 or 5 CKD; infants, en and adults that do not drink vitamin D fortiﬁed milk (e.g. lactose intolerant subjects, subjects with milk allergy, rians who do not consume milk, and breast fed s); ts with s; subjects with dark skin (e. g., in the US, 42% of African American women between 15 and 49 years of age were vitamin D deﬁcient compared to 4% of white women); the elderly (who have a reduced ability to synthesize n D and also are more likely to stay indoors); institutionalized adults (who are likely to stay indoors, including subjects with Alzheimer’s disease or mentally ill); subjects who cover all exposed skin (such as members of certain religions or cultures); ts who always use sunscreen (e. g., the ation of sunscreen with a Sun Protection Factor (SPF) value of 8 reduces production of vitamin D by 95%, and higher SPF values may ﬁlrther reduce vitamin D); subjects with fat malabsorption syndromes (including but not limited to cystic ﬁbrosis, cholestatic liver disease, other liver 2014/028132 disease, gallbladder disease, pancreatic enzyme deﬁciency, Crohn’s e, inﬂammatory bowel disease, sprue or celiac e, or surgical removal of part or all of the stomach and/or intestines); subjects with inﬂammatory bowel disease; subjects with Crohn’s disease; subjects who have had small bowel ions; subjects with gum disease; subjects taking medications that increase the catabolism of vitamin D, including phenytoin, fosphenytoin, phenobarbital, carbamazepine, and rifampin; subjects taking medications that reduce absorption of vitamin D, including cholestyramine, colestipol, orlistat, mineral oil, and fat substitutes; subjects taking tions that inhibit tion of vitamin D, including ketoconazole; subjects taking medications that decrease calcium absorption, including corticosteroids; subjects with obesity (vitamin D deposited in body fat stores is less bioavailable); subjects with osteoporosis; patients who have low bone mineral density and osteoporosis; and/or nopausal women.

According to the Institute of Medicine’s report on the Dietary Reference Intakes for vitamin D, food ption data suggest that median intakes of n D for both younger and older women are below current recommendations; data suggest that more than 50% of younger and older women are not consuming ended amounts of vitamin D.

Optionally excluded from the methods of the invention described herein are therapeutic treatment of subjects suffering from renal osteodystrophy (including osteomalacia and osteitis ﬂbrosa cystica).

In other s, the compositions and methods of the invention are useful for prophylactic or therapeutic treatment of vitamin D-responsive diseases, i.e., diseases where vitamin D, 25-hydroxyvitamin D or active vitamin D (e.g., l,25-dihydroxyvitamin D) prevents onset or progression of disease, or reduces signs or symptoms of disease. Such vitamin D- responsive diseases e cancer (e. g., breast, lung, skin, melanoma, colon, colorectal, rectal, prostate and bone cancer). 1,25-dihydroxyvitamin D has been observed to induce cell differentiation and/or inhibit cell proliferation in vitro for a number of cells. Vitamin D- responsive diseases also include autoimmune diseases, for example, type I diabetes, le sclerosis, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma, fibrosis, Grave's disease, Hashimoto's disease, acute or c transplant rejection, acute or chronic graft versus host disease, inﬂammatory bowel disease, s disease, systemic lupus erythematosis, Sjogren's Syndrome, eczema and psoriasis, dermatitis, including atopic dermatitis, contact dermatitis, ic dermatitis and/or c itis. Vitamin D-responsive diseases also WO 43941 e other inﬂammatory diseases, for example, asthma, chronic obstructive pulmonary disease, polycystic kidney disease, polycystic ovary syndrome, pancreatitis, nephritis, hepatitis, and/or infection. Vitamin D-responsive diseases have also been reported to include hypertension and cardiovascular diseases. Thus, the invention contemplates prophylactic or therapeutic treatment of subjects at risk of or suffering from cardiovascular diseases, for example, ts with atherosclerosis, arteriosclerosis, coronary artery disease, cerebrovascular e, peripheral vascular disease, myocardial infarction, myocardial ischemia, al ischemia, stroke, congestive heart failure, cardiomyopathy, obesity or other weight disorders, lipid disorders (e.g. hyperlipidemia, dyslipidemia including associated diabetic dyslipidemia and mixed dyslipidemia phalipoproteinemia, hypertriglyceridemia, hypercholesterolemia, and low HDL (high density lipoprotein)), metabolic disorders (e. g. Metabolic Syndrome, Type II diabetes mellitus, Type I diabetes mellitus, nsulinemia, impaired glucose tolerance, insulin resistance, diabetic complication ing neuropathy, pathy, retinopathy, diabetic foot ulcer and cataracts), and/or osis.

Diseases which can benefit from a modulation in the levels of vitamin D compounds, include, but are not d to: (i) in the parathyroid-- hypoparathyroidism, pseudohypo- parathyroidism, secondary hyperparathyroidism; (ii) in the pancreas--diabetes; (iii) in the thyroid--medullary carcinoma; (iv) in the psoriasis; wound g; (v) in the lung-- sarcoidosis and tuberculosis; (vi) in the kidney--chronic kidney disease, hypophosphatemic VDRR, vitamin D dependent rickets; (vii) in the bone--anticonvulsant treatment, enisis imperfecta ossium, osteitis ﬁbrosa cystica, osteomalacia, osteoporosis, osteopenia, osteosclerosis, renal osteodytrophy, rickets; (viii) in the intestine--glucocorticoid nism, idopathic hypercalcemia, malabsorption syndrome, steatorrhea, tropical sprue; and (ix) autoimmune disorders.

In embodiments of the invention, the disease that benefits from a modulation in the levels of vitamin D compounds are selected from cancer, dermatological disorders (for e, psoriasis), parathyroid disorders (for example, hyperparathyroidism and secondary hyperparathyroidism), bone disorders (for example, osteoporosis) and autoimmune disorders.

The formulation can be prepared by procedures well within the capabilities of the ordinary skilled artisan. For example, the components of the matrix (e.g. wax and oily vehicle) can be melted, if necessary, to provide a ﬁowable liquid thereby making it easier to obtain a homogeneous mixture. The active (e.g., 25-hydroxyvitamin D2 and/or 25-hydroxyvitamin D3) is added to the liquid carrier, for example dissolved in an alcohol such as anhydrous ethanol, and the ingredients are mixed to provide a homogeneous mixture. In one type of embodiment, the stabilizer can be added after all matrix components (e. g., waxes and oils) are blended and prior to combination with the . The mixture can be cooled and stored prior to later division into unit dosage forms, such as ﬁlled gelatin capsules.

In one type of method, a portion of the oily vehicle, controlled release agent, and emulsiﬁer are heated to a relatively high temperature (e.g., 65 CC) and mixed prior to adding an absorption enhancer, followed by additional mixing until homogenous, then cooling to an intermediate elevated temperature (e. g., 50 0C to 55 0C). In a separate vessel, an antioxidant preservative and the remainder of the oily vehicle are mixed and heated to an intermediate elevated temperature (e.g., 50 0C), then combined and mixed with the wax mixture until a homogenous solution is obtained. Next, the stabilizer is added, with mixing. Next, a solution of the vitamin D nd(s) in alcohol is combined with the homogenous waxy solution, mixed until a homogenous solution is obtained, preferably ﬁlled into capsules, and then cooled to room temperature. In another preferred method, a portion of the oily vehicle, controlled e agent, and ﬁer are heated at a temperature of 55 CC to 60 CC and mixed prior to adding an absorption enhancer, followed by additional mixing until nous. In a te vessel, an antioxidant preservative, the remainder of the oily vehicle, and the stabilizer are mixed and heated to a temperature of 55 0C to 60 0C, then combined and mixed with the wax e until a homogenous solution is obtained. Next, a on of vitamin D compound in alcohol is combined with the homogenous waxy on, mixed until a homogenous solution is obtained, preferably ﬁlled into capsules, and then cooled to room temperature.

The formulation preferably is placed in capsules prior to stration to the patient in need of treatment. Such capsules may be hard or soft, and soft capsules are particularly contemplated. The formulation may be ﬁlled into gelatin capsules using rd capsule ﬁlling machinery, such as by g the ation and inj ection-ﬁlling it into soft capsule shells.

Example soft capsule shells e VEGICAPS and OPTISHELL technologies (Catalent, Somerset, NJ, USA). In the alternative, the formulation can be made into a unit dosage form by any other suitable processes, for example to yield tablets, sachets, dragees, itories, or the like.

In one type of embodiment, the formulation is prepared for and administered by oral delivery. In another type of embodiment, the formulation is ed for and administered as a suppository, e. g. a rectal suppository.

The formulation and s of use and making are contemplated to include embodiments including any combination of one or more of the additional optional elements, features, and steps further described below, unless stated otherwise.

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

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

If the vitamin D compound is administered in combination with one or more other therapeutic agents, the proportions of each of the compounds in the combination being administered will be dependent on the particular disease state being sed. For example, one may choose to administer 25-hydroxyvitamin D2 and/or roxyvitamin D3 (e.g., orally) with one or more calcium salts (intended as a calcium supplement or dietary phosphate binder), bisphosphonates, calcimimetics, nicotinic acid, iron, phosphate binders, cholecalciferol, ergocalciferol, active Vitamin D sterols, glycemic and hypertension control agents, various antineoplastic agents and inhibitors of CYP24 and other cytochrome P450 enzymes that can degrade vitamin D agents. In addition, one may choose to intravenously administer 25- hydroxyvitamin D2 and/or 25-hydroxyvitamin D3 with cholecalciferol, ergocalciferol, active Vitamin D sterols, ic and ension control agents, various oplastic agents and inhibitors of CYP24 and other cytochrome P450 enzymes that can degrade vitamin D agents. In practice, higher doses of the compounds of the t invention are used where therapeutic treatment of a disease state is the desired end, while the lower doses are generally used for prophylactic purposes, it being understood that the specific dosage administered in any given case will be ed in accordance with the specific compounds being administered, the disease to be treated, the condition of the t and the other nt medical facts that may modify the activity of the drug or the response of the subject, as is well known by those skilled in the art.

As described above, the formulation is ably ﬁlled into gelatin capsules, but it may also be administered in neat form, or with one or more external coating layers, such as an enteric coating. It is also contemplated that the formulation can be pressed into tablets, and in such cases one or more tablet pressing excipients may be included.

In the compositions and methods described herein, preferred steps, preferred components, red compositional ranges thereof, and preferred combinations of the foregoing, can be selected from the various ic examples provided herein. For example, a preferred formulation includes 25-hydroxyvitamin D (e. g., about 30 ug, about 60 ug, or about 90 ug 25-hydroxyvitamin D3), about 2 wt% (e. g., 2.32 wt%) anhydrous ethanol, about 10 wt% (e. g., 9.75 wt%) GELUCIRE 44/14, about 20 wt% (e.g., 20.00 wt.%) hard in, about 23 wt% (e.g., 22.55 wt%) GMS, about 35 wt% (e.g., 35.36 wt%) liquid paraffin or mineral oil, about 10 wt% HPMC, and optionally a small amount of preservative (e. g., 0.02 wt% BHT). A variation on this formulation will e about 15% (e. g., 15.29 wt%) HPMC and about 30 wt% (e. g., 29.88 wt%) liquid paraffin or mineral oil.

The following Examples illustrate specific ations and s for their preparation. The Examples are provided for illustration and are not intended to limit the scope of the invention.

In vitro dissolution testing in the es was performed using USP Apparatus 2 (paddle method) as described in USP 29- NF 24, general chapter <711> Dissolution, using the Dissolution Medium described below. In general, the method proceeds according to the following steps. Place the stated volume of the Dissolution Medium (::1%)in the vessel of the specified apparatus, assemble the apparatus, equilibrate the Dissolution Medium to 37 :: 0.5°, and remove the thermometer. Place the dosage units in the apparatus, taking care to exclude air bubbles from the surface of the dosage units, and immediately e the tus at the specified rate. At each of the times stated, withdraw specimens from a zone midway between the surface of the Dissolution Medium and the top of the rotating blade, not less than 1 cm from the vessel wall. Replace the aliquots withdrawn for analysis with equal volumes of fresh Dissolution Medium at 37C) or. Keep the vessel covered for the duration of the test, and verify the temperature of the mixture under test at suitable times. Perform the is using a suitable assay method, ultra performance liquid chromatography (UPLC) in this case .

Six capsules of each formulation were tested per time point. The Dissolution Medium was 0.05 M pH 6.8 phosphate buffer/1% sodium dodecyl sulfate dissolution medium at 37 :: 0.5 0C, and the apparatus was operated at 100 rotations per . Samples were taken at 2, 4, 6, 8, and 12 hours and the 25-hydroxyvitamin D content of each sample was ined using UPLC.

Example 1 — In vitro Dissolution of ilized Sustained Release Formulations of 25- hydroxyvitamin D The dissolution of a formulation made from a mixture of 90 ug of 25-hydroxyvitamin D3, 19.98 wt% hard n, 37.85 wt% GMS, 9.76 wt% GELUCIRE 44/14, 2.36 wt% anhydrous ethanol, 29.88 wt% liquid paraffin, and 0.02 wt% BHT (Comparative Formulation l) was tested. The formulation did not se a cellulosic compound. The mean amount of 25- hydroxyvitamin D3 released, calculated as a mean percentage of the nominal drug g per dosage form (mean % of label claim, % LC) at T=0 and after controlled storage of the formulation at 5 0C and ambient humidity for up to 12 months are summarized in the table below. It was ined that the samples were stored for a period of about 3 months at a temperature in a range of 15 0C to 30 0C and ambient humidity, prior to testing. Thus, the sample which should have represented time zero is labeled as T=0p (pseudo time zero), and it should be understood that the nominal 1 month, 3 month, 6 month, 9 month, and 12 month aged samples also experienced the approximately 3-month aging period just described. To provide a more te baseline, a fresh batch of the same type of samples was prepared and tested without any aging; this data is labeled as T=0f to indicate fresh samples. The coefficient of variation (%CV) is also reported. The t change from the initial amount of 25- hydroxyvitamin D3 released by T=0p and T=0f lots is provided in brackets and double brackets, respectively.

Dissolution Followin_ Stora_e at 5 0C / Ambient Humidit Time T=0p T=—0f 1 Month 3 Months 6 months 9 months 12 months (hours) pseudo fresh (%CV) (% CV) (% CV) (% CV) (% CV) [% change [% change [% change [% change [% change from T=0p] from T=0p] from T=0p] from T=0p] from T=0p] [[% change [[% change [[% change [[% change [[% change from T=0f]] from T=0f]] from T=0f]] from T=—]]0f from T=—]]0f W0 2014/143941 [45.9] [157.4] [49.2] [149.2] [108.2] [[597]] [[290]] [[588]] [[312]] ] 4 14.5 52.0 20.7 22.3 22.9 25.2 24.7 (15.7) (4.6) (19.1) (15.6) (7.1) (19.2) (13.5) [42.8] [53.8] [57.9] [73.8] [70.3] [[602]] ]] ] [[515]] [[525]] 36.2 34.8 (20.5) (14.6) [31.2] [26.1] [[535]] [[553]] 53.0 (9.9) [16.0] [[452]] 12 89.7 112.3 100.0 78.9 76.9 74.1 78.8 (15.6) (1.6) (4.8) (8.1) (5.7) (17.3) (5.3) [11.5] [12.0] [14.3] [17.4] [12.2] [[110]] ] [[315]] [[340]] [[298]] The dissolution of Comparative Formulation 1 after storage at 25 0C and 60% relative humidity for 0 to 12 months was tested. The results are summarized in the table below.

Dissolution Followin_ Stora_e at 25 0C / 60% Relative Humidit Dissolution 1 Month 3 Months 6 months 9 months 12 months Time (hours) (%CV) (% CV) (% CV) (% CV) (% CV) [% change [% change [% change [% change [% change from T=0p] from T=0p] from T=0p] from T=0p] from T=0p] [[% change [[% change [[% change [[% change [[% change from from from from from T=0f]] T=0£11 T=0f]] T=0f]] T=0£11 .8 8.5 10.8 13.5 (15.7) (19.2) (15.8) (24.7) [77.0] [39.3] [77.0] [121.3] [[511]] [[615]] [[511]] [[389]] 18.7 22.8 17.9 24.5 (18.6) (23.7) (11.9) (17.4) [29.0] [57.2] [23.4] [69.0] [[640]] [[562]] [[656]] [[529]] .7 23.8 30.0 (29.6) (11.6) (15.7) [11.2] [13.8] [8.7] [[606]] [[694]] [[615]] 37.1 40.6 28.5 35.6 (18.1) (29.9) (13.2) (14.7) [18/8] [11.2] [37.6] [22.1] [[617]] [[581]] ] [[632]] 61.6 53.0 38.5 44.2 (16.6) (32.2) (12.2) (12.2) [31.3] [40.9] [57.1] [50.7] [[451]] [[528]] [[657]] [[606]] The dissolution of Comparative Formulation 1 after storage at 40 0C and 75% relative ty for 0, 1, 3, and 6 months was tested. The results are summarized in the table below.

Dissolution Followin_ Stora_e at 40 0C / 75% Relative Humidit Dissolution 1 Month 3 Months 6 Months Time (hours) (%CV) (%CV) (%CV) [% change from [% change [% change from T=0p] from T=0p] T=0p] [[% change [[% change [[% change from from T=0f]] from T=0f]] T=0f]] 16.9 1.8 (36.3) (75) [177.0] [70.5] [[235]] [[919]] 59.8 36.2 (31.3) (21.8) [312.4] [149.7] [[150]] [[304]] 87.0 97.8 76.7 (21.5) (24) (12.3) [215.2] [254.3] [177.9] [[117]] [[25.5]] [[15]] 107.3 110.9 101.2 (8.1) (13) (6.1) [134.8] [142.7] [121.4] [[108]] [[146]] [[45]] 118.7 115.1 112.6 (1.7) (3.7) (2.1) [32.3] [28.3] [25.5] [[57]] [[25]] [[03]] Without intending to be bound by any particular theory, the se in the extent of dissolution following storage at 40 0C compared to the pseudo T=0 values is believed to be due to a combination of the aging effect described above on the pseudo T=0 samples tested, and a temperature-dependent phase change in the ation when stored at 40 0C.

Aged product ing to Comparative Formulation 1 was heat cured and then subject to dissolution testing. Curing ts of applying a heat ent and has been shown to stabilize pharmaceutical formulations (see, e. g., US. Patent No. 6,645,527). Comparative Formulation 1 (aged samples) was heated at 40 0C for 72 hours for curing, and then was stored at room ature for 8 weeks. Release of 25-hydroxyvitamin D3 from the cured formulation was tested after storage for 0, 2, 4, and 8 weeks at room temperature. The results are summarized in the table below.

Dissolution Following Curing at 40 0C for 72 Hours (hours) % LC % LC % LC [% change] [% change] [% change] -2 17.4 12.4 11.4 8.2 -4 53.3 46.4 40.1 26.6 _86.2 76.2 69.0 44.8 —----103.8 102.0 95.8 66.6 -----12 115.7 110.5 119.8 103.3 Example 2 — In Vitro Dissolution of Stabilized Controlled e Formulations of 25- hydroxyvitamin D The dissolution of a sustained release formulation comprising 90 ug of 25- yVitamin D3, 19.88 wt% hard parafﬁn, 15.29 wt% hydroxypropyl methylcellulose, 22.55 wt% GMS, 9.76 wt% GELUCIRE 44/14, 2.36 wt % anhydrous l, 29.88 wt% liquid paraffin, and 0.02 wt% BHT (Example Formulation A) was tested after 0 to 11 weeks of storage at room temperature. The results are summarized in the table below.

Dissolution Following Storage at Room Temperature / Ambient Humidity Dissolution Time T=0 3 weeks 11 weeks (hours) % LC % LC [% ] [% change] 2 15.45 14.20 12.08 [8.1%] [21.8%] 4 36.3 38.80 37.13 [6.9%] [2.3%] 6 56.9 62.70 59.51 [10.2%] [4.6%] 8 71.1 71.90 69.76 [1.1%] [1.9%] 12 89.4 91.20 89.90 [2.0%] [0.6%] The dissolution of a sustained release formulation comprising 90 ug of 25- hydroxyVitamin D3, 19.88 wt% hard parafﬁn, 10.00 wt% hydroxyl propyl methylcellulose, 22.55 wt% GMS, 9.76 wt% GELUCIRE 44/14, 2.36 wt % anhydrous ethanol, 35.17 wt% liquid parafﬁn, and 0.02 wt% BHT (Example Formulation B) was tested after 0 to 26 weeks of storage at room temperature. The s are summarized in the table below. ution Following e at Room Temperature / Ambient Humidity Dissolution Time T=0 6 weeks 13 weeks 26 weeks (hours) % LC % LC % LC [% change] [% change] [% change] 2 30.15 25.40 25.20 21.10 [15.8%] [16.4%] [30.0%] [11.4%] [11.5%] [22.8%] —72.1 74.40 73.00 67.63 [3.2%] [1.2%] [6.2%] [4.7%] [4.9%] [4.0%] 91.8 94.10 94.40 91.16 [2.5%] [2.8%] [0.7%] Example Formulation B demonstrated a substantially stable dissolution proﬁle following storage for at least 26 weeks at room ature.

The stability of stabilized formulations comprising 30 ug (Example Formulation C), 60 ug (Example Formulation D), or 90 ug (Example ation E) of 25-hydroxyVitamin D3 was tested using storage ions of 25 0C and 60% relative humidity and 40 0C and 75% relative humidity. The compositions of Example Formulations C to E are summarized in the table below: -hydroxyVitamin D3 30 ug, 60 ug, or 90 ug n Wax 20.00 wt% Mineral Oil 35.36 wt% Hydroxy propyl Methylcellulose K100M CR 10.00 wt% (METHOCEL) Glycerol monostearate 22.55 wt% Lauroyl macrogolglycerides and polyoxylglycerides (GELUCIRE 44/14) Anhydrous Alcohol 2.32 wt% BHT 0.02 wt% Soft Capsule Shell (VEGICAPS) The formulations exhibited substantially stable dissolution proﬁles following storage at 25 0C and 60% relative ty for at least 24 months (Figure 1). The dissolution results (%LC and %CV) are ized in the table below.

Dissolution Following Storage at 25 0C/ 60% Relative Humidity T=0 1 month 3 mos. 6 mos. 9 mos. 12 mos. 18 mos. 24 mos.

%LC %LC %LC %LC %LC %LC %LC %LC (% CV) (% CV) (% CV) (% CV) (% CV) (% CV) (% CV) (% CV) ug 25-hydroxyVitamin D3 (Example Formulation C) 12.9 14.0 9.6 10.5 13.5 10.6 (25.2) (48.5) (38.3) (18.2) (35.8) (26.5) 48.8 45.9 36.8 37.2 50.2 39.3 (10.9) (29.9) (25) (11.1) (14.8) (22.9) 73.4 72.4 71.4 66.7 70.6 70.1 (9.2) (7.5) (6.8) (10.6) (11.5) (7.2) 89.6 88.4 88.4 85.2 85.4 84 (4.4) (4.7) (5.7) (4.9) (9) (5.1) 104.2 105.6 106.1 101.5 100.8 100.2 (1.9) (1.4) (1.6) (1.5) (3.9) (4.5) 60 ug 25-hydroxyVitamin D3 (Example Formulation D) (9.9) 84.9 108.7 111.9 104.5 103.1 104.7 99.8 (1.8) (1.1) (0.5) (0.8) (1.4) (4.6)* 90 ug 25-hydroxyVitamin D3 le Formulation E) 14.9 (8.6) (37.1) W0 2014/143941 4 49.9 46.9 52.4 49.7 45.9 51.8 36.8 34.4 (16.4) (10.2) (18.5) (16.4) (25.6) (14) (34.5) (24.9) 110 104.4 100.5 104.6 (1.3) (1.1) (2.4) (0.3) * 4 replicates instead of 6 The percent change between the amount of 25-hydroxyVitamin D3 ed following aging compared to the initial amount released is summarized in the table below. 1 month 3 mos. 6 mos. 9 mos. 12 mos. 18 mos. 24 mos. % change % change % change % change % change % change % change ug 25-hydroxyVitamin D3 (Example Formulation C) 27.7% 38.6% 5.0% 4.0% 33.7% 5.0% 30.7% 11.9% 5.3% 15.6% 14.7% 15.1% 9.9% 9.2% 11.7% 12.9% 14.1% 19.7% 15.0% 15.6% 16.6% 7.1% 8.3% 8.3% 11.6% 11.4% 12.9% 11.1% 12 10.0% 8.8% 8.4% 12.3% 13.0% 13.5% 11.1% 60 ug 25-hydroxyVitamin D3 (Example ation D) 6.9% 8.0% 1.1% 36.0% 18.3% 8.0% 29.1% 2.8% 0.4% 3.2% 18.5% 4.9% 1.3% 23.5% 6.2% 4.8% 6.6% 13.9% 10.6% 14.2% 22.9% 4.9% 2.0% 6.8% 12.3% 10 4% 14 4% 18 0% 12 3.7% 6.8% 0.3% 1.6% 0.1% 4.8% 3.0% 90 ug 25-hydroxyVitamin D3 le Formulation E) 0.0% 10.7% 9.4% 4.0% 0.7% 36.2% 43 0% 6.0% 5.0% 0.4% 8.0% 3.8% 26.3% 31.1% .1% 9.3% 17.0% 19.9% 13.9% 28.0% 27 9% 16.5% 5.5% 10.7% 12.5% .9% 23.9% 17 8% 3.6% 6.8% 1.4% 2.4% 1.6% 6.0% 0.2% Example Formulations C to E also exhibited substantially stable ution proﬁles following storage at 40 0C and 75% RH for at least 6 months (Figure 2). The dissolution results are summarized in the table below.

Dissolution Followin_ Stora_e at 40 0C/ 75% Relative Humidit 1 month 3 months 6 months %LC % LC % LC WO 43941 (%CV) (%CV) (%CV) (%CV) ug 25-hydroxyVitamin D3 (Example ation C) 2 10.1 11.3 13.5 11.1 (16.1) (54.3) (53.8) (14.8) 4 43.6 46 44.4 40.9 (12.7) (27.1) (23.9) (13.9) 83.1 72.7 62.8 .7 9.7 20.4 96.4 88.7 76.5 (6.5) (5) (12.5) 115.8 103.1 93.4 (4.5) (0.9) (7.6) 60 ug 25-hydroxyVitamin D3 (Example Formulation D) 17.5 12.9 15.5 (20) (40.7) (37) 53.6 50.7 54.4 (19.6) (18.5) (12) 83.9 75.8 78.3 (7.5) (9.7) (10.6) 99.2 91.2 91.6 (3.9) (7.9) (9.1) 104.8 100.7 104.1 (3.3) (5.1) (6.5) 90 ug 25-hydroxyVitamin D3 (Example Formulation E) 14.9 18.5 10.2 (19.9) (32.5) (44.6) The percent change between the amount of 25-hydroxyVitamin D3 released following exposure to storage conditions compared to the initial amount released is summarized in the table below.

Time (hours) 1 month 3 months 6 months % change % change % change ug 25-hydroxyVitamin D3 (Example Formulation C) 11.9% 33.7% 9.9% .5% 1.8% 6.2% 12.5% 24.4% 17.3% 8.0% 20.6% 14.4% WO 43941 12 11.0% 19.3% 16.8% 60 ug 25-hydroxyvitamin D3 (Example Formulation D) 2 26.3% 11.4% 20.6% 4 5.4% 1.5% 7.1% 6 9.7% 6.7% 11.0% 8 8.1% 7.7% 10.8% 12 3.9% 0.7% 3.1% 90 ug 25-hydroxyvitamin D3 (Example Formulation E) 2 24.2% 31.5% 44.3% 4 1.6% 5.8% 10.2% 6 16.4% 18.5% 18.3% 8 11.0% 14.8% 13.6% 12 2.8% 0.5% 1.9% ] The stability of Comparative Formulation 1, which does not contain a cellulosic compound, and Example Formulation E comprising hydroxyl propyl methylcellulose was evaluated following storage for 12 months at 25 0C and 60% relative humidity e 3). The dissolution results are summarized in the table below.

Dissolution Following Storage at 25 0C/ 60% Relative Humidity Dissolution Comparative Formulation 1 e Formulation E Time Initial 12 months Initial 12 months % LC %LC % LC 52.2 24.5 77.9 30.0 12 112.3 44.2 103.0 104.6 The percent change n the amount of 25-hydroxyvitamin D3 released following exposure to storage conditions compared to the initial amount released is summarized in the table below.

Dissolution Time ative Formulation 1 e Formulation E (hours) % change from initial % change from initial 2 38.9% 0.7% 4 53.1% 3.8% Example 3: In vivo Results for Unstabilized and Stabilized Controlled Release Formulations In vivo studies were conducted to te the clinical pharmacokinetics of unstabilized and stabilized controlled release formulations of 25-hydroxyvitamin D3 in human subjects. In Study A, 28 subjects with stage 3 or stage 4 CKD, secondary hyperparathyroidism (stage 3: 70-1000 pg/mL iPTH; stage 4: 110-1000 pg/mL iPTH), and vitamin D insufficiency (serum total baseline 25-hydroxyvitamin D of 15 ng/mL to 29 ng/mL) received a single oral dose of a controlled release e comprising 450 ug or 900 ug of 25-hydroxyvitamin D3, 20.00 wt% hard parafﬁn, 37.85 wt% GMS, 9.75 wt% GELUCIRE 44/14, 2.32 wt % ous ethanol, 30.06 wt% mineral oil, and 0.02 wt% BHT (Comparative Formulation 3) or a single intravenous dose of 448 ug 25-hydroxyvitamin D3 in an ethanol solution. None of the formulations comprised a cellulosic compound.

The serum concentration of 25-hydroxyvitamin D3 increased gradually following the administration of an oral dose. The increase in 25-hydroxyvitamin D3 was dose proportional and d an imate mean maximum observed serum concentration (Cmax) of 32 ng/mL following the administration of the 900 ug capsule. The time at which Cmax occurred (Tmax) was approximately 13 hours ose. In contrast, concentrations of 25-hydroxyvitamin D3 increased rapidly following the administration of the i.v. dose. Peak serum levels were achieved ately ing stration of the i.v. dose (Tmax = 0.5 hours) and reached an approximate mean Cmax of 134 ng/mL. The bioavailability of the oral doses was approximately 6 to 11%. The terminal half-life (tug) of 25-hydroxyvitamin D3 following the administration of the oral dose was approximately 12 to 22 days. No adverse effects on serum calcium or phosphorous, or urine calcium were observed in any treatment group.

The mean serum total ihydroxyvitamin D rose rapidly following the stration of the iv. injection, increasing from pre-treatment baseline by imately 13 pg/mL by 6 hours post-dose. In contrast, mean serum total 1,25-dihydroxyvitamin D increased dose proportionally and gradually by approximately 7 pg/mL by 48 hours post-dose following the administration of the 900 ug capsule.

Serum iPTH showed no meaningful change over the ﬁrst 96 hours after the i.v. dose was administered. In contrast, serum PTH declined gradually following dosing, reaching a maximum suppression of approximately 20% from pretreatment baseline for subjects who received the 900 ug capsule. The observed pharmacokinetic parameters for all the treatment groups are summarized in the table below. 450 pg po (N=9) 900 pg po (N=9) 448 pg iv (N=9) ter n Mean (SD) n Mean (SD) n Mean (SD) Median Median Median Range Range Range PK/PD Population Observed 25—hydroxyvitamin D3 AUG“: 43,. (ng*h/mL) 9 13353.12 9 21563.95 9 43463.51 (10606.47) 53) (12589.57) 12196.45 17940.11 47115.66 . 32885.95 9292.88. 38631.91 23340.59. 78 AUCo.1.s1(ng*h/mL) 9 13353.12 9 21563.95 9 43463.51 (10606.47) (9165.53) (12589.57) 45 17940.11 471 15.66 888.39. 32885.95 8. 38631.91 23340.59. 63006.78 AUCO-inf (ng‘h/mL) 9 81511.71 9 122901.73 9 137955.58 7.08) (114168.13) (66746.71) 54967.57 79902.04 123580.87 4927.95. 333366.90 25729.84. 378935.59 39282.49. 243322.76 cm. (ng/mL) 9 25.18 (10.134) 9 31.54 (15.765) 9 133.99 (19.31 1) .52 30.12 133.68 .35. 42.24 12.21. 67.01 91.71. 160.91 C15.(ng/mL) 9 18.11 (7.846) 9 19.08 (7.61 1) 9 35.07 (12.330) .84 21.37 36.91 .30. 29.80 7.30. 27.93 12.68. 53.39 t"... (h) 9 13.11 (9.597) 9 13.56 (9.989) 9 0.49 (0.638) .00 10.00 0.25 6.00, 36.00 2.00. 30.00 0.083. 2.00 l,(h") 9 0.0015 (0.0028) 9 0.0003 (0.0002) 9 0.0005 (0.0002) 0.0003 0.0004 0.0004 0.0001 . 0.0087 0.0001. 0.0005 0.0002. 0.0008 R2 9 0.89 (0.130) 9 0.90 (0.169) 9 0.91 (0.090) 0.96 0.99 0.93 0.662. 1.000 0.523. 0.998 0.730. 1.000 [1.12 (h) 9 2477.72 (2581.24) 9 3228.63 (2734.74) 9 6 (779.13) 2483.61 1937.32 1694.69 79.24. 8615.11 1300.13. 9646.71 871.46, 3297.78 3737 The baseline-adjusted pharmacokinetic parameters for all the ent groups are summarized in the table below.

In Study B, 20 healthy subjects with mean baseline serum 25-hydroxyvitamin D of about 24 ng/mL (range 11 ng/mL to 45 ng/mL) received a single oral dose of a stabilized controlled release e comprising 900 µg of 25-hydroxyvitamin D3, 20.00 wt% hard paraffin, 10.00 wt% HPMC, 22.55 wt% GMS, 9.75 wt% GELUCIRE 44/14, 2.32 wt % anhydrous ethanol, 35.36 wt% mineral oil, and 0.02 wt% BHT (Example Formulation F) or a single enous dose of 448 µg 25-hydroxyvitamin D3 in an l solution.

The gradual increase in 25-hydroxyvitamin D3 levels was demonstrated by the prolonged Tmax following administration of the stabilized oral formulation compared to the i.v. dose. The pharmacokinetic profile ing administration of the stabilized oral formulation demonstrated a gradual increase in 25-hydroxyvitamin D3 concentrations, with a mean Tmax of 28 hours, while avoiding rapid increases in blood levels in the majority of subjects.

Administration of the i.v. dose resulted in a rapid increase in 25-hydroxyvitamin D3 concentrations in all subjects. The avoidance of the rapid se in 25-hydroxyvitamin D3 levels was highlighted by the marked difference in the ed Cmax between the treatment groups. The Cmax following the oral dose was 58 ng/mL, compared to a Cmax of 153 ng/mL following the i.v. dose.

The re to 25-hydroxyvitamin D3 following administration of the controlled release capsule was approximately two-fold lower than following the i.v. dose despite the oral dose being approximately two-fold higher, resulting in a bioavailability of approximately 25%.

The t1/2, clearance (CL) and volume of distribution (Vd) appeared to be similar between treatment groups. The values for t1/2 and CL were consistent with the reported ged ation of 25-hydroxyvitamin D3. In addition, the Vd values suggested that 25- hydroxyvitamin D3 was maintained in systemic circulation, likely highly bound to the DBP. The ed pharmacokinetic parameters for all the treatment groups are summarized in the table below.

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

Parameter 900 pg CTAPIOI Capsules 448 pg CTAPIOI Injection (N=10) (N=10) AUC...(ng-1|/mL) Mean (SD) 6891.81 (6678.97) 13583.95 42) Median 4360.23 14853.46 Minimum. Maximum 1017.88. 20340.68 5302.50. 17194.59 AUCH" (ng-h/mL) Mean (SD) 9418.00 (9410.58) 17735.09 (5249.38) Median 5420.04 25 Minimum. Maximum I 179.07. 28031.64 9820.16. 25534.45 C..." (ng/mL) Mean (SD) 35.867 (39.3886) 133.653 (20.7925) Median 14.910 133.785 Minimum. Maximum 6.50. 120.52 103.88. 166.34 t-I\ (h) Mean (SD) 28.100 01 ) 0.272 (0.2914) Median 21.000 0.167 Minimum. Maximum 4.00. 96.00 0.05. 1.00 1m (1') Mean (SD) 270.61 (215.00) 264.08 (82.23) Median 194.00 269.57 m. Maximum 107.90. 832.70 132.46. 382.99 MOI") Mean (SD) 0.00362 (0.00182) 0.00292 (0.001 12) Median 0.00363 0.00257 Minimum. Maximum 0.00083. 0.00624 0.00181. 0.00523 CL (Uh) Mean (SD) 0.027 (0.0063) 0.028 3) Median 0.028 0.025 Minimum. Maximum 0.012. 0.033 0.018. 0.046 Vd (L) Mean (SD) 8.78 (3.08) 9.74 (2.02) Median 8.08 9.47 Minimum. Maximum 5.06. 14.17 6.54. 13.27 Mean (SD) 0.83 (0.22) 0.92 (0.072) Median 0.88 0.94 Minimum. Maximum 0.25. 1.0 0.74. 1.0 Mean (SD) 0.25 (0.24) N/A 4242 The study demonstrated that the stabilized controlled release ation modified the rate of absorption of 25-hydroxyvitamin D3, yielding a more gradual increase in serum 25- hydroxyvitamin D3 levels while maintaining the distribution and ation characteristics. The stabilized formulation demonstrated improved pharmacokinetic parameters, such as increased Tmax, AUC, and bioavailability, compared to the same dose of the ilized formulation in Study A.

In Study C, 78 subjects with stage 3 CKD (eGFR 25-70 mL/min/1.73m2), SHPT (>70 pg/mL plasma iPTH) and vitamin D iciency (serum total baseline 25-hydroxyvitamin D of ng/mL to 29 ng/mL) received daily oral doses of stabilized controlled release formulations comprising 30 µg, 60 µg, or 90 µg of 25-hydroxyvitamin D3, 20.00 wt% hard paraffin, 10.00 wt% HPMC, 22.55 wt% GMS, 9.75 wt% GELUCIRE 44/14, 2.32 wt % anhydrous ethanol, .36 wt% mineral oil, and 0.02 wt% BHT (Example Formulations C, D, and E from Example 2) or placebo for 6 weeks.

The mean ne serum 25-hydroxyvitamin D3 concentrations were comparable across treatment groups and ranged from approximately 16 to 20 ng/mL. Following ent with 25-hydroxyvitamin D3, mean levels of serum 25-hydroxyvitamin D3 increased gradually and in a dose-proportional manner following repeated daily administration of 25-hydroxyvitamin D3 and began to approach steady-state by 6 weeks (Figure 4). The mean baseline adjusted Cmax values were approximately 28, 60 and 86 ng/mL for the groups administered 30 µg, 60 µg and 90 µg of roxyvitamin D3, respectively. Mean exposures to 25-hydroxyvitamin D3, assessed as background adjusted AUC0-6 Weeks, were dose proportional across dose groups.

Following the last dose, mean serum roxyvitamin D3 levels declined slowly, but by the end of the study remained above baseline for all groups. Mean t1/2 was determined to be approximately between 25 to 50 days. The baseline-adjusted pharmacokinetic parameters for -hydroxyvitamin D3 are summarized in the table below.

Placebo 30 µg 60 µg 90 µg ne (ng/mL) Mean (SD) 16.4 (8.2) 16.2 (7.3) 19.8 (8.7) 18.4 (9.8) 2014/028132 Placebo 30 ug 60 118 90 ug Vledian 12.9 17.2 21.2 16.7 Vlinimum, Maximum 4.4, 30.4 5.0, 25.8 5.8, 32.5 6.7, 38.9 Cmax (ng/mL) Vlean (SD) 4.1 (3.5) 27.8 (8.2) 60.3 (19.0) 85.7 (26.9) Vledian 3.1 28.1 60.8 76.0 Vlinimum, Maximum 06,138 10.8, 43.4 30.3, 89.5 55.4, 146.4 AUCM Weeks (ng- d/mL) Vlean (SD) 45.9 (60.0) 709.2 (246.3) 1531.4 (374.8) 2134.3 (584.3) Vledian 32.1 6843.0 1573.0 1963.8 Vlinimum, Maximum -60.1, 222.3 307.8, 1249.0 712.7, 2221.8 1377.5, 3207.3 tmax (d) Vlean (SD) NA 37.8 (10.4) 41.1 (5.2) 42.6 (5.3) Vledian NA 42.50 43.0 43.0 Vlinimum, Maximum NA 8.0, 44.0 29.0, 45.0 35.0, 57.0 t1/2 (d) Vlean (SD) NA 25.8 (16.3) 33.1 (9.3) 50.1 (51.0) n NA 24.1 31.6 37.7 Vlinimum, Maximum NA 5.2, 52.6 17.4, 52.3 23.2, 224.0 Mean ne serum 1,25-dihydr0xyvitamin D concentrations were comparable across treatment groups and increased gradually, similar to the effect on serum 25- hydroxyvitamin D3 concentrations. Mean :: SD baseline-adjusted Cmax values were higher in the 60 ug and 90 ug groups (18.4 :: 6.24 and 19.9 :: 14.30 ng/mL, respectively) compared to the placebo and 30 ug groups (5.7 :: 6.35 and 6.4 :: 7.66 ng/mL, respectively). Mean exposures to 1,25-dihydroxyvitamin D, assessed as baseline-adjusted AUC0_6 weeks, were dose-proportional across the 25-hydr0xyvitamin D3 dose groups. The baseline-adjusted pharmacokinetic parameters for 1,25-dihydr0xyvitamin D are summarized in the table below.

Placebo 30 11g 60 11g 90 ug N=23 N=12 N=16 N=14 Baseline (pg/mL) Mean (SD) 20.8 ) 18.3 (7.53) 20.6 (7.62) 20.6 (7.29) Median 17.0 17.0 18.0 21.0 Minimum, m 7.0, 41.4 5.1, 30.7 8.2, 33.6 9.3, 34.5 Cmax(pg/mL) Mean (SD) 7.6 (5.71) 6.4 (7.66) 18.4 (6.24) 19.9 (14.30) Median 4.9 5.0 18.4 18.9 Minimum, Maximum 1.9, 22.6 -6.3, 21.0 7.3, 29.9 -11.6, 48.3 AUC0-6 Weeks(g' d/mL) Placebo 30 pg 60 pg 90 ug N=23 N=12 N=16 N=14 Mean (SD) 11.5 (112.97) 100.6 (185.38) 249.9 (198.83) 371.1 (290.81) Median 16.2 23.0 298.7 352.2 Minimum, Maximum -267.1, 219.8 -145.4, 452.3 -191.7, 563.6 -5.8, 1235.8 tmax ((1) Mean (SD) 24.4 (15.55) 16.8 (16.09) 26.4 ) 25.5 (13.88) Median 23.0 12.0 23.0 23.00 Minimum, Maximum 2.0, 45.0 1.0, 44.0 8.0, 44.0 1.0, 44.0 The stabilized controlled e formulations of 25-hydroxyvitamin D3 increased serum total 25-hydroxyvitamin D levels to 230 ng/mL in signiﬁcantly greater number of subjects in all active groups ed to o. Similarly, the stabilized formulations signiﬁcantly decreased mean plasma iPTH from baseline in all dose groups compared to placebo.

Daily administration of 25-hydroxyvitamin D3 in a ized controlled release formulation increased mean serum total 25-hydroxyvitamin D in proportion to the dose administered. The lowest stered dose (30 ug) increased serum total 25-hydroxyvitamin D at end of treatment by 15.6 :: 1.7 (SE) ng/mL from pre-treatment baseline (21 .7::l .8 ng/mL) and the highest dose (90 ug) increased serum total roxyvitamin D by 61 . 1::6.1 ng/mL ﬁom 21 8:1 .2 ng/mL. In contrast, a decrease at end of treatment of 1.2 :: 0.7 ng/mL was observed in the ed placebo . Differences between the treatment and placebo groups were signiﬁcant for all three dose levels studied (p<0.0001). The mean serum 25-hydroxyvitamin D level in the 30 ug dose group at the end of treatment was 37.3::1.8 ng/mL, (slightly higher than K/DOQI-speciﬁed minimum adequate level of 30 ng/mL), indicating that 30 ug was the minimum effective dose.

The percentage of treated ts achieving serum total 25-hydroxyvitamin D levels of 230 ng/mL at end oftreatment was 92.3%, 100.0% and 100.0% in the 30 ug, 60 ug and 90 ug dose groups compared with 0% in the placebo group. These differences in se rates between active and placebo treatment were all signiﬁcant (p<0.001).

Mean plasma iPTH decreased at end of treatment in proportion to the administered dose of 25-hydroxyvitamin D3. The lowest administered dose (30 ug) decreased iPTH by 20.2 :: .8 (SE) % ﬁom pre-treatment baseline, and the highest dose (90 ug) decreased iPTH by 35.9 :: 4.2%. An increase of 17.2 :: 7.8% was observed at end of treatment in the combined placebo groups. Differences between groups receiving roxyvitamin D3and placebo were signiﬁcant for all three dose levels studied (p<0.005) and they compared favorably with differences observed with longer treatment in placebo-controlled s with the more potent and calcemic oral vitamin D hormone replacement therapies (e. g., doxercalciferol, lcitol and calcitriol).

Percentages of subjects receiving 25-hydroxyvitamin D3 who achieved conﬁrmed reductions (i.e., two consecutive measurements) in iPTH of at least 20% or 30% from pre- treatment baseline at EOT sed with dose through 60 ug. Similar response rates were observed in the 60 and 90 ug treatment groups, indicating that no ﬁarther beneﬁt in iPTH lowering was observed in this study for the 90 ug dose. Response rates for a conﬁrmed 20% reduction in iPTH were 38.5%, 70.6% and 76.5% for the 30 ug, 60 ug and 90 ug dose groups respectively ed with 9.7% in the combined placebo group. Differences in the observed se rates for a 20% reduction were signiﬁcant only for the 60 ug and 90 ug dose groups (p<0.005) and for a 30% reduction were signiﬁcant in all three dose groups (p<0.05). The data supported the conclusion that 30 ug per day of 25-hydroxyvitamin D3 in a stabilized controlled release formulation is the minimum effective dose.

The stabilized formulations of 25-hydroxyvitamin D3 had no clinically signiﬁcant effect on corrected albumin-corrected serum m, serum phosphorus and y calcium excretion. There were no adverse s on serum calcium or serum phosphorus or urine calcium during the 6-week treatment period.

Pharmacokinetic analyses revealed that the stabilized formulations of 25- hydroxyvitamin D3 sed 25-hydroxyvitamin D3 exposure over 6 weeks (AUC and Cmax) in a dose proportional manner across the three dose groups with no difference in t1/2. Following 6 weeks of stration, the three treatment groups had not quite reached steady state. However, steady state modeling demonstrated that steady state would have been achieved by 7-9 weeks in all dose groups.

Data from this study clearly demonstrated that stabilized controlled release ations of 25-hydroxyvitamin D3 were effective in elevating serum total 25- yvitamin D to the minimum adequate level of 30 ng/mL and lowering plasma iPTH. The study also showed that stabilized formulations of 25-hydroxyvitamin D3 had no clinically meaningful impact on serum calcium or phosphorous at the doses investigated.

Example 4: Pharmacokinetic and codynamic Proﬁle 0fM0diﬁed-Release Calcifediol in CKD Subjects with Secondary Hyperparathyroidism and Vitamin D Insuﬁiciency A multi-center, randomized, double blind, placebo-controlled, repeat dose, safety, efficacy and PK/PD study of stabilized, sustained release 25-hydroxyvitamin D3 (calcifediol, 25D3) capsules was ted in 2 cohorts of subjects. Male and female subjects aged 18 to 85 years with stage 3 CKD (eGFR of 25-70 mL/min/1.73m2 ), vitamin D insufficiency (serum 25- hydroxyvitamin D 210 and 529 ng/mL), SHPT (plasma iPTH >70 pg/mL) and not requiring regular hemodialysis, were recruited for this study. Eligible subjects in the ﬁrst cohort were randomized into 3 treatment groups in a 1:1:1 ratio: 2 groups ed the capsules at daily oral doses of 60 or 90 ug, respectively, and 1 group received a matching placebo capsule. Subjects in cohort 2 were randomized into 2 treatment groups in a 1:1 ratio: 1 group ed 30 ug es daily and the other received placebo. Subjects in each cohort completed 6 weeks of ent and entered a 6 week follow-up period, during which PK and PD samples were collected .

Serum calcium (Ca), phosphorus (P), 25D3, total 1,25-dihydroxyvitamin D (1,25D) and plasma iPTH were red weekly during 6 weeks of treatment and 6 weeks of follow-up. ANCOVA models ed the association of 25D3 exposure with change from baseline for 1,25D and iPTH. Covariates included were baseline eGFR, body weight and height, gender, age, race, diabetic status, and baseline concentration of 1,25D or iPTH.

Figure 4 shows the resulting mean baseline-adjusted calcifediol concentrations by treatment group (PK population). Mean levels of serum calcifediol increased gradually and in a dose-proportional manner and began to ch steady-state by 6 weeks. After 6 weeks of follow-up, levels decreased but remained above baseline in all -treated groups.

Figure 5 shows the resulting summary ne-adjusted PK parameters for calcifediol concentrations by treatment group (PK population).

Figure 6 shows the resulting mean baseline-adjusted serum 1,25-dihydroxyvitamin D levels during the 6-week treatment (PK population). Mean baseline-adjusted serum total 1,25 dihydroxyvitamin D levels increased over time in those subjects administered the active capsules, ed to those subjects administered placebo.

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

Figure 8 shows the resulting mean percent of baseline in plasma iPTH levels during the 6-week ent (PK population). The active es cantly decreased mean plasma iPTH from baseline by 21%, 33% and 39% in all dose groups (30, 60 and 90 ug, respectively) compared to a 17% increase in the combined placebo group.

Figure 9 shows a summary of the ing baseline-adjusted repeat-dose PK parameters for plasma iPTH by ent group (PK population).

Figures 10 and 11 show the percent change from baseline at EOT for plasma iPTH relative to baseline-adjusted calcifediol and 1,25-dihydroxyvitamin D exposure (AUC0_6Wk) in the PK Population. Percent reductions in plasma iPTH from baseline to EOT increased as serum calcifediol and total 1,25 oxyvitamin D exposures during treatment (expressed as ne- adjusted AUC0_6wk) increased.

The ized, sustained release 25-hydroxyvitamin D3 es normalized 25D levels in the majority of subjects and signiﬁcantly reduced iPTH in all dose groups (30, 60 and 90 ug). The stabilized, sustained e 25-hydroxyvitamin D3 capsules increased serum 25D3 and serum 1,25D levels gradually with dose-dependent increases in exposure. Both 25D3 and total 1,25D exposure were signiﬁcantly and inversely associated with change from baseline for plasma iPTH. Only eGFR was a signiﬁcant covariate in both models. These ﬁndings demonstrate that the stabilized, sustained release 25-hydroxyvitamin D3 capsules reliably normalized 25D levels, increased serum 1,25D levels and suppressed elevated plasma iPTH without ally meaningful effects on serum Ca and P at the doses investigated.

The foregoing description is given for cleamess of understanding only, and no unnecessary limitations should be understood therefrom, as modiﬁcations within the scope of the invention may be apparent to those having ordinary skill in the art.

] Throughout this speciﬁcation and the claims which , unless the context requires otherwise, the word “comprise” and variations such as “comprises” and “comprising” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

] Throughout the speciﬁcation, where compositions are described as including components or materials, it is plated that the compositions can also consist essentially of, or consist of, any combination of the recited components or materials, unless described otherwise. Likewise, where methods are described as including particular steps, it is contemplated that the methods can also consist ially of, or consist of, any combination of the recited steps, unless described otherwise. The invention illustratively disclosed herein suitably may be practiced in the absence of any element or step which is not speciﬁcally disclosed herein.

The practice of a method disclosed , and individual steps thereof, can be performed manually and/or with the aid of electronic equipment. Although processes have been described with reference to ular embodiments, a person of ordinary skill in the art will readily appreciate that other ways of performing the acts associated with the methods may be used. For e, the order of various of the steps may be changed without departing from the scope or spirit of the method, unless described otherwise. In addition, some of the individual steps can be ed, omitted, or further subdivided into onal steps.

All patents, publications and references cited herein are hereby fully incorporated by reference. In case of conﬂict between the t disclosure and incorporated patents, ations and references, the present disclosure should control.

Embodiments contemplated in view of the foregoing description include those described in the following ed paragraphs. 1. A controlled release formulation of a vitamin D compound comprising one or both of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3, the ation comprising a matrix that releasably binds and controllably releases the vitamin D compound, the matrix comprising a cellulose derivative. 2. A stabilized formulation for controlled release of a n D compound in the gastrointestinal tract of a subject which ingests the formulation, the formulation comprising a mixture of: one or both of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3; and an effective amount of a stabilizing agent, which is optionally a osic compound, to maintain a difference of less than 30% between the amount of vitamin D compound released at any given time point after four hours during in vitro dissolution after two months exposure to storage conditions of 25 0C and 60% relative humidity and the amount released at the same dissolution time point during in vitro dissolution conducted prior to exposing the formulation to the storage conditions. 3. A stabilized formulation for controlled release of a vitamin D compound, said formulation comprising a mixture of: one or both of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3; a wax matrix; and a stabilizing agent, which is optionally a cellulosic compound. 4. A stabilized formulation for controlled release of a vitamin D compound in the gastrointestinal tract of a t which ingests the formulation, said ation comprising a mixture of: one or both of 25-hydroxyvitamin D2 and roxyvitamin D3; a wax matrix; and a stabilizing agent, which is optionally a cellulosic stabilizing agent. 5. A stabilized formulation for controlled release of a vitamin D, said formulation sing a mixture of: one or both of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3; a wax matrix; and an effective amount of a stabilizing agent, optionally a cellulosic compound, to maintain a difference of less than 30% between the amount of vitamin D compound ed at any given time point after four hours during in vitro dissolution testing after exposure for two months to storage conditions of 25 0C and 60% relative humidity and the amount released at the same dissolution time point during in vitro dissolution conducted prior to exposing the formulation to the storage conditions. 6. A ized formulation for controlled release of a vitamin D compound in the intestinal tract of a subject which ingests the formulation, said formulation comprising a mixture of: an -loaded wax matrix sing one or both of 25-hydroxyvitamin D2 and 25- hydroxyvitamin D3; and a cellulosic stabilizing agent; n the formulation es an amount of 25-hydroxyvitamin D during in vitro dissolution after two months re to storage of 25 0C and 60% relative humidity that varies at any given dissolution time point compared to the amount released at the same ution time point during in vitro dissolution conducted prior to exposing the formulation to the storage conditions by 30% or less in the absence of the cellulosic stabilizing agent. 7. In a formulation for controlled release of a vitamin D compound in the gastrointestinal tract of a subject which ingests the ation, the improvement comprising admixing a cellulosic stabilizing agent into the formulation. 8. In a formulation for controlled e of a vitamin D compound in the gastrointestinal tract of a subject which ingests the formulation, the improvement comprising an effective amount of a cellulosic compound admixed in the formulation to maintain a change of less than 30% in the amount of 25-hydroxyvitamin D released during in vitro dissolution after exposure to storage conditions of at least one month at 25 0C and 60% relative humidity at any given dissolution time point after four hours compared to the amount released at the same dissolution time point during in vitro dissolution conducted prior to exposing the ation to the storage conditions. 9. The formulation according to any of the preceding paragraphs, wherein the cellulosic compound or cellulosic stabilizing agent ses a cellulose ether. ] 10. The formulation according to paragraph 9, wherein the ose ether is selected from the group consisting of methylcellulose, yl propyl methylcellulose, hydroxyl ethyl methylcellulose, hydroxyl ethyl cellulose, and yl propyl cellulose. 11. The formulation according to paragraph 9, wherein the cellulosic nd or cellulosic stabilizing agent is hydroxyl propyl methylcellulose. 12. The formulation according to any of the preceding aphs, wherein the formulation releases an amount of 25-hydroxyvitamin D during in vitro ution after exposure to storage conditions for 2 months at 25 0C and 60% relative humidity that varies at any given dissolution time point after four hours compared to the amount ed at the same dissolution time point during in vitro dissolution conducted prior to exposing the formulation to the storage conditions, by 30% or less. 13. The formulation according to any of the preceding paragraphs, wherein the formulation releases an amount of 25-hydroxyvitamin D during in vitro dissolution after exposure to storage conditions for one month at 40 0C and 75% relative humidity that varies at any given dissolution time point after four hours compared to the amount released at the same dissolution time point during in vitro dissolution conducted prior to exposing the ation to the storage ions, by 30% or less. 14. The formulation according to any one of the preceding paragraphs, wherein the matrix ses a wax matrix comprising a controlled release agent, an emulsifier, and an absorption enhancer. 15. The formulation according to paragraph 14, wherein the controlled release agent comprises paraffin. 16. The formulation according to paragraph 14 or 15, wherein the emulsifier has a HLB value less than 7. 17. The formulation according to paragraph 16, wherein the emulsiﬁer comprises glycerol monostearate. 18. The formulation according to any one of paragraphs 14 to 17, wherein the absorption enhancer has a HLB value in a range of about 13 to about 18. 19. The formulation according to paragraph 18, wherein the absorption enhancer is a mixture of lauroyl macrogolglycerides and lauroyl polyoxylglycerides. 20. The ation according to any of the preceding aphs, wherein the Vitamin D compound comprises 25-hydroxyVitamin D3. 21. The formulation according to any of the ing paragraphs, ﬁarther comprising an oily vehicle. 22. The formulation according to paragraph 21, wherein the oily vehicle comprises mineral oil. 23. The formulation according to paragraph 22, wherein the formulation comprises about 20 wt% parafﬁn, about 20 wt% to about 25 wt% glycerol monostearate, about 10 wt% a mixture of lauroyl macrogolglycerides and lauroyl polyoxylglycerides, about 30 wt% to about 35 wt% mineral oil, and about 10 wt% to about 15 wt% hydroxyl propyl methylcellulose. 24. A formulation ing to any one of the preceding paragraphs, wherein the formulation comprises glycerol monostearate. 25. A formulation according to any one of the preceding paragraphs, wherein the formulation comprises one or more ycolized glycerides. 26. A sustained e dosage form in the form of a capsule, tablet, sachet, dragee, or suppository comprising a formulation according to any one of the preceding aphs. 27. The dosage form according to aph 26, comprising a capsule or tablet. 28. The dosage form according to paragraph 27, comprising a capsule. 29. The dosage form according to paragraph 26, comprising an oral capsule, tablet, sachet, . 30. A stabilized dosage form according to any one of the preceding paragraphs terized by a dissolution proﬁle providing a release of Vitamin D compound of less than 30% at 2 hours; r than 45% at 6 hours; and greater than 80% at 12 hours. 31. The stabilized dosage form ing to paragraph 26, wherein the release of Vitamin D compound at 6 hours is less than 60%. 32. A stabilized sustained release oral dosage form comprising a n D nd characterized by an in Vitro dissolution proﬁle providing release of Vitamin D compound of 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 aph 32, wherein the release of 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 according to paragraph 32 or 33, wherein the release of Vitamin D compound at 5 to 7 hours is less than 60%. 35. The dosage form according to paragraph 34, wherein the release of Vitamin D compound at 6 hours is less than 60%. 36. A stabilized sustained release oral dosage form comprising a Vitamin D compound characterized by an in Vitro dissolution proﬁle providing release of Vitamin D compound of about 20% to about 40% at 2 hours; at least 35% at 6 hours; and at least 70% at 12 hours. 37. The dosage form of paragraph 36, n the release of n D compound is about 25% to about 35% at 2 hours; at least 40% at 6 hours; and at least 75% at 12 hours. 2014/028132 38. The dosage form of paragraph 36 or 37, wherein the release of vitamin D compound is 75% or less at 6 hours. ] 39. The dosage form of paragraph 38, wherein the release of vitamin D compound is 65% or less at 6 hours. 40. The dosage form of aph 39, wherein the release of vitamin D compound is 60% or less at 6 hours. 41. A stabilized sustained release dosage form comprising a vitamin D compound characterized by a tmax following administration of the dosage form to a human patient, of at least 4 hours. 42. The dosage form of paragraph 41, wherein the tmax is at least 8 hours. 43. The dosage form of paragraph 42, wherein the tmax is at least 12 hours. 44. The dosage form of paragraph 43, wherein the tmax is at least 18 hours. 45. The dosage form of paragraph 44, wherein the tmax is at least 20 hours. 46. The dosage form of paragraph 45, wherein the tmax is at least 24 hours. 47. The dosage form of paragraph 46, wherein the tmax is at least 28 hours. 48. The dosage form of paragraph 41, wherein the tmax is in a range of 4 to 96 hours. 49. The dosage form of aph 48, wherein the tmax is in a range of 18 to 30 hours. 50. The dosage form of aph 49, wherein the tmax is in a range of 13 to 28 hours. 51. The dosage form of paragraph 50, wherein the tmax is about 28 hours. 52. A ized sustained release dosage form comprising a 25-hydroxyvitamin D compound, the dosage form characterized by ing a baseline-adjusted Cmax per ram of 25-hydroxyvitamin D in a range of about 0.0133 ng/mL to about 0.04 ng/mL when administered to an adult human. 53. A method of administering a stabilized sustained release dosage form comprising a 25-hydroxyvitamin D compound to a human patient, comprising administering an effective amount of the dosage form to the patient to provide a baseline-adjusted Cmax of at least about 0.2 ng/mL and less than 110 ng/mL. 54. The method of paragraph 53, sing administering an effective amount of the dosage form to provide a baseline-adjusted Cmax in a range of about 0.2 to about 24 ng/mL. 55. A method of administering a stabilized sustained e dosage form comprising a 25-hydroxyvitamin D nd to a human t, comprising administering an effective amount of the dosage form to the patient to provide a baseline-adjusted AUCO_inf of at least 52 ng*h/mL and less than 34500 ng*h/mL. ] 56. The method of paragraph 55, comprising administering an effective amount of the dosage form to the patient to provide a baseline-adjusted AUCO_infin a range of about 52 L to about 12,000 ng*h/mL. 57. A method of vitamin D supplementation comprising administering to a subject in need thereof a formulation or dosage form according to any one of the preceding paragraphs. 58. A method of treatment or prophylaxis of a vitamin-D responsive disease in a subject comprising administering to the subject a formulation or dosage form according to any one ofthe preceding paragraphs. 59. The method of paragraph 58, wherein the disease is selected from cancer (e. g., breast, lung, skin, melanoma, colon, colorectal, rectal, prostate and bone cancer), autoimmune diseases, for example, type I diabetes, multiple sclerosis, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma, ﬁbrosis, s disease, Hashimoto's disease, acute or chronic transplant rejection, acute or c graft versus host e, inﬂammatory bowel disease, Crohn's disease, systemic lupus erythematosis, Sjogren's Syndrome, eczema and sis, dermatitis, including atopic dermatitis, contact dermatitis, allergic dermatitis and/or chronic dermatitis, inﬂammatory diseases, for example, asthma, chronic obstructive pulmonary disease, polycystic kidney disease, polycystic ovary me, pancreatitis, nephritis, hepatitis, and/or infection, hypertension, cardiovascular diseases, for example, subjects with atherosclerosis, arteriosclerosis, coronary artery disease, cerebrovascular disease, peripheral vascular disease, myocardial infarction, myocardial ia, cerebral ischemia, stroke, tive heart failure, cardiomyopathy, obesity or other weight ers, lipid disorders (e. g. hyperlipidemia, dyslipidemia including ated diabetic dyslipidemia and mixed dyslipidemia hypoalphalipoproteinemia, hypertriglyceridemia, hypercholesterolemia, and low HDL (high y lipoprotein)), lic disorders (e. g. Metabolic Syndrome, Type II diabetes mellitus, WO 43941 Type I diabetes mellitus, hyperinsulinemia, impaired glucose tolerance, insulin resistance, diabetic complication including neuropathy, nephropathy, orosis, retinopathy, diabetic foot ulcer and cataracts), and/or thrombosis. 60.The method of paragraph 59, wherein the e is selected from (i) in the parathyroid-- hypoparathyroidism, Pseudohypo-parathyroidism, secondary arathyroidism; (ii) in the pancreas--diabetes; (iii) in the thyroid--medullary oma; (iV) in the skin-- psoriasis; wound healing; (V) in the lung--sarcoidosis and tuberculosis; (Vi) in the kidney-- chronic kidney disease, hypophosphatemic VDRR, Vitamin D dependent rickets; (Vii) in the bone--anticonvulsant treatment, nisis imperfecta ossium, osteitis ﬁbrosa cystica, osteomalacia, osteoporosis, osteopenia, osteosclerosis, renal osteodytrophy, rickets; (Viii) in the intestine--glucocorticoid antagonism, idopathic hypercalcemia, malabsorption syndrome, steatorrhea, tropical sprue; and (ix) autoimmune disorders. 61. The method of paragraph 60, wherein the disease is selected from cancer, dermatological disorders (for example psoriasis), parathyroid disorders (for example hyperparathyroidism and secondary hyperparathyroidism), bone disorders (for example osteoporosis) and autoimmune disorders. ] 62. The method of paragraph 61, wherein the disease is secondary hyperparathyroidism. 63. The method of paragraph 62, wherein the subject has chronic kidney disease (CKD). 64. The method of paragraph 63, wherein the CKD is Stage 3 or 4. 65. The method of aph 64, wherein the patient is n-D nt. 66. The method of any one of the preceding paragraphs, wherein the patient is human. 67. The method of paragraph 66, wherein the human is an adult human. 68. A composition as substantially herein described.

Claims

WHAT IS CLAIMED IS:

1. A controlled release oral formulation of a vitamin D compound comprising one or both of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3, the formulation comprising a matrix that releasably binds and controllably releases the vitamin D compound, the matrix comprising a stabilizing agent comprising a material selected from a cellulose compound ed from celluloronic acid, a ose ether, polyanionic cellulose, and combinations f, poloxamers, poly(ethylene oxide) polymers, povidones, fumed silicas, and ations thereof.

2. The formulation of claim 1, said formulation sing a mixture of: one or both of 25-hydroxyvitamin D2 and roxyvitamin D3; a wax matrix; and an effective amount of the release-stabilizing agent to maintain a difference of less than 30% between the amount of vitamin D compound released at any given time point after four hours during in vitro dissolution testing after exposure for two months to storage conditions of 25 oC and 60% relative ty and the amount released at the same dissolution time point during in vitro dissolution conducted prior to exposing the formulation to the storage conditions.

3. The ation of any one of the preceding claims, wherein the stabilizing agent ses a cellulose compound selected from celluloronic acid, a cellulose ether, polyanionic cellulose, and combinations thereof.

4. The formulation according to any one of the preceding claims, wherein the cellulosic compound or cellulosic release-stabilizing agent comprises a cellulose ether.

5. The formulation according to claim 4, wherein the cellulose ether is selected from the group consisting of methylcellulose, hydroxyl propyl methylcellulose, yl ethyl methylcellulose, hydroxyl ethyl cellulose, and hydroxyl propyl cellulose.

6. The formulation according to claim 4, wherein the cellulosic compound or cellulosic release-stabilizing agent comprises hydroxyl propyl methylcellulose.

7. The formulation according to any one of the ing claims, wherein the formulation releases an amount of 25-hydroxyvitamin D during in vitro dissolution after exposure to e conditions for one month at 40 oC and 75% relative humidity that varies at any given dissolution time point after four hours compared to the amount released at the same dissolution time point during in vitro dissolution conducted prior to exposing the formulation to the storage conditions, by 30% or less.

8. The formulation according to any one of the preceding claims, wherein the matrix comprises a wax matrix comprising a lled release agent, an emulsifier, and an absorption enhancer.

9. The formulation according to claim 8, wherein the controlled release agent comprises paraffin.

10. The formulation according to claim 8 or 9, wherein the emulsifier has a HLB value less than 7.

11. The formulation according to claim 10, wherein the emulsifier comprises glycerol monostearate.

12. The formulation according to any one of claims 8 to 11, wherein the absorption enhancer has a HLB value in a range of about 13 to about 18.

13. The formulation according to claim 12, wherein the absorption enhancer is a e of lauroyl olglycerides and lauroyl polyoxylglycerides.

14. The formulation according to any one of claims 8-13, further sing an oily vehicle.

15. The formulation according to claim 14, n the oily vehicle comprises l oil.

16. The formulation according to claim 15, n the formulation comprises about 20 wt% paraffin, about 20 wt% to about 25 wt% glycerol monostearate, about 10 wt% a mixture of lauroyl macrogolglycerides and lauroyl polyoxylglycerides, about 30 wt% to about 35 wt% mineral oil, and about 10 wt% to about 15 wt% hydroxyl propyl methylcellulose.

17. A formulation according to any one of claims 8-16 wherein the formulation comprises glycerol earate.

18. A formulation according to any one of claims 8-17, wherein the ation comprises one or more polyglycolized glycerides.

19. A sustained release dosage form in the form of a capsule, tablet, sachet, or , comprising a formulation according to any one of the preceding claims.

20. The dosage form according to claim 19, comprising a capsule or tablet.

21. The dosage form according to claim 20, comprising a capsule.

22. The dosage form according to claim 19, comprising an oral capsule, tablet, sachet, or dragee.

23. A formulation or stabilized dosage form according to any one of the preceding claims terized by a dissolution profile providing a release of vitamin D compound of less than 30% at 2 hours; greater than 45% at 6 hours; and greater than 80% at 12 hours.

24. The formulation or stabilized dosage form ing to claim 23, wherein the release of vitamin D compound at 6 hours is less than 60%.

25. A formulation or stabilized sustained release oral dosage form according to any one of claims 1 to 22, characterized by an in vitro dissolution profile providing e of vitamin D compound of 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.

26. The formulation or dosage form of claim 25, wherein the release of vitamin D compound is less than 30% at 2 hours; greater than 45% at 6 hours; and r than 80% at 12 hours.

27. The formulation or dosage form according to claim 25 or 26, wherein the release of vitamin D nd at 5 to 7 hours is less than 60%.

28. The formulation or dosage form according to claim 27, wherein the release of vitamin D compound at 6 hours is less than 60%.

29. A formulation or stabilized sustained release oral dosage form according to any one of claims 1 to 22, characterized by an in vitro dissolution profile providing release of vitamin D compound of about 20% to about 40% at 2 hours; at least 35% at 6 hours; and at least 70% at 12 hours.

30. The ation or dosage form of claim 29, wherein the release of vitamin D compound is about 25% to about 35% at 2 hours; at least 40% at 6 hours; and at least 75% at 12 hours.

31. The formulation or dosage form of claim 29 or 30, n the release of vitamin D compound is 75% or less at 6 hours.

32. The formulation or dosage form of claim 31, wherein the release of vitamin D compound is 65% or less at 6 hours.

33. The formulation or dosage form of claim 32, wherein the release of vitamin D compound is 60% or less at 6 hours.

34. A formulation or stabilized ned release dosage form according to any one of the preceding claims characterized by a tmax following administration of the dosage form to a human patient, of at least 4 hours.

35. The ation or dosage form of claim 34, wherein the tmax is at least 8 hours.

36. The formulation or dosage form of claim 35, wherein the tmax is at least 12 hours.

37. The formulation or dosage form of claim 36, wherein the tmax is at least 18 hours.

38. The formulation or dosage form of claim 37, wherein the tmax is at least 20 hours.

39. The formulation or dosage form of claim 38, wherein the tmax is at least 24 hours.

40. The formulation or dosage form of claim 39, wherein the tmax is at least 28 hours.

41. The formulation or dosage form of claim 34, n the tmax is in a range of 4 to 96 hours.

42. The formulation or dosage form of claim 41, wherein the tmax is in a range of 18 to 30 hours.

43. The formulation or dosage form of claim 42, wherein the tmax is in a range of 13 to 28 hours.

44. The formulation or dosage form of claim 43, wherein the tmax is about 28 hours.

45. A formulation or stabilized sustained release dosage form according to any one of the ing claims comprising a 25-hydroxyvitamin D compound, the formulation or dosage form characterized by providing a baseline-adjusted Cmax per microgram of 25- hydroxyvitamin D in a range of about 0.0133 ng/mL to about 0.04 ng/mL when stered to an adult human.

46. A formulation or stabilized sustained release dosage form according to any one of the preceding claims, the formulation or dosage form characterized by providing a baseline-adjusted Cmax of at least about 0.2 ng/mL and less than 110 ng/mL.

47. The formulation or stabilized sustained e dosage form of claim 47, wherein the formulation or dosage form provides a baseline-adjusted Cmax in a range of about 0.2 to about 24 ng/mL.

48. A ation or stabilized sustained release dosage form of any one of claims 1-45, wherein the formulation or dosage form es a baseline-adjusted AUC0-inf of at least 52 ng*h/mL and less than 34500 ng*h/mL.

49. The formulation of claim 48, n the baseline-adjusted AUC0-inf in a range of about 52 ng*h/mL to about 12,000 ng*h/mL.

50. Use of the formulation or dosage form according to any one of claims 1-45 in the manufacture of a medicament for vitamin D supplementation in a subject in need thereof.

51. Use of the formulation or dosage form according to any one of claims 1-45 in the manufacture of a medicament for treatment or prophylaxis of a vitamin-D sive disease.

52. The use of claim 51, wherein the disease is selected from cancer (including but not limited to breast, lung, skin, melanoma, colon, colorectal, rectal, prostate and bone cancer), autoimmune diseases, type I diabetes, multiple sis, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma, fibrosis, Grave's disease, Hashimoto's disease, acute or chronic transplant ion, acute or chronic graft versus host disease, inflammatory bowel disease, Crohn's disease, systemic lupus erythematosis, Sjogren's Syndrome, eczema and psoriasis, dermatitis, including atopic itis, contact itis, allergic dermatitis and/or chronic itis, inflammatory diseases, asthma, chronic obstructive pulmonary disease, polycystic kidney e, polycystic ovary syndrome, pancreatitis, nephritis, hepatitis, and/or infection, hypertension, cardiovascular diseases, including but not limited to atherosclerosis, arteriosclerosis, coronary artery disease, cerebrovascular disease, peripheral vascular disease, myocardial infarction, myocardial ischemia, cerebral ischemia, stroke, congestive heart failure, cardiomyopathy, obesity or other weight disorders, lipid disorders (e.g. hyperlipidemia, dyslipidemia including ated diabetic dyslipidemia and mixed dyslipidemia hypoalphalipoproteinemia, hypertriglyceridemia, hypercholesterolemia, and low HDL (high density lipoprotein)), metabolic disorders (e.g. Metabolic Syndrome, Type II es mellitus, Type I diabetes mellitus, nsulinemia, impaired glucose tolerance, insulin resistance, diabetic complication including neuropathy, nephropathy, osteoporosis, retinopathy, diabetic foot ulcer and cataracts), and/or thrombosis.

53. The use of claim 51, n the disease is ed from (i) in the yroid-- hypoparathyroidism, Pseudohypo-parathyroidism, ary hyperparathyroidism; (ii) in the pancreas--diabetes; (iii) in the d--medullary carcinoma; (iv) in the skin--psoriasis; wound healing; (v) in the lung--sarcoidosis and tuberculosis; (vi) in the kidney--chronic kidney e, hypophosphatemic VDRR, vitamin D dependent rickets; (vii) in the bone--anticonvulsant treatment, fibrogenisis imperfecta ossium, osteitis fibrosa cystica, osteomalacia, osteoporosis, enia, osteosclerosis, renal osteodytrophy, rickets; (viii) in the intestine--glucocorticoid antagonism, idopathic hypercalcemia, orption syndrome, steatorrhea, tropical sprue; and (ix) autoimmune disorders.

54. The use of claim 51, wherein the disease is selected from cancer, dermatological disorders (for e psoriasis), parathyroid disorders (for example hyperparathyroidism and secondary hyperparathyroidism), bone disorders (for example osteoporosis) and autoimmune disorders.

55. The use of claim 54, wherein the disease is secondary hyperparathyroidism.

56. The use of claim 55, wherein the subject has c kidney disease (CKD).

57. The use of claim 56, wherein the CKD is Stage 3 or 4.

58. The use of claim 57, wherein the patient is vitamin-D deficient.

59. The use of any one of claims 50-58, wherein the patient is human.

60. The use of claim 59, wherein the human is an adult human.

61. Use of the formulation or stabilized sustained release dosage form according to any one of claims 1-45 in the manufacture of a medicament for vitamin D mentation in a patient.