Hard capsule dosage forms and uses thereof

Abstract

The present invention relates to hard capsule dosage forms and uses thereof. The hard capsule dosage form comprises a hard-shell capsule, the hard-shell capsule contains a solid or semi-solid composition, the solid or semi-solid composition comprises a 25-hydroxyvitamin D compound, and the hard-shell capsule comprises cellulose ether and a gelling agent; and wherein the hard shell capsule is a capsule in the range of No. 3 to No. 5.

Description

[0001] Description of the case

[0002] This application is a divisional application of the invention patent application with an application date of May 31, 2021, national application number 202180038341.6, and invention name “Hard capsule dosage form and its use”.

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application is a continuation-of PCT application PCT / IB21 / 00220, filed on April 6, 2021, and hereby claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 032,714, filed on May 31, 2020, the disclosure of which is hereby incorporated by reference. Technical Field

[0005] The present disclosure generally relates to a dosage form suitable for use with vitamin D active compounds, for example, to a hard capsule formulation for delivery of 25-hydroxyvitamin D compounds and their use in therapy. Background Art

[0006] For example, extended-release calcifediol (ERC) dosage forms and related methods have been described in U.S. Patent Nos. 8,2207,149, 8,426,391, 9,861,644, U.S. Patent Application Publication No. 2019 / 0083513A1, and International Patent Application Publication No. WO 2020 / 044314 A1, the entire disclosures of which are incorporated herein by reference. In capsule form (Calcifediol) sustained-release capsules for sale. Summary of the Invention

[0007] One aspect of the present disclosure is a hard capsule dosage form comprising a hard shell capsule containing a solid or semisolid composition comprising a 25-hydroxyvitamin D compound, the hard shell capsule comprising a cellulose ether and a gelling agent.

[0008] Another aspect of the present disclosure is a hard capsule dosage form comprising a hard shell capsule containing a solid or semisolid composition comprising a 25-hydroxyvitamin D compound, the hard shell capsule comprising a cellulose ether.

[0009] Another aspect of the present disclosure is a method of delivering 25-hydroxyvitamin D or calcifediol to a subject in need thereof, the method comprising administering to the subject a hard shell capsule dosage form of the present disclosure. Similarly, an aspect of the present disclosure is the use of a hard shell capsule dosage form according to the present disclosure to a subject in need thereof. The subject in need thereof can be any person in need of 25-hydroxyvitamin D, or a person suffering from a disease or condition described herein.

[0010] Another aspect of the present disclosure is the use of a gelled hard capsule dosage form of the present disclosure, wherein the dosage form releases no more than about 5% of the 25-hydroxyvitamin D or calcifediol in a formulation contained in the dosage form within two hours in an acidic medium, optionally in an acidic medium at pH 1.2 or pH 1.5, and further optionally at 37° C., the hard capsule dosage form being for containing a composition comprising 25-hydroxyvitamin D or calcifediol and providing increased recovery and / or reduced degradation of the 25-hydroxyvitamin D or calcifediol after exposure of the dosage form to acidic conditions.

[0011] Another aspect of the present disclosure is the use of a gelled hard capsule dosage form of the present disclosure, wherein the dosage form releases no more than about 5% of the 25-hydroxyvitamin D or calcifediol in the formulation contained in the dosage form within two hours in an acidic medium, optionally in an acidic medium at pH 1.2 or pH 1.5, and further optionally at 37° C., the hard capsule dosage form being for containing a composition comprising 25-hydroxyvitamin D or calcifediol and for oral administration to a mammal.

[0012] Another aspect of the present disclosure is the use of a gelled hard capsule dosage form of the present disclosure, wherein the dosage form releases no more than about 5% of the 25-hydroxyvitamin D or calcifediol in the formulation contained in the dosage form within two hours in an acidic medium, optionally in an acidic medium at pH 1.2 or pH 1.5, and further optionally at 37° C., the hard capsule dosage form being used to contain a composition comprising 25-hydroxyvitamin D or calcifediol and exposing the dosage form to acidic conditions, optionally to acidic conditions of less than pH 4.5, and optionally less than pH 3.5.

[0013] Another aspect of the present disclosure is a method of preparing a hard shell capsule dosage form according to the present disclosure, the method comprising placing a formulation containing 25-hydroxyvitamin D in a gelled hypromellose hard shell capsule according to the present disclosure. The 25-hydroxyvitamin D formulation may optionally be heated before being placed in the shell, for example if the formulation is a solid or semisolid formulation that flows more easily when heated. The shell may optionally have a sealing solution applied thereto, such as a hypromellose sealing solution.

[0014] With respect to the compositions and methods described herein, optional features are contemplated, including but not limited to components, compositional ranges thereof, substituents, conditions, and steps, selected from various aspects, embodiments, and examples provided herein.

[0015] By reviewing the following detailed description in conjunction with the accompanying drawings, other aspects and advantages will be apparent to those skilled in the art. Although the methods, uses, and compositions may have various forms of embodiments, the following description includes specific embodiments with the understanding that the present disclosure is illustrative and is not intended to limit the invention to the specific embodiments described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] To further facilitate understanding of the present invention, eight drawings are attached herewith.

[0017] Figure 1 Shown are the mean serum concentration profiles of 25-hydroxyvitamin D3 following oral administration of 900 mcg modified-release calcifediol softgel capsules.

[0018] Figure 2 Shown is the in vitro dissolution profile of a hard capsule dosage form according to the present disclosure.

[0019] Figure 3 Repeated administration of ERC in adult patients with secondary hyperparathyroidism (SHPT), stage 3 or 4 chronic kidney disease (CKD), and vitamin D insufficiency according to Example 3 is shown. Time course of serum total 25-D concentrations with paricalcitol (calcifediol) extended-release capsules), IR calcifediol, high-dose cholecalciferol, and paricalcitol plus low-dose cholecalciferol.

[0020] Figure 4 Repeated administration of ERC in adult patients with secondary hyperparathyroidism (SHPT), stage 3 or 4 chronic kidney disease (CKD), and vitamin D insufficiency according to Example 3 is shown. Changes in VMR over time with paricalcitol (calcifediol) extended-release capsules), IR calcifediol, high-dose cholecalciferol, and paricalcitol plus low-dose cholecalciferol.

[0021] Figure 5 Repeated administration of ERC in adult patients with secondary hyperparathyroidism (SHPT), stage 3 or 4 chronic kidney disease (CKD), and vitamin D insufficiency according to Example 3 is shown. Serum total 25-hydroxyvitamin D response rates to calcifediol (calcifediol extended-release capsules), IR calcifediol, high-dose cholecalciferol, and paricalcitol plus low-dose cholecalciferol.

[0022] Figure 6Repeated administration of ERC in adult patients with secondary hyperparathyroidism (SHPT), stage 3 or 4 chronic kidney disease (CKD), and vitamin D insufficiency according to Example 3 is shown. The plasma iPTH-lowering responses to calcifediol (calcifediol) extended-release capsules), IR calcifediol, high-dose cholecalciferol, and paricalcitol plus low-dose cholecalciferol were also observed.

[0023] Figure 7 Shown are the dissolution profiles of the hypromellose capsule sample according to Example 5 in pH 6.8 medium (left) and a two-stage dissolution process (right).

[0024] Figure 8 Shown are the dissolution profiles of the plant capsule samples in pH 6.8 medium (left), a two-stage dissolution process (middle), and pH 1.2 medium (right / bottom).

[0025] Figure 9 and Figure 10 Dissolution profiles for pH 1.2 and 4.5 tests are presented separately. DETAILED DESCRIPTION

[0026] The dosage forms of the present disclosure are hard capsule formulations of a vitamin D compound, such as 25-hydroxyvitamin D. Although the general description below describes the compositions and uses of 25-hydroxyvitamin D, it is contemplated that in each case another vitamin D compound may be used in place of the 25-hydroxyvitamin D compound. It is also contemplated that in each case where 25-hydroxyvitamin D is mentioned, calcifediol may be the specific 25-hydroxyvitamin D compound. Another aspect of the present disclosure is a sustained-release hard capsule formulation containing a 25-hydroxyvitamin D compound, such as a sustained-release hard capsule formulation for oral administration. The formulation may also optionally have delayed-release properties. In any of the methods described herein, the 25-hydroxyvitamin D compound may be administered in the form of a hard capsule formulation as described herein.

[0027] It was surprisingly found that wax-based formulations (such as for (Calcifediol) in a wax-based formulation in a sustained-release capsule) using a two-stage dissolution process (2 hours at pH 1.2 followed by transfer to a pH 6.8 buffer medium) did not provide a matching dissolution release profile in the 0-2 hour and 0-4 hour timeframes. However, using a gelled HPMC hard capsule shell, such a dosage form can be prepared with comparable release profiles. (Calcifediol) sustained-release capsules closely match the dissolution profile. Figure 2 It was also found that the HPMC-based hard capsule shells, while providing a more consistent burst time than the soft capsules, provided an earlier burst time. (Calcifediol) sustained-release capsules closely match the dissolution-release profile, increasing the amount of wax to slow down the release rate of the active substance.

[0028] With respect to the compositions and methods described herein, it is contemplated that optional features are selected from the various aspects, embodiments, and examples provided herein, including but not limited to components, composition ranges thereof, substituents, conditions, and steps. Although the methods and compositions described herein can be embodied in the form of, the following description includes specific embodiments recognizing that the disclosure is illustrative and is not intended to limit the invention to the specific embodiments described herein.

[0029] U.S. Patents No. 5,264,223 and No. 5,431,917 describe capsules produced using HPMC and a gelling agent such as carrageenan. It is claimed that the production of such capsules is carried out at a temperature setting similar to that of gelatin capsules. Shionogi Qualicaps Co. (Japan) produces HPMC capsules containing carrageenan (e.g., kappa-carrageenan and / or iota-carrageenan) as a gelling aid and potassium chloride as a gelling accelerator. U.S. Patent No. 6,410,050 B1 describes cellulose capsules (including HPMC) containing pectin and glycerin. U.S. Patent No. 6,517,865 B2 describes HPMC capsules with a hydrocolloid such as gellan gum and a chelating agent such as EDTA, sodium citrate, and citric acid. For example, the US patent describes a capsule material comprising 90% to 99.98% by weight of at least one cellulose ether having a water content of 2% to 10% and a viscosity of 3 to 15 cps measured in a 2% aqueous solution at 20°C; 0.01% to 5% by weight of gellan gum; and 0.01% to 8% by weight of a chelating agent selected from the group consisting of EDTA, sodium citrate, citric acid, and combinations thereof. For example, it is contemplated to use HPMC capsules containing at least one cellulose ether, optionally HPMC, having a water content of 2% to 10% and a viscosity of 3 to 15 cps measured in a 2% aqueous solution at 20°C, and a gelling agent, optionally gellan gum, in an amount of about 0.01% to about 10% by weight, or about 1% to about 8% by weight, or about 2% to about 7% by weight, or about 4% to about 6% by weight, or about 5% by weight. The HPMC capsule of this type of gelling agent is used for the treatment of catalytic conversion of HPMC capsule.Compared with the HPMC capsule that does not contain gelling aid, this type of gelling HPMC capsule is considered to provide slower rupture or disintegration time, for example, in the stomach.Additionally or alternatively, the HPMC capsule can comprise enteric coating to delay or prevent the dissolving or disintegration of capsule shell in the gastric environment.The enteric coating material that acid-resistant medium dissolves and is dissolved in neutral and alkaline medium is known and comprises for example methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, methyl methacrylate-methacrylic acid copolymer, shellac, cellulose acetate trimellitate, sodium alginate, zein and comprise ethyl cellulose, medium chain triglyceride, oleic acid, sodium alginate and stearic mixture coating solution. Hard capsules containing no gelling agent or a small percentage of gelling agent (eg 0-4% w / w) may optionally be enteric coated to achieve minimal or zero release within a 0-2 hour period following administration.

[0030] The hard shell capsule is mainly based on cellulose ether or its mixture. The hard shell capsule of the present disclosure is not a gelatin-based capsule. Suitable cellulose ethers are cellulose ethers substituted with an alkyl group and / or a hydroxyalkyl group having 1 to 4 carbon atoms in the alkyl chain, such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylethylcellulose, hydroxypropylmethylcellulose, etc. Hydroxypropylmethylcellulose is commonly referred to as hypromellose and is specifically contemplated. Various examples and embodiments are described herein in conjunction with hypromellose, and in each case, it is more generally contemplated that the hard shell capsule can be based on another cellulose ether or its mixture, as described herein. The amount of the cellulose ether or cellulose ether mixture can be, for example, greater than 50% by weight of the hard shell capsule, or at least 60% by weight, or at least 70% by weight, or at least 80% by weight, or at least 90% by weight, such as 95% to 99.98% by weight of the hard shell capsule. The viscosity of the cellulose ether or blend in a 2% aqueous solution at 20°C may be in the range of 3 cps to 15 cps, or in the range of 5 cps to 10 cps, or about 6 cps.

[0031] The hard shell capsule contains a gelling agent. The gelling agent may comprise a hydrocolloid. The hydrocolloid may include, for example, a synthetic gum capable of gelling without the addition of alkali or alkaline earth metal ions. The hydrocolloid may be an anionic polysaccharide, such as gellan gum. The hydrocolloid may be selected from natural seaweed, natural seed gum, natural plant exudate, natural fruit extract, biosynthetic gum, and biosynthetic processed starch. The hydrocolloid may comprise one or more types selected from the group consisting of alginates, agar gum, guar gum, locust bean gum (carob), carrageenan (e.g., kappa and / or iota carrageenan), tara gum, gum arabic, gum ghatti, Khaya grandifolia gum, gum tragacanth, gum karaya, pectin, arabic (arabinan), xanthan gum, gellan gum, starch, konjac mannan, galactomannans, harugan, and other exopolysaccharides such as xanthan gum, acetylated gum, gellan gum, welan gum, rhamnose gum, furcellaran, succinoglycan, scleroglucan, schizophyllan, tamarind gum, curdlan gum, pullulan, and dextran. The amount of hydrocolloid in the hard shell capsule can be 0.01% to 50% by weight, or 0.1% to 30% by weight, or 0.1% to 20% by weight, or 0.1% to 10% by weight, or 0.1% to 2% by weight, or 0.1% to 1.0% by weight of the hard shell capsule. The hard capsule shell can contain about 0.01% to about 10% by weight of a gelling agent. The gelling agent can include gellan gum.

[0032] The hard shell capsule may further include a gelling agent. The gelling agent may be selected from, for example, ammonium, calcium, magnesium, potassium, or sodium cations, or from calcium, potassium, or sodium cations. The cations may be provided by using water-soluble ammonium salts, calcium salts, magnesium salts, potassium salts, or sodium salts. The gelling agent may be provided by a water-soluble salt of an organic acid or a water-soluble salt of an inorganic acid, and may be referred to herein as a gelling agent precursor. For example, the gelling agent precursor may be one or more compounds selected from the following group: ammonium chloride, ammonium acetate, calcium pantothenate, calcium chloride, calcium bromide, calcium lactate, calcium nitrate, magnesium sulfate, potassium acetate, potassium chloride, potassium phosphate, and sodium chloride. Citric acid may be used as a gelling agent. For example, the amount of the gelling agent precursor may be in the range of approximately 0.1% to 20% by weight, or 0.5% to 15% by weight, or 0.5% to 10% by weight of the hard shell capsule.

[0033] The hard shell capsule may contain one or more adjuvants selected from the group consisting of plasticizers, lubricants, chelating agents, colorants, opacifiers, and adjuvants for residual moisture (e.g., 1% to 10% by weight of the hard shell capsule), and amounts typically used for such purposes. The hard shell capsule may be purchased commercially or prepared by methods known in the art.

[0034] For example, the hard capsule shell can have any suitable number to contain the formulation placed therein at the desired active strength, for example within the standard number range from 000 to 5, such as 000, 00E, 00, 0E, 0, 1, 2, 3, 4 or 5, or within the range of 3 to 5, or specifically 3 or specifically 4.

[0035] Once filled, the hard shell can optionally be bonded / sealed with a solution of hypromellose, such as a solution made from a low viscosity grade (e.g., E3 grade) having a viscosity of 3 mPa·s as a 2% solution at 20° C. For example, the sealing solution can be applied in any suitable amount, such as in the range of about 0.002 g / cap to 0.02 g / cap. For example, in one aspect, the solution can be applied at a rate that does not affect the dissolution characteristics, but can protect the capsule from leaking when using liquid contents, or at elevated temperatures encountered in hot zones (e.g., 35° C. to 50° C.), where the contents may soften or become liquid.

[0036] The hard shell capsule contains a vitamin D formulation that can be a 25-hydroxyvitamin D formulation. In various aspects, the dosage form is prepared for oral administration of a 25-hydroxyvitamin D compound. In various examples, the 25-hydroxyvitamin D compound includes 25-hydroxyvitamin D2 or 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3. It is specifically contemplated that in any and every aspect and embodiment of the compositions and methods disclosed herein, the 25-hydroxyvitamin D compound can be 25-hydroxyvitamin D3. As used herein, the term "25-hydroxyvitamin D compound" 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 thereto, preferred embodiments are 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 agent may comprise one or both of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3, specifically 25-hydroxyvitamin D3.

[0037] The hard shell capsule contains a 25-hydroxyvitamin D formulation, also known as a fill formulation, which can take various forms, as described below. Such formulations can be sustained-release formulations and further optionally can have delayed-release properties (e.g., used alone or as a result of being used to gel a cellulose ether hard capsule shell according to the present disclosure).

[0038] The 25-hydroxyvitamin D compound can be administered to the subject by any suitable means. Formulations suitable for oral administration may consist of or comprise: (a) a liquid solution or suspension, such as an effective amount of a 25-hydroxyvitamin D compound dissolved or suspended in a diluent such as water, saline, milk, oil or other carrier; (b) such as a solid or granular body; (c) a powder; and (d) a suitable emulsion. Liquid formulations may comprise a diluent such as water or an alcohol, such as ethanol, benzyl alcohol and polyvinyl alcohol, with or without the addition of a pharmaceutically acceptable surfactant. Capsule forms may contain, for example, a carrier such as an oil, wax or other lipid, a surfactant, a lubricant and an inert filler such as lactose, sucrose, calcium phosphate and corn starch. The hard shell capsule may contain tablet pieces, and such tablet forms may include one or more of the following: lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, gum arabic, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid and other excipients, colorants, diluents, buffers, disintegrants, wetting agents, preservatives, flavorings and other pharmacologically compatible excipients. The 25-hydroxyvitamin D compound may be dissolved in an alcohol (e.g., ethanol) for distribution in a carrier or excipient.

[0039] The oil that can be used for parenteral formulations comprises petroleum, animal oil, vegetable oil or synthetic oil. Specific examples of oils comprise peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, paraffin oil and mineral oil. Some embodiments contemplate indigestible oils. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.

[0040] The 25-hydroxyvitamin D compound can be dispersed in a polymer composition. The 25-hydroxyvitamin D compound can be embedded in a polymer network. For example, the polymer can be water-insoluble and, optionally, swellable. The formulation can be a spheronized pellet formulation comprising the 25-hydroxyvitamin D compound and a pharmaceutically acceptable excipient. Such pellets can optionally be enteric-coated; alternatively, the pellets can be placed in a capsule shell that can be enteric-coated. The formulation can comprise the 25-hydroxyvitamin D compound dispersed in a mixture of fatty acid glycerides. The formulation can consist of or comprise a nano / microparticle formulation comprising the 25-hydroxyvitamin D compound and a pharmaceutically acceptable excipient. The formulation can consist of or comprise a lipid microparticle formulation comprising the 25-hydroxyvitamin D compound and a pharmaceutically acceptable lipid. The formulation may consist of or comprise a non-pareil seed formulation comprising a 25-hydroxyvitamin D compound and a pharmaceutically acceptable excipient. The formulation may consist of or comprise a 25-hydroxyvitamin D compound and a pharmaceutically acceptable excipient, one or more excipients selected from the group consisting of an absorption enhancer, a spheronization aid, a water-insoluble polymer, and a binder. The formulation may consist of or comprise a spray-coagulated lipid vitamin D formulation comprising a 25-hydroxyvitamin D compound, a sustained-release agent, and a surfactant. In various embodiments, the formulation may be a sustained-release formulation, such as one for oral use.

[0041] As used herein, a formulation comprising a 25-hydroxyvitamin D compound can be a stable formulation, wherein a "stable formulation" refers to a formulation that exhibits a stable in vitro dissolution profile (according to any of the parameters further described herein) and controlled release (e.g., sustained release) of the vitamin D compound in vivo over a period of time after initial manufacture, such as under actual shelf storage or accelerated stability storage conditions. The release of the active ingredient can be measured using a suitable in vitro dissolution method, such as one of the methods known in the art. In principle, the United States Pharmacopeia, USP 43-NF 38 2S, Dissolution <711> Physical Testing and Determination, United States Pharmacopeial Convention, Inc., Rockville, Md., 2020; Any of the dissolution studies described in European Pharmacopoeia 2.9.3 Dissolution Testing of Solid Dosage Forms or Japanese Pharmacopoeia 6.10 Dissolution Testing can be used to determine whether a formulation is stable. For the purposes of this disclosure, the single medium in vitro dissolution method is United States Pharmacopoeia, USP 43-NF 38 2S, Dissolution <711> Physical Testing and Determination, United States Pharmacopeial Convention, Rockville, MD, USA, 2020, using Apparatus 2 (Paddle Method), as described in the Examples below. Alternatively, a 2-stage method can be used to measure dissolution properties, such as USP 43-NF38 2S, Dissolution <711> Method 2, using apparatus 1 or 2, optionally apparatus 2.

[0042] The amount of 25-hydroxyvitamin D released in in vitro dissolution of a stable formulation according to the present disclosure after storage for a period of time is not significantly different from the dissolution of the same formulation immediately after manufacture and prior to storage. For example, in one embodiment, the amount of 25-hydroxyvitamin D released during in vitro dissolution of a formulation after exposure to storage conditions of 25° C. and 60% relative humidity for two months varies by 30% or less at any given dissolution time point after four hours compared to the amount released at the same dissolution time point during in vitro dissolution performed before the formulation was exposed to storage conditions (i.e., a freshly produced product).

[0043] The following table provides examples of the degree of favorable storage stability envisioned for embodiments of the present invention after storage for various times after initial manufacture at 25°C and 60% RH, and alternatively at 40°C and 75% RH, as well as for various times during dissolution testing. The degree of storage stability is expressed as the maximum deviation from the nominal active potency, i.e., the maximum % change from the LC. Alternative examples of maximum deviation are also provided.

[0044]

[0045]

[0046]

[0047] In one type of embodiment, the formulation will have a favorable degree of stability immediately following that described in the above table at multiple time points throughout the dissolution test, for example, at least at the 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 the fresh product. Alternatively, the formulation has a favorable degree of stability immediately following that described in the above table at least at the 2, 6, and 12 hour time points. Alternatively, the formulation has a favorable degree of stability immediately following that described in the above table at least at the 4, 8, and 12 hour time points. Alternatively, the formulation has a favorable degree of stability immediately following that described in the above table at least at the 2, 4, and 6 hour time points. Alternatively, the formulation has a favorable degree of stability immediately following that described in the above table at least at the 4, 6, 8, and 12 hour time points, or at all time points at 4 hours and thereafter.

[0048] In any and all embodiments described in the table immediately above, it is envisioned that the deviation can be positive (more release) or negative (less release) relative to the fresh product. In one type of embodiment, it is envisioned that the deviation will be in the negative (less release) direction at various time points. Still further, in one type of embodiment, if there is no stabilizer in the formulation, it is envisioned that the dissolution release deviation at various time points will be negative (less release).

[0049] In various examples, the formulation comprising a 25-hydroxyvitamin D compound comprises a matrix component (e.g., a lipophilic matrix) that releasably binds to the vitamin D compound and controllably releases the vitamin D compound and a stabilizer (e.g., a cellulose compound). In various examples, the stabilizer is a cellulose compound. Unless otherwise indicated, the term "cellulose compound" as used herein may include cellulose (C6H 10 O5) nOr cellulose derivatives. In various aspects, the cellulose compound is a cellulose ether. "Cellulose ether" is a cellulose derivative that has been chemically modified to produce partially or completely etherified hydroxyl groups in the cellulose molecule. Examples of cellulose derivatives that can be used as stabilizers include, but are not limited to, cellulose uronic acid, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyanionic cellulose, and combinations thereof. The term also encompasses different grades of each cellulose compound or stabilizer corresponding to variations in, for example, molecular weight, viscosity, solubility, and hydration.

[0050] In one embodiment, the stable formulation comprises one or both of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3, a wax matrix, and a cellulose compound. In one aspect, the stable formulation comprises one or both of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3, a wax matrix, and a cellulose stabilizer. In another aspect, the formulation comprises one or both of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3, a wax matrix, and an effective amount of a cellulose compound to provide a favorable degree of stability as described herein, for example, with respect to the immediately preceding table or consistent with any of the examples described below. For example, the amount can be effective to provide a difference of 30% or less between the amount of active substance released during in vitro dissolution after exposure to storage conditions at 25° C. and 60% relative humidity at the dissolution time point for at least one month and the amount released during in vitro dissolution performed before exposing the formulation to the storage conditions at the same dissolution time point, while a comparative formulation lacking the stabilizer results in a greater difference in dissolution release under the same storage conditions.

[0051] In one aspect, the formulation is an improved formulation for controlled release of a vitamin D compound in the gastrointestinal tract of a subject who ingests the formulation. In one embodiment, the improvement comprises incorporating a cellulose stabilizer into the formulation for controlled release of a vitamin D compound in the gastrointestinal tract of a subject who ingests the formulation. In another embodiment, the improvement comprises incorporating an effective amount of a cellulose compound into the formulation for controlled release of a vitamin D compound in the gastrointestinal tract of a subject who ingests the formulation to provide a favorable degree of stability as described herein, e.g., with respect to the immediately preceding table or consistent with any of the examples described below. For example, the amount can be effective to provide a difference of 30% or less between the amount of active substance released during in vitro dissolution after exposure to storage conditions at 25° C. and 60% relative humidity for at least one month at the dissolution time point and the amount released during in vitro dissolution performed at the same dissolution time point before exposing the formulation to the storage conditions, whereas a comparative formulation lacking the stabilizer would result in a greater difference in dissolution release under the same storage conditions.

[0052] Stabilizers may include cellulose compounds. Examples of cellulose compounds and stabilizers for stable formulations of the present disclosure may include, but are not limited to, cellulose uronic acid, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyanionic cellulose, and combinations thereof. One or more of poloxamers (e.g., poloxamer 407), poly(ethylene oxide) polymers (e.g., POLYOX polymers from Dow), povidone, and fumed silica (e.g., AEROSIL 200, Evonik Industries AG, Essen, Germany) are also contemplated. Based on the total weight (wt%) of the formulation not including any additional coating or shell, stabilizers, such as cellulose compounds, are preferably present in an amount of at least about 5% of the formulation. For example, the cellulose compound can be present in an amount of at least 5 wt % of the formulation, or at least 10 wt % of the formulation, or at least 15 wt % of the formulation, or greater than 5 wt % of the formulation, or greater than 10 wt % of the formulation, or greater than 15 wt % of the formulation. Suitable ranges include 5 wt % to 30 wt %, 10 wt % to 20 wt %, 10 wt % to 15 wt %, 5 wt % to 15 wt %, and 7.5 wt % to 12.5 wt %. Examples include about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %, about 10 wt %, about 11 wt %, about 12 wt %, about 13 wt %, about 14 wt % and about 15 wt %. It should be understood that the stabilizer referred to herein is an agent that stabilizes the dissolution release profile (and therefore also stabilizes the in vivo release profile) to prevent significant changes over time during storage conditions (e.g., typical shelf storage conditions). Other agents known in the art as preservatives for preventing degradation of the active ingredient itself are not intended to be encompassed within the term "stabilizing agent" or "stabilizer," although such preservatives are also contemplated for use in the formulations of the present invention.

[0053] In one class of embodiments, the cellulose compound is a cellulose ether. Examples of cellulose ethers include, but are not limited to, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and combinations thereof.

[0054] Hydroxypropyl methylcellulose (HPMC, hypromellose) is particularly contemplated. HPMC is characterized by one or more of the following features, specifically contemplated, alone or in combination. The methoxy component % in HPMC can be in the range of 19 to 24. The hydroxypropyl component % can be in the range of 7 to 12. The apparent viscosity (2% aqueous solution at 20°C) can be at least 50,000 cP or at least 80,000 cP, or in the 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. Specifically, the apparent viscosity (2% aqueous solution at 20°C) can be in the range of 80,000 to 120,000 cP. The pH value (1% aqueous solution) can be in the range of 5.5 to 8.0. For example, a suitable hydroxypropyl methylcellulose having all of the aforementioned properties, including an apparent viscosity (2% aqueous solution at 20° C.) in the range of 80,000 to 120,000 cP, is METHOCEL K100M CR (Dow Wolff Cellulosics, Midland, Mich.).

[0055] In one type of embodiment, the cellulose compound will be insoluble in the matrix formulation at the melting point of the major components of the matrix (eg, at 65°C or in the range of 60°C to 75°C).

[0056] In one type of embodiment, the cellulose compound will be hydrophilic. Stable wax matrix formulations (e.g., Type fill formulations) can have a filling into a hard shell capsule according to the present disclosure, rather than like (Calcifediol) sustained-release capsules filled into the soft The following composition in the plant polysaccharide shell: calcifediol at 0.02 wt% of the capsule fill, paraffin at 20.0 wt% of the capsule fill, mineral oil at 35.34 wt% of the capsule fill, hypromellose at 10.0 wt% of the capsule fill, mono- and diglycerides at 22.56 wt% of the capsule fill, lauroyl polyoxylglycerides at 9.75 wt% of the capsule fill, dehydrated alcohol at 2.32 wt% of the capsule fill, and BHT at 0.02 wt% of the capsule fill.

[0057] Pharmaceutical formulations according to the present disclosure comprising one or more of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 and a cellulose compound have improved stability compared to formulations lacking the cellulose compound. In one embodiment, the stable formulation according to the present disclosure comprises a mixture of a lipophilic matrix loaded with an active substance and a cellulose stabilizer, wherein the lipophilic matrix comprises one or both of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3, wherein the amount of 25-hydroxyvitamin D released during in vitro dissolution after exposure to storage conditions of 25° C. and 60% relative humidity for at least one month varies by 30% or less at any given dissolution time point compared to the amount released at the same dissolution time point during in vitro dissolution performed on a freshly prepared product.

[0058] After the composition is stored for a certain period of time, unstable formulations exhibit a change in the amount of active ingredient released. Unstable formulations can release a change in the amount of 25-hydroxyvitamin D at a given dissolution time point after exposure to storage conditions, for example, more than 30% of the amount released at the same dissolution time point during in vitro dissolution on a freshly prepared product. The change may be an increase or decrease in the dissolution rate at a given time point, and such a change may produce a dissolution profile that differs in shape from the initial dissolution profile. After storage as described herein, for example, at 25°C and 60% RH for 3 months or more, unstable formulations also exhibit different in vivo effects than stable formulations according to the present disclosure. After storage as described herein, for example, at 25°C and 60% RH for 3 months or more, stable formulations exhibit different clinical pharmacokinetic parameters, such as improved bioavailability, than unstable formulations. Stable formulations according to the present disclosure may have a base formulation that is storage-unstable and a stabilizer that renders the formulation storage-stable, as described herein.

[0059] The matrix that releasably combines and controllably releases the active ingredient can be, for example, a lipophilic matrix, comprising a wax matrix. The wax matrix can provide a formulation that is solid or semisolid at room temperature and solid, semisolid or liquid at body temperature, and preferably semisolid or liquid at body temperature. On the one hand, the wax matrix includes a controlled release agent, an emulsifier, and an absorption enhancer.

[0060] Examples of suitable controlled-release agents include, but are not limited to, waxes, including synthetic waxes, microcrystalline waxes, paraffin wax, carnauba wax, and beeswax; polyethoxylated castor oil derivatives, hydrogenated vegetable oils, glyceryl mono-, di-, or tri-behenate; long-chain alcohols, such as stearyl alcohol, cetyl alcohol, and polyethylene glycol; and mixtures of any of the foregoing. Non-digestible waxy substances such as hard paraffin are preferred.

[0061] Controlled release agent can exist with at least 5wt% of stable matrix formulation or greater than the amount of about 5wt% of formulation.For example, depend on employed controlled release agent, controlled release agent can account for at least 5wt% of formulation or at least 10wt% of formulation or at least 15wt% of formulation or at least 20wt% of formulation or at least 25wt% of formulation or greater than 5wt% of formulation or greater than 10wt% of formulation or greater than 15wt% of formulation or greater than 20wt% of formulation and / or greater than 25wt% of formulation.Controlled release agent can exist with 50wt% or still less, 40wt% or still less, 35wt% or still less or 30wt% or still less amount.Suitable scope comprises 5wt% to 40wt%, 10wt% to 30wt% and 15wt% to 25wt%. 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%.

[0062] Examples of emulsifiers suitable for use in stable matrix formulations 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; mixtures of fatty acid monoglycerides and diglycerides; lipophilic polyglycerol esters; glycerides including monoolein, diolein, monostearin, distearin, monopalmitin, and dipalmitin; glyceryl-lacto esters of fatty acids; propylene glycol esters, including propylene glycol monopalmitate, propylene glycol monostearate and propylene glycol monooleate; sorbitol esters, including sorbitol monostearate and sorbitol sesquioleate; fatty acids and soaps thereof, including stearic acid, palmitic acid and oleic acid; and mixtures thereof; glyceryl monooleate, glyceryl dioleate, glyceryl monostearate, glyceryl distearate, glyceryl monopalmitate and glyceryl dipalmitate; lactic acid and fatty acid glycerides; propylene glycol esters, including propylene glycol monopalmitate, propylene glycol monostearate and propylene glycol monooleate; sorbitol esters, including sorbitol monostearate and sorbitol sesquioleate; fatty acids and soaps thereof, including stearic acid, palmitic acid and oleic acid; and mixtures thereof.

[0063] Preferred lipid agents for use in stable matrix formulations are selected from the group consisting of glycerides and their derivatives.Preferred glycerides are selected from the group consisting of medium or long chain glycerides, octylcanoyl macrogol glycerides and mixtures thereof.

[0064] Preferred medium chain glycerides include, but are not limited to, medium chain monoglycerides, medium chain diglycerides, caprylic / capric triglyceride, glyceryl monolaurate, glyceryl monostearate, caprylic / capric glyceride, glyceryl monocaprylate, glyceryl monodicaprylate, caprylic / capric linoleic triglyceride, and caprylic / capric / succinic triglyceride.

[0065] Monoglycerides with low melting points are preferred for preparing stable matrix formulations. Preferred monoglycerides include, but are not limited to, glyceryl monostearate, glyceryl monopalmitate, glyceryl monooleate, glyceryl monocaprylate, glyceryl monocaprate, glyceryl monolaurate, and the like, preferably glyceryl monostearate (GMS). GMS is a natural emulsifier. It is oil-soluble but poorly soluble in water. The HLB value of GMS is 3.8. For example, the lipophilic emulsifier can be present in an amount of about 10 wt % to about 40 wt % or about 20 wt % to about 25 wt %. Other examples include about 20 wt %, about 21 wt %, about 22 wt %, about 23 wt %, about 24 wt % and about 25 wt %.

[0066] Examples of suitable absorption enhancers for stable matrix formulations include, but are not limited to, octyl caproyl polyglycol glycerides such as polyglycol glycerides, which are also referred to as polyglycol glycerides or polyglycol glycerides. The polyglycol glycerides that can be used in the composition include, but are not limited to, monoglycerides, diglyceryl esters, and triglyceride mixtures and monoesters and diesters of polyethylene glycol, polyglycol almond glycerides, polyglycol corn glycerides, and polyglycol caprylic / capric triglycerides. The HLB value of the absorption enhancer can be 13 to 18 or 13 to 15.

[0067] A preferred absorption enhancer is known under the trade name GELUCIRE (Gattefossé Corporation, Paramus, NJ, USA). GELUCIRE is a well-known excipient that is a family of fatty acid esters of glycerol and PEG esters, also known as polyethylene glycol glycerides. GELUCIRE is used in various applications, including the preparation of sustained-release pharmaceutical compositions. GELUCIRE compounds are inert semisolid waxy materials that are amphiphilic and have different physical properties, such as melting point, HLB, and solubility in various solvents. The GELUCIRE compounds are essentially surface-active and disperse or dissolve in aqueous media that form micelles, microscopic globules, or vesicles. The GELUCIRE compounds are identified by their melting point / HLB values. Melting points are expressed in degrees Celsius. One or a mixture of different grades of GELUCIRE excipients can be selected to achieve the desired properties of melting point and / or HLB value. A preferred GELUCIRE composition is GELUCIRE 44 / 14, a mixture of lauroyl macrogol glycerides and lauroyl polyoxylglycerides having a melting point of 44°C and an HLB of 14. For example, the absorption enhancer may be present in an amount of from about 5 wt% to about 20 wt% or from about 8 wt% to about 15 wt%. Other examples include about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, and about 15 wt%.

[0068] The low melting point of the wax matrix provides a method for incorporating pharmaceutical active ingredients, such as vitamin D compounds such as 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or both, at temperatures above the melting point of the wax matrix, from about 0°C to about 50°C, and then filling the melt (solution and / or dispersion) into a suitable capsule. The capsule can be of any type compatible with the melt filling temperature, including soft or hard gelatin capsules, and animal or vegetable gelatin capsules. When cooled to room temperature, the melt solidifies within the capsule.

[0069] In one aspect, the stable matrix formulation may further include an oily vehicle for 25-hydroxyvitamin D2 and / or 25-hydroxyvitamin D3. Any pharmaceutically acceptable oil may be used. Examples include animal (e.g., fish), vegetable (e.g., soybean) and mineral oils. The oil will preferably readily dissolve the 25-hydroxyvitamin D compound used. Preferably, the oily vehicle comprises an indigestible oil such as mineral oil, specifically liquid paraffin and squalene. For example, the oily vehicle may be present in a concentration ranging from about 10 wt% to about 50 wt% of the formulation, or from about 15 wt% to about 45 wt%, or from about 20 wt% to about 40 wt%, or from about 30 wt% to about 40 wt%. In one type of embodiment, a suitable liquid paraffin is characterized by one or more of the following parameters: a specific gravity of about 0.88 to 0.89; a kinematic viscosity (40°C) of about 64 cSt to about 70 cSt; a molecular weight of 424; a % paraffin of about 59; and a pour point of -24°C. The ratio between the wax base and the oily vehicle can be optimized to achieve the desired release rate of the vitamin D compound. Thus, if a heavier oil component is used, relatively less wax base can be used, and if a lighter oil component is used, relatively more wax base can be used.

[0070] The stable, controlled-release compositions according to the present disclosure are preferably designed to contain 25-hydroxyvitamin D2 and / or 25-hydroxyvitamin D3 at a concentration of, for example, 1 to 1000 μg per unit dose and are prepared in such a manner as to affect a controlled or substantially constant release of 25-hydroxyvitamin D2 / 25-hydroxyvitamin D3 over an extended period of time, optionally into the ileum of the gastrointestinal tract of humans or animals. Exemplary dosages include 1 μg to 1000 μg, 1 μg to 600 μg, 1 μg to 500 μg, 1 μg to 450 μg, 1 μg to 400 μg, 1 μg to 200 μg, 1 μg to 100 μg, 5 μg to 90 μg, 30 μg to 80 μg, 20 μg to 60 μg, 30 μg to 60 μg, 35 μg to 50 μg, 5 μg to 50 μg, and 10 μg to 25 μg, for example, 20 μg, 25 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, and 100 μg per unit dose.

[0071] The hard capsule formulation of a type has a release regulator, and the release regulator comprises lipophilic (optionally waxy) filling, emulsifier and absorption enhancer, for example, identical or similar to the wax-based matrix formulation described above, or omits wax, but comprises other lipophilic releasers of higher concentration.Under the normal temperature of room temperature and human body, matrix can be solid or semisolid.The matrix starts to slowly release and controls the active substance to release at least 4 hours or at least 8 hours or at least 10 hours or at least 12 hours cycle in a substantially constant manner, optionally in 4 to 24 hours or 6 to 20 hours or 8 to 18 hours or 10 to 16 hours or in the scope of approximately 12 hours.For example, the release mechanism can be controlled by mechanical erosion and / or gradually disintegrating into the lumen contents of lower small intestine and / or colon.

[0072] The composition comprising a 25-hydroxyvitamin D compound in a gelled hydroxypropyl methylcellulose shell can be any of the compositions described herein, such as a solid or semi-solid composition, optionally in a wax matrix. The amount of wax can be from about 20 wt.% to about 36 wt.%, based on the weight of the solid or semi-solid composition. The wax in the wax matrix can comprise a non-digestible wax, optionally paraffin. The composition comprising the 25-hydroxyvitamin D compound can further comprise an oily vehicle, optionally in an amount from about 25 wt.% to about 41 wt.%, based on the weight of the solid or semi-solid composition. The oily vehicle can comprise or consist of a non-digestible oil, optionally a mineral oil. The composition comprising the 25-hydroxyvitamin D compound can further comprise a stabilizer, optionally in an amount ranging from about 2 wt.% to about 18 wt.%, based on the weight of the solid or semi-solid composition. The stabilizer can comprise a cellulose ether, such as hydroxypropyl methylcellulose. The composition comprising the 25-hydroxyvitamin D compound may further comprise an emulsifier, for example, in an amount ranging from about 10 wt.% to about 26 wt.%, based on the weight of the solid or semisolid composition. For example, the emulsifier may comprise mono- and diglycerides of long-chain saturated and unsaturated fatty acids. The composition comprising the 25-hydroxyvitamin D compound may further comprise an absorption enhancer, optionally in an amount ranging from about 3 wt.% to about 17 wt.%, based on the weight of the solid or semisolid composition. The absorption enhancer may comprise or consist of a fatty acid ester of glycerol and a PEG ester, optionally lauroyl polyoxylglyceride. The composition comprising the 25-hydroxyvitamin D compound may further comprise a solvent for the 25-hydroxyvitamin D, optionally in an amount ranging from about 0.2 wt.% to about 6 wt.%, based on the weight of the solid or semisolid composition. The solvent may comprise or consist of an alcohol, optionally ethanol. For example, a hard capsule dosage form may comprise the 25-hydroxyvitamin D compound in an amount ranging from about 0.1 μg to about 2 mg. The 25-hydroxyvitamin D compound can comprise or consist of 25-hydroxyvitamin D3. For example, the dosage form can comprise 6 μg to 500 μg of bioavailable 25-hydroxyvitamin D. The hard capsule dosage form can be used to treat secondary hyperparathyroidism in patients with stage 3, 4, or 5 chronic kidney disease. The formulation types of this paragraph are also contemplated for use in non-gelled hard capsule shells, such as the formulations of Example 1 (0%, 10%, 20%, 30%, and 40% paraffin types) and Example 2 (Test 3 and Test 4 types).

[0073] Thus, another aspect of the present disclosure is a composition comprising a 25-hydroxyvitamin D compound as described herein and contained in a non-gelled hydroxypropyl methylcellulose shell. For example, the composition can be a solid or semi-solid composition, optionally with a wax matrix. The amount of wax can be from about 20 wt.% to about 36 wt.%, based on the weight of the solid or semi-solid composition. The wax in the wax matrix can comprise a non-digestible wax, optionally paraffin. The composition comprising the 25-hydroxyvitamin D compound can further comprise an oily vehicle, optionally in an amount from about 25 wt.% to about 41 wt.%, based on the weight of the solid or semi-solid composition. The oily vehicle can comprise or consist of a non-digestible oil, optionally a mineral oil. The composition comprising the 25-hydroxyvitamin D compound can further comprise a stabilizer, optionally in an amount ranging from about 2 wt.% to about 18 wt.%, based on the weight of the solid or semi-solid composition. The stabilizer can comprise a cellulose ether, such as hydroxypropyl methylcellulose. The composition comprising the 25-hydroxyvitamin D compound may further comprise an emulsifier, for example, in an amount ranging from about 10 wt.% to about 26 wt.%, based on the weight of the solid or semisolid composition. For example, the emulsifier may comprise mono- and diglycerides of long-chain saturated and unsaturated fatty acids. The composition comprising the 25-hydroxyvitamin D compound may further comprise an absorption enhancer, optionally in an amount ranging from about 3 wt.% to about 17 wt.%, based on the weight of the solid or semisolid composition. The absorption enhancer may comprise or consist of a fatty acid ester of glycerol and a PEG ester, optionally lauroyl polyoxylglyceride. The composition comprising the 25-hydroxyvitamin D compound may further comprise a solvent for the 25-hydroxyvitamin D, optionally in an amount ranging from about 0.2 wt.% to about 6 wt.%, based on the weight of the solid or semisolid composition. The solvent may comprise or consist of an alcohol, optionally ethanol. For example, a hard capsule dosage form may comprise the 25-hydroxyvitamin D compound in an amount ranging from about 0.1 μg to about 2 mg. The 25-hydroxyvitamin D compound can comprise or consist of 25-hydroxyvitamin D3. For example, the dosage form can comprise 6 μg to 500 μg of bioavailable 25-hydroxyvitamin D. The hard capsule dosage form can be used to treat secondary hyperparathyroidism in patients with stage 3, 4, or 5 chronic kidney disease.

[0074] The following formulations can be placed in non-gelled HPMC hard capsules.

[0075]

[0076] For example, calcifediol hard capsule formulations can be prepared by any suitable method, including filling the capsule shell with a flowable material, or filling the capsule shell with a mass or block of solid or semi-solid material, or encapsulating or coating a solid or semi-solid mass with a shell composition. The size of the hard capsule can be adjusted, for example, from size 3 to size 4, based on a specific filling ratio of paraffin and other excipients to further control the release of the drug.

[0077] The following table provides examples of HPMC hard capsule formulations of 25-hydroxyvitamin D with varying percentages of excipients (all percentages are by weight based on the weight of the fill material in the capsule).

[0078]

[0079] A design of experiments (DOE) study was conducted, varying the paraffin wax (excluding shell material) between 20% and 40% by weight of the formulation, lauroyl polyoxylglycerides between 4.75% and 14.75% by weight of the formulation, mono- and diglycerides between 22.5% and 12.5% ​​by weight of the formulation, and HPMC between 6% and 14% by weight of the formulation. Mineral oil was kept constant at 30% in all formulations. From this DOE, it was found that in order to achieve a specific (Calcifediol) The sustained-release capsules have a slower in vitro release profile, the paraffin percentage can be greater than >35% and the lauroyl polyoxylglyceride is about 4.75%.

[0080] The following table provides additional wax-based hard capsule formulations, Examples of the formulations of the type soft capsule (reference) and modified wax-based soft plant-based capsule formulations. For example, the soft capsule can be Plant-based capsule containing modified starch and carrageenan.

[0081]

[0082]

[0083] The following table describes another hard capsule formulation of 25-hydroxyvitamin D with a gelled HPMC capsule shell. Gellan gum is a hydrophilic polymer and has similar properties to the carrageenan used in the vegetable capsule shell of the reference soft capsule formulation described above. The gelled HPMC capsules had a slower rupture / disintegration time in the stomach than the non-gelled HPMC capsules.

[0084] Filling material Filling weight % mg / capsule Calcifediol 0.0194％ 0.03 paraffin 27.95％ 43.32 mineral oil 32.26％ 50 Hydroxypropyl methylcellulose k100 9.98％ 15.47 Monoglycerides and diglycerides 17.5％ 27.13 Lauroyl Polyoxyglyceryl 9.73％ 15.08 Dehydrated ethanol 2.54％ 3.94 BHT 0.02％ 0.03 total 100％ 155 Shell material Shell weight % mg / capsule Hydroxypropyl methylcellulose qsp100 35.283 Gellan gum 5 1.9 Titanium dioxide 2 0.76 organic colorants 0.15 0.057 total 100 38

[0085] The composition can be filled in size 4 gelled HPMC capsule shells, such as HPMC capsules containing gellan gum.

[0086] Thus, another aspect of the present disclosure is a gelled HPMC hard capsule formulation of 25-hydroxyvitamin D. The formulation can include 0.1 μg to about 2 mg of a 25-hydroxyvitamin D compound, optionally 25-hydroxyvitamin D2 and / or 25-hydroxyvitamin D3, per unit dose. The amount of the 25-hydroxyvitamin D compound can further be in the range of about 1 μg to about 1 mg, or about 10 μg to about 900 μg, or about 20 μg to about 600 μg, or about 30 μg to about 300 μg, or about 60 μg to about 300 μg, for example, about 20 μg, or about 25 μg, or about 30 μg, or about 40 μg, or about 50 μg, or about 60 μg, or about 70 μg, or about 80 μg, or about 200 μg, or about 300 μg, or about 600 μg, or about 900 μg. Based on the gross weight of the filling material in the hard capsule shell, composite can include the wax of about 20wt.% to about 36wt.%, optionally indigestible wax, such as paraffin.The amount of wax can further be in the range of about 22wt.% to about 34wt.% or about 24wt.% to about 32wt.% or about 26wt.% to about 30wt.%, such as about 25wt.%, about 26wt.%, about 27wt.%, about 28wt.%, about 29wt.%, about 30wt.%, about 31wt.%, about 32wt.% or about 33wt.%.Based on the gross weight of the filling material in the hard capsule shell, composite can include the oily vehicle of about 25wt.% to about 41wt.%, optionally one described above, such as indigestible oil, such as mineral oil. The amount of the oily vehicle can further be in the range of about 27 wt.% to about 39 wt.%, or about 29 wt.% to about 37 wt.%, or about 31 wt.% to about 35 wt.%, for example, about 29 wt.%, about 30 wt.%, about 31 wt.%, about 32 wt.%, about 33 wt.%, about 34 wt.%, about 35 wt.%, about 36 wt.% or about 37 wt.%. Based on the total weight of the fill material in the hard capsule shell, the formulation can include about 2 wt.% to about 18 wt.% of a stabilizer, optionally one of the above-described ones, for example a cellulose ether, such as hypromellose. The amount of stabilizer can further be in the range of about 4 wt.% to about 16 wt.%, or about 6 wt.% to about 14 wt.%, or about 8 wt.% to about 12 wt.%, for example, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 11 wt.%, about 12 wt.%, or about 13 wt.%. Based on the total weight of the fill material in the hard capsule shell, the formulation can include about 10 wt.% to about 26 wt.% of an emulsifier, optionally one of the ones described above, for example, a mixture of monoglycerides and diglycerides comprising long-chain saturated and unsaturated fatty acids, for example, monoglyceryl and diglyceryl NF.The amount of the emulsifier can further be in the range of about 12 wt.% to about 24 wt.%, or about 14 wt.% to about 22 wt.%, or about 16 wt.% to about 20 wt.%, such as about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, about 20 wt.%, about 21 wt.%, about 22 wt.% or about 23 wt.%. Based on the total weight of the fill material in the hard capsule shell, the formulation can include about 3 wt.% to about 17 wt.% of an absorption enhancer, optionally one of the above-described ones, such as fatty acid esters of glycerol and PEG esters, such as lauroyl polyoxylglycerides (44 / 14). The amount of the absorption enhancer can further range from about 5 wt.% to about 15 wt.%, or from about 7 wt.% to about 13 wt.%, or from about 9 wt.% to about 11 wt.%, for example, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 11 wt.%, about 12 wt.%, or about 13 wt.%. The 25-hydroxyvitamin D active substance can be dissolved in an alcohol carrier, such as ethanol, which is present in the formulation in an amount of about 0.2 wt.% to about 6 wt.%, or about 0.5 wt.% to about 5 wt.%, or about 1 wt.% to about 4 wt.%, or about 2 wt.% to about 4 wt.%, for example, about 1.5 wt.%, or about 2.0 wt.%, or about 2.5 wt.%, or about 3 wt.%, or about 3.5 wt.%, or about 4 wt.%. The formulation may contain a small amount of a preservative, eg, an antioxidant, such as BHT, eg, in the range of about 0.005 wt.% to about 1 wt.% or about 0.01 wt.% to about 0.05 wt.%, eg, about 0.02 wt.%.

[0087] Variations of the aforementioned types of dosage forms may have the following characteristics:

[0088] Filling material Filling weight % Calcifediol About 0.01% to 0.03% paraffin About 25% to 30% mineral oil About 30% to 35% Hydroxypropyl methylcellulose k100 About 7% to 13% Monoglycerides and diglycerides About 14.5% to 20.5% Lauroyl Polyoxyglyceryl About 7% to 13% Dehydrated ethanol About 2% to 4% BHT About 0.05% to 0.05% Shell material Shell weight % Hydroxypropyl methylcellulose qsp100 Gellan gum About 1% to 10% Titanium dioxide About 0.01% to 4%

[0089] The amount of fill material may be less than 170 mg and fit into a standard size 4 hard shell capsule, for example in the range of about 150 mg to 160 mg or 155 mg.

[0090] In alternative hard capsule formulation types, the wax can be omitted and the concentration of the emulsifier and / or absorption enhancer increased, for example. The formulation can include 0.1 μg to about 2 mg of a 25-hydroxyvitamin D compound, optionally 25-hydroxyvitamin D2 and / or 25-hydroxyvitamin D3, per unit dose. The amount of the 25-hydroxyvitamin D compound can further be in the range of about 1 μg to about 1 mg, or about 10 μg to about 900 μg, or about 20 μg to about 600 μg, or about 30 μg to about 300 μg, or about 60 μg to about 300 μg, for example, about 20 μg, or about 25 μg, or about 30 μg, or about 40 μg, or about 50 μg, or about 60 μg, or about 70 μg, or about 80 μg, or about 200 μg, or about 300 μg, or about 600 μg, or about 900 μg. Based on the gross weight of the filling material in hard capsule shell, composite can include the oily vehicle of about 25wt.% to about 50wt.%, optionally a kind of described above, for example indigestible oil, for example mineral oil.The amount of oily vehicle can be further in the scope of about 25wt.% to about 45wt.%, or about 27wt.% to about 45wt.%, or about 27wt.% to about 39wt.%, or about 29wt.% to about 37wt.% or about 31wt.% to about 35wt.%, for example, about 30wt.%, about 32wt.%, about 34wt.%, about 36wt.%, about 38wt.%, about 40wt.%, about 42wt.%, about 44wt.% or about 46wt.%.Based on the gross weight of the filling material in hard capsule shell, composite can include the stabilizer of about 2wt.% to about 20wt.%, optionally a kind of described above, for example cellulose ether, for example hypromellose. The amount of stabilizer can further be in the range of about 4 wt.% to about 16 wt.%, or about 6 wt.% to about 14 wt.%, or about 8 wt.% to about 12 wt.%, for example, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 11 wt.%, about 12 wt.%, or about 14 wt.%. Based on the total weight of the fill material in the hard capsule shell, the formulation can include about 15 wt.% to about 45 wt.% of an emulsifier, optionally one of the ones described above, for example, a mixture of monoglycerides and diglycerides comprising long-chain saturated and unsaturated fatty acids, for example, monoglycerides and diglycerides NF.The amount of emulsifier can further be in the range of about 17 wt.% to about 42 wt.%, or 18 wt.% to about 40 wt.%, or 20 wt.% to about 36 wt.%, or 20 wt.% to about 34 wt.%, or about 20 wt.% to about 32 wt.%, or about 20 wt.% to about 30 wt.%, or about 22 wt.% to about 28 wt.%, or for example about 18 wt.%, about 20 wt.%, about 22 wt.%, about 24 wt.%, about 26 wt.%, about 28 wt.%, about 30 wt.%, about 32 wt.%, about 34 wt.%, about 36 wt.% to about 40 wt.%. Based on the total weight of the fill material in the hard capsule shell, the formulation can include about 8 wt.% to about 22 wt.% of an absorption enhancer, optionally one described above, such as a fatty acid ester of glycerol and a PEG ester, such as lauroyl polyoxylglyceride (44 / 14). The amount of the absorption enhancer can further be in the range of about 8 wt.% to about 20 wt.%, or about 9 wt.% to about 18 wt.%, or about 10 wt.% to about 16 wt.%, for example, about 9 wt.%, about 10 wt.%, about 11 wt.%, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, or about 16 wt.%. The 25-hydroxyvitamin D active substance can be dissolved in an alcohol carrier, such as ethanol, which is present in the formulation in an amount of about 0.2 wt.% to about 6 wt.%, or about 0.5 wt.% to about 5 wt.%, or about 1 wt.% to about 4 wt.%, or about 2 wt.% to about 4 wt.%, for example, about 1.5 wt.%, or about 2.0 wt.%, or about 2.5 wt.%, or about 3 wt.%, or about 3.5 wt.%, or about 4 wt.%. The formulation may contain a small amount of a preservative, eg, an antioxidant, such as BHT, eg, in the range of about 0.005 wt.% to about 1 wt.% or about 0.01 wt.% to about 0.05 wt.%, eg, about 0.02 wt.%.

[0091] On the other hand, the 25-hydroxyvitamin D compound can be administered in the form of a formulation as described in International (PCT) Application Publication No. WO 2020 / 044314A1, including such formulations suitable for administration to pediatric patients. Such formulations can be sustained-release formulations and further optionally can have delayed-release properties (e.g., used alone or as a result of being used to gel a cellulose ether hard capsule shell according to the present disclosure).

[0092] Such formulations can comprise a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, embedded in a polymer network. The polymer can be water-insoluble and optionally swellable. In various embodiments, the formulation can be a sustained-release formulation, such as a sustained-release formulation for oral use.

[0093] Such formulations can include spheronized pellet formulations comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, and a pharmaceutically acceptable excipient. In various embodiments, the formulation can be a sustained-release formulation, such as a sustained-release formulation for oral administration. In various embodiments, the formulation can be a delayed-release formulation, or a delayed-sustained-release formulation. The spheronized pellets can be placed in a capsule, which is optionally enteric-coated. Alternatively, the pellets can be enteric-coated.

[0094] Such formulations may include a vitamin D formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, dispersed in a mixture of fatty acid glycerides. In various embodiments, the formulation may be a sustained release formulation, such as a sustained release formulation for oral use.

[0095] Such formulations may include nano / microparticle formulations comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, and a pharmaceutically acceptable excipient. In various embodiments, the nano / microparticle formulations may provide sustained release of the vitamin D compound, for example, by using a sustained release polymer as an excipient.

[0096] Such formulations may contain a lipid microparticle formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, and a pharmaceutically acceptable lipid. In various embodiments, the formulation may be a sustained release formulation, such as a sustained release formulation for oral use.

[0097] Such formulations can include non-powdered seed formulations comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, and a pharmaceutically acceptable excipient. In various embodiments, the formulation can be a sustained-release formulation, such as a sustained-release formulation for oral use. In various embodiments, the excipient can include a sustained-release polymer coating.

[0098] Such formulations can comprise a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, and a pharmaceutically acceptable excipient, including one or more excipients selected from the group consisting of an absorption enhancer, a spheronization aid, a water-insoluble polymer, and a binder. In various embodiments, the formulation can be a sustained-release formulation, such as a sustained-release formulation for oral use.

[0099] Such formulations may comprise a spray-coagulated lipid vitamin D formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, a sustained-release agent, and a surfactant. In various embodiments, the formulation may be a sustained-release formulation, such as a sustained-release formulation for oral use.

[0100] In various embodiments, the shell composition of any hard capsule can be a composition that is stable in a low pH environment.

[0101] In one type of embodiment, the 25-hydroxyvitamin or calcifediol fill formulation is an extruded spheronized ethylcellulose (EC)-based formulation. The amount of 25-hydroxyvitamin or calcifediol can be any amount that provides the strength of the dosage form according to the present disclosure, for example, in the range of about 0.01 wt.% to about 1 wt.%, or about 0.01 wt.% to about 0.5 wt.%, or about 0.01 wt.% to about 0.1 wt.%. For example, based on the amount of the fill composition, the amount of EC can be in the range of about 5 wt.% to about 60 wt.%, or about 1 wt.% to about 20 wt.%, or about 1 wt.% to about 10 wt.%, or about 2 wt.% to about 10 wt.%, or about 10 wt.% to about 30 wt.%. Additives such as one or more fatty acid glycerides (e.g., glyceryl behenate) can be used as a sustained-release agent. Such compounds act as thickeners or gelling agents and are suitable for use as sustained-release agents and include, for example, glyceryl behenate (e.g., Compritol 888ATO). The compounds may be added in weight percentages ranging from 5 wt.% to 25 wt.%, or from 5 wt.% to 40 wt.%, or from 10 wt.% to 30 wt.%, based on the weight of the fill formulation, with higher concentrations specifically contemplated when glyceryl behenate is the primary or sole sustained-release agent. The composition may include absorption enhancers such as medium-chain triglycerides (e.g., Miglyol 812N) and polyglycolyzed glycerides (e.g., Gelucire 48 / 16); spheronization aids such as microcrystalline cellulose (e.g., Avicel PH 101); diluents and pore formers such as lactose monohydrate or HPMC; binding aids such as low-viscosity hydroxypropyl methylcellulose (e.g., Methocel K3 Premium LV); lubricants such as talc or glyceryl behenate; flavorings such as caramel; and purified water as a process diluent (e.g., a dissolution binder). The spheronization aid may be present in a concentration of about 30 wt.% to about 90 wt.% or about 30 wt.% to about 50 wt.%. The absorption enhancer may be present in a concentration of about 3 wt.% to about 25 wt.% or about 10 wt.% to about 20 wt.%. Binders such as low viscosity hydroxypropyl methylcellulose (e.g., Methocel K3) can be present in a concentration of about 3 wt.% to about 10 wt.% or about 3 wt.% to about 8 wt.%. Lubricants such as talc can be present in a weight concentration of about 0.5 wt.% to about 2 wt.% or 1 wt.% to about 2 wt.%. Antioxidants, such as butylated hydroxytoluene (BHT), can be present in a range of about 0.01 wt.% to about 0.05 wt.%. Flavoring agents are optional and can be present in a range of about 0.01 wt.% to about 2 wt.%. Such formulations can be sustained-release formulations and further optionally can have delayed-release properties (e.g., used alone, or as a result of being used to gel a cellulose ether hard capsule shell according to the present disclosure).

[0102] Example formulations are described below, where all percentages are by weight based on the total weight of the filler material.

[0103]

[0104] In any embodiment contemplated herein, the dissolution release profile of the formulation can have the characteristics of any of the examples provided below. For example, the formulation is characterized in that, in a pH 6.8 medium, the dissolution release profile provides a release of the vitamin D compound of less than 30% at 2 hours, greater than 45% at 6 hours, and greater than 80% at 12 hours, and further optionally less than 60% at 6 hours.

[0105] In another type of embodiment, the formulation is characterized in that the in vitro dissolution profile provides for release of the vitamin D compound in a pH 6.8 medium 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. In another type of embodiment, the formulation is characterized in that the in vitro dissolution profile provides for release of the 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, in a pH 6.8 medium, the release of the vitamin D compound is optionally less than 60% at 5 to 7 hours, or less than 60% at 6 hours.

[0106] In another type of embodiment, the formulation is characterized in that, in a pH 6.8 medium, the in vitro dissolution profile provides a release of the 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 is characterized in that, in an in vitro dissolution profile, the release of the vitamin D compound is about 25% to about 35% at 2 hours, at least 40% at 6 hours, and at least 75% at 12 hours. In these types of embodiments, for example, in a pH 6.8 medium, the release of the vitamin D compound is optionally 75% or less at 6 hours, or 65% or less at 6 hours, or 60% or less at 6 hours.

[0107] In another type of embodiment, the formulation is characterized by an in vitro dissolution profile that provides a biphasic release of the vitamin D compound in acid (pH 1.2, 2 hours) followed by ≤30% at 2 hours, ≥50% and ≤75% at 6 hours, and ≥80% at 12 hours in a pH 6.8 buffered medium at 37°C.

[0108] The hard capsule formulation can also effectively prevent early release of the API within the first two hours after administration. Accordingly, the present invention includes a sustained-release dosage form of calcifediol having an in vitro dissolution profile under biphasic acidic / neutral conditions, such as 2 hours at pH 1.0 to 2.0, or 1.1, or 1.2, or 1.5, followed by transfer to a buffered aqueous medium at pH 6.5 or 6.8, wherein no more than about 7%, or about 5%, or about 4%, or about 3%, or about 2%, or about 1% of calcifediol is released during the first two-hour period. In one aspect, the dissolution method can be 2 hours at pH 1.5, followed by transfer to a pH 6.5 buffer medium. In another aspect, the dissolution method can be 2 hours at pH 1.2, followed by transfer to a pH 6.8 buffer medium. In another aspect, the dissolution method can be 2 hours at pH 1.1, followed by transfer to a pH 6.8 buffer medium. For example, the dissolution method can be according to USP-NF method <711> , using Apparatus 1 or 2 and Method B (draining 1000 mL of 0.1 N HCl at 37° C. for 2 hours and then adding 1000 mL of pH 6.8 phosphate buffer), optionally Apparatus 2. Thereafter, in pH 6.8 buffered medium, the release of calcifediol may be up to about 40% or 36% at 4 hours (measured from the start of the 2-stage dissolution test process), at least 60% or 62% at 6 hours, and at least 80% or 84% at 8 hours. The dissolution conditions may be standard conditions as further described herein.

[0109] As in Example 2 Figure 2 As described in Example 6, the gelled hypromellose hard shell capsule dosage form according to the present disclosure was shown to resist dissolution under acidic conditions for up to two hours. The release profile in this test showed approximately 5% release at the 1 hour mark, while the release measured at the 2 hour time point was lower. Without intending to be bound by any particular theory, two possibilities are envisioned. According to the first theory, the higher release at the 1 hour time point is an aberrant variation possibility affected by the early rupture of a single capsule. However, in conjunction with the Figure 9 It seems to show Thus, according to another theory, both hard capsules and plant (carrageenan) based capsule shells may exhibit higher rates of active substance diffusion at early time points before the shell material (or its components) has fully swollen, and swelling of the capsule shell subsequently slows down the diffusion rate.

[0110] In various aspects, the 25-hydroxyvitamin D compound is administered in the form of a modified-release formulation. As used herein, the terms "controlled-release" and "modified-release" are used interchangeably and refer to the release of the administered vitamin D compound in a manner other than immediate-release. The modified-release formulation can be a sustained-release formulation. Optionally, the modified-release formulation can include a delayed-release aspect. As used herein, the terms "sustained-release," "extended-release," and "prolonged-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-release formulation.

[0111] The hard capsule formulation of 25-hydroxyvitamin D can be used to treat any patient in need of 25-hydroxyvitamin D. Patients in need of vitamin D supplementation include: healthy subjects and subjects at risk of or suffering from vitamin D insufficiency or deficiency, for example, subjects with stage 1, 2, 3, 4 or 5 CKD; infants, children and adults who do not drink vitamin D fortified milk (e.g., lactose intolerant subjects, subjects with milk allergy, vegetarians who do not consume milk, and breastfed infants); subjects with rickets; subjects with dark skin (e.g., in the United States, 42% of African American women aged 15 to 49 are vitamin D deficient, compared to 4% of white women); the elderly (whose skin synthesizes vitamin D after exposure to sunlight); subjects who cover all exposed skin (such as members of certain religions or cultures); subjects who regularly use sunscreen (for example, applying a sunscreen with a sun protection factor (SPF) of 8 reduces vitamin D production by 95%, and higher SPFs may further reduce skin vitamin D production); subjects with fat malabsorption syndromes (including but not limited to cystic fibrosis, cholestatic liver disease, other liver diseases, gallbladder disease, pancreatic enzyme deficiency, Crohn's disease, and leukemia). disease), inflammatory bowel disease, stomatitis or celiac disease, or surgical resection and / or bypass of part or all of the stomach and / or intestine); subjects with inflammatory bowel disease; patients with Crohn's disease; subjects who have undergone small bowel resection; subjects with gum disease; subjects taking medications that increase vitamin D catabolism including phenytoin, fosphenytoin, phenobarbital, carbamazepine and rifampicin; subjects taking medications that reduce vitamin D absorption including cholestyramine, colestipol, orlistat, mineral oil and fat substitutes; subjects taking medications that inhibit vitamin D activation including ketoconazole; subjects taking medications that reduce calcium absorption including corticosteroids; subjects with obesity (vitamin D deposited in body fat stores has low bioavailability); subjects with osteoporosis and / or postmenopausal women. According to the Institute of Medicine's report on Dietary Reference Intakes for Vitamin D, food consumption data indicate that median vitamin D intakes for younger and older women are below current recommendations; data indicate that more than 50% of younger and older women do not consume the recommended amounts of vitamin D.

[0112] In various aspects, the patient's baseline serum total 25-hydroxyvitamin D level can be less than about 30 ng / mL, or less than about 20 ng / mL, or in the range of 20 ng / mL to 30 ng / mL, or in the range of about 20 ng / mL to about 25 ng / mL.

[0113] In other aspects, the compositions and methods of the present invention can be used to prevent or treat vitamin D-responsive diseases, that is, diseases in which vitamin D, 25-hydroxyvitamin D, or active vitamin D (e.g., 1,25-dihydroxyvitamin D) prevents the onset or progression of the disease, or reduces the signs or symptoms of the disease. Such vitamin D-responsive diseases include cancer (e.g., breast cancer, lung cancer, skin cancer, melanoma, colon cancer, colorectal cancer, rectal cancer, prostate cancer, and bone cancer). 1,25-dihydroxyvitamin D has been observed to induce cell differentiation and / or inhibit cell proliferation in many cells in vitro. Vitamin D responsive diseases also include autoimmune diseases, such as type I diabetes, multiple sclerosis, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma, fibrosis, Graves' disease, Hashimoto's disease, acute or chronic transplant rejection, acute or chronic graft-versus-host disease, inflammatory bowel disease, Crohn's disease, systemic lupus erythematosus, Sjögren's syndrome, eczema and psoriasis, dermatitis, including atopic dermatitis, contact dermatitis, allergic dermatitis and / or chronic dermatitis. Vitamin D responsive diseases also include other inflammatory diseases, such as asthma, chronic obstructive pulmonary disease, polycystic kidney disease, polycystic ovary syndrome, pancreatitis, nephritis, hepatitis and / or infection. It is reported that vitamin D responsive diseases also include hypertension and cardiovascular disease. Thus, the present invention contemplates prophylactic or therapeutic treatment of a subject at risk for or suffering from cardiovascular disease, e.g., 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 the related diabetic dyslipidemia and mixed dyslipidemia hypoalphalipoproteinemia, hypertriglyceridemia, hypercholesterolemia and low HDL (high-density lipoprotein)), metabolic disorders (e.g., metabolic syndrome, type II diabetes, type I diabetes, hyperinsulinemia, impaired glucose tolerance, insulin resistance, diabetic complications, including neuropathy, nephropathy, retinopathy, diabetic foot ulcers and cataracts) and / or thrombosis.

[0114] Diseases that may benefit from modulation of vitamin D compound levels include, but are not limited to: (i) in the parathyroid gland—hypoparathyroidism, pseudohypoparathyroidism, secondary hyperparathyroidism; (ii) in the pancreas—diabetes mellitus; (iii) in the thyroid—medullary carcinoma; (iv) in the skin—psoriasis; wound healing; (v) in the lungs—sarcoidosis and tuberculosis; (vi) in the kidney—chronic renal disease, hypophosphatemic VDRR, vitamin D-dependent rickets; (vii) in the bone—anticonvulsant therapy, fibroblastogenesis imperfecta, osteitis fibrosa cystica, rickets, osteomalacia, osteoporosis, osteopenia, osteosclerosis, renal osteodystrophy, rickets; (viii) in the intestine—glucocorticoid antagonism, idiopathic hypercalcemia, malabsorption syndrome, steatorrhea, tropical sprue; and (ix) autoimmune disorders.

[0115] In various embodiments, the disease that benefits from the regulation of the level of vitamin D compounds is selected from cancer, skin diseases (e.g., psoriasis), parathyroid diseases (e.g., hyperparathyroidism and secondary hyperparathyroidism), bone diseases (e.g., osteoporosis), and autoimmune disorders. In various embodiments, the hard capsule 25-hydroxyvitamin D formulation can be used to treat SARS-CoV-2 infection. In various embodiments, the hard capsule formulation can be used to treat secondary hyperparathyroidism in patients with chronic kidney disease, optionally stage 3, 4, or 5 CKD, optionally stage 3 or 4 CKD, optionally stage 5 CKD, and optionally hemodialysis. The hard capsule formulation of 25-hydroxyvitamin D can be used to reduce serum iPTH levels.

[0116] Without limitation, the formulations and dosage forms described herein can be used to treat patients with chronic kidney disease (stage 3, 4, or 5) and secondary hyperparathyroidism, as well as to treat vitamin D insufficiency and symptoms associated with COVID-19. The formulations are particularly suitable for controlling the release of calcifediol over an extended period of time to effectively lower parathyroid hormone in CKD patients and / or treating patients infected with SARS-CoV-2.

[0117] As described herein, administration of 25-hydroxyvitamin D and treatment of COVID-19 can be performed with or without additional therapy. As an example, agents that enhance the effects of vitamin D, such as CYP24 inhibitors that can slow the catabolism of 25-hydroxyvitamin D compounds and 1,25-dihydroxyvitamin D compounds, can be administered.

[0118] The subject to be treated or administered with the formulations described herein may be a mammal, preferably a human.

[0119] With respect to the presently disclosed methods, the amount of 25-hydroxyvitamin D compound is effective to achieve and maintain a serum total 25-hydroxyvitamin D level of at least 50 ng / mL in the subject during the treatment period. Optionally, the amount is effective to achieve and maintain a serum total 25-hydroxyvitamin D level of at least 60 ng / mL during the treatment period. The methods may comprise achieving such serum levels, e.g., at least or greater than 50 ng / mL or at least or greater than 60 ng / mL, within the first 24 hours of treatment. In various embodiments, the serum levels during treatment may be 200 ng / mL or less or 100 ng / mL or less. For example, the methods may comprise achieving a serum level of at least 50 ng / mL and less than 100 ng / mL within the first 24 hours of treatment. In various examples, the amount is effective to achieve and maintain in the subject greater than 60 ng / mL, e.g., greater than 70 ng / mL, greater than 80 ng / mL, greater than 90 ng / mL, greater than 100 ng / mL, greater than 125 ng / mL, greater than 150 ng / mL, greater than 175 ng / mL, greater than 200 ng / mL, greater than 250 ng / mL, greater than 300 ng / mL, greater than 350 ng / mL, greater than 400 ng / mL, greater than 450 ng / mL, or up to 500 ng / mL, or a serum total 25-hydroxyvitamin D level within the range of about 50 ng / mL to about 100 ng / mL, or about 60 ng / mL to about 100 ng / mL, or greater than 60 ng / mL to about 100 ng / mL during the treatment period.

[0120] In various aspects, the 25-hydroxyvitamin D compound is administered according to any regimen, including, for example, daily (once a day, twice a day, three times a day, four times a day, five times a day, six times a day), three times a week, twice a week, every two days, every three days, every four days, every five days, every six days, every week, every two weeks, every three weeks, every month, or every two months.

[0121] In various examples, the methods of using the hard capsule formulations described herein comprise administering to the subject a loading dose of a 25-hydroxyvitamin D compound prior to one or more maintenance doses of the 25-hydroxyvitamin D compound. In various aspects, the loading dose is greater than about 90 μg, or at least 100 μg, or at least 200 μg, or at least 250 μg, or greater than about 250 μg, or greater than about 500 μg. Optionally, the loading dose is about 1200 μg or less, 1000 μg or less. In various aspects, the loading dose is about 90 μg to about 250 μg, or about 500 μg to about 900 μg, about 500 μg to about 800 μg, about 500 μg to about 700 μg, about 500 μg to about 600 μg, about 600 μg to about 1000 μg, about 700 μg to about 1000 μg, about 800 μg to about 1000 μg, or about 900 μg to about 1000 μg. In various examples, the loading dose is at least or about 900 μg ± 90 μg of 25-hydroxyvitamin D compound. Any of the foregoing doses can be administered in a fasting state, for example, at least 3 hours after a meal, including at bedtime, and without food. Any of the foregoing doses can be administered as a sustained-release oral formulation with a bioavailability of about 25%. In various embodiments, the loading dose can be the first dose, for example, the day 1 dose. In other embodiments, the loading dose is administered in divided doses, for example, over a period of one or more days, for example, 1 to 5 days or 2 to 5 days. For example, the loading dose can be administered over a period of two or more days or three days, for example, a 900 μg loading dose can be administered at 300 μg per day on days 1, 2, and 3, followed by a maintenance dose as described herein, or a 900 μg loading dose can be administered at 450 μg per day on days 1 and 2, followed by a maintenance dose as described herein. In various embodiments, the loading dose is administered in the fasting state.

[0122] In various aspects, one or more daily maintenance doses are at least 25 μg, or at least 30 μg, or greater than 30 μg, or greater than about 50 μg of a 25-hydroxyvitamin D compound. Optionally, each maintenance dose is less than or about 100 μg of a 25-hydroxyvitamin D compound. In various examples, each maintenance dose is about 50 μg to about 100 μg, about 50 μg to about 80 μg, about 50 μg to about 70 μg, about 50 μg to about 60 μg, about 60 μg to about 100 μg, about 70 μg to about 100 μg, about 80 μg to about 100 μg, or about 90 μg to about 100 μg. In various examples, each maintenance dose is about 60 μg ± 6 μg of a 25-hydroxyvitamin D compound. Any of the foregoing doses can be administered in a fasting state, for example, at least 3 hours after a meal, including at bedtime, and without food. Any of the foregoing doses can be administered as a sustained-release oral formulation with a bioavailability of about 25%. In various embodiments, the maintenance dose is administered in the fasting state. The maintenance dose can be administered daily, or the daily maintenance dose can be administered in divided doses throughout the day, or an equivalent amount of 25-hydroxyvitamin D can be administered less frequently than daily, for example, 60 μg every other day instead of 30 μg daily, or about 210 μg weekly instead of 30 μg daily.

[0123] The loading and maintenance doses can be further adjusted based on the subject's weight, ie, so that patients with relatively high BMI levels receive relatively more 25-hydroxyvitamin D.

[0124] The loading dose and maintenance dose can be further adjusted based on the subject's serum total 25-hydroxyvitamin D level. For example, a patient who is not vitamin D insufficient or deficient but whose serum total 25-hydroxyvitamin D level is still less than 50 ng / ml or 60 ng / ml can receive a relatively lower loading dose compared to a subject who is vitamin D insufficient or deficient.

[0125] It is contemplated that doses, e.g., loading doses and / or maintenance doses can be provided in an amount to maintain a subject's serum total 25-hydroxyvitamin D level of at least 40 ng / ml, or at least 50 ng / ml or at least 60 ng / ml, e.g., within the range of 40 ng / ml to 100 ng / ml, or 50 ng / ml to 200 ng / ml, 50 ng / ml to 100 ng / ml, or 60 ng / ml to 100 ng / ml or 40 ng / ml to 80 ng / ml.

[0126] In various examples, the method comprises administering to the subject a daily maintenance dose, optionally for at least 3 days, 5 days, 1 week, 10 days, 12 days, 13 days, 2 weeks, 19 days, 20 days, 3 weeks, 26 days, 4 weeks, or longer. Optionally, the method comprises administering to the subject a 900 μg loading dose of the 25-hydroxyvitamin D compound, followed by a daily maintenance dose for at least 1 week, or at least 2 weeks, or at least 19 days, at least 20 days, or at least 26 days. In various examples, each daily maintenance dose can be 60 μg of the 25-hydroxyvitamin D compound. Optionally, the method comprises administering a daily maintenance dose for at least 13 days, or at least 2 weeks, or at least 19 days, or at least 20 days, optionally at least 3 weeks, or at least 26 days, or at least 4 weeks, or longer.

[0127] In the fasting state, a 900 μg loading dose of (Calcifediol) extended-release capsules (approximately 25% bioavailability) will increase serum total 25-hydroxyvitamin D levels by approximately 20 ng / mL to 30 ng / mL over approximately 10 hours, depending on the subject's weight (the higher the weight, the lower the expected increase in serum total 25-hydroxyvitamin D). A daily maintenance dose of 60 μg of (calcifediol) extended-release capsules will increase serum total 25-hydroxyvitamin D by an additional 0.6 ng / mL. Thus, when administered in the fasting state, a subject with a baseline serum total 25-hydroxyvitamin D level of approximately 25 ng / mL will reach a level of approximately 45 ng / mL to 55 ng / mL after a loading dose, a level of approximately 53-63 ng / mL after 14 days of maintenance dosing, and a level of 61-71 ng / mL after 26 days of maintenance dosing. In other embodiments, methods and formulations can be selected to provide serum total 25-hydroxyvitamin D levels of at least 50 ng / mL, or at least 60 ng / mL, and up to 200 ng / mL, or up to 100 ng / mL within the first 24 hours after the initial dose.

[0128] Compared with the fasting state, in the fed state, After administration of the (calcifediol) extended-release capsules, serum total 25-hydroxyvitamin D levels will increase approximately 3- to 4-fold. For this reason, and to improve the consistency of dosing absorption, it is envisioned that all dosing can be performed at bedtime (defined as at least about 3 hours after the subject's last meal, and optionally at least about 4 hours after the last meal, in the fasting state).

[0129] Oral and other routes of administration dosages of other formulations can be adjusted by one of ordinary skill based on their bioavailability and / or pharmacokinetics. (Calcifediol) extended-release capsules have a bioavailability of approximately 25%, and another type of formulation having three times the bioavailability can have a loading dose greater than the bioavailable amount of about 63 μg or greater than the bioavailable amount of 25-hydroxyvitamin D delivered by the formulation. Optionally, the loading dose is less than the bioavailable amount of about 250 μg of 25-hydroxyvitamin D delivered by the formulation. In various aspects, the loading dose is from about 125 μg to about 300 μg, from about 125 μg to about 225 μg, from about 125 μg to about 200 μg, from about 125 μg to about 175 μg, from about 125 μg to about 150 μg, from about 150 μg to about 250 μg, from about 175 μg to about 250 μg, from about 200 μg to about 250 μg, or from about 225 μg to about 250 μg bioavailable. Similarly, the one or more maintenance doses can be at least about 7 μg, or greater than 7 μg, or greater than about 12 μg of bioavailable 25-hydroxyvitamin D. Optionally, each maintenance dose is less than or about 25 μg of bioavailable 25-hydroxyvitamin D. In various examples, each maintenance dose can be about 12 μg to about 25 μg, about 12 μg to about 20 μg, about 12 μg to about 17 μg, about 12 μg to about 15 μg, about 15 μg to about 25 μg, about 17 μg to about 25 μg, about 20 μg to about 25 μg, or about 22 μg to about 25 μg of bioavailable 25-hydroxyvitamin D. In various examples, in such formulations, each maintenance dose is about 15 μg ± 1.5 μg of bioavailable 25-hydroxyvitamin D.

[0130] From another perspective, due to The bioavailability of (Calcifediol) sustained-release capsules is about 25%, so the dosage can be expressed based on the bioavailable amount of 25-hydroxyvitamin D in any type of formulation. In various aspects, the loading dose is greater than about 22 μg, or at least 25 μg, or at least 50 μg, or at least 62 μg, or greater than about 62 μg, or greater than about 125 μg of bioavailable 25-hydroxyvitamin D. Optionally, the loading dose is less than about 250 μg. In various aspects, the loading dose is about 22 μg to about 62 μg, or about 125 μg to about 225 μg, about 125 μg to about 200 μg, about 125 μg to about 175 μg, about 125 μg to about 150 μg, about 150 μg to about 250 μg, about 175 μg to about 250 μg, about 200 μg to about 250 μg, or about 225 μg to about 250 μg. In various examples, the loading dose is at least or about 225 μg ± 22 μg of bioavailable 25-hydroxyvitamin D. Any of the foregoing doses can be administered in a fasting state, for example, at least 3 hours after a meal, including at bedtime, and without food. In various aspects, the one or more daily maintenance doses are at least 6 μg, or at least 7 μg, or greater than 7 μg, or greater than about 12 μg of bioavailable 25-hydroxyvitamin D compound. Optionally, each maintenance dose is less than or about 25 μg of bioavailable 25-hydroxyvitamin D. In various examples, each maintenance dose is about 12 μg to about 25 μg, about 12 μg to about 20 μg, about 12 μg to about 18 μg, about 12 μg to about 15 μg, about 15 μg to about 25 μg, about 17 μg to about 25 μg, about 20 μg to about 25 μg, or about 22 μg to about 25 μg of bioavailable 25-hydroxyvitamin D compound. In various examples, each maintenance dose is about 15 μg ± 1.5 μg of 25-hydroxyvitamin D compound. Any of the foregoing doses can be administered in the fasting state, for example, at least 3 hours after a meal, including at bedtime, and without food.

[0131] A rapid increase or excess of intracellular vitamin D hormone stimulates the expression of a cytochrome P450 enzyme called CYP24A1 in cells containing the vitamin D receptor. The CYP24A1 enzyme catabolizes 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, and vitamin D with high specificity, thereby restoring normal intracellular vitamin D hormone levels. This is an important feedback mechanism that limits excessive and potentially harmful local exposure to vitamin D hormone. Therefore, it is contemplated that 25-hydroxyvitamin D can be administered without upregulating CYP24A1 expression. Alternatively, based on the availability of 25-hydroxyvitamin D, such as to correct vitamin D deficiency, to provide a rapid response when needed, such as an immune response, it is contemplated that total serum 25-hydroxyvitamin D levels can be safely increased within the first 24 hours of administration, for example, to at least 50 ng / mL, or greater than 50 ng / mL, or at least 60 ng / mL, or greater than 60 ng / mL, and optionally to no more than 200 ng / mL or no more than 100 ng / mL. Similarly, it is contemplated that the formulations for use in the methods herein can provide an in vivo Tmax in the range of, for example, 4 to 24 hours, or 4 to 18 hours, or 4 to 16 hours, or 4 to 12 hours, or 4 to 8 hours.

[0132] The patient's vitamin D metabolite ratio (VMR, calculated as 100 times the ratio of serum 24,25-dihydroxyvitamin D3 to serum 25-hydroxyvitamin D3 after administration of a vitamin D3 product, such as 25-hydroxyvitamin D3, or the ratio of 24,25-dihydroxyvitamin D3 to serum 25-hydroxyvitamin D3) can be used as an indicator of CYP24A1 induction. See Strugnell SA, Sprague SM, Ashfaq A, et al., "Rationale for Raising Current Clinical Practice Guideline Target for Serum 25-Hydroxyvitamin D in Chronic Kidney Disease," Am. J. Nephrol. 2019; 49(4): 284-293. Strugnell et al. show that in patients with CKD phase 3 and 4 suffering from vitamin D deficiency and SHPT, and treated with 30 or 60 μg ERC for more than 26 weeks, the average post-treatment VMR is only moderately elevated (maximum 4.8), which indicates that CYP24A1 is not significantly induced. Similarly, as described in Example 7 below, in patients with CKD phase 3 and 4 suffering from vitamin D deficiency and SHPT, and treated with 60 μg ERC for 8 weeks, the average post-treatment VMR is also maintained at less than 5 (maximum of about 4.2). The VMR after administration of 25-hydroxyvitamin D is dose-dependent. When a sufficiently high dose of 25-hydroxyvitamin D is administered, particularly rapid-release 25-hydroxyvitamin D, VMR can achieve higher levels. Similarly, in the case of sufficiently frequent repeated administration of 25-hydroxyvitamin D, VMR can increase over time and achieve a level higher than expected. In addition, along with the sufficiently rapid and effective delivery of 25-hydroxyvitamin D, the rate of VMR increases proportionally. Thus, in one aspect, the methods of treatment herein optionally will employ a dosing regimen in which the VMR remains substantially constant over a period of at least 28 days, further optionally during a maintenance dosing period. In another aspect, the methods of treatment herein optionally will employ a dosing regimen in which the VMR decreases over a period of at least 28 days, further optionally during a maintenance dosing period. In another aspect, the methods of treatment herein optionally will employ a sustained-release dosing regimen in which the rate of change in the VMR is less than the rate of change in the VMR of a bioequivalent amount of 25-hydroxyvitamin D administered by immediate release, for example, over a 28-day period.In another aspect, the methods of treatment herein will optionally employ a dosing regimen in which the VMR does not exceed 12, or does not exceed 11, or does not exceed 5, or does not exceed 4.8. In other aspects, recognizing that patients may benefit from correction of vitamin D insufficiency and achieving a serum total 25-hydroxyvitamin D level of at least 50 ng / ml as described herein, the methods of treatment herein will optionally employ a dosing regimen in which the VMR may exceed 4.8, or 5, or 11, or 12 during the loading dose phase and does not exceed 11, or does not exceed 5, or does not exceed 4.8 during the maintenance dose phase. In yet another aspect, the methods of treatment herein will optionally employ a dosing regimen in which the VMR does not exceed 12 (e.g., within the range of 4 to 12) during the loading dose phase and does not exceed 11 (e.g., within the range of 3 to 11) during the maintenance dose phase.

[0133] In any of the formulations described herein, the hard shell capsule dosage form or its use can be designed to provide an increase in serum total 25-hydroxyvitamin D of at least 7 ng / ml and no more than 30 ng / ml, or at least 8 ng / ml and no more than 16 ng / ml, or at least 10 ng / ml and no more than 14 ng / ml within the first 24 hours after administration. Optionally, such an increase can be achieved with a nominal dose of at least 30 μg, or at least 300 μg, or at least 350 μg, or at least 400 μg of 25-hydroxyvitamin D or calcifediol, for example, within the range of 30 μg to 1800 μg, or 450 μg to 1800 μg, or 30 μg to 1000 μg, or 30 μg to 300 μg. From an effective dose perspective, taking into account bioavailability, it is envisioned that a dose of one type of 25-hydroxyvitamin D or calcifediol can be in the range of about 30 μg to about 130 μg based on bioavailability within the first 24 hours after administration. For a formulation with 10% bioavailability calculated over a 42-day period after administration, an effective dose may be greater than 45 μg, at least 50 μg, at least 60 μg, at least 70 μg, at least 80 μg, or at least 90 μg, for example, in the range of 50 μg to 180 μg or in the range of 70 μg to 110 μg. In another type of embodiment, the dosage form provides an increase in serum total 25-hydroxyvitamin D of less than 3 ng / ml in adults within the first 24 hours after administration.

[0134] The hard capsule dosage form is characterized by its For example, according to US FDA standards and the March 2021 FDA draft guidance on calcifediol, hard capsule dosage forms can be bioequivalent to (Calcifediol) sustained-release capsules are bioequivalent. In summary, for example, a 900mcg dose can be used in a fasting study on healthy males and non-pregnant, non-lactating females, using a single dose, two treatments, two-cycle in vivo crossover to evaluate bioequivalence. On the other hand, a 900mcg dose can be used in a fasting study on healthy males and non-pregnant, non-lactating females, using a single dose, two treatments, in vivo parallel to evaluate bioequivalence. The subject can optionally have a baseline calcifediol concentration of less than 30ng / mL. The subject can optionally have a baseline calcifediol concentration of less than 35ng / mL. In an alternative, the study can be conducted in the fed state. Baseline-corrected calcifediol concentrations can be measured at -12, -6, and 0 hours before dosing, with the average of those concentrations used for baseline correction. In one type of embodiment, the hard capsule formulations according to the present disclosure will achieve 90% confidence interval (CI) of 80% to 125% of the baseline adjusted Cmax (35.87 ng / mL, or about 36 ng / ml) of the (calcifediol) extended-release capsule. In a contemplated alternative, the hard capsule formulation according to the present disclosure would achieve A 90% CI of about 74% to about 136% of the baseline adjusted Cmax for the (calcifediol) extended-release capsules (35.87 ng / mL, or about 36 ng / ml); optionally, in this embodiment, the geometric mean baseline adjusted Cmax for the hard capsules would be 80% to 125% of the Cmax of the (calcifediol) sustained-release capsule. The hard capsule formulation according to the present disclosure can achieve The 90% CI for the baseline-adjusted AUC (0-∞) of 80% to 125% for Calcifediol extended-release capsules (9418 ng·hr / mL) was 1.

[0135] In any of the uses or methods of use or treatment described herein, for example, in secondary hyperparathyroidism of stage 3, stage 4, or stage 5 CKD, a dosage form can be delivered to result in a baseline-adjusted steady-state Cmax of serum 25-hydroxyvitamin D or calcifediol in the range of 25 ng / ml to 98 ng / ml, for example, using a 30 μg dose of 25-hydroxyvitamin D or calcifediol, or in the range of 12.5 ng / ml to 104.9 ng / ml, for example, using a 60 μg daily dose of 25-hydroxyvitamin D or calcifediol. Responders (who met the primary endpoint of a greater than 30% decrease in iPTH from baseline) in the two pivotal studies that led to the approval of calcifediol (calcifediol) extended-release capsules showed that daily dosing was associated with a greater than 30% decrease in iPTH from baseline. At the end of six months of treatment with extended-release 25-hydroxyvitamin D capsules, baseline-adjusted steady-state serum calcifediol concentrations ranged from 25 to 98 ng / ml (CV 42.18%) for responders taking 30 mcg daily and from 12.5 to 104.9 ng / ml (CV 33.18%) for responders taking a dose gradually increased to 60 mcg daily. These wide ranges of effective therapeutic concentrations of calcifediol suggest that the effects of extended-release 25-hydroxyvitamin D are independent of maintaining a Cmax within a narrow range. In addition, (Calcifediol) sustained-release capsules are used daily for chronic conditions and the Cmax parameter is not as critical as with immediate-release formulations required for the treatment of acute conditions.

[0136] As described below in conjunction with Example 3, The extended-release calcifediol capsule (ERC) achieved a 100% response rate in serum total 25-hydroxyvitamin D at both the end of the first month of treatment (EAP1) and the end of the second month of treatment (EAP2) using a target of 30 ng / mL (P < 0.001). In contrast, the immediate-release calcifediol (IRC) achieved a 20% response rate in EAP2 using the same target (P < 0.001). Figure 5 Using a target of 50 ng / mL, ERC achieved a response rate of over 80% at EAP1 and 100% at EAP2 (P < 0.001), whereas no other treatment was able to raise serum 25-hydroxyvitamin D to this level. Figure 6 The plasma iPTH lowering responses observed in EAP1 and EAP2 for all four treatment groups are summarized in Table 1. The response rate for ERC was significantly higher than that for IRC. It is expected that the hard capsule formulations according to the present disclosure, for example, A bioequivalent formulation of sustained-release (calcifediol) capsules would show the same benefits as immediate-release calcifediol.

[0137] As described below in conjunction with Example 4, calcifediol exhibits degradation when exposed to acidic conditions, and in particular at elevated temperatures, including the 37°C temperature characteristic of physiological conditions. Furthermore, as shown below in Example 5, conventional HPMC hard shell capsules can be dissolved within two hours under such conditions. Figure 2 As described, the gelled hypromellose hard shell capsule dosage form according to the present disclosure was shown to resist dissolution for up to two hours under such conditions and more closely resembled the gelled hypromellose hard shell capsule dosage form comprising a plant-based soft capsule shell. Thus, one aspect of the present disclosure contemplates the use of a gelled hard capsule dosage form according to the present disclosure, wherein the dosage form releases no more than about 5% of the 25-hydroxyvitamin D or calcifediol in the formulation contained in the dosage form within two hours in an acidic medium, optionally in an acidic medium at pH 1.2 or pH 1.5, and further optionally at 37° C., the hard capsule dosage form being used to contain a composition comprising 25-hydroxyvitamin D or calcifediol and providing increased recovery and / or reduced degradation of the 25-hydroxyvitamin D or calcifediol after the dosage form is exposed to acidic conditions. Another aspect contemplates the use of a gelled hard capsule dosage form according to the present disclosure, wherein the dosage form releases no more than about 5% of the 25-hydroxyvitamin D or calcifediol in the formulation contained in the dosage form within two hours in an acidic medium, optionally in an acidic medium at pH 1.2 or pH 1.5, and further optionally at 37° C., the hard capsule dosage form being for containing a composition comprising 25-hydroxyvitamin D or calcifediol and for oral administration to a mammal. Another aspect contemplates the use of a gelled hard capsule dosage form according to the present disclosure, wherein the dosage form releases no more than about 5% of the 25-hydroxyvitamin D or calcifediol in the formulation contained in the dosage form in an acidic medium (optionally at pH 1.2 or pH 1.5), and further optionally at 37° C., within two hours, to contain a composition comprising 25-hydroxyvitamin D or calcifediol and exposing the dosage form to acidic conditions, for example, optionally less than pH 4.5, or less than pH 4.0, or less than pH 3.5, or within the range of about pH 1.2 to 3.5 or about pH 1.5 to 3.5.

[0138] Unless otherwise stated, it is contemplated that the methods encompass embodiments comprising any combination of one or more of the additional optional elements, features, and steps further described below, including those shown in the Figures.

[0139] In jurisdictions that prohibit patenting of methods practiced on humans, the meaning of "administering" a composition to a human subject should be limited to providing a controlled substance that a human subject can self-administer by any technique (e.g., oral, inhalation, topical application, injection, insertion, etc.). This is intended to be the broadest reasonable interpretation consistent with the law or regulation defining patentable subject matter. In jurisdictions that do not prohibit patenting of methods practiced on humans, "administering" a composition encompasses both the method and the aforementioned activities performed on humans.

[0140] As used herein, the term "comprising" indicates that other reagents, elements, steps or features may be included in addition to those specified.

[0141] Examples

[0142] The following examples are provided for illustration and are not intended to limit the scope of the invention.

[0143] Example 1

[0144] The following table provides HPMC hard capsule formulations of 25-hydroxyvitamin D with varying percentages of paraffin and mineral oil (weight percent), and the associated in vitro dissolution release rates.

[0145]

[0146]

[0147] Compared to the 20 wt.% paraffin formulation, reducing paraffin to below 20% (to 10% and 0%), with the associated increase in mineral oil, did not provide a significantly faster release profile compared to the comparative softgel formulation containing 20% ​​paraffin. On the other hand, increasing paraffin to 20% to 30% and above 40%, with the associated decrease in mineral oil, did show a significant decrease in the in vitro release rate, particularly after the 2 hour time point.

[0148] Example 2

[0149] The following table provides additional wax-based hard capsule formulations, Examples of a type soft capsule formulation (reference) and modified wax-based soft plant-based capsule formulations that are intended to provide relatively slower and faster release compared to the reference formulation. Plant-based capsules containing modified starch and carrageenan. The softgels fasting (Test 1) were formulated to have a rapid release rate compared to the reference by adjusting the concentration of the excipients. The softgels rapid batch incorporated increased amounts of lauroyl polyoxylglycerides and reduced amounts of paraffin. Without intending to be bound by any particular theory, such modifications to the matrix properties, reduced solid formulations and higher concentrations of absorption enhancers are intended to enhance the solubility of the active substance and therefore increase the release rate and the amount absorbed in the body compared to the reference formulation, although it did not show a faster release rate in vitro. The table also contains the pharmacokinetic curves generated by administering a 900 μg dose to each of 16 adult subjects (extracted from the mean baseline corrected serum concentration curves, Figure 1 ).

[0150]

[0151]

[0152] Figure 1Shown are the mean serum concentration profiles of 25-hydroxyvitamin D3 following oral administration of 900 μg of modified-release calcifediol softgels. Increasing paraffin from 20% to 39% did slow both in vitro and in vivo release compared to the reference, while decreasing paraffin from 20% to 5% did not exhibit a rapid in vitro release rate under the dissolution conditions tested. This result suggests that below 20% paraffin, erosion is likely not the primary release mechanism for these formulations. Calcifediol dissolved to the same extent in both the fast and reference batches, and adding more emulsifier did not increase solubility. Increasing the percentage of absorption enhancer from 9.75% to 14.75% had little effect in vitro under the conditions tested, but increased in vivo absorption, which is thought to be through other mechanisms, such as tissue penetration. The slow batch performed as expected in vitro in both the hard and soft capsules. The slow batch softgels also performed as expected in vivo. The matrix in this batch is relatively rigid, and erosion of the active substance by the rigid matrix is ​​likely the primary mechanism in this formulation.

[0153] The following table provides the dissolution time profiles according to USP Apparatus II (paddles with sinker) for the formulations described above.

[0154]

[0155]

[0156]

[0157] The following table describes another hard capsule formulation of 25-hydroxyvitamin D with a gelled HPMC capsule shell. Gellan gum is a hydrophilic polymer and has similar properties to the carrageenan used in the vegetable capsule shell of the reference soft capsule formulation. The gelled HPMC capsules had a slower rupture / disintegration time in the stomach than the non-gelled HPMC capsules.

[0158] Filling material Filling weight % mg / capsule Calcifediol 0.0194％ 0.03 paraffin 27.95％ 43.32 mineral oil 32.26％ 50 Hydroxypropyl methylcellulose k100 9.98％ 15.47 Monoglycerides and diglycerides 17.5％ 27.13 Lauroyl Polyoxyglyceryl 9.73％ 15.08 Dehydrated ethanol 2.54％ 3.94 BHT 0.02％ 0.03 total 100％ 155 Shell material Shell weight % mg / capsule Hydroxypropyl methylcellulose qsp100 35.283 Gellan gum 5 1.9 Titanium dioxide 2 0.76 organic colorants 0.15 0.057 total 100 38

[0159] Paraffin wax at 27.95% wax was used instead of 20% in the reference softgel formulation described above, and the mineral oil and mono- and diglyceride concentrations were slightly changed. The matrix fill per capsule was reduced from 170 mg to 155 mg, and the composition was filled into size 4 gelled HPMC capsule shells.

[0160] The in vivo dissolution profiles of the gelled HPMC hard capsule formulations, the reference soft capsule formulation, and the Test 4 formulation described above are shown in the table below (USP Apparatus II (paddles with settling device), 75 RPM, medium 5 mM sodium dihydrogen phosphate monohydrate with 0.5% SDS, pH 6.8, 37 ± 0.5°C, volume 500 ml).

[0161]

[0162]

[0163] Similarly, a modified in vitro dissolution method was used to measure capsule dissolution (2 capsules in a container, 900 ml of medium, and 60 RPM) and the results are shown in the table below (average of 5 reference batches).

[0164]

[0165] A two-stage dissolution method was also used (2 hours at pH 1.2 followed by a shift to pH 6.8) and the results are presented below and Figure 2 (Average of 3 reference batches, diamond markers, and gelled HPMC formulation, triangle markers) are shown in FIG. 1 . The dissolution profile of the gelled hard capsule formulation closely matches that of the plant-based soft capsule formulation.

[0166]

[0167]

[0168] The gelled HPMC hard capsule formulation and the reference soft capsule formulation were administered to the subjects in the fasting state. As described above, the pharmacokinetic values ​​and curves (Cmax, AUC, Tmax) produced by administration of the gelled HPMC hard capsule formulation more closely matched those produced by administration of the reference formulation than such values ​​and curves produced by administration of non-gelled HPMC hard capsules.

[0169] Example 3

[0170] In adult patients with secondary hyperparathyroidism (SHPT), stage 3 or 4 chronic kidney disease (CKD), and vitamin D insufficiency, ERC ( Repeated dosing of paricalcitol (calcifediol) extended-release capsules), IR calcifediol ("IRC"), high-dose cholecalciferol ("HDC"), and paricalcitol plus low-dose cholecalciferol ("PLDC") was studied.

[0171] This is an open-label study designed to collect comparative data evaluating ERC, IR calcifediol, high-dose cholecalciferol, and paricalcitol plus low-dose cholecalciferol. Eligible subjects were randomized 1:1:1:1 to receive 8 weeks of one of the listed study medications and sufficient non-alcoholic beverages to allow for capsule swallowing:

[0172] 1) ERC capsule 60 μg, once daily before bedtime, except on days 1 and 29, when it is administered as a Phase 1 unit in the morning before breakfast;

[0173] 2) On the mornings of days 1 and 29, take IR calcifediol 266 μg before breakfast in Phase 1 units;

[0174] 3) Cholecalciferol 300,000 IU (high dose) taken in Phase 1 units before breakfast on the mornings of Days 1 and 29; and

[0175] 4) Paricalcitol 1 μg (may be increased to 2 μg daily on day 29) plus cholecalciferol 800 IU (low dose) once daily in the morning before breakfast, except on the mornings of days 1 and 29, when the Phase 1 unit is administered before breakfast. After 4 weeks of treatment, the dose of paricalcitol is doubled to 2 μg plus cholecalciferol 800 IU once daily in the morning before breakfast for subjects receiving paricalcitol, provided that (a) plasma iPTH has not decreased by at least 30% compared to pretreatment BL and remains above 70 pg / mL, (b) corrected serum calcium is <9.8 mg / dL, and (c) serum phosphorus is <5.5 mg / dL.

[0176] At study entry and on Study Day 29, subjects were housed in the Phase 1 unit for approximately 14 to 26 hours to provide the required blood samples.

[0177] Subjects who were receiving calcitriol or other 1α-hydroxylated vitamin D analogs or vitamin D supplements prior to the study completed a 4-week washout period before the baseline (BL) assessment and remained on these non-study medications during the study. Subjects were excluded from enrollment if they had received calcimimetic therapy within 12 weeks prior to screening.

[0178] Blood samples were collected weekly from all subjects during the screening and BL periods and during the 8-week treatment period.During the study, subjects maintained a dietary intake of approximately 1,000-1,500 mg of elemental calcium per day through dietary counseling and, if necessary, took prescribed calcium supplements daily.

[0179] When plasma iPTH was confirmed to be <30 pg / mL, corrected serum calcium was confirmed to be >10.3 mg / dL, or serum phosphorus was confirmed to be >5.5 mg / dL, the subject's dose of study drug was reduced according to the following schedule. If plasma iPTH was confirmed to be <15 pg / mL or corrected serum calcium was confirmed to be >11.0 mg / dL, the subject's dose was withheld and resumed according to the following dosing schedule when plasma iPTH was ≥30 pg / mL and corrected serum calcium was <9.8 mg / dL.

[0180] ERC: Reduce from 60 μg per day to 30 μg per day

[0181] IR Calcifediol: Maintain Day 29 dose

[0182] Cholecalciferol 300,000 IU: Maintain Day 29 dose

[0183] Paricalcitol: Reduce the dose (from 2 μg per day) to 1 μg per day

[0184] Cholecalciferol 800IU will not be adjusted

[0185] If a subject receiving the minimum dose of ERC (30 μg daily) or paricalcitol (1 μg daily) requires a dose reduction, dosing will be withheld and resumed at the same minimum dose when iPTH is ≥30 pg / mL and corrected serum calcium is <9.8 mg / dL.

[0186] Dose resumption (if necessary):

[0187] ERC: 30 μg per day

[0188] Paricalcitol 1 μg daily

[0189] Changes in mean serum total 25-hydroxyvitamin D concentration over time Figure 3 (ERC group represented by diamonds, IR calcifediol group represented by triangles, cholecalciferol group represented by circles, and paricalcitol + cholecalciferol group represented by squares). The ERC group achieved serum concentrations greater than 50 ng / ml and approached 90 ng / ml, while the VMR of this group remained below 5 (maximum mean value at the end of treatment was approximately 4.2). Changes in VMR over time are shown in Figure 4 Shown in.

[0190] ERC treatment achieved a 100% response rate for serum total 25-hydroxyvitamin D at the end of both the first month of treatment (EAP1) and the second month of treatment (EAP2) using a target of 30 ng / mL (P < 0.001). In contrast, in EAP2 using the same target, the response rates for HDC, IRC, and PLDC were 44%, 20%, and 14%, respectively ( Figure 5 Using a target of 50 ng / mL, ERC achieved a response rate of over 80% at EAP1 and a 100% response rate at EAP2 (P < 0.001), whereas no other treatment was able to raise serum 25-hydroxyvitamin D to this level. Serum 25-hydroxyvitamin D levels achieved at EAP2 in all groups showed a significant inverse relationship with body weight and BMI.

[0191] Figure 6The plasma iPTH-lowering responses observed in EAP1 and EAP2 for all four treatment groups are summarized in Figure 2. The response rate for ERC was directionally lower in EAP2 but was not significantly different from the response rate for PLDC, regardless of whether "response" was defined as a reduction of ≥10%, 20%, or 30% from pretreatment baseline. The response rates for HDC and IRC were even lower in EAP2 (P < 0.05). Using a threshold of ≥10% to define "response," the response rates for ERC and PLDC in EAP2 were 76.5% and 85.7%, respectively, which were significantly higher than those in the other two treatment groups (P < 0.05). Using a threshold of ≥20%, the response rates for ERC and PLDC in EAP2 were 70.6% and 78.6%, respectively, compared with 20.0% and 37.5% for the IRC and HDC groups, respectively (P < 0.05). Using a ≥30% threshold, ERC achieved a response rate of 41.2% in EAP2, compared with 64.3% for PLDC (P=NS), 6.7% for IRC (P<0.01), and 25.0% for HDC (P<0.5).

[0192] According to the present disclosure, the gelled hypromellose capsule dosage form is at least substantially A bioequivalent dosage form of the (calcifediol) extended-release capsule will demonstrate substantially the same 25-hydroxyvitamin D response rate and plasma iPTH lowering response as the ERC dosage form.

[0193] Example 4

[0194] The stability of calcifediol in acidic dissolution media was tested using 30 μg of calcifediol extended-release capsules at ambient / light conditions at 37°C, 20°C, and 10°C, as well as in the dark. The results are summarized in the table below. Calcifediol proved to be highly unstable in pH 1.2 media, with approximately 90% degradation observed after 6 hours at 37°C. Stability was significantly improved after neutralization.

[0195]

[0196] *HCl samples were neutralized with sodium acetate and brought to a pH of approximately 4

[0197] **AS = Autosampler. Neutralized samples cannot be stored at 10°C in the autosampler due to SDS precipitation.

[0198] Example 5 - Comparative Example

[0199] A series of dissolution tests were conducted on various calcifediol extended-release dosage forms based on different capsule shells to better understand the release properties in media with different pH conditions, such as those found in the mammalian gastrointestinal tract, and the associated effects on the active 25-hydroxyvitamin D component (calcifediol in this case).

[0200] 5a

[0201] Twelve 30mcg monitored in acidic media containing alcohol Dissolution rate of sustained-release calcifediol capsules. The test was performed in an acidic medium (0.1N HCl) at 37°C using a paddle at 100 rpm for 2 hours, with a point pull every 15 minutes. Four groups of 12 capsules were used in each group: (1) no alcohol in the dissolution solution; (2) 5% v / v ethanol in the dissolution solution; (3) 20% v / v ethanol in the dissolution solution; and (4) 40% v / v ethanol. Detection was performed by UPLC with UV.

[0202] Even at the 2-hour time point in acidic medium and acidic medium containing 5% and 20% ethanol, no calcifediol was released. A small amount of calcifediol was released in acidic medium containing 40% ethanol (approximately 2-3% of the label claim for 30 mcg), but the levels at all draw points were below the limit of quantitation (5% of the label claim for a 30 mcg capsule). Visual observations conducted during the test confirmed the results. After 2 hours, the blue coating on the original capsule was observed to dissolve, leaving the fill material intact in the sedimentation device at the bottom of the dissolution vessel.

[0203] 5b

[0204] Dissolution test was performed on two groups of samples, each repeated six times: (1) 30mcg (Calcifediol) sustained-release capsules; (2) non-gelled hypromellose-based 30mcg Calcifediol capsules containing The fill in both samples was the same. The dosage form with the HPMC shell was a size 3 capsule containing 170 mg of fill (the same as in the plant-based softgel shell). The fill amount of calcifediol sustained-release capsules is the same).

[0205] All samples were subjected to dissolution testing in pH 6.8 buffered dissolution medium at 1, 2, 3, 4, 5, 6, 7, 8, 10, and 12 h sampling points.

[0206] Acidic dissolution testing was performed on the samples of group (1) described above. 500 mL of acidic HCl buffer pH 1.2 containing 0.5% SDS was used as the dissolution medium. The buffer was prepared according to USP, except that sodium chloride was used instead of potassium chloride to avoid precipitation of potassium lauryl sulfate. Due to the high instability of calcifediol in acidic solutions, sodium acetate solution (150 μL of 273 mg / mL sodium acetate in water) was used to neutralize / stabilize the samples at 1, 2, 3, 4, 5, 6, 7, 8, 10, and 12 hours after sample extraction.

[0207] All samples were subjected to a two-stage dissolution test. The first acidic stage was conducted in 500 mL of HCl acid buffer at pH 1.2, as described in the acidic dissolution test immediately above. Sampling time points were 1 hour and 2 hours. The samples were also neutralized / stabilized with the same sodium acetate solution described in the acidic dissolution test immediately above. After 2 hours, the capsules were removed from the container and the medium was replaced with 500 mL of phosphate buffer at pH 6.8. The second stage was conducted immediately after the dissolution medium was replaced, with sampling points at 1, 2, 3, 4, 5, 6, 7, 8, 10, and 12 hours thereafter.

[0208] Figure 7 Shown are the dissolution profiles of hypromellose capsule samples (average of six) in pH 6.8 medium (left) and a two-stage dissolution process (right). Figure 8 Shown are the dissolution profiles of plant capsule samples (each with a mean value of 6) in pH 6.8 medium (left), a two-stage dissolution process (center), and pH 1.2 medium (right / bottom).

[0209] In both dissolution media tested (pH 6.8 and pH 1.2), the shell of the hypromellose capsule dosage form disintegrated after approximately 30 to 60 minutes. During the two-stage dissolution process, when the capsule residue was transferred to the pH 6.8 formulation after the acidic stage, the outer shell appeared to be completely disintegrated, with only capsule fill residue observed in the sedimentation apparatus. At the end of any dissolution test, there was no residual fill material in any container.

[0210] 30mcg The shell of the (calcifediol) sustained-release capsule disintegrated after about 1 to 2 hours in pH 6.8 dissolution medium and after about 2 hours in acidic medium. During the change of dissolution medium for the two-stage dissolution, the shell appeared to be completely or almost completely dissolved, with only discontinuous blue coloration of the fill surface (from the original shell color) being observed. A small amount of fill residue was detected at the end of the pH 6.8 dissolution test, the pH 1.2 test, and the two-stage dissolution in some containers.

[0211] The dissolution rate of Hydroxypropyl Methylcellulose Capsules in pH 6.8 deployment seems faster, particularly in the first two hours (corresponding to the acidic phase in the two-stage dissolution test). In pH 6.8 medium, final calcifediol release is also higher than the release after the two-stage dissolution. This indicates that some calcifediols are likely to decompose during the acidic phase. From these tests, it is unclear whether the slower dissolving in the acidic phase can be attributed to calcifediol decomposition, or for example, owing to the slower decomposition of shell or from the slower release of filling material compared with the corresponding cycle of pH 6.8 medium dissolution.

[0212] Example 6 - Comparative Example

[0213] For 30μg strength The dissolution and release characteristics of (calcifediol) sustained-release capsules in dissolution media with different acidic properties were tested.

[0214] Dissolution testing was performed in two different media—hydrochloric acid buffer, pH 1.2, and acetate buffer, pH 4.5, supplemented with 0.5% SDS. Buffer solutions were prepared according to USP (Buffer Solutions, p. 2165), with one modification: in the case of hydrochloric acid buffer, sodium chloride was used instead of potassium chloride due to precipitation of potassium lauryl sulfate. Due to the instability of calcifediol in pH 1.2 media, these samples were neutralized with sodium acetate solution (150 μL of a 273 mg / mL solution) at the time of sampling. Results from pH 1.2 dissolution testing were corrected for dilution due to the addition of the neutralizer.

[0215] The test was repeated six times in each medium. The dissolution time points were set as follows: 1-2-3-4-5-6-8-10-12 hours, with a nominal paddle speed of 75 RPM, then changed to 250 RPM, and sampling at 13 hours.

[0216] Figure 9 and Figure 10 The dissolution profiles for the pH 1.2 and 4.5 tests are presented in Figure 1. The lower calcifediol assay in pH 1.2 medium is due to the degradation of calcifediol in this medium during the dissolution run.

[0217] Example 7

[0218] The 30 μg strength calcifediol gelled hard capsule formulation according to the present disclosure and the 30 μg strength (Calcifediol) sustained-release capsules were subjected to a two-stage dissolution test for comparison.

[0219] The hard gelatin capsule filling has the following formulation:

[0220] Filling material Filling weight % mg / capsule Calcifediol 0.0194％ 0.03 paraffin 27.95％ 43.32 mineral oil 32.26％ 50 Hydroxypropyl methylcellulose k100 9.98％ 15.47 Monoglycerides and diglycerides 17.5％ 27.13 Lauroyl Polyoxyglyceryl 9.73％ 15.08 Dehydrated ethanol 2.54％ 3.94 BHT 0.02％ 0.03 total 100％ 155 Shell material Shell weight % mg / capsule Hydroxypropyl methylcellulose qsp100 35.283 Gellan gum 5 1.9 Titanium dioxide 2 0.76 organic colorants 0.15 0.057 total 100 38

[0221] To also test whether the batch of hot-fill formulations changed during the packaging process, potentially leading to changes in dissolution profiles, samples were tested at the beginning, middle, and end of the packaging process.

[0222] The dissolution apparatus was USP Apparatus 2 with paddles equipped with a JP settling device, operated at 75 RPM and 37 ± 0.5°C. The acidic phase dissolution medium was 0.1N HCl in 0.5% SDS, pH 1.2. 500 mL of 0.5% SDS in 5 nM sodium phosphate buffer was used as the pH 6.8 dissolution medium. One capsule was used per container, and 12 replicates were tested. After 2 hours in the acidic medium, the capsules were removed from the container and the medium was replaced with 500 mL of phosphate buffer, pH 6.8.

[0223] Example 8

[0224] A study was conducted to compare the oral bioavailability of Calcifediol 30 mcg extended-release hard capsules with gelled hypromellose hard shell capsules (test product) in healthy adult subjects.

[0225] The purpose of this study was to compare the test product with the reference product ( The study was designed to assess the bioavailability of Calcifediol (30mcg softgel capsules) after a single oral dose of 900mcg under fasting conditions; to evaluate and compare the effect of food on the bioavailability of the test product; and to assess reference-to-reference intra-subject CV. The primary endpoint was the baseline-adjusted pharmacokinetic (PK) parameter of Calcifediol, Cmax AUC0-336.

[0226] The study was designed as a single-center, randomized, single-dose, laboratory-blinded study. Eligible subjects were randomized in a 2:2:1:1 ratio as follows:

[0227]

[0228] Inclusion criteria included a body mass index of 18.5 kg / m 2 Up to 30.0kg / m 2 weight ≥60 kg; non-smokers or former smokers; and serum 25-hydroxyvitamin D level ≥10 and ≤35 ng / mL or ≥25 and ≤87 nmol / L (depending on the units used in the biomedical laboratory).

[0229] Exclusion criteria included the following: ingestion of calcifediol within 60 days before study drug administration; ingestion of IP within 28 days before study drug administration; unavoidable consumption of foods and beverages very high in vitamin D within 10 days before study drug administration; unavoidable excessive consumption (i.e., more than once per day) of foods and beverages relatively high in vitamin D within 10 days before study drug administration; travel to sunny destinations (e.g., the southern United States and Central America) within 28 days before study drug administration or plans to travel to such destinations during the study period, outdoor occupations, or plans to participate in prolonged outdoor activities during the study period; and sunbathing and tanning bed use within 10 days before study drug administration.

[0230] A single oral dose of 900 mcg of calcifediol (30 x 30 mcg extended-release capsules) will be administered in the morning.For each subject, all planned post-dose activities and assessments will be performed relative to the time of study drug administration.

[0231] The subjects were administered an oral dose of the specified formulation over a 5-minute period. The subjects took up to 3 study drug capsules at a time, along with approximately 240 mL of water at ambient temperature, and, if necessary, up to 240 mL of additional water. The dosing time was set to the time the first capsule was administered to the subject. The complete dosing procedure was completed within 5 minutes, and dosing procedures completed within a maximum of 2 minutes outside the allowed time window were not considered protocol deviations but were recorded. The start and end times and the amount of water ingested during the study drug administration period were recorded. The capsules were swallowed whole and not chewed or crushed.

[0232] Food intake was controlled during each delivery cycle and for all participants. Meals provided during delivery were low in vitamin D to reduce exogenous calcifediol levels. The following items were not included in the meal assigned to participants: fish and seafood; egg yolks; tofu; soy, almond, or rice beverages; cheese; mushrooms; beef liver; and any products fortified with vitamin D (including fortified milk, orange juice, margarine, and cereals). Meals were identical (with the same vitamin D content) at baseline and on the dosing day.

[0233] For Treatment 1 and Treatment 2 (fasting conditions):

[0234] Subjects fasted overnight (no food or beverages except water) for at least 10 hours prior to dosing.

[0235] For Treatment-3 (Dietary Condition - High-Fat, High-Calorie Meal):

[0236] After an overnight fast of at least 10 hours, subjects received a standardized high-fat, high-calorie meal 30 minutes before drug administration. The sample meal consisted of two eggs fried in butter, two strips of bacon, two slices of toast with butter, 4 ounces of hash browns, and 8 ounces of whole milk. Alternatives to the test meal were permitted if they provided a similar amount of calories from protein, carbohydrates, and fat and had a comparable meal volume and texture. Subjects were required to consume the entire contents of the meal within 30 minutes or less.

[0237] Subjects were asked to fast for at least 4 hours after dosing, after which a standardized lunch was provided. Thereafter, dinner, light snacks, and other meals were provided at appropriate times, but not before 9 hours after dosing.

[0238] Twenty-seven (27) blood samples were collected for PK evaluation. In order to assess baseline concentration, blood samples (each 1 × 6 mL) were collected 12, 6 and 0.25 hours before drug administration. Thereafter, blood samples (each 1 × 6 mL) were collected 1, 2, 4, 6, 7, 8, 9, 10, 11, 12, 14, 16, 20, 24, 30, 36, 42, 48, 72, 96, 144, 216, 288 and 336 hours after drug administration. For each cycle, baseline concentration was measured approximately 12, 6 and 0.25 hours before drug administration. The mean value of these 3 pre-dose concentrations was used for baseline correction, and any negative value obtained from baseline correction was designated as zero.

[0239] For each of the main PK parameters (baseline-adjusted C max and AUC 0-336 ) Determine the reference-to-reference within-subject standard deviation (s wr ).

[0240] Subjects who provided evaluable PK data for two cycles of the reference product (included in sequence 3) were included in the s wr to determine whether the reference ratio bioequivalence procedure can be used to assess the bioequivalence between the test product and the reference product administered under fasting conditions (data from subjects included in sequences 1 and 2).

[0241] Average bioequivalence :

[0242] If s wrIf the ISCV is less than 0.294 (equivalent to ISCV = 30%), then the two-sided testing procedure for bioequivalence assessment will be used for the specific parameters that meet the criteria. A mixed effects model will be performed for the ln-transformed parameters, including sequence, period, and treatment as fixed effects and subject nested within sequence as a random effect. The test product is considered bioequivalent to the reference product if the ratio of the geometric LSmean calculated from the difference index between the test product and the reference product for the ln-transformed parameters with the corresponding 90% confidence interval (CI) is within the range of 80.00% to 125.00% bioequivalence.

[0243] Average bioequivalence of the reference ratio:

[0244] If s wr If the ratio of the geometric LSmean with the corresponding 90% CI is within the expanded acceptance criteria (determined as exp(±0.893*s)), the procedure for the reference ratio of the bioequivalence assessment will be used to meet the specific parameters of the criteria. The same mixed effects model as defined above will be performed. wr )*100), then the test product is considered bioequivalent to the reference product.

[0245] Because C max and AUC 0-336 May have different wr values, so the procedure for the reference scale will only be used for s wr A two-sided testing procedure will be used for specific PK parameters ≥0.294. wr PK parameters <0.294.

[0246] Baseline unadjusted calcifediol results are presented as supporting information.

[0247] Food Impact Assessment

[0248] The C obtained by comparing the tests performed under fed conditions with those performed under fasting conditions max and AUC 0-336 Comparisons were performed to determine the effect of food on baseline-adjusted calcifediol.

[0249] The absence of food effects on the PK profile will be determined by the following procedure: A model with food condition as a fixed effect will be performed on the ln-transformed parameters. max and AUC 0-336If the ratio of the difference index calculated between the tests performed under fed conditions and the tests performed under fasting conditions with the corresponding 90% CI is within the range of 80.00% to 125.00%, then it can be concluded that there is no food effect.

[0250] Baseline unadjusted calcifediol results are presented as supporting information. max Conduct descriptive analysis.

[0251] The foregoing description has been given for clearness of understanding only, and no unnecessary limitations are to be understood therefrom, as modifications within the scope of the invention may be apparent to one skilled in the art.

[0252] Unless otherwise indicated herein or clearly contradicted by context, the terms "a," "an," and "the," and similar referents used in the context of describing the present disclosure (particularly in the context of the following claims), should be interpreted as covering both the singular and the plural. Unless otherwise indicated, the terms "comprise," "have," "include," and "contain" should be interpreted as open-ended terms (i.e., meaning "including, but not limited to"). Thus, throughout this specification and the appended claims, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" should be understood to imply the inclusion of stated integers or steps or groups of integers or steps, but not the exclusion of any other integers or steps or groups of integers or steps.

[0253] Recitation of ranges of values ​​herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range and each endpoint, unless otherwise indicated herein, and each separate value and endpoint is incorporated into the specification as if it were individually recited herein.

[0254] Throughout this specification, unless otherwise described, when a composition is described as comprising components or materials, it is contemplated that the composition can also consist essentially of or consist of any combination of said components or materials. Similarly, unless otherwise described, when a method is described as comprising specific steps, it is contemplated that the method can also consist essentially of or consist of any combination of said steps. The invention illustratively disclosed herein can suitably be practiced in the absence of any element or step not specifically disclosed herein.

[0255] The practice of the methods disclosed herein and their individual steps can be performed manually and / or by means of an electronic device or automation provided by the electronic device. Although various methods have been described with reference to specific embodiments, it will be readily apparent to those skilled in the art that other execution modes of the behavior associated with the methods can be used. For example, unless otherwise described, the order of the various steps can be changed without departing from the scope or spirit of the methods. In addition, some of the individual steps can be combined, omitted, or further subdivided into additional steps.

[0256] All patents, publications, and references cited herein are hereby incorporated by reference in their entirety. In the event of a conflict between the present disclosure and the incorporated patents, publications, and references, the present disclosure shall control.

Claims

1. A hard capsule dosage form comprising a hard shell capsule containing a solid or semisolid composition comprising a 25-hydroxyvitamin D compound, the hard shell capsule comprising a cellulose ether and a gelling agent; and wherein the hard shell capsule is a capsule in the size range of 3 to 5.

2. A hard capsule dosage form comprising a hard shell capsule containing a solid or semisolid composition comprising a 25-hydroxyvitamin D compound and a stabilizer, wherein the hard shell capsule is a gelled hard shell capsule comprising a cellulose ether and a gelling agent; and wherein the hard capsule dosage form is a controlled release dosage form and the controlled release dosage form releases ≤30% of the 25-hydroxyvitamin D in the formulation within the first two hours of a two-stage dissolution test at pH 1.

2.

3. A hard capsule dosage form, comprising a hard shell capsule, wherein the hard shell capsule contains a solid or semisolid composition, wherein the solid or semisolid composition comprises a 25-hydroxyvitamin D compound and a stabilizer, and the hard shell capsule comprises hydroxypropyl methylcellulose and a gelling agent.

4. A hard capsule dosage form, comprising a hard shell capsule containing a solid or semisolid composition comprising a 25-hydroxyvitamin D compound and a stabilizer, wherein the hard shell capsule comprises hydroxypropyl methylcellulose and gellan gum.

5. The hard capsule dosage form according to any one of claims 1 to 4, wherein the 25-hydroxyvitamin D comprises or consists of calcifediol.

6. The hard capsule dosage form according to any one of claims 1 to 4, wherein the composition comprising the 25-hydroxyvitamin D comprises a mixture of the following components, wherein all amounts are specified by weight based on the total weight of the composition contained in the hard shell capsule: Calcifediol: approximately 0.01% to 0.03% or 0.0194%; Paraffins: about 25% to 30% or 27.95%; Mineral oil: approximately 30% to 35% or 32.26%; Hypromellose K100: approximately 7% to 13% or 9.98%; Mono- and diglycerides: approximately 14.5% to 20.5% or 17.5%; Lauroyl polyoxylglycerides: approximately 7% to 13% or 9.73%; Dehydrated ethanol, approximately 2% to 4% or 2.54%; and BHT: about 0.05% to 0.05% or 0.02%.

7. The hard capsule dosage form according to any one of claims 1 to 4, wherein the hard shell capsule comprises a mixture of the following components, wherein all amounts are specified by weight based on the total dry weight of the hard shell capsule: Gellan gum: about 1% to 10% or 5%; Titanium dioxide: about 0.01% to 4% or 2%; and Hydroxypropyl methylcellulose: qsp100.

8. The hard capsule dosage form according to any one of claims 1 to 3, wherein the gelling agent is present in an amount ranging from 0.1% to 10% by weight of the hard shell capsule.

9. The hard capsule dosage form according to any one of claims 1 to 3, wherein the gelling agent is one or more selected from the group consisting of natural seaweed, natural seed gum, natural plant exudate, natural fruit extract, biosynthetic gum and biosynthetic processed starch.

10. The hard capsule dosage form according to any one of claims 1 to 3, wherein the gelling agent is one or more selected from the group consisting of alginate, agar gum, guar gum, locust bean gum (carob), carrageenan, tara gum, gum arabic, gum ghatti, Khaya grandifolia gum, gum tragacanth, gum karaya, pectin, arabic (arabinan), xanthan gum, starch, konjac mannan, galactomannan, haran, gellan, exopolysaccharide, xanthan gum, acetylated gum, gellan gum, welan gum, rhamnose gum, furcellaran, succinoglycan, scleroglucan, schizophyllan, tamarind gum, curdlan gum, pullulan, and dextran.

11. The hard capsule dosage form according to any one of claims 1 to 3, wherein the gelling agent is one or more selected from the group consisting of gellan gum, carrageenan, pectin, and pullulan.

12. The hard capsule dosage form according to claim 1 or 2, wherein the cellulose ether is present in the hard shell capsule in an amount ranging from about 90% to 99.98% by weight of the hard shell capsule.

13. The hard capsule dosage form according to claim 1, wherein the hard shell capsule is a size 4 capsule.

14. The hard capsule dosage form of claim 2, wherein the solid or semisolid composition comprising the 25-hydroxyvitamin D comprises from about 2 weight percent to about 18 weight percent of the stabilizer, based on the total weight of the composition contained in the hard shell capsule.

15. The hard capsule dosage form according to any one of claims 2 to 4, wherein the stabilizer comprises a cellulosic stabilizer.

16. The hard capsule dosage form of claim 15, wherein the cellulose stabilizer comprises carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyanionic cellulose, and combinations thereof.

17. The hard capsule dosage form of claim 2, wherein the dosage form releases no more than about 7% of the 25-hydroxyvitamin D in the formulation within two hours in an acidic medium.

18. The hard capsule dosage form of claim 17, wherein the release in acidic medium is measured in a pH 1.2 medium at 37°C for two hours followed by dissolution measurement in a pH 6.8 buffered medium, and the dosage form releases up to 40% of the 25-hydroxyvitamin D in the formulation at the 4 hour time point.

19. The hard capsule dosage form of claim 18, wherein the dosage form releases at least 60% of the 25-hydroxyvitamin D in the formulation at a 6 hour time point.

20. The hard capsule dosage form of claim 19, wherein the dosage form releases at least 80% of the 25-hydroxyvitamin D in the formulation at an 8 hour time point.

21. The hard capsule dosage form of claim 17, wherein the release in acidic medium is measured in a pH 1.2 medium at 37°C for two hours followed by dissolution measurement in a pH 6.8 buffered medium, and wherein the dosage form releases up to 30% of the 25-hydroxyvitamin D in the formulation at the 2 hour time point, ≥50% and ≤75% of the 25-hydroxyvitamin D in the formulation at the 6 hour time point, and ≥80% of the 25-hydroxyvitamin D in the formulation at the 12 hour time point.

22. Use of a hard capsule dosage form according to any one of claims 1 to 4 in the manufacture of a dosage form for providing increased recovery and / or reduced degradation of 25-hydroxyvitamin D or calcifediol in the dosage form after exposure of the dosage form to acidic conditions, the dosage form comprising 25-hydroxyvitamin D or calcifediol, the use comprising disposing a formulation comprising 25-hydroxyvitamin D or calcifediol in a hard shell capsule to form the dosage form.

23. Use of a hard capsule dosage form according to any one of claims 1 to 4 as a medicament for delivering 25-hydroxyvitamin D or calcifediol to a subject in need thereof.

24. The use of claim 23, wherein the hard capsule formulation is delivered as repeated dosing to provide a baseline-adjusted steady-state Cmax of serum 25-hydroxyvitamin D or calcifediol in the range of about 25 ng / ml to about 98 ng / ml, optionally using a 30 μg dose of 25-hydroxyvitamin D or calcifediol.

25. The use of claim 23, wherein the hard capsule formulation is delivered as repeat dosing to provide a baseline-adjusted steady-state Cmax of serum 25-hydroxyvitamin D or calcifediol within the range of about 12.5 ng / ml to about 104.9 ng / ml of 25-hydroxyvitamin D or calcifediol, optionally using a 60 μg daily dose of 25-hydroxyvitamin D or calcifediol.

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