Vitamin d pediatric dosage forms, and methods of making and using the same

Abstract

To provide pediatric and modified release dosage forms of vitamin D compounds, and methods of making and using the same.SOLUTION: Provided is a vitamin D formulation comprising a vitamin D compound dispersed in a polymer composition.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS The benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 62 / 725,940, filed August 31, 2018, is hereby claimed, the disclosure of which is incorporated herein by reference.

[0002] FIELD OF THE DISCLOSURE This disclosure relates generally to dosage forms of vitamin D compounds, such as calcifediol, including forms suitable for pediatric use, and methods of making and using the same. [Background technology]

[0003] Brief description of the related art Vitamin D compounds have traditionally been administered in immediate release formulations. More recently, several modified release dosage forms of vitamin D compounds have been described, for example, in wax matrix form. The present disclosure relates to vitamin D preparations, including sustained release preparations and those suitable for use in pediatric patient populations. Formulations for delivering active vitamin D, its analogs, and its prohormones, including several sustained release dosage forms, have been disclosed. One such formulation is a product approved for treating secondary hyperparathyroidism in patients with stage 3 and 4 chronic kidney disease (CKD), and is sold in the United States under the trade name RAYALDEE® (calcifediol). The prescribing information for this drug indicates that the sustained release formulation of RAYALDEE® is a wax-based sustained release formulation of 25-hydroxyvitamin D3. Summary of the Invention

[0004] One aspect of the disclosure herein is a vitamin D formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, dispersed in a polymeric composition. In embodiments, the formulation can be an extended release formulation, e.g., for oral use.

[0005] Another aspect of the present disclosure is a vitamin D formulation comprising 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 an embodiment, the formulation can be a sustained release formulation, for example for oral use.

[0006] Another aspect of the present disclosure is a spheronized pellet formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, and a pharma- ceutically acceptable excipient. In an embodiment, the formulation may be a sustained release formulation, for example for oral use.

[0007] Another aspect of the disclosure herein is a vitamin D formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, dispersed in a fatty acid glyceride mixture. In embodiments, the formulation may be a sustained release formulation, e.g., for oral use.

[0008] Another aspect of the present disclosure is a nano / microparticle formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, and a pharma- ceutically acceptable excipient. In embodiments, the nano / microparticle formulation can provide sustained release of the vitamin D compound, for example, by using a sustained release polymer as an excipient.

[0009] Another aspect of the present disclosure is a lipid microparticle formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, and a pharma- ceutically acceptable lipid. In embodiments, the formulation may be a sustained release formulation, e.g., for oral use.

[0010] Another aspect of the present disclosure is a nonpareil seed formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, and a pharma- ceutically acceptable excipient. In an embodiment, the formulation may be a sustained release formulation, e.g., for oral use. In an embodiment, the excipient may comprise a sustained release polymer coating.

[0011] Another aspect of the disclosure herein is a pharmaceutical composition comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, and a pharma- ceutically acceptable excipient selected from one or more of the following groups: absorption enhancers, spheronization aids, water-insoluble polymers, and binders. In an embodiment, the formulation may be a sustained release formulation, e.g., for oral use.

[0012] Another aspect of the disclosure herein is a spray-congealed lipid vitamin D formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, a sustained release agent, and a surfactant. In embodiments, the formulation can be a sustained release formulation, e.g., for oral use.

[0013] Another aspect of the present disclosure is a pharmaceutical batch of a dosage form comprising a formulation according to the present disclosure, further characterized by low dosage form-to-form variability in in vitro dissolution release. In an embodiment, the dosage form may be a sustained release dosage form, e.g., for oral use.

[0014] Another aspect of the disclosure herein is a pharmaceutical batch of a dosage form comprising a formulation according to the disclosure herein, further characterized by low batch-to-batch variability in in vitro dissolution release. In an embodiment, the dosage form may be a sustained release dosage form, e.g., for oral use.

[0015] Another aspect of the present disclosure is the method of preparing pharmaceutical formulations and dosage forms.In an embodiment, this method can be a method of preparing sustained release pharmaceutical formulations, comprising further compounding vitamin D compound with water-insoluble polymer, and optionally with at least one pharma- ceutically acceptable excipient selected from one or more diluents, absorption enhancers, and binders.

[0016] Another aspect of the disclosure herein is a method for improving batch-to-batch consistency in the in vitro release profile of a sustained release vitamin D compound formulation, the method comprising compounding a vitamin D compound with a water-insoluble polymeric material and, optionally, with one or more additional excipients.

[0017] Another aspect of the disclosure herein is a method of treating a vitamin D responsive disease or condition comprising administering to a patient in need thereof a formulation or dosage form according to the disclosure herein.

[0018] For the compositions and methods described herein, optional features are contemplated to be selected from the various aspects, embodiments, and examples provided herein, including, but not limited to, components, compositional ranges thereof, alternatives, conditions, and steps.

[0019] Further aspects and advantages will become apparent to those skilled in the art upon review of the following detailed description in conjunction with the drawings. While the compositions and methods are susceptible to embodiment in various forms, the following description includes specific embodiments with the understanding that the disclosure is illustrative and is not intended to limit the invention to the specific embodiments described herein.

[0020] To facilitate a further understanding of the present invention, four drawings are attached hereto. [Brief description of the drawings]

[0021] [Figure 1]1 shows the dissolution release profile of Eudragit-based pellets loaded with calcifediol according to the present disclosure compared to the dissolution release profile of a wax matrix-based soft capsule formulation. [Diagram 2] FIG. 1 shows the dissolution release profile of ethylcellulose (EC)-based pellets loaded with calcifediol according to the present disclosure compared to the dissolution release profile of a wax matrix-based soft capsule formulation. [Diagram 3] 1 shows the dissolution release profile of a spray-dried nano / microparticle formulation containing calcifediol according to the present disclosure compared to the dissolution release profile of a wax matrix-based soft capsule formulation. [Figure 4] FIG. 1 shows the dissolution release profile of a spray-congealed lipid-based formulation containing calcifediol according to the present disclosure compared to the dissolution release profile of a wax matrix-based soft capsule formulation. [Diagram 5] 1 shows the dissolution release profile of soft capsule wax-based calcifediol formulation and nano / microparticle formulation described in Example 3. [Figure 6] FIG. 1 shows the dissolution release profiles of comparative batches of Eudragit-based pellet formulations according to the present disclosure, demonstrating batch-to-batch consistency. [Figure 7] FIG. 1 shows the dissolution release profiles of comparative batches of Eudragit-based pellet formulations according to the present disclosure, demonstrating batch-to-batch consistency. [Figure 8] FIG. 1 shows the dissolution release profiles of comparative batches of Eudragit-based pellet formulations according to the present disclosure, demonstrating batch-to-batch consistency. [Figure 9] 1 shows baseline and dose-adjusted mean serum calcifediol concentration-time profiles of sustained release formulations tested in minipigs according to Examples 1, 2, and 7. [Figure 10] 1 shows baseline corrected serum cacifediol concentration-time profiles of sustained release formulations tested in humans according to Example 9. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] There is a need for improved formulations for safer delivery of vitamin D compounds, including calcifediol, such as sustained release formulations, and similarly improved formulations suitable for delivery to pediatric patients. The present invention embodiments can meet these needs and provide a range of sustained release dosage forms and improved processes for manufacturing such formulations and dosage forms. These formulations can be bioequivalent to commercially approved wax-based systems, but are also suitable for providing distinct in vitro sustained release dissolution profiles and in vivo bioavailability. They can be made suitable for both pediatric and adult patient populations, and can be used, for example, to increase serum 25-hydroxyvitamin D levels, thus treating vitamin D deficiency, as well as other disorders, including renal diseases and conditions.

[0023] The need to develop a pediatric 25-hydroxyvitamin D formulation prompted development efforts to explore several different strategies to achieve an easy-to-swallow, palatable, bioavailable, sustained-release oral dosage form. These strategies included pellets produced using extrusion-spheronization technology with or without coating, coating inert seeds such as nonpareil seeds using fluidized bed (Wurster) technology, nano / microparticle technology, and lipid microparticles via spray congealing / spray quenching / spray chilling technologies.

[0024] Efforts to produce age-appropriate sustained release oral formulations have yielded some surprising and unexpected results. For example, several attempts involving spray congealing of wax-based mixtures have yielded sustained dissolution release profiles, but none have adequately matched the target dissolution release profiles of previous wax-based matrix formulations. Instead, aqueous-based polymer pellet formulations using extrusion and spheronization techniques have yielded improved 25-hydroxyvitamin D sustained release formulations. Such formulations met all the criteria required for pediatric use, and furthermore, were suitable for adult use based on in vitro dissolution data. In embodiments, aqueous-based polymer pellet formulations can eliminate the need for coating to obtain a bioequivalent product, providing consistent and reproducible properties and consistent and reproducible in vitro release profiles per unit dose and per batch.

[0025] Disclosed and described herein are sustained release vitamin D formulations, including formulations suitable for delivery to pediatric patients in need of such treatment. Such formulations may also be useful in treating adults in need of such treatment, for example, for vitamin D deficiency, as well as secondary hyperparathyroidism in CKD and other vitamin D-related diseases and conditions. Using the formulations and formulation strategies described herein, it is possible to provide formulations that are bioequivalent to commercially approved calcifediol sustained release formulations, but in a form that can be delivered to pediatric patients. Such forms include traditional capsules, "easy-open" capsules, or sachets that can be administered by emptying the entire contents into a small amount of liquid or onto a small amount of soft food. In addition to developing multiple suitable formulations for pediatric patients, the present invention also provided a process for improving the variability of dissolution profiles between unit doses and between batches, as well as such improved formulations with more consistent in vitro and in vivo dissolution release profiles.

[0026] In one embodiment, the sustained release formulation comprises a vitamin D compound and a sustained release component. In another embodiment, such a sustained release formulation is in the form of a spheronized pellet or multiparticulate. In one embodiment, the formulation comprises a spheronized pellet comprising a sustained release component selected from a polymer and / or lipid component. The polymer is selected from a water-insoluble polymer, and can optionally comprise a water-soluble polymer. An active agent, such as calcifediol, can be embedded in the polymer network for sustained release in vivo. In another embodiment, the formulation can be a nano / microparticle formulation, for example, produced by emulsion followed by spray drying / freeze drying, for example, the emulsion-spread-spray / dry-freeze drying technique described herein. In another embodiment, the formulation can be a powder formulation, for example, produced by spray congealing. In another embodiment, the formulation can be a sustained release coating seed. In another embodiment, the formulation can be an active agent-containing granule.

[0027] The formulations and / or dosage forms according to the disclosures herein may be free of waxes. In embodiments, the formulations and / or dosage forms may be free of hydrocarbon waxes. In embodiments, the formulations and / or dosage forms may be free of paraffins. The formulations and / or dosage forms according to the disclosures herein may be free of hydrocarbon oils. In embodiments, the formulations and / or dosage forms may be free of mineral oils. In another aspect, the dosage forms may be free of capsule shells. In embodiments, the dosage forms may be free of soft capsule shells. For example, the formulations and / or dosage forms according to the disclosures herein may be free of hydrocarbon waxes and hydrocarbon oils.

[0028] US Patent Nos. 8,207,149 and 8,361,488 state that previous wax-based formulations provided solid or semi-solid waxy pharmaceutical formulations that releasably bind and controllably release calcifediol in the gastrointestinal (GI) tract. The formulations include a waxy controlled release carrier agent, a lipid agent, an oil vehicle, and a calcifediol compound that provides a formulation that is solid or semi-solid at room temperature and semi-solid or liquid at body temperature. US Patent No. 9,861,644 describes wax-based formulations that are suitable as therapeutic agents and have a long shelf life. These patents state that the lipid agent releases calcifediol in the subject's GI tract, and without intending to be bound by a particular theory of operation, the lipid agent can perform one or more favorable functions, such as creating a microemulsion of the oil vehicle in gastrointestinal fluids; providing prolonged gastric retention, for example, by bioadhesive properties, so that the formulation interacts with the mucosal layer of the stomach and / or intestine; and enhancing the absorption of the calcifediol compound.

[0029] Hard paraffin wax acts as a controlled release agent, producing a solid to semi-solid lipid system at body temperature, producing a formulation that gradually releases the active ingredient during the process of erosion. This wax acts as a rate control agent and is primarily involved in the mechanical erosion mechanism. The gastrointestinal media penetrates the wax, promoting the slow release of calcifediol. Mineral oil is a refined liquid mixture of saturated aliphatic and cyclic hydrocarbons obtained from petroleum. Mineral oil has been used as a vehicle in previous formulations and may also affect the absorption of calcifediol. Hypromellose in the previous formulation acts as a release stabilizer that helps stabilize the release of calcifediol upon rest / stabilization. Hypromellose stabilizes the release characteristics of the previous wax formulation over the intended shelf life of the product. Glycerol Monostearate 40·55 (Type I) is an amphiphilic surfactant that forms mixed micelles with lauroyl macrogol-32 glyceride (Gelucire 44 / 14). Gelucire is formed by the esterification reaction of polar polyethylene glycol (PEG) with non-polar vegetable oils or fatty acids. The primary fatty acids in Gelucire are stearic, palmitic, and lauric, depending on their grade. They are non-ionic, water-soluble, or water-dispersible pure surfactants that solubilize hydrophobic APIs such as vitamin D compounds (e.g., calcifediol) to enhance their oral bioavailability. Gelucire has unique surfactant properties that enhance the solubility and wettability of APIs (e.g., calcifediol) both in vitro and in vivo. Improved in vivo drug solubility enhances absorption and thereby bioavailability. Gelucire acts as an emulsifier / solubilizer, promoting the dissolution of insoluble calcifediol by emulsification and solubilization mechanisms, thereby enhancing the bioavailability of calcifediol. These lipid agents also perform one or more favorable functions, such as creating a microemulsion of the oily vehicle in the gastrointestinal fluids; providing prolonged gastric retention, e.g., through bioadhesive properties, so that the formulation interacts with the mucosal layer of the stomach and / or intestine; and enhancing absorption of the calcifediol compound.Wax formulations are released gradually through mechanical erosion and / or gradual disintegration of the waxy composition. Waxes, and emulsifiers, may aid absorption and may also provide bioadhesion to calcifediol, enhancing its retention in the gastrointestinal tract, allowing it to be absorbed in a more prolonged and systematic manner, enhancing biopharmaceutical parameters.

[0030] The insoluble polymer-based formulations described herein (including pellet versions thereof) release the active agent via diffusion and / or erosion mechanisms. The active agent(s), such as calcifediol, can be embedded in the polymer network. The surface of the formulation (e.g., pellets) forms capillaries through which the gastrointestinal media permeates, facilitating the slow release of the active agent by diffusion through the polymer network of the pellet(s) or other types of doses. In these formulations, medium-chain triglycerides (e.g., Miglyol) act as solubilizers, increasing the solubility of, for example, calcifediol. In the absence of specially selected additional ingredients, there is no microemulsion and no bioadhesive mechanism, as in the case of previous wax-based formulations. The extent and kinetics of disintegration of the wax and polymer may also vary in these two different formulations.

[0031] The formulations and dosage forms, and their associated methods of manufacture, are intended to include embodiments that include any combination of one or more of the additional optional elements, features, and steps further described below (including those shown in the drawings), unless otherwise stated.

[0032] In jurisdictions that prohibit the patenting of methods performed on the human body, the meaning of "administering" a composition to a human subject shall be limited to prescribing a controlled substance for the human subject to self-administer by any technique (e.g., orally, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation consistent with any statute or regulation defining patentable subject matter is intended. In jurisdictions that do not prohibit the patenting of methods performed on the human body, "administering" a composition shall include the acts described above as well as methods performed on the human body.

[0033] As used herein, the term "comprising" indicates that other agents, elements, steps or features may be included in addition to those specified.

[0034] As used herein, the term weight percent refers to parts by weight based on the total weight of what is being described, e.g., by default, based on the total weight of the vitamin D-containing area or based on the total weight of the formulation, where applicable, as stated by context or explicitly.

[0035] As used herein, the terms "controlled release" and "modified release" are used interchangeably and refer to the release of a vitamin D compound in a manner that deviates from immediate release. As used herein, the terms "sustained release," "extended release," and "extended release" are used interchangeably and refer to the release of a vitamin D compound over a longer period of time than a comparable immediate release formulation.

[0036] As used herein, the term "25-hydroxyvitamin D" refers to one or more of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, 25-hydroxyvitamin D4, 25-hydroxyvitamin D5, 25-hydroxyvitamin D7, and combinations thereof. In any embodiment described herein, it is specifically contemplated that 25-hydroxyvitamin D can consist of or include 25-hydroxyvitamin D3, 25-hydroxyvitamin D2, or a combination of 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2. For example, in any embodiment described herein, it is specifically contemplated that 25-hydroxyvitamin D can consist of or include 25-hydroxyvitamin D3. Serum total 25-hydroxyvitamin D refers to the sum of all such 25-hydroxyvitamin D forms measured by assay, unless a specific 25-hydroxyvitamin D form is mentioned.

[0037] As used herein, the term "1,25-dihydroxyvitamin D" refers to one or more of 1,25-dihydroxyvitamin D2, 1,25-dihydroxyvitamin D3, 1,25-dihydroxyvitamin D4, 1,25-dihydroxyvitamin D5, 1,25-dihydroxyvitamin D7, and combinations thereof. For example, 1,25-dihydroxyvitamin D can include 1,25-dihydroxyvitamin D2, 1,25-dihydroxyvitamin D3, or a combination of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3. In any embodiment described herein, it is specifically contemplated that 1,25-dihydroxyvitamin D can consist of or include 1,25-dihydroxyvitamin D3, 1,25-dihydroxyvitamin D2, or a combination of 1,25-dihydroxyvitamin D3 and 1,25-dihydroxyvitamin D2. For example, in any of the embodiments described herein, it is specifically contemplated that 1,25-dihydroxyvitamin D can consist of or include 1,25-hydroxyvitamin D2. Unless a specific 1,25-dihydroxyvitamin D form is referenced, total serum 1,25-dihydroxyvitamin D should be understood to refer to the sum of all such 1,25-dihydroxyvitamin D forms by assay.

[0038] The vitamin D compound may comprise one or more of any desired vitamin D compound, whether natural or synthetic. In certain embodiments, the vitamin D compound may comprise one or more of 25-hydroxyvitamin D compounds, such as 25-hydroxyvitamin D3, 25-hydroxyvitamin D3, or 25-hydroxyvitamin D4. In other embodiments, the vitamin D compound may comprise an active vitamin D compound or analog, such as 1,25-dihydroxyvitamin D2, 1,25-dihydroxyvitamin D3, 1α-hydroxyvitamin D2 (doxercalciferol), paricalcitol, 22-oxacalcitriol, dihydrotachysterol, or 26,26,26,27,27,27-hexafluorocalcitriol (falecalcitriol).

[0039] The vitamin D compound is combined with one or more excipients (eg, via dissolution, mixing, emulsion, or any combination thereof) to form a vitamin D formulation, as described below.

[0040] The concentration of the vitamin D compound in a formulation according to the present disclosure can be any suitable amount. For example, in an embodiment of a formulation according to the present disclosure (e.g., one that includes a water-insoluble polymer as a sustained release reservoir), the concentration of calcifediol ranges from about 0.01% to about 1% by weight, or from about 0.01% to about 0.6% by weight, or from about 0.01% to about 0.3% by weight, or from about 0.03% to about 0.09% by weight, e.g., 0.03% by weight, or 0.06% by weight, or about 0.09% by weight.

[0041] In one embodiment, poly(meth)acrylate polymers, including Eudragit polymers, are contemplated as water-insoluble, swellable polymeric components. These polymers function as sustained release excipients to create sustained release profiles. Two main mechanisms are possible for drug release via Eudragit polymers: drug release can occur by erosion or diffusion. Eudragit polymers are copolymers derived from esters of acrylic and methacrylic acid, whose physicochemical properties are optionally influenced by functional groups. They are mostly available in different physical forms, such as aqueous dispersions, organic solutions, granules, and powders. Eudragit RL and Eudragit RS (CAS number 33434-24-1) are cationic copolymers of ethyl acrylate, methyl methacrylate, and a low content of methacrylic acid esters with quaternary ammonium groups. The copolymers are water insoluble but contain ammonium groups present as salts to make the polymers permeable to water. Eudragit RS has relatively few ammonium groups and is less permeable (poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1), whereas Eudragit RL has relatively more ammonium groups and is more permeable (poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2). Eudragit RS and RL show pH-independent swelling in water. The ratio of Eudragit RS to RL in the formulation can be adjusted to achieve the desired release profile. Powder forms of Eudragit RS and RL can be used, alternative granular forms, aqueous dispersions, and organic solutions (e.g., in acetone and / or alcohol) are available. Other suitable poly(meth)acrylate polymers include Eudragit NE and Eudragit NM (CAS number 9010-88-2), which are neutral ester copolymers based on ethyl acrylate and methyl methacrylate (poly(ethyl acrylate, methyl methacrylate) 2:1).Eudragit NE and Eudragit NM are also permeable to water and exhibit pH-independent swelling in water. In an embodiment of an extrusion-spheronization type formulation according to the present disclosure, the amount of EudragitRL PO is, for example, in the range of about 20% to about 80% by weight, or at least 70% by weight. In one embodiment, the weight percentage is in the range of 40% to 60% by weight of EudragitRL PO in the formulation. Such ingredients are preferably used in an aqueous extrudable wet mass that forms granules, which are then spheronized to form pellets.

[0042] In another embodiment, EC polymers are contemplated as non-swellable, water-insoluble polymeric materials. These polymers also function as sustained release components that delay release or facilitate replicating a target sustained release profile or creating a unique sustained release profile. There are two main mechanisms of drug release through EC polymers: diffusion (concentration-dependent) and erosion. EC is a derivative of cellulose, in which some of the hydroxyl groups of the repeating anhydroglucose units are modified to ethyl ether groups. The physical properties and drug release properties of EC can be influenced by its molecular weight (e.g., indirectly specified by its viscosity), its degree of substitution (ethoxyl content), and particle size. For example, EC is commercially available in three classes of ethoxyl content, called K, N, and T types, which include ethoxyl contents of 44% to 47.9%, 48% to 49.5%, and 49.6% to 51.0%, respectively. Alternatively, they are available in so-called "medium" grades with ethyloxyl contents of 45.0% to 47.0%. In certain embodiments, the EC will have an ethoxyl content ranging from about 48% to about 49.5%. EC viscosity is measured as a 5% solution at 25° C. in a solvent consisting of 80% toluene and 20% ethanol. The viscosity of EC for use in the compositions described herein can range, for example, from about 3 cP to about 50 cP, or from about 3 cP to about 22 cP, or from about 3 cP, about 15.4 cP, or from about 6 cP to about 15.4 cP, or from about 6 cP to about 11 cP, or from about 9 cP to about 15.4 cP, or from about 9 cP to about 11 cP. In other embodiments, the viscosity of EC for use in the compositions described herein can range, for example, from about 18 cP to about 110 cP, or from 18 cP to 22 cP, or from 41 cP to 49 cP, or from 90 cP to 110 cP, or from 18 cP to 49 cP, or from 41 cP to 110 cP. In general, smaller particle sizes solidify more efficiently and result in slower release rates, although porosity control agents can offset this effect.The particle size is not particularly limited, but in certain embodiments, it is contemplated to use an average particle size in the range of more than 40 microns, or from about 40 microns to about 500 microns, or from about 250 to 500 microns, or from about 100 microns to about 400 microns, or from about 200 microns to about 300 microns. Optionally, the particle size can include particles greater than 100 microns, or greater than 140 microns, or greater than 150 microns. For example, the EC can be characterized by a viscosity in the range of 9 to 11 cP, an ethoxyl content of about 48% to 49.5%, and a particle size in the range of about 250 to about 500 microns. A suitable EC is commercially available under the trade name Ethocel Standard 10 Premium. In other embodiments, the ethyl cellulose can have a particle size characterized by a maximum of 150 microns, or 140 microns, or 100 microns. Optionally, the minimum particle size can be 3 microns, 5 microns, or 30 microns. In additional embodiments, the ethylcellulose can be characterized by an average particle size ranging from 5 to 15 microns, or 3 to 5 microns, or 30 to 60 microns. Ethylcellulose products are available from Dow Chemical under the trade name Ethocel, with grades designated, for example, as 4 Premium, 7 Premium, 7 FP Premium, 10 Premium, 10 FP Premium, 20 Premium, 45 Premium, 100 Premium, and 100 FP Premium. In one embodiment according to the present disclosure, the amount of EC ranges, for example, from about 5% to about 60% by weight. In an embodiment of an extrusion-spheronization type formulation according to the present disclosure, the amount of EC ranges, for example, from about 5% to about 60% by weight. Other contemplated ranges include about 1% to about 20% by weight, or about 1% to about 10% by weight, or about 2% to about 10% by weight. These or other EC-based formulations can include a weight percent of lactose monohydrate of about 20% to 50% by weight. Such ingredients can be used in an aqueous extrudable wet mass to form granules, which are then spheronized to form pellets.

[0043] In another embodiment, low-substituted hydroxypropyl cellulose (L-HPC) polymers are contemplated as water-insoluble polymeric materials. L-HPC is a low-substituted hydroxypropyl ether of cellulose, in which only a small portion of the hydroxypropyl groups are replaced by hydroxyl groups of glucose units. Hydroxypropyl cellulose (having a molar substitution of about 3) is soluble in both water and alcohol, whereas L-HPC (having a molar substitution of about 0.2-0.4) swells and is insoluble only in water. Alternatively, the degree of substitution can be characterized by the hydroxypropyl content in the polymer. For example, the hydroxypropyl content can range from about 5% to about 15%, or from about 8% to about 14%, or from about 10% to 12%, or 11%. As with EC, the particle size is not particularly limited, but an average particle size of, for example, 10 microns to 60 microns, or 10 microns to 45 microns, or 10 microns to 30 microns, or 15 microns to 25 microns, or 20 microns is contemplated. In another embodiment, the particle size D90 value can range from about 50 microns to about 200 microns, or from about 50 microns to about 135 microns, or from about 50 microns to about 125 microns, or from about 50 microns to about 100 microns, or from about 60 microns to about 80 microns, or about 70 microns, or less than 100 microns. For example, L-HPC can have a hydroxypropyl content of about 11%, an average particle size of about 20 microns, and a particle size D90 of about 70 microns. A suitable L-HPC is commercially available under the trade name L-HPC LH-31.

[0044] In another aspect, polyvinyl acetate polymer (PVA, CAS number 9003-20-7) is contemplated as the water-insoluble polymeric material. This polymer is also used as a sustained release component in an aqueous extrudable wet mass that can be used to form granules and to form spheronized pellets. In certain embodiments, the insoluble polyvinyl acetate is blended with polyvinylpyrrolidone (PVP, CAS number 9003-39-8), for example, such blends are commercially available under the trade name Kollidon SR. For example, with water-soluble PVP, the PVP is leached out of the composition, leaving pores in the PVA component. For example, PVP can be characterized by a 1% solution viscosity at 25°C ranging from about 20 cP to about 40 cP, or from about 25 cP to about 35 cP. Alternatively, the PVP can have a weight average molecular weight (e.g., by light scattering measurement) ranging from about 7,000 to about 100,000, or from about 25,000 to about 60,000, or from about 40,000 to about 55,000. The ratio of PVA to PVP can be adjusted to affect the release characteristics. For example, the ratio of PVA to PVP can be in the range of about 10:1 to about 1:10, or from about 10:1 to about 1:1, or from about 10:1 to about 2:1, or from about 8:1 to about 2:1, or from about 6:1 to about 2:1, or from about 5:1 to about 3:1, such as about 4:1. The particle size is not particularly limiting, but an average particle size ranging from about 50 microns to about 250 microns is contemplated for certain embodiments. Optionally, the PVA / PVP blend may contain small amounts of sodium lauryl sulfate (SLS, e.g., 0.8% by weight) and colloidal silica (e.g., 0.2% by weight) as stabilizers, e.g., in the form of KOLLIDON SR.

[0045] Drug release from insoluble polymer-based formulations is controlled by both erosion and concentration-dependent diffusion mechanisms (Fickian or non-Fickian) through the channels or capillaries of the polymer formulation in the dissolution medium (e.g., channel / pore formers (e.g., lactose with EC and hydrophilic HPMC with Eudragit polymers). There are various processes that come into play as part of the release mechanism: wetting of the polymer formulation with the medium; penetration of the medium into the polymer formulation; phase transition of the excipients; dissolution of the drug and excipients; and diffusion of the drug and / or excipients out of the dosage form. In some cases, formulations of these insoluble polymers are , ideally remain intact during the drug release process. However, as the medium penetrates the pellet, active pharmaceutical ingredient (API) molecules can diffuse through the polymer network. For swelling polymers, the dimensions of the polymer formulation also increase with dissolution time, whereas for non-swelling polymers they generally remain the same. The dimensions of the polymer formulation form, the distribution of the drug in the polymer formulation, and the content and properties of the polymer formulation (such as wettability and solubility) are important parameters that affect the processes governing drug release. Slightly poorly soluble active ingredients (e.g. calcifediol) have a slow dissolution rate, which delays their release.

[0046] In yet another embodiment, additives such as glyceryl behenate can be used as a sustained release agent. Such compounds are used as thickening or gelling agents and are suitable as sustained release agents, including, for example, glyceryl behenate (e.g., Compritol 888ATO). It can be added at a weight percentage between 5% and 25% by weight, or 5% and 40% by weight in the wet granulation aqueous blend. Higher concentrations are specifically contemplated, for example, when glyceryl behenate is the primary or only sustained release agent.

[0047] The inventors have shown that polymer-based pellet formulations using extrusion and spheronization techniques provide improved 25-hydroxyvitamin D sustained release formulations. Such formulations meet all the necessary criteria for pediatric use, and are also suitable for adult use based on in vitro dissolution data. Extrusion-spheronization process embodiments can provide one or more advantages over other processes: (1) they are more cost-effective compared to the manufacture of coated beads or pellets; (2) they can provide a formulation that is bioequivalent to approved sustained release calcifediol capsules without the need for a coating step; (3) they provide a formulation with consistent and reproducible properties per unit dose; and (4) they provide a formulation with consistent and reproducible in vitro release profile per unit dose and / or per batch (e.g., RSD between dosage forms measured from analysis of six sample sizes at 2, 4, 6, 10, and 12 hour dissolution time points of less than about 16, about 10 or less, or about 8 or less, or about 7 or less, or about 6 or less, or about 5 or less).

[0048] For example, the formulation was designed to be 100% faster than the mean AUC 0-inf The mean AUC after oral administration to humans in the fasted state is 80% to 125% of 0-inf In another embodiment, the formulation can be bioequivalent to approved sustained-release calcifediol (e.g., Rayaldee®) by providing a mean AUC 0-inf The mean AUC after oral administration to humans in the fasted state is 80% to 120% of 0-infIn another embodiment, the formulation can be bioequivalent to an approved sustained release calcifediol by providing a mean Cmax after oral administration to humans in a fasted state that is 80%-125% of the Cmax after oral administration in a fasted state of an approved sustained release calcifediol product. In another embodiment, the formulation can be bioequivalent to an approved sustained release calcifediol by providing a mean Cmax after oral administration to humans in a fasted state that is 80%-120% of the Cmax after oral administration in a fasted state of an approved sustained release calcifediol product. In one embodiment, the fasted state can be defined by fasting for at least 10 hours.

[0049] For example, a formulation according to the disclosure herein can be formulated to provide a mean baseline adjusted value within 80%-125%, or 80%-120%, of one or more of the values ​​set forth in Table 1 below, when administered in a single 900 μg dose to healthy adults in a fasted state and measured over a 650 hour period. [Table 1]

[0050] In another embodiment, the formulations disclosed herein can be formulated to provide an average baseline adjusted value within 80%-125%, or 80%-120%, of one or more of the values ​​set forth in Table 2 below, when administered at a dose of 30 μg to healthy adults in a fasted state and measured over a 650 hour period. [Table 2]

[0051] In another embodiment, the formulations disclosed herein can be administered to stage 3 or stage 4 CKD patients in a fasted state according to the dosages set forth in the table and formulated to provide a mean baseline adjusted value within 80%-125%, or 80%-120%, of one or more of the values ​​set forth in Table 3 below, when measured after a 6 week period after initiation of administration. [Table 3]

[0052] Such spheronized pellets produced from the aqueous-based wet granulation process described herein can also have other components of the granulation blend including absorption enhancers, diluents and spheronization aids, pore formers, binders, additional sustained release agents, binding aids, fillers and water.

[0053] In another class of embodiments, one or more fatty acid glycerides, such as glyceryl behenate, are contemplated as the water-insoluble material. Glyceryl behenate is a mixture of glycerides of fatty acids, primarily behenic acid (e.g., at least 50% or at least 80% behenic acid). In certain embodiments, the 1-monoglyceride content can be limited to a range of 12.0-18.0%. In another class of embodiments, the glycerides can be characterized as a hydrophobic mixture of mono- (12-18% w / w), di- (45-54% w / w), and tri- (28-32% w / w) behenates of glycerol with a melting point in the range of 69-74°C and a hydrophilic lipophilic balance (HLB) of about 2. In another embodiment, the glyceride can be characterized as a mixture of diacylglycerols (40-60% w / w), monoacylglycerols (13-21% w / w), and triacylglycerols (21-35% w / w).A suitable glyceryl behenate is commercially available under the trade name Compritol 888 ATO.

[0054] In another embodiment, the water-insoluble formulation can be based on one or more water-insoluble polymeric materials and can optionally include a smaller amount of fatty acid glycerides. In another embodiment, the water-insoluble formulation can be based on fatty acid glycerides and can include a smaller amount of one or more water-insoluble polymeric materials.

[0055] In certain embodiments, the water-insoluble polymeric material is the major material in the formulation, e.g., present in an amount of at least 40% by weight, or at least 50% by weight, or in a range of 40% to 90% by weight, or about 40% to about 80% by weight, or about 40% to about 70% by weight, or about 40% to about 60% by weight, or about 40% to about 50% by weight. For example, certain polymer formulations can include about 50% to about 60% by weight, or about 55% by weight of poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 (e.g., Eudragit RL). As another example, the formulation can include a blend including about 40% to about 50% by weight of Eudragit RL polymer in combination with a minor amount (e.g., 1% to about 10% by weight) of one or more other water-insoluble polymeric materials, e.g., L-HPC as described herein, or EC as described herein, or a combination thereof.

[0056] In another type of embodiment, for example when the water-insoluble polymer has a relatively low permeability, the water-insoluble polymeric material is not the major material in the composition. For example, the water-insoluble polymeric material can be included in an amount of 1% to about 40% by weight, or about 1% to about 30% by weight, or 1% to about 20% by weight, or about 1% to about 10% by weight, or about 2% to about 10% by weight, or about 3% to about 8% by weight, or about 5% by weight. The composition can further include a release modifier, for example a pore-forming agent.

[0057] The formulations may optionally include one or more additional functional additives, including, but not limited to, release modifiers (including pore formers), absorption enhancers, fillers (also called diluents), binders (including dry binders), spheronization aids, flavorings, and lubricants.

[0058] For example, excipients useful for the spheronized pellets described herein include absorption enhancers such as Miglyol 812N; diluents and spheronization aids such as MCC (Avicel PH 101); diluents and pore formers such as lactose monohydrate or HPMC; compression / gelling / slow release agents such as glyceryl behenate (Compritol 888 ATO, with a melting range of 65°C to 77°C and an HLB of 2); sustained release matrix formers / extrusion and spheronization aids such as low-substituted hydroxypropylcellulose (L-HPC LH-31); binding aids such as Methocel K3 Premium LV; lubricants such as talc powder or glyceryl behenate; flavorings such as caramel; and purified water as a process diluent (e.g., to dissolve the binder). The diluents and / or spheronization aids can be present in concentrations of about 30% to about 90% by weight. The absorption enhancer may be present at a concentration of about 3% to about 10% by weight. The binding aid, such as Methocel K3, may be present at a concentration of about 5% to about 10% by weight. The lubricant, such as talc, may be present at a weight concentration of about 1% to about 2% by weight. The concentration of the sustained release matrix former / extrusion and spheronization aid, such as L-HPC LH-31, may range from about 5% to 25% by weight.

[0059] The release modifier may include hydrocolloids, pore formers, and disintegrants. Pore formers include, for example, sugars (e.g., lactose, sucrose), sugar alcohols (e.g., mannitol), water-soluble salts (sodium chloride), and water-soluble polymers (polyethylene glycol, PVP, hypromellose, methylcellulose). In certain embodiments, EC can be used as a water-insoluble polymer (e.g., 1-10% by weight, or 5% by weight), and pore formers, such as lactose monohydrate, can be used in relatively large amounts (e.g., 20% by weight to 40% by weight). Other examples include about 25% by weight, about 30% by weight, and about 35% by weight.

[0060] The composition may optionally include an absorption enhancer. Examples of suitable absorption enhancers include, but are not limited to, caprylocaproyl macrogol glycerides, such as polyethylene glycosylated glycerides, also known as polyglycolized glycerides or PEGylated glycerides. PEGylated glycerides that may be used in the composition include, but are not limited to, mixtures of monoglycerides, diglycerides, and triglycerides, as well as monoesters and diesters of polyethylene glycol, polyethylene glycosylated almond glycerides, polyethylene glycosylated corn glycerides, and polyethylene glycosylated caprylic / capric triglycerides. The absorption enhancer may have an HLB value of 11-18, or 13-18, or 13-16, or 13-15, or 11-12.

[0061] One preferred absorption enhancer is known under the trade name GELUCIRE (Gattefosse Corporation, Paramus, New Jersey, USA). GELUCIRE is a well-known excipient belonging to the family of fatty acid esters of glycerol and PEG esters, also known as polyglycolized glycerides. GELUCIRE is used in a variety of applications, including the preparation of sustained release pharmaceutical compositions. GELUCIRE compounds are inert, semi-solid, waxy materials that are amphiphilic and available with a variety of physical properties, such as melting point, HLB, solubility in various solvents, etc. They are surface active in nature and disperse or solubilize in aqueous media to form micelles, microscopic globules or vesicles. They are specified by their melting point / HLB value. The melting point is expressed in degrees Celsius. One or a mixture of different grades of GELUCIRE excipients can be selected to achieve the desired properties of melting point and / or HLB value. One GELUCIRE composition is GELUCIRE 44 / 14, a mixture of lauroyl macrogol glycerides and lauroyl polyoxyglycerides, with a melting point of 44° C. and an HLB of 11. Another GELUCIRE composition is GELUCIRE 48 / 16, also known as PEG-32-stearate, also known as PEG 32 mono- and diesters of stearic and palmitic acids, which has a nominal melting point of 48° C. (range of 46° C. to 50° C.) and an HLB of 12. Another polyglycosylated glyceride absorption enhancer is caprylocaproyl macrogol-8-glyceride (CAS numbers 85536-07-8 and 84963-88-2). It is a mixture of mono-, di-, and triesters of glycerol and PEG 400 with medium chain fatty acids (C8-C10) and is sold, for example, under the trade name LABRASOL® by Gattefosse Corporation, Paramus, New Jersey, USA.LABRASOL has an HLB value of 14 and the following weight composition: about 4% C8-C10 monoglycerides, about 17% C8-C10 diglycerides, about 6% C8-C10 triglycerides, about 14% C8-C10 monoesters of PEG 400, about 36% C8-C10 diesters of PEG 400, about 20% free PEG 400, and about 3% free glycerol. Another type of absorption enhancer is a triglyceride, such as a medium chain triglyceride. For example, a mixture of C8-C10 triglycerides can be used. In certain embodiments, the C8-C10 triglycerides can include about 50-65% caprylic triglyceride and about 30-45% capric triglyceride. A suitable triglyceride is commercially available under the trade name Miglyol 812N. The absorption enhancer can be present in any suitable amount, for example, about 1% to about 20% by weight, or about 1% to about 15% by weight, or about 1% to about 10% by weight, or about 3% to about 10% by weight, or about 5% to about 10% by weight, or about 3% to about 5% by weight. Other examples include about 3% by weight, about 5% by weight, and about 10% by weight. Optionally, when the formulation includes a hydrophilic excipient, e.g., a release aid, having an HLB of more than 10, e.g., in the range of 11-18, or 13-18, it also includes a lipophilic excipient, e.g., having an HLB of less than 10, e.g., 1-6, or 1-3, or 3-6.

[0062] The formulation may also include one or more fillers, also referred to as diluents. Fillers include, but are not limited to, for example, lactose, saccharose, glucose, starch, microcrystalline cellulose (MCC), microfine cellulose, mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate, amorphous silica, sodium chloride, starch, and dibasic calcium phosphate dihydrate. In certain embodiments, the filler may absorb water but is not water-soluble. As mentioned above, when mixed with other ingredients (e.g., water-insoluble polymers), the filler can function as a pore former. In certain embodiments, the filler is a spheronization aid. The spheronization aid may include, for example, one or more of crospovidone, carrageenan, chitosan, pectic acid, glycerides, β-CD, cellulose derivatives, MCC, powdered cellulose, polyplasdone crospovidone, and polyethylene oxide. In one embodiment, the filler or spheronization aid includes MCC. The MCC can have any suitable particle size, for example, an average particle size ranging from about 10 microns to about 200 microns, or from about 20 microns to about 100 microns, or about 20 microns, or about 50 microns, or about 100 microns. The MCC can be characterized, for example, by a crystallinity ranging from about 60% to about 80%. Suitable commercially available MCCs are available, for example, under the trade name AVICEL in PH grades 101, 102, 104, 105, 112, 113, 200, 200 LM, 301, and 302. In one embodiment, the MCC is AVICEL PH 101. In another embodiment, the MCC is AVICEL PH 201.

[0063] The amount of the filler is not particularly limited, and may be, for example, at least about 1% by weight, or 5% by weight, or 10% by weight, or 20% by weight, or 30% by weight, or 40% by weight, or 50% by weight, or 60% by weight, or 70% by weight, or 80% by weight, and up to about 95% by weight, or about 90% by weight, or about 80% by weight, or about 70% by weight, or about 60% by weight, or about 50% by weight, or about 40% by weight, or about 30% by weight, or a range formed from any of the above values. For example, the filler may be within the range of, for example, about 1% by weight to about 95% by weight, or 30% by weight to about 85% by weight, or about 70% by weight to about 90% by weight. The spheronization aid may be included in such a range, or, for example, about 35% by weight to about 60% by weight, or about 35% by weight to about 40% by weight, or about 40% by weight to about 60% by weight.

[0064] The formulation may include one or more binders, including dry binders. Binders include, for example, relatively low viscosity hydrophilic cellulose ethers, and PVP. In other embodiments, the binders may include carboxymethylcellulose, starch, pregelatinized starch, acacia, tragacanth, gelatin, sodium alginate, low substituted hydroxypropylcellulose, and the lowest viscosity grades of hydroxypropylmethylcellulose (HPMC). For example, the binder may be selected from low viscosity hypromellose, e.g., having an aqueous viscosity of 2% ranging from about 2 to about 6 cP, or about 2 to about 4 cP, or about 2.4 to about 3.6 cP at 20°C. A suitable low viscosity hydroxypropylmethylcellulose is commercially available under the trade name Methocel K3 Premium LV. For example, the hypromellose may have a methoxyl% ranging from about 19 to about 30, or about 19 to about 24, or about 25 to about 35, or about 28 to 30. For example, the hypromellose can have a hydroxypropyl % of from about 5 to about 15, or from about 7 to about 12.

[0065] Pharmaceutically acceptable lubricants are known in the art and may include, but are not limited to, stearic acid, magnesium stearate, calcium stearate, aluminum stearate, talc, and siliconized talc. In certain embodiments, the lubricant is talc. Small amounts of lubricants, such as about 0.1% to about 5% by weight, or about 0.5% to about 3% by weight, such as 0.5%, 0.7%, 1%, 1.5%, or 2% by weight, may often be used.

[0066] The formulation can optionally include a topcoat or overcoat to adjust the release profile. For example, a topcoat can be used to delay or slow the release for the first few hours after administration, for example to counteract an initial burst release or to otherwise slow an initial release that is more rapid than desired. Suitable topcoat materials include, for example, film-forming polymers. Topcoat materials can be water-soluble, for example, water-soluble polymers as described herein (e.g., hypromellose, PVP), or water-swellable polymers that further include a pore-forming agent (e.g., EC as described herein with a pore-forming agent, e.g., hypromellose). The topcoat can optionally include a lubricant, for example, talc. A suitable EC topcoat material is commercially available under the trade name SURELEASE, which is sold as an aqueous emulsion dispersion of plasticized EC. A suitable hypromellose pore former can have a 2% solution viscosity of about 3 cP at 20° C., a methoxyl % ranging from about 19 to about 30, or from about 19 to about 24, or from about 25 to about 35, or from about 28 to 30, and a hydroxypropyl % ranging from about 5 to about 15, or from about 7 to about 12. For example, the hypromellose can be that commercially available as PHARMACOAT 603. The ratio of the topcoat material, e.g., EC, to the pore former, e.g., hypromellose, can be adjusted to provide a desired release profile, and can range, e.g., from 80:20 to 20:80, or from 70:30 to 30:70, or from 60:40 to 40:60, e.g., 65:45, or 60:40, or 55:45, or 50:50. Similarly, the amount of topcoat can be adjusted to provide a desired release profile. The amount of topcoat material applied can be measured, for example, as the weight gain of the formulation particles when the topcoat is sprayed onto the particles. For example, the amount of topcoat on the formulation particles can range from about 1% to about 40% by weight, or 1% to about 30% by weight, or about 5% to about 25% by weight, e.g., 10% by weight, or 15% by weight, 20% by weight, or 25% by weight.Alternative coating materials that provide delayed release include enteric coating materials, such as those that provide release based on the pH of the gastrointestinal medium. Examples of such materials include shellac (esters of allergenic acids), cellulose acetate phthalate, poly(methacrylic acid-co-methyl methacrylate), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), and hydroxypropyl methylcellulose phthalate (HPMCP).

[0067] An alternative process for producing pediatric formulations according to the present invention includes the preparation and use of nano / microparticles.Nano / microparticles are colloidal carriers that have been shown to offer great potential in oral drug administration.In this type of embodiment, vitamin D compounds (e.g., calcifediol) can be encapsulated in a liquid oily core surrounded by a solid shell material of sustained release polymer.

[0068] Sustained release nano / microparticles can be prepared using emulsion-diffusion-spray drying / freeze drying techniques. For APIs with low water solubility (e.g. calcifediol), single emulsion techniques are more desirable.

[0069] The emulsion can be converted into a powder formulation using freeze-drying or spray-drying techniques. The solvent blend for homogenization to create the emulsion can include a discontinuous phase solvent, such as ethyl acetate, and a continuous solvent, such as water. The final formulation of the sustained release particles can be presented as an aqueous suspension, a non-aqueous suspension (e.g., with triglycerides, such as fatty acid triglycerides), or in the form of sprinkles in a sachet.

[0070] For example, Eudragit RL PO can be used as the sustained release polymer and poly(vinyl alcohol) can be used as the emulsion stabilizer. For example, the amount of Eudragit to stabilizer can be, for example, about 80:1 to about 5:1, or about 50:1 to about 5:1, or about 40:1 to 10:1, or about, 30:1 to 20:1, or 25:1. The weight percentage of the sustained release polymer can broadly range from 0.5% to 98% by weight, and in some embodiments, can range, for example, from 75% to about 98% by weight. The amount of polymer (e.g., Eudragit and poly(vinyl alcohol)) to API can range, for example, from about 80:1 to about 5:1, or about 50:1 to about 5:1, or about 40:1 to 10:1, or about 30:1 to 20:1, or 25:1 weight ratio. Alternatively, EC or other sustained release polymers as described herein can be used as the solid shell material. The release profile can be altered by varying the sustained release polymer type and ratio of polymer to produce a sustained release profile that matches the target profile of previous wax-based calcifediol systems, for example. Examples of various formulation approaches are shown in Table 4 below. [Table 4]

[0071] The sequential method of performing the approaches is described below in Table 5. It will be understood by one of skill in the art that this sequence is representative and not limiting. [Table 5]

[0072] Processing and product parameters may be varied and may include inlet temperature, suction percentage, column airflow, cyclone size, homogenization speed and conditions, polymer solvent concentration, discontinuous to continuous phase ratio to provide acceptable product yields.

[0073] In addition to wet granulation / pellet formation and spray-dried emulsion, spray congealing is an alternative processing approach for producing formulations according to the present disclosure, including sustained release formulations of vitamin D compounds such as calcifediol. If desired, the process may be solvent-free. Hot melt processing may include, for example, spray cooling / solidification to obtain small particle sizes. Spray cooling, also called spray congealing or spray quenching, is a process of converting a melt into well-defined, e.g., spherical, particles. This process uses spray drying techniques with a rapid cooling process. It can produce free-flowing lipid microparticles, for example, in the size range of about 10 microns to 1000 microns. For example, a hot melt mixture of lipid, API (e.g., calcifediol), and optional surfactant can be sprayed into the column to produce a fine mist of particles while cold nitrogen gas is circulated through the column or other vessel. The particles can be optionally coated with a topcoat of sustained release polymer and pore former.

[0074] Lipids that are solid or semi-solid at room temperature can be used as sustained release aids, and surfactants can be used to aid in the solubility and complete release of the API. Such lipids include, but are not limited to, one or more of paraffin, glycerol monostearate (Geleol 40-55), Gelucire (e.g., grades 44 / 14, 43 / 01 (CAS number 157710-38-8)), glyceryl distearate / palmitostearate (e.g., Precirol ATO 5, melting range 50°C-60°C, HLB is 2), and glyceryl dibehenate (e.g., Compritol 888 ATO). Gelucire 43 / 01 is a hydrophobic lipid with an HLB value of 1 and a melting point of 43°C. It is a blend of saturated triglycerides of different fatty acids: C8-3%, C10-2%, C12-29%, C14-2%, C16-17%, and C18-36%. Gelucire 43 / 01 can also be used in combination with other grades of Gelucire to tailor drug release for oral administration. Other lipids can be selected from mixtures of mono-, di-, and tri-acylglycerols of fatty acids selected from palmitic acid, tallow acid, stearic acid, oleic acid, linoleic acid, linoleic acid, arachidic acid, behenic acid, erucic acid, and combinations thereof, such as palmitic acid and stearic acid. Surfactants include, but are not limited to, one or more PEGs (e.g., PEG 6000) and Tweens (e.g., Tween 80).

[0075] The spray solidification can be produced using a suitable spray solidification unit in a closed loop setup (e.g., supplied by Buchi, Flawil, Switzerland; GEA Group, Dusseldorf, Germany; or ProCepT NV, Zelzate, Belgium). A chiller can be used to cool the gas in the column. Nitrogen gas can be used throughout the system to bring the temperature in the system below 0°C. The temperature of the melt can be kept as low as possible. The melt can be atomized using a heated two-fluid nozzle. The product can be introduced by a pressure vessel. Example process parameters are shown in Table 6 below. [Table 6]

[0076] The active agent-containing formulation can be prepared in any suitable form. The drug-containing formulation can occupy the entire dosage form or can be a region of the dosage form, for example as a core or as a coating (e.g., on an inert seed core such as a nonpareil). In certain embodiments, the formulation is in particulate form, optionally topcoated. The particles can be of any size or shape, for example pellets or mini tablets. In another type of embodiment, the active agent-containing particles are made and then compressed, for example, into pill, tablet, or dragee form. In another type of embodiment, the active agent-containing particles (optionally coated) are filled into capsule shells, pouches, or sachets to obtain a multiparticulate dosage form. Multiparticulates (dosage forms made of multiple particulate units, for example pellets or mini tablets) provide an increased surface area in contrast to monolithic matrix tablets, allowing for better release profiles and bioavailability. Unlike monolithic matrix tablets, multiparticulates are spread evenly throughout the gastrointestinal tract. Multiparticulates are less susceptible to over-release and their therapeutic effect is more predictable and reproducible than monolithic reservoir type (matrix) formulations. Pellets reduce the possibility of burst effects compared to matrix tablets and minimize inter- and intra-individual variability in the gastrointestinal tract. Multiparticulates also have a lower risk of local irritation compared to single unit matrix tablets due to the minute amount of drug they carry. For monolithic matrix tablets, the rate of gastrointestinal transit is highly dependent on the rate of gastric emptying and gastrointestinal motility, whereas multiparticulates (egg pellets), due to their relatively small size, achieve a reproducible rate of gastrointestinal transit, thus minimizing inter- and intra-subject variability compared to single unit formulations. Other advantages of multiparticulates such as pellets over monolithic matrix tablets include: providing superior flow properties, high loading ratio, low friability; flexibility to provide different drug substances requiring different release patterns that can be combined in a single dosage unit; and flexibility in adjusting the dose by increasing or decreasing the amount of pellets, unlike monolithic matrix tablets.

[0077] The capsule shell may optionally be a HMPC shell or a hard gelatin shell. In another type of embodiment, the granules prepared from aqueous-based wet granulation may be directly compressed into tablets or micro- or mini-tablets, which may or may not be coated.

[0078] In one type of particulate form, the particle size (diameter) ranges from about 0.2 mm to about 2.8 mm, or from about 0.2 mm to about 2.5 mm, or from about 0.2 mm to about 2.0 mm, or from about 0.7 mm to about 2.5 mm, or from about 0.7 mm to about 2.8 mm, or from about 0.5 mm to about 2.8 mm, or from about 0.8 mm to about 1.7 mm, or from about 0.5 mm to about 1.2 mm, or from about 0.5 mm to about 1.0 mm. For example, the target particle size may be up to 2.5 mm, with a variation of 10% or less on this size, with a maximum size of 2.8 mm. The particles can be sorted into the desired size range by sieving according to known methods. The formulation can also be characterized by an average particle size in any of the aforementioned ranges or amounts. If the particle size becomes too large, the particles are too large for use in pharmaceuticals that are indicated to be administered by sprinkling onto a substrate (e.g., onto applesauce or other soft foods such as jelly) and swallowed without chewing, or administered via an enteral feeding tube. In another type of dosage form and associated administration method, the multiparticulates disclosed herein can be dispersed in a suspension base and administered as a powder for oral suspension. The suspension base can include, for example, purified water, and can optionally include one or more excipients. The suspension base can include, for example, at least 50% water by weight, more than about 50% water by weight, at least about 80% water by weight, at least about 90% water by weight, at least about 95% water by weight, at least about 99% water by weight, or 100% water by weight. The suspension base can be, for example, a sugar-based syrup. The suspension base can optionally include a suspending agent or thickening agent. Suitable suspension and thickening agents include, for example, methylcellulose, starch, xanthan gum, and glycerin. In another embodiment, the suspending base is non-aqueous, for example, containing or consisting of a triglyceride.

[0079] For sprinkle-type dosage forms, a narrow particle size distribution below 1.0 mm, optionally below 0.5 mm in size, is desirable to avoid grittiness and unpleasant mouthfeel in infants.Sugar spheres are preferred over MCC spheres because the sweet taste of sugar also acts as a taste masking aid.

[0080] As another alternative, a layered formulation is contemplated. This type of formulation includes a starter seed (e.g., nonpareil seed) with a layer of vitamin D compound, which further has a seal coating (e.g., low viscosity hypromellose) to smooth the surface of the seed after API layer / coating and also achieve uniform coating(s) in subsequent steps. On top of the seal coating is a sustained release polymer coating (e.g., a water-insoluble polymer with a pore-forming agent as described herein). This embodiment can further include an optional taste masking coating and an additional optional seal coating on top of the sustained release polymer coating and under the taste masking coating, if desired.

[0081] In one type of approach, for example, seeds (aka pellets or spheroids) can be made using one or more process techniques including extrusion with spheronization, rotating fluidized bed processing, and spray congealing. The seeds can optionally have the API within the seed itself, for example, in the range of 0.01% to 10% by weight of the seed. These seeds are coated with one or more coating layers, for example, using fluidized bed processing using Wurster coating technology. For example, the seeds can have a first seal coating in the range of 1% to 5% by weight based on the weight of the seed and a functional release coating in the range of 3% to 50% by weight based on the weight of the seed. For example, there can be an optional second seal coating in the range of 1% to 5% by weight based on the weight of the seed and a second functional release coating in the range of 3% to 50% by weight based on the weight of the seed. Following the optional second functional release coating, there can be a third optional seal coating, for example, in the range of 1% to 5% by weight based on the weight of the seed. The formulation may also include an aesthetic (non-functional) coating, for example in the range of 1% to 5% by weight based on the weight of the seed.

[0082] In another type of approach, inert nonpareil seeds can be used to be coated with different layers, for example, using fluidized bed processing using Wurster coating technology, to achieve the desired release profile. In this approach, inert nonpareil seeds can be selected with a particular size average or range, for example, in the range of 150 μm to 1000 μm. A drug loaded layer is made on the seeds, for example, with a loading of 0.01% to 10% by weight of the seeds. These seeds are coated with one or more coating layers, for example, using fluidized bed processing using Wurster coating technology. For example, the drug coated seeds can have a first seal coating in the range of 1% to 5% by weight based on the weight of the seeds and a functional release coating in the range of 3% to 50% by weight based on the weight of the seeds. There can be an optional second seal coating, for example, in the range of 1% to 5% by weight based on the weight of the seeds, and a second functional release coating, for example, in the range of 3% to 50% by weight based on the weight of the seeds. Following the optional second functional release coating, there may be a third optional seal coating, for example in the range of 1% to 5% by weight based on the weight of the seed. The formulation may also include an aesthetic (non-functional) coating, for example in the range of 1% to 5% by weight based on the weight of the seed.

[0083] The excipients of the seed and coating materials may be selected from those known in the art, including those described herein. For example, the nonpareil seed materials may be selected from microcrystalline cellulose, silicon dioxide, mannitol, other sugars, and combinations thereof. The functional coating excipients may be selected from cellulosics, HPMC, ethylcellulose, waxes, glyceryl monostearate, acrylic polymers (including Eudragit), and combinations thereof. The seal coating excipients may be selected from cellulosics, such as HMPC. The pore formers may be selected from cellulose, HMPC, and lactose. The plasticizers may be used for the seal, functional, and aesthetic coatings, and may be selected from, for example, dibutyl sebacate, triethyl citrate, and PEG. The aesthetic coating materials may be selected from commercially available coating products, such as hypromellose, polyvinyl alcohol, and Opadry® coatings. The coatings may be applied as aqueous or non-aqueous solutions.

[0084] The final dosage form can contain any desired amount of vitamin D compound in a unit dose. For example, the capsule shell can be filled with sufficient formulation material, such as granules, particles, or pellets, to obtain a dosage form having an amount of calcifediol ranging from about 1 μg to about 1 g, or about 10 μg to about 600 μg, or about 10 μg to about 300 μg, or about 10 μg to about 100 μg, or about 30 μg to about 90 μg, for example, 30 μg or about 60 μg or about 90 μg. Dosage forms other than capsules, such as sachets, pills, or tablets, can have the same or similar strength. Dosage forms including granules, pellets, sachets, capsules, etc. can be stored with a desiccant.

[0085] As described below in connection with the Examples, various exemplary dosage forms (e.g., EC-based formulations) have demonstrated in vivo exposure characteristics that differ from the currently approved Rayaldee® sustained release calcifediol capsule product. The administration of such products could be scaled based on their in vivo exposure characteristics (e.g., based on AUC(0-inf) compared to Rayaldee® sustained release capsules, or based on AUC(0-t) compared to Rayaldee® sustained release capsules). For example, the pellets of Example 9 could have a dose of 60mcg calcifediol instead of the 30mcg Rayaldee® sustained release capsules.

[0086] In principle, the formulations described herein can be characterized by any sustained release profile.

[0087] In certain embodiments, the target dissolution profile of a formulation according to the present disclosure may be within the specification limits of the in vitro dissolution profile of a sustained release 25-hydroxyvitamin D capsule (30 mg) in a lipophilic wax matrix formulation (Table 7), e.g., Rayaldee®. Specification limits may be applied based on the dissolution of individual units. For example, ≦30% of the label claim dissolves in 2 hours, 53-78% of the label claim dissolves in 6 hours, and ≧80% of the label claim dissolves in 12 hours. Solubility may be measured, for example, using the following dissolution method: [Table 7]

[0088] Figure 1 shows comparative in vitro dissolution release profiles of such 30 μg dosage forms, representative of 52 commercial batches. The results are grouped into relatively "slow," "medium," and "fast" release profiles. Relative standard deviations were evaluated across all dissolution release profiles. [Table 8]

[0089] The delta (Δ) between A and C at a given time point was about 3% at 2 hours, 11% at 4 hours, 15% at 6 hours, 13% at 8 hours, 8% at 10 hours, and 3% at 12 hours. The formulations of the present invention can be designed to be essentially comparable to any one of formulations A, B, or C, or a combination thereof (e.g., the average of any two, or the average of all three, A, B, and C). For example, the formulations can be characterized by in vitro dissolution release values ​​that are about 14% to about 18% at 2 hours; or about 36% to about 48% at 4 hours; or about 56% to about 73% at 6 hours; or about 74% to about 88% at 8 hours; or about 89% to about 100% at 10 hours; or about 97% to at least 100% at 12 hours, or any combination thereof, e.g., have a dissolution release profile characterized by a combination of all such time points. In another embodiment, the formulation is characterized by an in vitro dissolution release profile with less than 20% release of active agent in 2 hours, 35%-45% in 4 hours, 55%-80% in 6 hours, 65%-85% in 8 hours, 85% to at least 100% in 10 hours, and 90% or more (e.g., 90%-110%) in 12 hours. In another embodiment, the formulation is characterized by an in vitro dissolution release profile with 14-18% release in 2 hours, 36%-45% in 4 hours, 55%-69% in 6 hours, 74%-88% in 8 hours, 89% to at least 100% in 10 hours, and 97% or more (e.g., 97%-110%) in 12 hours.

[0090] Alternatively, formulations according to the disclosure herein can be made to create unique or customized sustained release dissolution profiles. Formulations according to the disclosure herein can also be made to have in vitro dissolution profiles per unit dose with limited intra-batch or inter-batch variability. For example, dissolution profiles can be measured using USP apparatus II (paddle with sinker) at 75 RPM in a medium of 0.5% SDS in 5 mM sodium dihydrogen phosphate monohydrate, pH 6.8, 37±0.5°C, and 500 mL volume. In one embodiment, variability can be expressed as RSD (%) at any dissolution time point of 2 hours or more, as measured from six dosage forms. For example, the RSD can be the dissolution dictionaries of 2, 4, 6, 8, 10, and 12 hours. In another embodiment, the RSD can be the dissolution time points of 4, 6, 8, 10, and 12 hours. In another embodiment, the RSD can be the dissolution time points of 2, 6, and 12 hours. For example, as shown in the Examples below, such RSD values ​​may be less than 16%, or 10% or less, or 8% or less, or 6% or less, or 5% or less.

[0091] Methods for preparing formulations and final dosage forms according to the disclosure herein are also contemplated. Formulations containing vitamin D compounds can be made by any suitable process, including, but not limited to, direct compression, granulation, extrusion, fluidized bed coating, or any combination thereof.

[0092] Such processes include aqueous-based extrusion / spheronization to produce granules / pellets suitable for sustained release formulations containing vitamin D compounds (e.g., 25-hydroxyvitamin D or calcifediol), coating processes to coat seeds or active substance-containing granules, and processes to produce vitamin D sustained release formulations from nanoparticles or microparticles. One embodiment of a process for producing a suitable pediatric vitamin D formulation in which the active substance is 25-hydroxyvitamin D or calcifediol includes aqueous-based extrusion / spheronization to form multiparticulate granules / pellets that may be coated or uncoated. Suitable controlled release polymers for use in the preparation of such granules can be selected, for example, from Eudragit RL PO, Eudragit RS PO, EC, L-HPC, LH-31, Compritol 888 ATO, and Kollidon SR. In one embodiment, other excipients including binders and / or absorption enhancers, lipid agents, diluents, spheronization aids, flavoring agents, and pore formers can be used in aqueous-based extruded granule formulations. In certain embodiments, the pellets are easily made from the extrudable aqueous-based formulation without the need for additional coating(s) to achieve targeted sustained release in vitro and in vivo profiles. Such a process may include (1) forming an aqueous-based extrudable mass containing active and inactive excipients, (2) extruding such mass to form active-containing granules, (3) spheronizing the granules to form pellets, and (4) drying the pellets. The dried pellets can be optionally coated with a lubricant and / or flavoring, e.g., talc and flavoring. More specifically, the process may include wetting a powder mixture of API and excipients, forming an extrudate by extrusion, milling and rounding the extrudate by spheronization, and drying the finished pellets. The pellets can have a size ranging from, for example, 200 μm to 2 mm in diameter. The aqueous-based formulation used to form the wet extrudable mass may contain a significant proportion of water (wt / wt).The percentage of water may range from 10% to 90% by weight, or at least 50% by weight. The granules produced by this process (aqueous vs. non-aqueous) have the necessary strength and integrity to provide workable, extrudable, and functional spheronized pellets. The pellets may be referred to as beads or spheroids. The enhanced properties may include one or more properties including: optimal flow properties; reproducible presentation into capsules or other drug delivery vehicles; optimal density / hardness properties for handling, and coating if necessary; improved hardness and friability (e.g., 1.0 percent or less); and more consistent batch-to-batch in vitro and in vivo drug delivery and release profiles. The pellets may provide one or more of the following advantages: improved drug absorption, minimized overdose release, reduced peak plasma fluctuations, and minimized side effects by dispersing freely in the gastrointestinal tract; avoiding high local concentrations of API in the gastrointestinal tract; reducing processing steps, e.g., by avoiding the use of coatings; improving flow properties, e.g., for capsule or sachet filling; providing narrow particle size distribution; and providing uniform packing properties.

[0093] In one embodiment, the formulation is formed by granulating a mixture of the vitamin D compound with a material (e.g., a water-insoluble polymer) and one or more other optional excipients, and optionally fine-tuning the formulation process to a desired particle size range, for example, by extrusion parameters and / or optionally in combination with one or more steps including sieving, fractional sieving, and milling. In another embodiment, the formulation can be formed by extrusion and spheronization of a mixture of the vitamin D compound with a material (e.g., a water-insoluble polymer) and one or more other optional excipients described herein. For example, an extruder can be fitted with an extrusion screen of the desired size, for example, 0.1 mm to 5 mm, or 0.5 mm to 2 mm. Additionally or alternatively, a spheronizer can be fitted with plates of the desired dimensions and configuration, for example, 0.1 to 5 mm crosshatch plates, or 0.5 to 2 mm crosshatch plates. Granulation processes can include, for example, fluid bed granulation, wet granulation, hot melt granulation, and spray congealing. Other processes include slugging and roller compaction. As is commonly known in the art, the mixture to be granulated can first be dry blended. The dry blended dry ingredients can be mixed with water prior to extrusion.

[0094] For example, in one embodiment of the method for producing spheronized pellets, the dry ingredients are combined with about 50% to 80% water by weight, blended and mixed, and wet granulated to form a wet extrudable mass. The extrudable mass of ingredients combined in a weight ratio selected depending on the sustained release polymer(s) and excipients is blended, extruded, spheronized, and dried to form the desired pellets for use in the pediatric or adult formulation(s). For example, a mixture of calcifediol and triglyceride can be added to a premixed blend of dry excipients, and then a binder solution can be added to prepare a wet mass for extrusion. Drying can be performed, for example, by tray drying, vacuum drying, or fluidized bed drying.

[0095] The sequential method of performing the approaches is set forth below in Table 8. It will be understood by one of skill in the art that this sequence is representative and not limiting. [Table 9]

[0096] It has been found that extrusion and spheronization of a mixture of a vitamin D compound and a sustained release component (e.g., a water-insoluble polymer) as described herein can provide desirable vitamin D-containing polymer particles (e.g., containing calcifediol) with dissolution release characteristics similar or comparable to commercially available sustained release wax matrix formulations of calcifediol, e.g., Rayaldee®. It is contemplated to use calcifediol as the vitamin D compound in extrusion-spheronization type formulations. Rayaldee® type formulations can be filled into OptiShell® vegetable polysaccharide soft shells with the following compositions: capsule fill of 0.02% by weight calcifediol, capsule fill of 20.0% by weight paraffin, capsule fill of 35.34% by weight mineral oil, capsule fill of 10.0% by weight hypromellose, capsule fill of 22.56% by weight mono- and di-glycerides, capsule fill of 9.75% by weight lauroyl polyoxyglyceride, capsule fill of 2.32% by weight dehydrated alcohol, and capsule fill of 0.02% by weight BHT.

[0097] The formulations described herein may be directly processed as final dosage forms, or may be further processed to produce final dosage forms. For example, the formulations may be coated. Coating may be performed, for example, by fluidized bed coating in top, tangential, or bottom spray configurations. As another example, the formulations may be compressed, for example, into pill or tablet form. In another type of embodiment, the particles of the formulations described herein (optionally coated) may be filled into capsule shells, or presented in sachet form, or provided with a suspension as a vehicle for suspending these pellets before they are administered.

[0098] A batch of extruded / spheronized calcifediol pellets described in the following examples and using Compritol 888 ATO showed a reduced dissolution profile in accelerated storage stability testing. The lipid-containing formulations described herein (e.g., those containing Gelucire or Compritol components) can be heat-cured to stabilize the formulation against structural changes during long-term storage. If not heat-cured, the lipid components can migrate over time during storage and block hydrophilic sites or pores, thus altering the dissolution release profile compared to the formulation at time zero. Further optionally, the formulations described herein with higher melting lipids can be combined with lower melting lipids so that the formulation can be heat-cured at lower temperatures. For example, a formulation containing glyceryl behenate (e.g., Compritol 888 ATO), which has a melting range of 65°C to 77°C and an HLB of 2, can be heat cured around 60°C and below 65°C (compared to glyceryl behenate), and thus can be formulated or partially replaced with glyceryl distearate / palmitostearate (e.g., Precirol ATO 5), which has a melting range of 50°C to 60°C, e.g., 54°C and an HLB of 2, to avoid calciphediol degradation. Optionally, heat curing can be performed over a period ranging from minutes to weeks, e.g., 1 hour to 1 week, or 1 to 24 hours, e.g., 2 hours, 3 hours, 4 hours, 6 hours, 12 hours, or 24 hours, e.g., 48 hours, or 72 hours, or 96 hours, or 1 week.

[0099] Dosage of dosage forms according to the present disclosure can be based on the weight of active ingredient in the formulation. For example, administration of a calcifediol-containing formulation can be in an amount of 1 μg of calcifediol to about 1 g of calcifediol. The dosage forms can be orally administered to patients suffering from conditions for which a vitamin D compound is indicated, including, but not limited to, vitamin D deficiency, vitamin D insufficiency, secondary hyperparathyroidism associated with CKD (e.g., any of stages 1-5, including stage 3, stage 4, stage 5, stage 3-5, or stage 3-3 CKD). In any of the methods or uses described herein, treatment of humans is contemplated. In any of the methods or uses described herein, treatment of mammals is contemplated. In any of the formulations, dosage forms, uses, and methods described herein, oral formulations and oral administration are contemplated. The compositions of the present disclosure can be used in combination with other therapies useful for the indicated diseases and disorders.

[0100] Additionally, or alternatively, the formulations described herein can be used in the preparation of a medicament for use in treating a vitamin D responsive condition or disease.

[0101] The compositions and methods described herein are useful for the prophylactic or therapeutic treatment of vitamin D-responsive diseases, i.e. diseases in which 25-hydroxyvitamin D or activated 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 hyperparathyroidism, hyperparathyroidism secondary to CKD (e.g., either individually or in a range of stages 1, 2, 3, 4, or 5), hyperparathyroidism secondary to CKD in patients undergoing hemodialysis, or tertiary hyperparathyroidism. 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). Activated vitamin D (e.g., calcifediol) has been observed to induce cell differentiation and / or inhibit cell proliferation in vitro in many cells. Vitamin D responsive diseases also include autoimmune diseases, such as type I diabetes, multiple sclerosis, rheumatoid arthritis, polymyositis, dermatomyositis, sclerosing dermatitis, fibrosis, Graves' disease, Hashimoto's disease, acute or chronic graft rejection, acute or chronic graft-versus-host disease, inflammatory bowel disease, Crohn's disease, systemic lupus erythematosus, Sjogren's syndrome, eczema and psoriasis, atopic dermatitis, contact dermatitis, allergic dermatitis and / or chronic dermatitis. Vitamin D responsive diseases also include other inflammatory diseases, such as asthma, autism (or autism spectrum disorder), chronic obstructive pulmonary disease, Parkinson's disease, polycystic kidney disease (PKD), polycystic ovarian syndrome, pancreatitis, nephritis, hepatitis and / or infectious diseases. Vitamin D responsive diseases are also reported to include hypertension and cardiovascular disease.Thus, the methods contemplate prophylactic or therapeutic treatment of subjects at risk for or suffering from cardiovascular disease, e.g., subjects having 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 associated diabetic dyslipidemia and mixed dyslipidemia, hypoalphalipoproteinemia, hypertriglyceridemia, hypercholesterolemia, and low HDL (high density lipoprotein)), metabolic disorders (e.g., diabetic complications including metabolic syndrome, diabetes mellitus type II, diabetes mellitus type I, hyperinsulinemia, impaired glucose tolerance, insulin resistance, neuropathy, nephropathy, retinopathy, diabetic foot ulcers and cataracts), and / or thrombosis. Any of the formulations described herein, including Rayaldee® sustained release capsules, are contemplated for use in treating or preventing such diseases, e.g., preventing the onset or progression of a disease or alleviating a sign or symptom of a disease.

[0102] Patients who require vitamin D supplementation include healthy subjects and subjects at risk for vitamin D insufficiency or deficiency, e.g., subjects with stage 1, 2, 3, 4, or 5 CKD; infants, children, and adults who do not consume vitamin D fortified milk (e.g., lactose intolerant subjects, subjects with milk allergies, vegetarians who do not consume milk, breast-fed infants); subjects with rickets; dark-skinned subjects (e.g., in the United States, 42% of African-American women aged 15-49 years are vitamin D deficient compared to 4% of white women); elderly people (who have a reduced ability to synthesize vitamin D in the skin during exposure to sunlight and are more likely to remain indoors); institutionalized adults (who are more likely to remain indoors, including subjects with Alzheimer's disease or psychiatric illness); subjects who cover all exposed skin (such as members of a particular religion or culture); subjects who regularly use sunscreen (e.g., application of a sunscreen with a sun protection factor (SPF) of 8 reduces vitamin D production by 95%, and higher SPFs may further reduce vitamin D production in the skin); oily subjects subjects with fat malabsorption syndromes (including but not limited to cystic fibrosis, cholestatic liver disease, other liver disease, gallbladder disease, pancreatic enzyme deficiency, Crohn's disease, inflammatory bowel disease, sprue or celiac disease, or surgical removal and / or bypass of part or all of the stomach and / or intestine); subjects with inflammatory bowel disease; subjects with Crohn's disease; subjects who have undergone small bowel resection; subjects with periodontal disease; bilirubin, including phenytoin, fosphenytoin, phenobarbital, carbamazepine, and rifampin. Subjects taking medications that increase the catabolism of vitamin D; subjects taking medications that reduce vitamin D absorption, including cholestyramine, colestipol, orlistat, mineral oil, and fat substitutes; subjects taking drugs that inhibit the activation of vitamin D, including ketoconazole; subjects taking medications that reduce calcium absorption, including corticosteroids; subjects with obesity (vitamin D stored in body fat depots has low bioavailability); subjects with osteoporosis and / or postmenopausal women.According to the Institute of Medicine report on dietary reference intakes for vitamin D, food consumption data suggests that the median vitamin D intake of both young and elderly women is below the current recommended value, and data suggests that more than 50% of young and elderly women do not consume the recommended amount of vitamin D. Optionally, the therapeutic treatment of subjects suffering from renal osteodystrophy (including osteomalacia and osteitis fibrosus) is excluded from this method. It is contemplated that any formulation described herein, including Rayaldee® sustained release capsule, is administered to such subjects.

[0103] Formulations described herein having a particle size limit of 2.8 mm or less, or 2.5 mm or less, or 2.0 mm or less can be administered by sprinkling (e.g., onto applesauce or other soft foods such as jelly) so that they can be swallowed without chewing. Alternatively, such formulations may be administered via an enteral feeding tube. In these embodiments, a capsule containing the particles can be opened or a packet or sachet containing the particles can be opened prior to sprinkling. For example, easy-to-open hard gelatin capsules are available from Capsugel under the trade name CONISNAP.

[0104] The formulations can be administered to adult or pediatric patients. In embodiments, the pediatric patient can be 8-17 years old, 12-17 years old, 8-11 years old, 1 month to 7 years old, 6 months to 8 years old, or 6 years old or younger, e.g., 4 years old or younger, or 2 years old or younger.

[0105] Formulations having a particle size limit of 2.8 mm or less may be packaged with instructions for sprinkling the particles onto soft foods (eg, applesauce) and, optionally, swallowing the particles and the food without chewing.

[0106] Formulations having a particle size limit of 2.8 mm or less may be packaged with instructions for administration through an enteral feeding tube.

[0107] The formulation may be used with a dosing regimen that includes a dose reduction aspect. For example, the dose may be reduced, if necessary, by one unit dose per week (e.g., 30 mcg unit dose) at most every other week, provided that an elevation in serum phosphorus is associated with calcifediol administration and appropriate and sustained action is being taken to control serum phosphorus by initiating or adjusting any phosphorus binder therapy, if any one of the following four criteria is met: plasma iPTH is confirmed to be <35 pg / mL (for subjects with stage 3 CKD) or <70 pg / mL (for subjects with stage 4 CKD), serum calcium (corrected) is confirmed to be >10.3 mg / dL, serum total 25-hydroxyvitamin D is confirmed to be >100 ng / mL, or serum phosphorus is confirmed to be >5.5 mg / dL (ages 12-18) or >6.0 mg / dL (ages 8-12).

[0108] Dose reduction may be achieved by consistently reducing the dose on certain days of the week, for example: First dose reduction: Reduce the dose on one day of the week, e.g. every Monday (M). · Second Dose Reduction: Reduce the dose on two non-consecutive days of the week, e.g., every M and Wednesday (W). · Third Dose Reduction: Reduce the dose on 3 non-consecutive days of the week, e.g., every M, W, and Friday (F). · Fourth Dose Reduction: Reduce the dose on four days of the week, two or three of which are non-consecutive, e.g., every M, W, F, and Sunday (S). -Terminate treatment if further dose reduction is required.

[0109] As noted above, the non-consecutive days may consist of or include alternating days, e.g., M, W, F. EXAMPLES

[0110] The following examples are offered for illustrative purposes and are not intended to limit the scope of the present invention.

[0111] Example 1 - Eudragit Polymer Formulation Examples 1.1-1.4, including Eudragit-based polymer pellets, were made by extrusion-spheronization using the excipients specified in Table 9 below. Calcifediol was dissolved in ethanol. An extrudable wet mass was prepared, extruded, and spheronized. The extrusion / spheronization process followed the general sequence set out in Table 8 above. The extruder was a Caleva Benchtop Screen Extruder 20 with a 1 mm screen size and operated at a speed of about 30-35 RPM. The spheronizer was a Caleva MultiBowl Spheronizer / MBS 250 operating at about 1000-2500 RPM. The sieves used for fractionation were 1.4 mm, 1.0 mm, 850 μm, 500 μm, and 250 μm. The pellets finally selected for different batches are 500 μm, 850 μm, and 1.0 mm. The pellets in formulation 1.2 had an average diameter of approximately 500 μm, and the pellets in formulations 1.1, 1.3, and 1.4 had an average diameter of approximately 1.0 mm. All pellets assayed to at least 94% of the expected API and demonstrated satisfactory flow properties, friability, and acceptable levels of related substance impurities. The pellets contained no more than approximately 4-6% water by weight by Karl Fischer titration. [Table 10]

[0112] The dissolution release profile of the pellets was measured and compared to the dissolution release of a representative batch of calcifediol sustained release wax matrix extended release soft capsules. 50 mg of pellets were filled into hard capsule shells and tested for dissolution release using a USP Apparatus II (paddle with sinker) at 75 RPM in a medium of 0.5% SDS in 5 mM sodium dihydrogen phosphate monohydrate, pH 6.8, 37±0.5° C., volume of 500 mL. The dissolution results are shown in FIG. 1 and for Examples 1.1-1.4 in Table 10 below. The mean dissolution times and relative standard deviation (RSD) values ​​were derived from the dissolution tests for six capsules. [Table 11]

[0113] Example 2 - EC Polymer Formulation Examples 2.1-2.4, including EC-based polymer pellets, were made by extrusion-spheronization using the excipients specified in Table 11 below. An extrudable wet mass was prepared, extruded, and spheronized. The extrusion / spheronization process followed the general sequence set forth in Table 8 above. The extruder was a Caleva Benchtop Screen Extruder 20 with a 1 mm screen size and operated at a speed of about 30-35 RPM. The spheronizer was a Caleva MultiBowl Spheronizer / MBS 250 operating at about 1000-2500 RPM. The pellets of formulations 2.1 and 2.2 had an average diameter of about 500 μm. The pellets of formulation 2.3 had an average diameter of about 850 μm. The pellets of formulation 2.4 had an average diameter of about 850 μm before coating. Example 2.4 included a topcoat containing a 60:40 weight ratio mixture of Surelease sustained release polymer and Pharmacoat 603 pore former, applied at 25% weight gain using purified water as the dispersion vehicle and then dried. All pellets assayed to at least 93% of the expected API and exhibited satisfactory flow properties, friability, and acceptable levels of related substance impurities. The pellets contained approximately 5.5% water or less by Karl Fischer titration. [Table 12]

[0114] The dissolution release profile of the pellets was measured and compared to the dissolution release of a representative batch of calcifediol sustained release wax matrix extended release soft capsules. 50 mg of pellets were filled into hard capsule shells and tested for dissolution release using a USP Apparatus II (paddle with sinker) at 75 RPM in a medium of 0.5% SDS in 5 mM sodium dihydrogen phosphate monohydrate, pH 6.8, 37±0.5° C., volume of 500 mL. The dissolution results are shown in FIG. 2 and for Examples 2.1-2.4 in Table 12 below. The mean dissolution times and relative standard deviation (RSD) values ​​were derived from the dissolution tests for six capsules. [Table 13]

[0115] Example 3 - Nano / Microparticles Nano / microparticle formulations having 1 part by weight of calcifediol, 25 parts by weight of EudragitRL PO, and 1 part by weight of poly(vinyl alcohol) were prepared by emulsion diffusion-spray drying technique. An emulsion was formed with API and excipients using ethyl acetate as the discontinuous phase solvent and water as the continuous phase solvent. The emulsion was homogenized and spray dried through a cyclone using a Buchi Mini Spray Dryer B-191 and the general procedure and parameters listed in Table 5 above. The product powders were produced in satisfactory yields with particle sizes ranging from about 900 nm to about 10 microns, including spherical to donut-shaped particles.

[0116] Table 13 below shows the formulations that were analyzed for dissolution. [Table 14]

[0117] The batch produced from the above composition produced a fine spray dried powder with a product yield of 53%. Figure 3 provides an initial comparison of the spray dried formulations of Table 13 compared to various slow, medium, and fast batches of wax-based sustained release 25-hydroxyvitamin D3 capsules.

[0118] Additional batches of nano / microparticle formulations are made by the same process with formulation differences according to Table 14 below to target the release profiles of the slow and medium soft capsule wax-based formulations as described above. The release profiles are shown in Figure 5. [Table 15]

[0119] Example 4 - Spray congealing Batches 4.1-4.13 of lipid particles containing calcifediol with one or more lipids and optional surfactants were produced by spray congealing, as shown in Tables 15 and 16 below. The spray congeals were produced using a ProCepT spray congealing unit in a closed loop setup. A chiller was used to cool the gas in the column. Nitrogen gas was used throughout the system to keep the temperature in the system below 0°C. The melt temperature was kept as low as possible. The melt was atomized using a heated two-fluid nozzle. The product was introduced by a pressure vessel. The process parameters used are listed in Table 6 above.

[0120] The resulting product was free-flowing and in the size range of 100–700 μm (d 50 ). Examples 4.1-4.9 were assayed for calcifediol content and related substances and yielded at least 86% of the expected amount of calcifediol. Examples 4.1-4.9 were also assayed for water content by Karl Fischer titration and showed less than about 0.3% water by weight. [Table 16] [Table 17]

[0121] Figure 4 shows the release profiles of several test formulations compared to slow, medium, and fast Soft Cap 25-hydroxyvitamin D3 batches. These embodiments provide a range of release characteristics with different in vitro dissolution profiles, as shown in Figure 4, demonstrating that the particular formulation used in the process can be altered to provide the desired dissolution release profile.

[0122] Example 5 - Batch-to-batch reproducibility Two batches were prepared relating to the formulations of Examples 1.1, 1.2, and 1.4 above. The batches were identical except that the flavoring (0.5 wt%) in each comparative batch was reduced and offset by including an equivalent increase in the MCC content. Dissolution characteristics were measured using a USP Apparatus II (paddle with sinker) at 75 RPM in a medium of 0.5% SDS in 5 mM sodium dihydrogen phosphate monohydrate, pH 6.8, 37±0.5°C, and a volume of 500 mL. Comparative dissolution release profiles are shown in Figures 6-8, with the batches without flavoring designated 1.1a, 1.2a, and 1.4a. The results indicate that the formulations exhibited good batch-to-batch consistency.

[0123] Example 6 - Friability test Ten grams of dust-free pellets from each of Examples 1.1 and 2.1 were weighed and the pre-test weight (B 重量 The pellets were placed in a crusher along with 200 3 mm solid glass beads. The pellets and beads were rotated at 25 RPM for 10 minutes. The pellets were collected from the crusher and dust was removed by gently sieving through a 250 μm sieve. The weight of the pellet fraction retained on the 250 μm sieve was recorded as the post-test weight (A 重量 ) was recorded. The percent fracture was calculated using the formula ((B 重量 -A 重量 ) / B 重量) × 100. The results showing good friability of the formulations disclosed herein are shown in Table 17 below (replicated three times). [Table 18]

[0124] Example 7 - In vivo pharmacokinetics in minipigs Formulations of Examples 1.1-1.4 and 2.1-2.4 were used in a single oral dose pharmacokinetic study conducted on naïve male Yucatan minipigs weighing approximately 8-12 kg on day 1. Two control arms, a wax matrix-based soft capsule (Rayaldee® type formulation) and an immediate release oral product, served as control arms. Animals were acclimated for at least 21 days with a 12-hour light / 12-hour dark cycle to stabilize baseline calcifediol blood levels. All animals were maintained on a standardized diet from the start of acclimation until the end of the study. A sample size of 5 animals per formulation was determined to be adequate to achieve the study objectives. Animals were fasted overnight for at least 10 hours and not fed for at least 4 hours before and after dosing. Animals were also not allowed access to water for 1 hour after dosing. Multiple baseline and post-dose blood samples were collected up to 120 hours after administration of the test article. Serum 25-hydroxyvitamin D3 (calcifediol) concentrations are assayed using a qualified method. The following pharmacokinetic parameters of calcifediol are calculated by standard non-compartmental methods: AUC0 -t : Area under the concentration-time curve from measured time zero to the time of the last non-zero concentration; C max : maximum observed concentration; Tmax: observed C max Time.

[0125] This study was conducted to evaluate the absorption phase of the pharmacokinetic (PK) profile of various modified-release calcifediol multiparticulate capsule formulations following a single oral dose of 270 μg compared with a wax-matrix-based modified-release soft capsule and an immediate-release calcifediol product administered at oral doses of 270 μg and 266 μg, respectively.

[0126] PK studies demonstrated the potential of the pellet formulation concept in extending the release of calcifediol in vivo. The extent of absorption (AUC0-t) observed with ethylcellulose (EC)-containing formulations, especially 2.1, 2.2, and 2.3, was greater compared to Eudragit-containing formulations (1.1-1.4). The median time to reach maximum concentration (Tmax) ranged from 8 to 16 hours after administration for all multiparticulate formulations, while the median Tmax observed was approximately 24 hours and 4 hours for wax matrix-based modified release soft capsules 270 μg and immediate release calcifediol 266 μg, respectively. See Figure 9 and Table 18. [Table 19] [Table 20] [Table 21] [Table 22]

[0127] Although the Eudragit-containing formulations extended calcifediol release (Tmax) in vivo, these particular formulations exhibited a relatively low rate and extent of absorption compared to the non-Eudragit formulations. Formulations 2.2 and 2.3 exhibited an overall high absorption profile, of which 2.2 had a longer Tmax than 2.3. Without intending to be bound by any particular theory, it is believed that the enhanced absorption profile of ethylcellulose formulations 2.1-2.4 compared to Eudragit-containing formulations 1.1-1.4 may be attributed to absorption enhancing excipients such as Miglyol and solubilizing excipients such as lactose and HPMC.

[0128] These formulations demonstrated the pellet / multiparticulate dosage form for extended release of calcifediol in vivo.

[0129] Example 8 - Additional EC polymer formulations Following the studies in Example 7, another phase of formulation development work was carried out to investigate the dissolution and human pharmacokinetic properties of polymer-based pellets produced by extrusion-spheronization. In this effort, formulation 2.2 was selected as the lead formulation and development studies were based on this composition.

[0130] As seen from the porcine PK data in Example 7, the Eudragit formulation showed a relatively low rate and extent of absorption. Without intending to be bound by any particular theory, it was believed that this was likely due to the low concentration of Miglyol and the high concentration of hydrophobic Eudragit polymer. As a result of the hydrophobicity of the Eudragit matrix formed, it may have hindered the release of hydrophobic calcifediol. However, the hydrophobic matrix helped to extend the release of calcifediol and therefore its Tmax in vivo.

[0131] On the contrary, the EC formulation showed a higher rate and extent of absorption. Without intending to be bound by any particular theory, it is believed that the higher rate and extent of absorption in the EC-based formulation is due to the presence of higher concentrations of solubilizing excipients such as Miglyol, lactose and HPMC, which help make the matrix more hydrophilic, allowing for better absorption in the vicinity of the matrix for the calcifediol.

[0132] Considering these results, the development was focused on incorporating soluble type excipients into the matrix to promote the solubility / absorption / bioavailability of calcifediol and at the same time prevent this solubilized calcifediol from being released too rapidly by the use of sustained release matrix forming agents. Furthermore, since calcifediol is a BCS class IV compound and therefore this formulation system may lend itself to a proper hydrophilic-lipophilic balance (HLB), it was also envisaged that efforts would be made to incorporate suitable lipid agents to meet this hypothesis.

[0133] To balance the HLB and prevent the matrix from becoming hydrophobic, Gelucire was used as a hydrophilic agent with HLB 11-12, and glyceryl behenate (Compritol 888 ATO) was used as a lipophilic agent with HLB 2. Other hydrophilic sustained-release agents such as Methocel E50 Premium LV and Methocel K4M Premium CR were also evaluated with the view to achieving a hydrophilic sustained-release matrix containing calcifediol. Gelucire was also used as a bioavailability enhancer. Based on its physical properties and suitability for the extrusion and spheronization processes, Gelucire 48 / 16 grade (PEG-32-stearate, also known as PEG 32 mono- and diesters of stearic and palmitic acids, with an HLB of 12, CMC of 153±31 mg / L, helps to increase the solubility of hydrophobic and lipophobic molecules, solid at ambient temperature, melt temperature 48°C) was adopted. Compritol 888 ATO was used as a lipid sustained release matrix agent for two purposes: one was to balance the lipophilic portion of the HLB (i.e., have an HLB of 2), and the other was to provide sustained release through a non-hydrophobic matrix, such that Compritol itself is a sustained release agent.

[0134] Examples 8.1-8.28 were made by extrusion-spheronization using the excipients specified in Table 19 below. An extrudable wet mass was prepared, extruded, and spheronized. The extrusion / spheronization process followed the general procedure set forth in Table 8 above, with appropriate modifications to incorporate Comprtol 888 ATO in the dry mix and Gelucire in the binder solution. The extruder was a Caleva Benchtop Screen Extruder 20 with a 1 mm screen size and operated at a speed of about 30-35 RPM. The spheronizer was a Caleva MultiBowl Spheronizer / MBS 250 operating at about 1000-2500 RPM. The pellets had an average diameter of about 500 μm. All pellets exhibited satisfactory flow properties, friability, and acceptable levels of related substance impurities. The pellets contained less than about 5.5% water by weight by Karl Fischer titration. Table 19 below also includes initial assay results for calcifediol content, where available. [Table 23] [Table 24] [Table 25]

[0135] Typically, 100 mg pellets were filled into hard capsule shells and tested for dissolution release using USP Apparatus II (paddle with sinker) at 75 RPM in a medium of 0.5% SDS in 5 mM sodium dihydrogen phosphate monohydrate, pH 6.8, 37±0.5° C., volume of 500 mL. Example 8.16 had a higher concentration of calcifediol and a fill weight of 50 mg. Dissolution results, when available, are shown in Table 20 below. Mean dissolution time values ​​were derived from dissolution testing for six capsules. A comparison with Rayaldee® soft capsules is provided. [Table 26] [Table 27] [Table 28]

[0136] First, compared to the formulations of Examples 1 and 2, Gelucire 48 / 16 was added to the binder solution to replace Methocel K3 Premium LV from the binder solution and added to the dry mix as a dry binder (Examples 8.1-8.12). Developments on this process resulted in a burst effect releasing 53%-86% of calcifediol in 2 hours. These tests with Gelucire 48 / 16 showed high solubility and rapid release of calcifediol, even though the release profile could not be fully controlled as desired. These results supported the use of Gelucire as a bioavailability enhancer. It was observed that these pellets were relatively soft pellets, and without intending to be bound by any particular theory, it was believed that the softness of the pellets could be the reason behind the burst release.

[0137] Considering the above results, in subsequent tests (Examples 8.13-8.28), Methocel K3 Premium LV was added to the binder solution and removed from the dry mix. Further development using Gelucire 48 / 16 together with Methocel K3 in the binder solution was well suited to the process and was also effective in restoring the burst release to less than 40% at 2 hours. The pellets were also observed to be harder than those with HMPC added to the dry mix.

[0138] To counterbalance the enhanced solubility provided by Gelucire, further studies were performed using Compritol and EC as sustained release agents to effectively control the release profile and provide sustained release properties to calcifediol. Some studies also varied from using lower levels of lactose to no lactose providing a slower release. A general trend for these matrix formulations tested was observed in that reducing the initial release also reduced the overall release. Thus, the formulation was primarily optimized using 20% ​​EC and 20% Compritol as sustained release agents and Gelucire 48 / 16 at 5% concentration as a bioavailability enhancer.

[0139] In parallel with the development of this release profile, BHT antioxidant was added to the formulation to provide stability to the API in the formulation, resulting in a significant reduction in related substances as shown in Table 21.

[0140] To complete the Phase 2 development work, formulation 8.21 was selected as the second prototype formulation for human clinical trials (Example 9 below). A total of two formulation prototypes were included in the PK study. One formulation was based on a conservative approach, i.e., porcine data (same formulation as Example 2.2; new Example 8.27), and the other was a batch of Examples 8.21 and 8.28, which is a modified formulation of Example 2.2. [Table 29]

[0141] Example 9: Single oral pharmacokinetic study of two calcifediol 30mcg pellet formulations in healthy adult human subjects under fasting conditions. The objective of this study was to evaluate the pharmacokinetics of two calcifediol 30mcg pellet formulations after a single oral dose in humans under fasting conditions. This single-dose study was designed in accordance with EMA and FDA regulatory guidelines with the aim to characterize the bioavailability and PK of calcifediol in two novel formulations in healthy subjects. The primary endpoints of the study were the baseline-adjusted PK parameters Cmax and AUC 0-T The objective of this study was to quantify the rate and extent of absorption from the formulation.

[0142] After a single oral dose under fasting conditions, baseline-adjusted mean peak concentrations and extent of exposure of calcifediol were slightly higher for the formulations of Example 8.27 compared to Example 8.28. For the formulations of Examples 8.27 and 8.28, the mean Cmax was 25.65 ng / mL and 22.01 ng / mL, respectively, and the extent of absorption (AUC 0-T ) were 2390.05 ng h / mL and 2059.61 ng h / mL, respectively. The time to reach peak concentration (Tmax) was similar between both formulations, with median Tmax of 6.00 and 6.05 hours for formulations of Example 8.27 and Example 8.28, respectively. The same trends in mean peak concentrations and extent of exposure were observed for unadjusted calcifediol, although the magnitude of differences was smaller compared to baseline-adjusted calcifediol results. Overall, the tested formulations were generally safe and well tolerated by the subjects included in this study (see Figure 10 and Table 22). [Table 30]

[0143] Example 10: Heat-cured formulation for storage stability Previous batches of Example 8 using Compritol as the matrix agent showed a decline in dissolution profile after 3 months of accelerated stability testing at 40°C and 75% RH. Without intending to be bound by any particular theory, the observed variation (decrease) in drug release after storage at accelerated conditions may be the result of a change in the distribution of lipid components within the matrix structure. Lipids may migrate within the matrix structure and increase the hydrophobicity of the pellet matrix if adequate stabilization is not found. The hydrophobicity of the matrix in turn reduces the rate of diffusion of water into and drug out of the matrix. This may result in a stable slower release rate. To reduce the decline in dissolution under these conditions, a curing / sintering step can be utilized. This additional step stabilizes the lipids within the matrix at an early stage of formulation manufacturing.

[0144] However, higher melting lipids (e.g., glyceryl behenate, Compritol 888 ATO, with a melting point range of 65-77°C) require higher curing temperatures, and curing above this temperature may degrade the API (e.g., calciphediol). Thus, lower melting components with similar functionality may be used in addition to, or partially or completely replace, the higher melting components. For example, glyceryl distearate / palmitostearate (e.g., Precirol ATO 5) is a lipid similar in function to glyceryl behenate, but with a lower melting point of 54°C. Curing at 60°C may melt the Precirol in the matrix, providing a cement-like network, which may help strengthen and stabilize the Compritol network against further changes during storage, e.g., during accelerated stability testing.

[0145] The formulation of Example 8.28 above was diversified by the addition of glyceryl distearate / palmitostearate and offsetting changes to other formulation ingredients to prepare Formulation Examples 10.1-10.5, as described below in Table 23. Pellets were prepared as generally described in Example 8 above. Precirol ingredients were added to the dry mix for processing. [Table 31]

[0146] The resulting pellets of Examples 10.1 and 10.2 were tested for dissolution profiles as described in Example 8 above either in the uncured state or after curing at 60° C. for defined times, as shown in Table 24 below with initial dissolution results. [Table 32]

[0147] As shown in Table 24, although curing showed some reduction in release, curing did not substantially change the initial release profile of the formulation.

[0148] After storage at accelerated stability conditions, i.e., 40° C. and 75% RH, the cured formulations exhibit a release profile more similar to the initial release profile, whereas the uncured formulations tend to exhibit a reduced release profile due to the non-stabilized lipids present in the formulation.

[0149] Example 11: Pediatric studies The Phase 3, multicenter, randomized, double-blind, placebo-controlled trial will be conducted primarily or entirely within the United States (US). The trial will include approximately 108 eligible subjects aged 8-18 years, with secondary hyperparathyroidism (SHPT), stage 3 or 4 CKD, and vitamin D insufficiency (VDI), balanced for gender and CKD stage. Approximately 72 subjects aged 12-18 years will be enrolled initially (Cohort 1), and approximately 36 additional subjects aged 8-12 years will be enrolled (Cohort 2). Subjects in both cohorts will be randomized in a 2:1 ratio into two treatment arms to receive either (a) a calcifediol extended-release formulation described herein or (b) a matching placebo daily at bedtime for 26 weeks. Subjects in Cohort 1 assigned to treatment with calcifediol formulations will begin treatment at 30 mcg / day with upward dose titration to 60 mcg / day at the end of 12 weeks of treatment, provided that (a) plasma iPTH has not declined by at least 30% from pretreatment baseline, (b) serum calcium (corrected for albumin) is <9.8 mg / dL, (c) serum phosphorus is ≤5.5 mg / dL, and (d) serum total 25-hydroxyvitamin D is ≤65 ng / mL. The initial dose for Cohort 2 will be determined based on an interim analysis of data obtained from Cohort 1, as described below. The efficacy of calcifediol formulations in treating SHPT will be assessed from multiple plasma iPTH and serum 25-hydroxyvitamin D levels obtained during the Efficacy Assessment Period (EAP), defined as the last 6 weeks of the 26-week treatment period.

[0150] An Interactive Response System (IRS) will provide treatment group assignment (using computer-generated randomization codes provided by the IRS vendor) and dose adjustments. An independent, open-label Data Safety Monitoring Board (DSMB) will be established to oversee the IRS, validate all dose adjustments, and monitor subject safety and efficacy of the calcifediol formulation at regular intervals.

[0151] Members of the DSMB also conduct periodic reviews of study conduct to ensure that all necessary data are captured to a sufficiently high degree (>95%) and within the specified timeframe (usually within 5 days), and promptly recommend appropriate corrective actions to address any noted deficiencies to minimize missing data. The specific responsibilities and activities of the DSMB are defined in the charter approved at the pre-study organizational meeting. These responsibilities include completing an interim analysis of data obtained from cohort 1 to justify the starting dose of cohort 2, and completing an interim analysis of data obtained from cohort 2 to justify the starting dose of a separate Phase 2 study in subjects aged 1 month to 8 years.

[0152] Subjects receiving treatment with calcitriol or another 1α-hydroxylated vitamin D analogue prior to study enrollment, or with a calcimimetics prior to study enrollment, will refrain from further administration of these agents for the duration of the study and will complete an 8-week washout period prior to baseline assessment.

[0153] Subjects receiving vitamin D supplementation at rates greater than 1,700 IU / day or greater than 50,000 IU (1,250 mcg) per month prior to study enrollment will have their dose reduced to 1,700 IU / day or less for the duration of the study, with an 8-week washout period prior to baseline assessment if serum total 25-hydroxyvitamin D is ≥ 30 ng / mL. Subjects who do not require a washout period if serum total 25-hydroxyvitamin D is < 30 ng / mL will complete a 6-week follow-up (FU) period after completing the 26-week treatment period or after early termination (ET).

[0154] Blood samples will be collected at 1-week, 2-week, or 1-month intervals during the 10-week pre-treatment / baseline period, the 26-week treatment period, and the 6-week post-treatment FU period. Sparse PK samples will be collected from all subjects at 0 (pre-dose), 6, 12, 24 hours (pre-dose on day 84), and 48 hours (pre-dose on day 85) on day 83. Additional PK blood samples will be collected in both cohort 1 and cohort 2 in a subset of 10 subjects treated with the calcifediol formulation and 5 subjects treated with placebo during the last 3 days of week 12 of treatment (before dose escalation). Additional PK samples will be collected as follows: Day 83: -2, 2, 4, and 8 hours. End-of-study PK blood samples will be collected in another subset of approximately 20 subjects (20 subjects from each cohort) during the post-treatment FU period. In each cohort, an attempt will be made to collect PK samples from 10 subjects at each dose level of the calcifediol formulation (30 or 60 mcg) to establish the terminal elimination half-life (t1 / 2) of 25-hydroxyvitamin D3 at each final dose level.

[0155] All subjects, study personnel, and sponsors will be blinded to the treatment administered, and plasma iPTH, serum total 25-hydroxyvitamin D, and serum 25-hydroxyvitamin D3 data until the last subject completes 26 weeks of treatment. Unblinded data will be provided to all study sites in the final clinical study report.

[0156] An interim analysis of data from 15 subjects in Cohort 1 who provide intensive PK samples during the last 3 days of treatment week 12 will be conducted by the DSMB to determine the appropriate starting dose for Cohort 2. A second interim analysis of data from 15 subjects in Cohort 2 who provide intensive PK samples during the last 3 days of treatment week 12 will be conducted by the DSMB to determine the appropriate starting dose for a separate Phase 2 study in subjects aged 1 month to 8 years.

[0157] Each subject will participate in the study for up to approximately 42 weeks (2 weeks screening / baseline, 8 weeks washout period if necessary, 26 weeks of treatment with a calcifediol formulation or matching placebo, and 6 weeks of FU evaluation).

[0158] Key parameters monitored at regular intervals during the study include: plasma iPTH, serum calcium (corrected for serum albumin), serum phosphorus, serum CaxP product, serum total 25-hydroxyvitamin D, serum 25-hydroxyvitamin D3, and urinary calcium:creatinine ratio. Vital signs (VS) and adverse events (AE) will be monitored at each study visit. Other parameters monitored less frequently include brief physical examination (PE), laboratory tests (hematology and clinical and urine chemistry), and patient-reported palatability and tolerability. A 12-lead electrocardiogram (ECG) will be obtained at baseline and at the end of treatment or ET. Additional exploratory parameters including serum 1,25-dihydroxyvitamin D3, serum 24,25-dihydroxyvitamin D3, plasma FGF23 and serum bone markers (bone-specific alkaline phosphatase (BAP), C-terminal telopeptide of type 1 collagen (CTx), N-terminal propeptide of procollagen type 1 (P1NP), and tartrate-resistant acid phosphatase 5b (TRAP 5b)) will be monitored at specified intervals.

[0159] Subjects in cohort 1 will receive two unit doses (e.g., capsules) and / or matching placebo unit doses daily at bedtime to achieve a target initial daily dose of 30 mcg calcifediol (one calcifediol formulation and one placebo formulation) or 0 mcg calcifediol (two placebo unit doses). Any food intake within 60 minutes of dosing will be recorded. At the end of 12 weeks of treatment, subjects assigned to active treatment will receive an upward dose escalation to 60 mcg (two calcifediol unit doses) per day, provided that (a) plasma iPTH has not decreased by at least 30% from pretreatment baseline, (b) corrected serum calcium is <9.8 mg / dL, (c) serum phosphorus is ≦5.5 mg / dL, and (d) serum total 25-hydroxyvitamin D is ≦65 ng / mL. Subjects in Cohort 2 will receive an initial bedtime dose determined based on an interim analysis of data from Cohort 1 and will be upwardly titrated to a new daily dose twice higher than the starting dose at the end of 12 weeks, provided that (a) plasma iPTH has not decreased by at least 30% from pretreatment baseline, (b) corrected serum calcium is <9.8 mg / dL, (c) serum phosphorus is >6.0 mg / dL, and (d) serum total 25-hydroxyvitamin D is ≤65 ng / mL.

[0160] Reduce the dose in subjects in both cohorts by one capsule per week, as needed, and no more frequently than at biweekly intervals, if any of the following four criteria are met, provided that the investigator determines that the elevated serum phosphorus is related to calcifediol administration and appropriate and sustained action is being taken to control serum phosphorus by initiating or adjusting any phosphorus binder therapy: plasma iPTH is confirmed to be <35 pg / mL (for subjects with stage 3 CKD) or <70 pg / mL (for subjects with stage 4 CKD); serum calcium (corrected) is confirmed to be >10.3 mg / dL; serum total 25-hydroxyvitamin D is confirmed to be >100 ng / mL; or serum phosphorus is confirmed to be >5.5 mg / dL (ages 12-18) or >6.0 mg / dL (ages 8-12)

[0161] Dose reduction is achieved by consistently reducing the dose on specific days of the week, as follows: □1st Dose Reduction: Reduce the dose every Monday (M). □Second dose reduction: Reduce the dose every M and Wednesday (W). □Third Dose Reduction: Reduce the dose every M, W, and Friday (F). □Fourth dose reduction: Reduce the dose on all M, W, F and Sundays (S).

[0162] Subjects requiring further dose reduction will discontinue study drug and immediately begin a 6-week FU period.

[0163] Subjects undergoing dose taper will be permitted an unscheduled safety visit if the investigator determines it is appropriate to perform a FU blood draw within 48 hours of dose taper.

[0164] Table 23 below provides a summary of the initial and post-reduction weekly dose levels in mcg after each of the four possible reductions. [Table 33]

[0165] If plasma iPTH is persistently <30 pg / mL (for three consecutive visits) or serum calcium (corrected) is confirmed to be >11.0 mg / dL, subjects will suspend dosing and resume when iPTH is ≥35 pg / mL and serum calcium is <9.8 mg / dL at the next lower dose level.

[0166] The primary estimate is a reduction in mean plasma iPTH of at least 30% from pretreatment baseline. The primary efficacy endpoint is the proportion of subjects in the intent-to-treat (ITT) population (ages 8-18 years) who achieved a mean reduction in plasma iPTH of at least 30% from pretreatment baseline compared to placebo during the EAP.

[0167] Safety and tolerability will be assessed in the safety population by AEs, PEs, VS, hematology and clinical chemistry, and ECGs.

[0168] The interim analysis will involve repeat-dose (steady-state) PK measurements in a subset of subjects from both Cohort 1 and Cohort 2 by analyzing the relationship between serum 25-hydroxyvitamin D3 concentrations recorded during administration of either the calcifediol formulation (n=10) or placebo (n=5) over the last 3 days of 12 weeks of treatment versus time.

[0169] The final analysis will involve repeat-dose (steady-state) PK measurements in both Cohort 1 and Cohort 2 by analyzing the relationship between recorded serum 25-hydroxyvitamin D3 concentrations and time (a) during the administration of calcifediol or placebo on the last 3 days of 12 weeks of treatment and (b) after the last dose in each active treatment group.

[0170] The following PK parameters will be calculated using observed and baseline-adjusted 25-hydroxyvitamin D3 concentrations: (a) area under the curve (AUC), maximum concentration (Cmax), time to maximum concentration (tmax), and steady-state concentration (Css); and (b) where feasible, t1 / 2, clearance (CL / F), and volume of distribution (Vd / F). Relative exposure and dose proportionality will be examined.

[0171] Secondary efficacy endpoints included the proportion of subjects in the per-protocol (PP) population who achieved a mean decrease in plasma iPTH of at least 30% from pre-treatment baseline during the EAP, and the proportion of subjects in the ITT and PP populations who achieved a mean serum total 25-hydroxyvitamin D of at least 30 ng / mL overall and at the mean weekly test dose in the EAP. Additional secondary endpoints included the time course of mean absolute change from pretreatment baseline in serum total 25-hydroxyvitamin D and plasma iPTH; the effect of PD on mean serum calcium (corrected), serum phosphorus, serum CaxP products, and urinary calcium:creatinine ratio; the proportion of subjects in each treatment group with hypercalciuria (>200 mg calcium / g creatinine), hypercalcemia (2 consecutive visits with serum calcium >10.3 mg / dL), or hyperphosphatemia (2 consecutive visits with serum phosphorus >5.5 mg / dL considered related to study drug) (ages 12-18) or >6.0 mg / dL (ages 8-12); and the proportion of subjects achieving two consecutive plasma iPTH values ​​of ≤70 pg / mL.

[0172] Exploratory endpoints include treatment-related changes in serum FGF23, serum BAP, serum CTx, serum P1NP, serum 1,25-dihydroxyvitamin D3, serum 24,25-dihydroxyvitamin D, and serum TRAP5b.

[0173] The foregoing description is set forth merely for clarity of understanding, and no unnecessary limitations should be understood therefrom, since modifications within the scope of the invention may be apparent to those skilled in the art.

[0174] Throughout this specification and the claims that follow, unless the context requires otherwise, the term "comprise", and variations such as "comprises" and "comprising", will be understood to mean the inclusion of a stated integer or step, or group of integers or steps, but not the exclusion of any other integers or steps, or group of integers or steps.

[0175] Throughout this specification, when a composition is described as comprising a component or material, it is contemplated that the composition may consist essentially of, or consist of, any combination of the listed components or materials, unless otherwise stated. Similarly, when a method is described as comprising a particular step, it is contemplated that the method may consist essentially of, or consist of, any combination of the listed steps, unless otherwise stated. The inventions illustratively disclosed herein may be suitably practiced in the absence of any element or step not specifically disclosed herein.

[0176] The implementation of the methods disclosed herein and their individual steps can be performed manually and / or with the aid of automation provided by electronic devices. Although the methods have been described with reference to specific embodiments, those skilled in the art will readily recognize that other means of performing the acts associated with the methods can be used. For example, the order of various steps may be changed without departing from the scope or spirit of the method, unless otherwise stated. In addition, some of the individual steps can be combined, omitted, or further subdivided into additional steps.

[0177] All patents, publications, and references cited herein are hereby incorporated by reference in their entirety. In the event of a conflict between this disclosure and the incorporated patents, publications, and references, this disclosure shall control.

Claims

1. A sustained release vitamin D formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, dispersed in a polymeric composition.

2. The formulation of claim 1 , wherein the polymer composition comprises a water-insoluble and water-permeable polymer.

3. The formulation of claim 2 , wherein the polymer comprises a methacrylic acid polymer.

4. 4. The formulation of claim 3, wherein the polymer comprises poly(ethyl acrylate, methyl methacrylate).

5. The formulation of claim 2 , wherein the polymer comprises ethyl cellulose.

6. 3. The formulation of claim 2, wherein the polymer comprises a low-substituted hydroxypropyl cellulose polymer.

7. The formulation of claim 2 , wherein the polymer comprises a polyvinyl acetate polymer.

8. The formulation of claim 1 , wherein the vitamin D compound-containing composition is disposed with a release-controlling membrane.

9. The formulation of claim 8 , wherein the release controlling membrane comprises a water soluble polymer.

10. 9. The formulation of claim 8, wherein the release controlling membrane comprises a mixture of a water insoluble polymer and a pore forming agent.

11. The formulation of claim 10, wherein the water insoluble polymer is present in an amount that exceeds the amount of the pore-forming agent.

12. The formulation according to any one of claims 1 to 11, wherein the composition is in the form of spheronized pellets.

13. The vitamin D compound is 25-hydroxyvitamin D and / or 25-hydroxyvitamin D 3 The formulation according to any one of claims 1 to 12, wherein

14. The vitamin D compound is 25-hydroxyvitamin D 3 The formulation of claim 13, wherein

15. A spheronized pellet formulation comprising 25-hydroxyvitamin D and a pharma- ceutically acceptable excipient.

16. The formulation of claim 15, wherein the pharma- ceutically acceptable excipient comprises a sustained release polymer.

17. 17. The formulation of claim 16, wherein the sustained release polymer is one or more selected from the group of Eudragit RL PO, Eudragit RS PO, ethylcellulose, and Kollidon SR.

18. 18. The formulation of any one of claims 16 and 17, further comprising at least one pharma- ceutically acceptable excipient selected from one or more of the group of diluents, absorption enhancers, and binders.

19. 19. The formulation of claim 18, wherein the diluent is selected from one or more of the group: lactose, saccharose, glucose, starch, microcrystalline cellulose, microfine cellulose, mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate, amorphous silica, and sodium chloride, starch, and dibasic calcium phosphate dihydrate.

20. 20. The formulation of claim 19, wherein the diluent is a pore-forming agent.

21. 20. The formulation of claim 18 or 19, wherein the absorption enhancer is selected from one or more of the group of triglycerides, medium chain triglycerides, caprylocaproyl macrogol glycerides, and polyglycolized glycerides.

22. 22. The formulation of any one of claims 18 to 21, wherein the binder is selected from one or more of the group: low viscosity hydrophilic cellulose ethers, PVP, carboxymethylcellulose, starch, pregelatinized starch, acacia, tragacanth, gelatin, sodium alginate, and low-substituted hydroxypropylcellulose.

23. A formulation according to any one of claims 18 to 22, wherein said diluent is a spheronisation aid, optionally MCC.

24. 23. The formulation according to any one of claims 18 to 22, wherein the binder is a spheronization aid, optionally low substituted hydroxypropylcellulose.

25. A formulation according to any one of claims 1 to 24, wherein the particles, granules or spheronised pellets are characterised by a friability of less than or equal to 1.0%.

26. The 25-hydroxyvitamin D is 25-hydroxyvitamin D 3 The formulation according to any one of claims 1 to 25,

27. A sustained release vitamin D formulation comprising a vitamin D compound dispersed in a mixture of fatty acid glycerides.

28. 28. The formulation of claim 27, wherein the fatty acid glyceride mixture comprises glyceryl behenate.

29. A nano / microparticle formulation comprising 25-hydroxyvitamin D and a pharma- ceutically acceptable excipient.

30. 30. The nano / microparticle formulation of claim 29, wherein the pharma- ceutically acceptable excipient is a slow release polymer.

31. 30. The nano / microparticle formulation of claim 29, wherein the excipients include an insoluble polymer and a stabilizer.

32. 32. The nano / microparticle formulation of claim 31, wherein the insoluble polymer is selected from a methacrylate polymer.

33. 33. The nano / microparticle formulation of claim 31 or 32, wherein the stabilizer comprises polyvinyl alcohol.

34. 34. The nano / microparticle formulation of any one of claims 29 to 33, characterized by an average particle size in the range of 100 nm to 10 microns, or 900 nm to 10 microns.

35. The vitamin D compound is 25-hydroxyvitamin D and / or 25-hydroxyvitamin D 3 The formulation according to any one of claims 1 to 34, wherein

36. The vitamin D compound is 25-hydroxyvitamin D 3 36. The formulation of claim 35, wherein

37. A lipid microparticle formulation comprising 25-hydroxyvitamin D, optionally calcifediol, and a pharma- ceutically acceptable lipid.

38. 38. The lipid microparticle formulation of claim 37, wherein the pharma- ceutically acceptable excipient is a lipid that is a solid or semi-solid at room temperature.

39. A nonpareil seed formulation comprising 25-hydroxyvitamin D and a pharma- ceutically acceptable excipient.

40. 40. The formulation of claim 39, wherein the pharma- ceutically acceptable excipient comprises a sustained release polymer coating.

41. A sustained release dosage form comprising uncoated granules, particles or pellets, said uncoated granules, particles or pellets comprising a vitamin D compound and a sustained release agent.

42. 42. The sustained release dosage form of claim 41, wherein the vitamin D compound is selected from 25-hydroxyvitamin D.

43. 43. The sustained release dosage form of claim 41 or 42, wherein the sustained release agent is selected from the group consisting of water insoluble polymeric components.

44. 44. The sustained release dosage form of claim 43, wherein the water-insoluble polymer component has pH-independent swelling properties and is permeable and / or dispersible.

45. 44. The sustained release dosage form of claim 43, wherein the polymer component is selected from ammonioalkyl methacrylate copolymers.

46. 46. ​​The sustained release dosage form of any one of claims 43 to 45, wherein the polymer component comprises ethylcellulose.

47. 47. The sustained release dosage form of any one of claims 43 to 46, wherein the polymer component comprises a blend of PVA and PVP.

48. 48. The sustained release dosage form of any one of claims 43 to 47, further comprising a lipophilic compound.

49. The sustained release dosage form according to any one of claims 41 to 48, which is in the form of spheronized pellets.

50. The 25-hydroxyvitamin D is 25-hydroxyvitamin D 3 50. The sustained release dosage form of any one of claims 42 to 49, wherein

51. A pharmaceutical composition comprising 25-hydroxyvitamin D, optionally calcifediol, and a pharma- ceutically acceptable excipient selected from one or more excipients from the group of absorption enhancers, spheronization aids, water-insoluble polymers, and binders.

52. 52. The pharmaceutical composition of claim 51, wherein the absorption enhancer is selected from one or more of the group of triglycerides, medium chain triglycerides, caprylocaproyl macrogol glycerides, and polyglycolized glycerides.

53. 53. The pharmaceutical composition of claim 51 or 52, wherein the spheronization aid is selected from one or more of the group: crospovidone, carrageenan, chitosan, pectic acid, glycerides, β-CD, cellulose derivatives, microcrystalline cellulose, powdered cellulose, polyplasdone crospovidone, and polyethylene oxide.

54. 54. The pharmaceutical composition of any one of claims 51 to 53, wherein the water insoluble polymer is selected from one or more of the group of methacrylate polymers, poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride), poly(ethyl acrylate, methyl methacrylate), cellulosic polymers, ethyl cellulose, low substituted hydroxypropyl cellulose, polyvinyl acetate, polyvinylpyrrolidone, and polyvinyl acetate blended with polyvinylpyrrolidone.

55. 55. The pharmaceutical composition of any one of claims 51-54, further comprising a lipid release modifier, optionally one or more mono-, di-, and tri-acylglycerols of fatty acids selected from one or more of palmitic acid, tallow acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, behenic acid, and combinations thereof.

56. 56. The pharmaceutical composition of claim 55, wherein the lipid release modulating agent is selected from one or more mono-, di-, and tri-acylglycerols of fatty acids selected from one or more of palmitic acid, stearic acid, and behenic acid.

57. 57. The pharmaceutical composition of claim 55 or 56, wherein the lipid release modulating agent has an HLB in the range of 2-6.

58. A spray-congealed lipid vitamin D formulation comprising 25-hydroxyvitamin D, a sustained release agent, and a surfactant.

59. 59. The formulation of claim 58, wherein the sustained release agent is selected from one or more of the group: paraffin, glycerol monostearate, fatty acid esters of glycerol, fatty acid esters of PEG, blends of fatty acid esters of glycerol and fatty acid esters of PEG, lauroyl macrogol glycerides, lauroyl polyoxyglycerides, blends of lauroyl macrogol glycerides and lauroyl polyoxyglycerides, Gelucire, caprylocaproyl macrogol-8-glycerides, glyceryl distearate, Precirol, glyceryl dibehenate, and Compritol 888.

60. 60. The formulation of claim 58 or 59, wherein the surfactant is selected from one or more of the group: PEG, PEG 4000, Tween and Tween 80.

61. 61. The formulation of any one of claims 58 to 60 having a moisture content (KF) of less than 0.30% by weight.

62. 1. An extrusion-spheronized sustained-release vitamin D formulation comprising about 0.01 to about 0.1% by weight of calcifediol, about 40% to about 60% by weight of poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 sustained-release polymer, about 1% to about 5% by weight of a triglyceride, about 30% to about 50% by weight of a mixture of microcrystalline cellulose spheronization aids, and optionally about 1% to about 20% by weight of ethyl cellulose, and optionally about 1% to about 10% by weight of an additional binder, optionally low-substituted hydroxypropyl cellulose or methyl cellulose, wherein the formulation is free of hydrocarbon waxes and hydrocarbon oils.

63. 1. An extruded, spheronized sustained release vitamin D formulation comprising about 0.01 to about 0.1% by weight of calcifediol, about 1% to about 10% by weight of an ethylcellulose sustained release polymer, about 20% to about 40% by weight of a filler, optionally lactose, about 40% to about 60% by weight of a microcrystalline cellulose spheronization aid, about 1% to about 15% by weight of a mixture of triglycerides, and optionally about 1% to about 10% by weight of ethylcellulose, and optionally about 1% to about 15% by weight of an additional binder, optionally methylcellulose or low-substituted hydroxypropylcellulose, wherein the formulation is free of hydrocarbon waxes and hydrocarbon oils.

64. 64. The formulation of any one of claims 1 to 63, having a particle size in the range of about 500 nm to about 2.8 mm.

65. 65. The formulation of claim 64 having a particle size in the range of about 250 microns to about 2.8 mm.

66. 66. The formulation of claim 65 having a particle size in the range of about 250 microns to about 2 mm.

67. The formulation according to any one of claims 1 to 66, characterized by the following in vitro dissolution release profile (USP Apparatus II (paddle with sinker), 75 RPM, medium of 0.5% SDS in 5 mM sodium dihydrogen phosphate monohydrate (pH 6.8, 37±0.5°C), volume 500 mL): Less than 20% in 2 hours, 35% to 45% in 4 hours, 55% to 80% in 6 hours, 65% to 85% in 8 hours, 85% to at least 100% in 10 hours, and 90% to at least 100% in 12 hours.

68. The formulation according to any one of claims 1 to 67, characterized by the following in vitro dissolution release profile (USP Apparatus II (paddle with sinker), 75 RPM, medium of 0.5% SDS in 5 mM sodium dihydrogen phosphate monohydrate (pH 6.8, 37±0.5° C.), volume 500 mL): 14% to 18% in 2 hours, 36% to 45% in 4 hours, 55% to 69% in 6 hours, 74% to 88% in 8 hours, 89% to at least 100% in 10 hours, and 97% to at least 100% in 12 hours.

69. 69. A formulation according to any one of claims 1 to 68, or a dosage form comprising a formulation according to any one of claims 1 to 68, wherein the formulation or dosage form does not contain any hydrocarbon waxes, including paraffin.

70. 70. A formulation according to any one of claims 1 to 69, or a dosage form comprising a formulation according to any one of claims 1 to 69, wherein the formulation or dosage form does not comprise a hydrocarbon oil, including mineral oil.

71. 71. A pharmaceutical batch of dosage forms comprising the formulation of any one of claims 1 to 70, characterized by a dosage form to dosage form variation in in vitro dissolution release of less than 15% RSD or less than 10% RSD at 2, 4, 6, 8, 10, and 12 hours as determined by measurement of six dosage forms (USP Apparatus II (paddle with sinker), 75 RPM, medium of 0.5% SDS in 5 mM sodium dihydrogen phosphate monohydrate, pH 6.8, 37±0.5° C., volume 500 mL).

72. 72. A pharmaceutical batch of a dosage form comprising the formulation of any one of claims 1 to 71 characterized by a batch-to-batch variation in in vitro dissolution release of less than 15% RSD or less than 10% RSD at 2, 4, 6, 8, 10, and 12 hours as determined by measurement of a representative dosage form from six batches (USP Apparatus II (paddle with sinker), 75 RPM, medium of 0.5% SDS in 5 mM sodium dihydrogen phosphate monohydrate, pH 6.8, 37±0.5° C., volume 500 mL).

73. 73. An oral dosage form comprising the formulation of any one of claims 1 to 72.

74. 74. The oral dosage form of claim 73, comprising the formulation of any one of claims 1 to 73 disposed within a capsule shell, optionally an HPMC shell or a hard gelatin shell.

75. 75. An oral dosage form according to claim 73, comprising a formulation according to any one of claims 1 to 74 disposed within a sachet.

76. 80. Use of a formulation or dosage form according to any one of claims 1 to 75 for the manufacture of a medicament for treating a vitamin D responsive disease or condition.

77. 77. The use of claim 76, wherein the medicament is for treating a pediatric patient.

78. 77. The use of claim 76, wherein the medicament is for treating an elderly patient.

79. 79. The use according to any one of claims 76 to 78, wherein the medicament is for administration by a method comprising sprinkling the formulation onto a substrate prior to oral ingestion of the formulation and substrate.

80. 79. The use according to any one of claims 76 to 78, wherein the medicament is for administration by a method comprising dispersing the formulation in a suspending base prior to orally ingesting the formulation and suspending base.

81. The use according to any one of claims 76 to 80, wherein the medicament treats patients with hyperparathyroidism secondary to chronic kidney disease.

82. A method for improving batch-to-batch consistency in the in vitro release profile of a sustained release vitamin D compound formulation, comprising compounding the vitamin D compound with a water-insoluble polymeric material and optionally one or more additional excipients.

83. 83. The method of claim 82, wherein the combining comprises wet granulation.

84. 84. The method of claim 83, wherein said compounding comprises extrusion-spheronization.

85. 85. The method of any one of claims 82 to 84, wherein the water insoluble polymer comprises one or more polymers selected from the group of methacrylic acid polymers and ethyl cellulose.

86. 86. The method of any one of claims 82-85, wherein the one or more additional excipients comprise one or more selected from the group of diluents, absorption enhancers, and binders.

87. A method of producing a sustained release pharmaceutical formulation, optionally a formulation according to any one of claims 1 to 86, comprising further combining a vitamin D compound with a water-insoluble polymer and optionally at least one pharma- ceutically acceptable excipient selected from one or more of a diluent, an absorption enhancer, and a binder.

88. 88. The method of claim 87, wherein the water insoluble polymeric material comprises one or more polymers selected from the group of methacrylic acid polymers and ethyl cellulose.

89. 89. The method of any one of claims 87-88, comprising combining the vitamin D compound and water insoluble polymer with a diluent selected from one or more of the group: lactose, saccharose, glucose, starch, microcrystalline cellulose, microfine cellulose, mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate, amorphous silica, and sodium chloride, starch, and dibasic calcium phosphate dihydrate.

90. 90. The method of any one of claims 87 to 89, comprising combining the vitamin D compound and water-insoluble polymer with a diluent that is a pore-forming agent.

91. 91. The method of any one of claims 87-90, comprising combining the vitamin D compound and water-insoluble polymer with an absorption enhancer selected from one or more of the group: triglycerides, medium chain triglycerides, caprylocaproyl macrogol glycerides, and polyglycolized glycerides.

92. 92. The method of any one of claims 87-91, comprising combining the vitamin D compound and water-insoluble polymer with a binder selected from one or more of the group: low viscosity hydrophilic cellulose ethers, PVP, carboxymethylcellulose, starch, pregelatinized starch, acacia, tragacanth, gelatin, sodium alginate, microcrystalline cellulose, and low substituted hydroxypropyl cellulose.

93. 93. The method of claim 92, wherein the binder is a spheronization aid, optionally MCC.

94. 94. The method of any one of claims 85-93, wherein the combining comprises wet granulation.

95. The method of any one of claims 85 to 94, wherein the compounding comprises extrusion and spheronization.

96. 96. The method of any one of claims 82 to 95, further comprising removing hydrocarbon waxes, and optionally paraffin, from the formulation.

97. 97. The method of any one of claims 82 to 96, further comprising removing hydrocarbon oils, and optionally mineral oils, from the formulation.

98. The method according to any one of claims 85 to 97, wherein the spheronized pellets are spheronized matrix pellets.

99. 99. The method of any one of claims 83-98, comprising creating a liquid mixture of the vitamin D compound, a solubilizing binding agent, and an absorption enhancer, and applying the liquid mixture to a dry composition comprising the water-insoluble polymeric material while mixing.

100. 20. A formulation, dosage form, or method substantially as described herein.

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