Children dosage forms, methods of manufacture and use

Abstract

The present invention relates to children's dosage forms, methods of manufacture and use. In particular, children and regulated release dosage forms of vitamin D compounds and methods of making and using the same are disclosed.

Description

[0001] Division Statement

[0002] This application is a divisional application of the patent application for invention with the application date of August 30, 2019, national application number 201980064183.4, and invention name "Pediatric Dosage Forms, Methods of Manufacture and Use".

[0003] Cross - reference to related applications

[0004] This application claims the benefit of U.S. Provisional Patent Application Serial No. 62 / 725,940, filed on August 31, 2018, and the disclosure thereof is incorporated herein by reference. Technical Field

[0005] The present disclosure generally relates to dosage forms of vitamin D compounds (such as calcifediol), including forms suitable for use in children, and methods of manufacture and use thereof. Background Art

[0006] Traditionally, vitamin D compounds have been administered in immediate-release formulations. More recently, modified-release dosage forms of some vitamin D compounds have been described, such as in the form of wax matrices. The present disclosure relates to vitamin D formulations, including extended-release formulations and formulations suitable for the pediatric patient population. Formulations for delivering active vitamin D, its analogs, and prohormones have been disclosed, including some extended-release dosage forms. One such formulation is sold in the United States under the trade name (calcifediol), which is a product approved for the treatment of secondary hyperparathyroidism in patients with stage 3 and 4 chronic kidney disease (CKD). The prescribing information for this drug specifies a sustained-release formulation for to be a wax-based extended-release formulation of 25-hydroxyvitamin D3. Summary of the Invention

[0007] One aspect of the present disclosure is a vitamin D formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, dispersed in a polymer composition. In an embodiment, the formulation can be, for example, an extended-release formulation for oral use.

[0008] 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 can optionally be swellable. In an embodiment, the formulation can be, for example, an extended-release formulation for oral use.

[0009] Another aspect of the present disclosure is a spheronized pellet formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, and a pharmaceutically acceptable excipient. In an embodiment, the formulation can be, for example, an extended release formulation for oral use.

[0010] Another aspect of the present disclosure is a vitamin D formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, dispersed in a mixture of fatty acid glycerides. In an embodiment, the formulation can be, for example, an extended release formulation for oral use.

[0011] Another aspect of the present disclosure is a nano / microparticle formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, and a pharmaceutically acceptable excipient. In an embodiment, the nano / microparticle formulation can provide extended release of the vitamin D compound, for example, by using an extended release polymer as an excipient.

[0012] Another aspect of the present disclosure is a lipid microparticle formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, and a pharmaceutically acceptable lipid. In an embodiment, the formulation can be, for example, an extended release formulation for oral use.

[0013] Another aspect of the present disclosure is a blank core formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, and a pharmaceutically acceptable excipient. In an embodiment, the formulation can be, for example, an extended release formulation for oral use. In an embodiment, the excipient can include an extended release polymer coating.

[0014] Another aspect of the present disclosure is a pharmaceutical composition comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, and one or more pharmaceutically acceptable excipients selected from the group consisting of absorption enhancers, spheronization aids, water-insoluble polymers, and binders. In an embodiment, the formulation can be, for example, an extended release formulation for oral use.

[0015] Another aspect of the present disclosure is a spray congealed lipid vitamin D formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, an extended release agent, and a surfactant. In an embodiment, the formulation can be, for example, an extended release formulation for oral use.

[0016] Another aspect of the present disclosure is a pharmaceutical batch of a dosage form comprising a formulation according to the present disclosure and further characterized by low between-dosage form variability in in vitro dissolution release. In an embodiment, the dosage form can be, for example, an extended release dosage form for oral use.

[0017] Another aspect of the present disclosure is a pharmaceutical batch of a dosage form, which comprises a formulation according to the present disclosure and is further characterized by low between-batch variability in in vitro dissolution release. In an embodiment, the dosage form can be, for example, an extended-release dosage form for oral use.

[0018] Another aspect of the present disclosure is a method for manufacturing a pharmaceutical formulation and a dosage form. In an embodiment, the method can be a method for manufacturing an extended-release pharmaceutical formulation, which comprises admixing a vitamin D compound with a water-insoluble polymer and optionally further admixing at least one pharmaceutically acceptable excipient selected from one or more of a diluent, an absorption enhancer, and a binder.

[0019] Another aspect of the present disclosure is a method for improving between-batch consistency in the in vitro release characteristics of an extended-release vitamin D compound formulation, the method comprising admixing a vitamin D compound with a water-insoluble polymer material and optionally one or more additional excipients.

[0020] Another aspect of the present disclosure is a method for treating a vitamin D-responsive disease or condition, which comprises administering to a patient in need a formulation or dosage form according to the present disclosure.

[0021] For the compositions and methods described herein, optional features including, but not limited to, components, their compositional ranges, substitutions, conditions, and steps are expected to be selected from the various aspects, embodiments, and examples provided herein.

[0022] A review of the following embodiments in conjunction with the figures will make other aspects and advantages apparent to those of ordinary skill in the art. Although the compositions and methods are susceptible to various forms of embodiments, the following description includes specific embodiments, where it is understood that the disclosure is illustrative and not intended to limit the invention to the specific embodiments described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] To further facilitate understanding of the present invention, 4 drawings are attached herewith.

[0024] Figure 1 Shows the dissolution release characteristics of calcifediol-loaded Eudragit-based pellets according to the present disclosure compared to the dissolution release characteristics of a wax matrix-based soft capsule formulation.

[0025] Figure 2 Shows the dissolution release characteristics of calcifediol-loaded ethylcellulose (EC)-based pellets according to the present disclosure compared to the dissolution release characteristics of a wax matrix-based soft capsule formulation.

[0026] Figure 3Show the dissolution release characteristics of a spray-dried nano / microparticle formulation comprising calcifediol according to the present disclosure, compared to the dissolution release characteristics of a wax matrix-based soft capsule formulation.

[0027] Figure 4 Show the dissolution release characteristics of a spray congealed lipid-based formulation comprising calcifediol according to the present disclosure, compared to the dissolution release characteristics of a wax matrix-based soft capsule formulation.

[0028] Figure 5 Show the dissolution release characteristics of a soft capsule wax-based calcifediol formulation and a nano / microparticle formulation as described in Example 3.

[0029] Figures 6 to 8 Each show the dissolution release characteristics of comparable batches of an Eudragit-based pellet formulation according to the present disclosure, demonstrating batch-to-batch consistency.

[0030] Figure 9 Show the baseline and dose-corrected mean serum calcifediol concentration-time curves of an extended release formulation tested in minipigs according to Examples 1, 2, and 7.

[0031] Figure 10 Show the baseline-corrected serum calcifediol concentration-time curve of an extended release formulation tested in humans according to Example 9. Detailed Description

[0032] There is a need for an improved formulation for the safe delivery of vitamin D compounds, including calcifediol, including extended release formulations and similar improved formulations suitable for delivery to pediatric patients. Embodiments of the present invention meet these needs and provide a range of extended release dosage forms and improved methods for manufacturing such formulations and dosage forms. These formulations can be bioequivalent to commercially approved wax-based systems, but are also capable of providing different in vitro extended release dissolution characteristics and in vivo bioavailability. They can be made suitable for pediatric patient populations as well as adult patient populations, and can be used, for example, to increase serum 25-hydroxyvitamin D levels and thus treat vitamin D deficiency and other conditions, including kidney diseases and disorders.

[0033] The need to develop pediatric 25-hydroxyvitamin D formulations has led to research efforts that have examined several different strategies to achieve a palatable, bioavailable, extended release oral dosage form that is easy to swallow. These strategies include using fluid bed (Wurster) technology, nano / microparticle technology, pellets made using extrusion spheronization technology with and without coatings, coating inert seeds (such as blank cores), and lipid microparticles made by spray congealing / spray freezing / spray cooling.

[0034] The work of formulating age-appropriate extended-release oral formulations has yielded some surprising and unexpected results. For example, although several attempts at spray congealing wax-based mixtures produced extended-release dissolution profiles, none of them adequately matched the target dissolution profiles of the prior wax-based matrix formulations; instead, aqueous polymer pellet formulations using extrusion and spheronization techniques produced improved extended-release formulations of 25-hydroxyvitamin D. Such formulations meet all the criteria required for pediatric use and, additionally, are suitable for adult use based on in vitro dissolution data. In an embodiment, the aqueous polymer pellet formulation can eliminate any need for a coating to obtain a bioequivalent product and provides consistent and reproducible properties and consistent and reproducible in vitro release profiles on a unit-dose and batch-to-batch basis.

[0035] Disclosed and described herein are extended-release vitamin D formulations, including formulations suitable for delivery to pediatric patients in need thereof. Such formulations may also be suitable for treating adults in need thereof, such as for vitamin D deficiency and for secondary hyperparathyroidism and other vitamin D-related diseases and conditions associated with CKD. The formulations and formulation strategies described herein can be used to provide formulations that are bioequivalent to commercially approved extended-release calcifediol formulations but in a form that can be delivered to pediatric patients. Such forms include conventional capsules, "easy-open" capsules or sachets, which can be administered by emptying the entire contents into a small amount of liquid or a small amount of soft food. In addition to developing a variety of suitable formulations for pediatric patients, the present invention also yields a method for improving the variability of dissolution characteristics between unit doses and between batches, and such improved formulations have more consistent in vitro and in vivo dissolution profiles.

[0036] In one aspect, the extended-release formulation comprises a vitamin D compound and an extended-release component. In another aspect, such extended-release formulations are in the form of spheronized pellets or multiparticulates. In one aspect, the formulation comprises spheronized pellets comprising an extended-release component selected from polymeric and / or lipid components. The polymer is selected from water-insoluble polymers and may optionally include water-soluble polymers. The active substance (such as calcifediol) can be embedded in the polymer network for extended release in vivo. In another aspect, the formulation can be a nano / microparticle formulation, such as manufactured by emulsion, followed by spray drying / lyophilization (such as the emulsion-diffusion-spray / dry-freeze drying technique described herein). In another aspect, the formulation can be a powder formulation, such as manufactured by spray congealing. In another aspect, the formulation can be an extended-release coated seed. In another aspect, the formulation can be an active granule.

[0037] Formulations and / or dosage forms according to the present disclosure may be wax-free. 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 paraffin wax. Formulations and / or dosage forms according to the present disclosure may be free of hydrocarbon oils. In embodiments, the formulations and / or dosage forms may be free of mineral oil. In another aspect, the dosage form may be free of a capsule shell. In embodiments, the dosage form may be free of a soft capsule shell. For example, formulations and / or dosage forms according to the present disclosure may be free of hydrocarbon waxes and hydrocarbon oils.

[0038] U.S. Patent Nos. 8,207,149 and 8,361,488 describe prior wax-based formulations that provide 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, a lipid agent, an oily vehicle, and a calcifediol compound, which provide a formulation that is solid or semi-solid at room temperature and semi-solid or liquid at body temperature. U.S. Patent No. 9,861,644 describes a wax-based formulation that is suitable as a therapeutic agent and has a long shelf life. The patent describes that the lipid agent releases calcifediol in the GI tract of an individual, and without intending to be bound by any particular theory of operation, the lipid agent may provide one or more advantageous functions, such as forming a microemulsion of the oily vehicle in GI fluid; providing prolonged gastric retention, such as by bioadhesive properties that cause the formulation to interact with the mucus layer of the stomach and / or intestine; and enhancing the absorption of the calcifediol compound.

[0039] Hard paraffin wax is used as a controlled release agent which produces a solid to semi-solid lipid system at body temperature and produces a formulation that gradually releases the active ingredient through an erosion process. This wax acts as a rate controlling agent and is mainly responsible for the mechanical erosion mechanism. The GI medium penetrates into the wax and subsequently facilitates the slow release of calcifediol. Mineral oil is a mixture of refined liquid saturated aliphatic and cyclic hydrocarbons obtained from petroleum. Mineral oil was used as a vehicle in the previous formulation and can also affect the absorption of calcifediol. Hypromellose in the previous formulation was used as a release stabilizer which helps to stabilize the release of calcifediol on standing / stability. Hypromellose stabilizes the release characteristics of the previous wax formulation over the intended shelf-life of the product. Glyceryl monostearate 40·55 (type I) is an amphiphilic surfactant which forms mixed micelles with lauroyl macrogolglycerides (Gelucire 44 / 14). Gelucire is formed by the esterification reaction between a polar polyethylene glycol (PEG) and a non-polar vegetable oil or fatty acid. The main fatty acids of Gelucires are stearic acid, palmitic acid and lauric acid depending on their grade. These are non-ionic water-soluble or water-dispersible pure surfactants which solubilize and increase the oral bioavailability of hydrophobic APIs such as vitamin D compounds (e.g., calcifediol). Gelucire has unique surfactant characteristics which enhance the solubility and wettability of APIs such as calcifediol both in vitro and in vivo. The improved in vivo drug solubility promotes absorption and thus promotes oral bioavailability. Gelucire is used as an emulsifier / solubilizer which facilitates the dissolution of insoluble calcifediol through emulsification and solubilization mechanisms and thus improves the bioavailability of calcifediol. These lipid agents also have one or more functions such as forming a microemulsion of an oily vehicle in GI fluid; providing longer gastric retention, for example through bioadhesive properties, such that the formulation interacts with the mucus layer of the stomach and / or intestine; and enhancing the absorption of the calcifediol compound. The wax formulation is gradually released through the mechanical erosion and / or gradual disintegration of the waxy composition. The wax as well as the emulsifier can contribute to absorption and can also provide bioadhesive properties for calcifediol. This can enhance the retention of calcifediol in the GI tract and absorb it in a longer and more systematic manner, thus enhancing the biopharmaceutical parameters.

[0040] Insoluble polymer-based formulations as described herein (including its pellet form) release active substances via diffusion and / or corrosion mechanisms.Activating agent (e.g., calcifediol) can be embedded in the polymer network.The surface (e.g., pellet) of the formulation forms capillaries, into which the GI medium infiltrates, promoting the slow release of the activating agent via diffusion through the polymer network in the pellet or other dosage forms.In these formulations, medium-chain triglycerides (e.g., Miglyol) are used as solvents, which enhance the solubility of, for example, calcifediol.In the absence of the additional ingredients selected specifically, there is no microemulsion and bioadhesion mechanism, as in the case of previous wax-based formulations.In these two different formulations, the degree and kinetics of wax and polymer disintegration may also change.

[0041] Unless otherwise stated, formulations and dosage forms, and related methods of making the same, are contemplated to encompass any combination comprising one or more of the additional optional elements, features, and steps further described below, including those shown in the Figures.

[0042] In jurisdictions that prohibit patenting of methods practiced on humans, the meaning of "administering" a composition to a human subject shall be limited to prescribing a controlled substance to be self-administered by the human subject by any technique (e.g., oral, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation consistent with the law or regulation defining patentable subject matter is contemplated. In jurisdictions that do not prohibit patenting of methods practiced on humans, "administering" a composition includes methods practiced on humans as well as the foregoing activities.

[0043] As used herein, the term "comprising" indicates that other reagents, elements, steps or features may be included in addition to those specified.

[0044] Parts by weight are based on the total weight of the thing in question, e.g. by default by the total weight of the region containing vitamin D, or by the total weight of the formulation, where the context or explicit description applies.

[0045] 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 "extended release," "sustained release," and "long-term 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.

[0046] 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. Specifically, it is contemplated that in any of the embodiments described herein, 25-hydroxyvitamin D may consist of or include 25-hydroxyvitamin D3, 25-hydroxyvitamin D2, or a combination of 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2. For example, specifically, it is contemplated that in any of the embodiments described herein, 25-hydroxyvitamin D may consist of or include 25-hydroxyvitamin D3. Unless a specific 25-hydroxyvitamin D form is mentioned, total serum 25-hydroxyvitamin D refers to the sum of all such 25-hydroxyvitamin D forms measured by assay.

[0047] 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 may include 1,25-dihydroxyvitamin D2, 1,25-dihydroxyvitamin D3, or a combination of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3. Specifically, it is contemplated that in any of the embodiments described herein, 1,25-dihydroxyvitamin D consists of or includes 1,25-dihydroxyvitamin D3, 1,25-dihydroxyvitamin D2, or a combination of 1,25-dihydroxyvitamin D3 and 1,25-dihydroxyvitamin D2. For example, specifically, it is contemplated that in any of the embodiments described herein, 1,25-dihydroxyvitamin D may consist of or include 1,25-hydroxyvitamin D2. Unless a specific 1,25-dihydroxyvitamin D form is mentioned, total serum 1,25-dihydroxyvitamin D is understood to refer to the sum of all such 1,25-dihydroxyvitamin D forms measured by assay.

[0048] Whether natural or synthetic, vitamin D compounds can include one or more of any desired vitamin D compounds. In one type of embodiment, the vitamin D compound will include a 25-hydroxy vitamin D compound, such as one or more of 25-hydroxyvitamin D3, 25-hydroxyvitamin D3, or 25-hydroxyvitamin D4. In other embodiments, the vitamin D compound can include 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).

[0049] The vitamin D compound (e.g., via dissolution, mixing, emulsification, or any combination thereof) is mixed with one or more excipients to form a vitamin D formulation as described below.

[0050] The concentration of the vitamin D compound in the formulation according to the invention can be any suitable amount. For example, in one embodiment of the formulation according to the invention (e.g., a formulation including a water-insoluble polymer as an extended release reservoir), the concentration of calcidiol is in the range of about 0.01 wt% to about 1 wt%, or about 0.01 wt% to about 0.6 wt%, or about 0.01 wt% to about 0.3 wt%, or about 0.03 wt% to about 0.09 wt%, such as 0.03 wt%, or 0.06 wt%, or about 0.09 wt%.

[0051] In one aspect, poly(meth)acrylate polymers that are expected to include Eudragit polymers are used for the water-insoluble swellable polymer component. These polymers act as extended-release excipients to form extended-release characteristics. Two main mechanisms may be used for drug release via Eudragit polymers: it is possible to release the drug by erosion or via diffusion. Eudragit polymers are copolymers derived from acrylates and methacrylates, and their physicochemical properties are optionally affected by functional groups. They are generally provided in different physical forms, such as aqueous dispersions, organic solutions, fine 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 methacrylate with a quaternary ammonium group. The copolymer is water-insoluble, but includes ammonium groups present in the form of salts to make the polymer permeable to water. Eudragit RS has relatively fewer ammonium groups and lower permeability (poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate) 1:2:0.1), while Eudragit RL has relatively more ammonium groups and higher permeability (poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2). Eudragit RS and RL exhibit pH-independent swelling in water. The ratio of Eudragit RS to RL in the formulation can be adjusted to obtain the desired release characteristics. The powder forms of Eudragit RS and RL can be used, and in an alternative, granular forms, aqueous dispersion liquids, and organic solutions (such as 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 example of an extrusion-spheronization type formulation according to the present invention, the amount of Eudragit RL PO is in the range of, for example, about 20 wt% to about 80 wt%, or at least 70 wt%. In one embodiment, the weight percentage is in the range of Eudragit RL PO in the 40 wt% to 60 wt% formulation. Such components are preferably used in aqueous wet-extrudable substances, which form granules and are subsequently spheronized to form pellets.

[0052] In another aspect, EC polymers are contemplated as insoluble and non-swelling water-insoluble polymeric materials. These polymers also act as extended release components that slowly release or promote replication of the extended release characteristics of the target or form unique extended release characteristics. Two main mechanisms can be used for drug release via EC polymers: diffusion (concentration-dependent) and erosion. EC is a derivative of cellulose in which some of the hydroxyl groups on the repeating anhydroglucose units are modified to ether groups. The physical and drug release properties of EC can be affected by its molecular weight (indirectly specified by its viscosity, for example), its degree of substitution (ethoxy content), and particle size. For example, EC is commercially available in three classes of ethoxy content called types K, N, and T, which contain 44% to 47.9%, 48% to 49.5%, and 49.6% to 51.0% ethoxy content, respectively. Alternatively, it can be obtained in a so-called "medium" grade with an ethoxy content of 45.0% to 47.0%. In one type of embodiment, the ethoxy content of EC is in the range of about 48% to about 49.5%. The EC viscosity is measured in a 5% solution in a solvent consisting of 80% toluene and 20% ethanol at 25°C. The EC viscosity for the compositions described herein can be in the range of, for example, about 3 cP to about 50 cP, or about 3 cP to about 22 cP, or about 3 cP to about 15.4 cP, or about 6 cP to about 15.4 cP, or about 6 cP to about 11 cP, or about 9 cP to about 15.4 cP, or about 9 cP to about 11 cP. In other embodiments, the EC viscosity for the compositions described herein can be in the range of, for example, about 18 cP to about 110 cP, or 18 cP to 22 cP, or 41 cP to 49 cP, or 90 cP to 110 cP, or 18 cP to 49 cP, or 41 cP to 110 cP. Generally, smaller particle sizes can consolidate more effectively and result in slower release rates, while porosity modifiers can counteract this effect. Although the particle size is not particularly limited, in one type of embodiment, an average particle size greater than 40 microns, or in the range of about 40 microns to about 500 microns, or about 250 to 500 microns, or about 100 microns to about 400 microns, or about 200 microns to about 300 microns is contemplated. Optionally, the particle size can include particles greater than 100 microns, or greater than 140 microns, or greater than 150 microns. For example, EC can be characterized by a viscosity in the range of 9 - 11 cP, an ethoxy 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 particle size of ethyl cellulose can be characterized by a maximum of 150 microns, or 140 microns, or 100 microns; optionally, the minimum particle size can be 3 microns, or 5 microns, or 30 microns. In additional embodiments, ethyl cellulose can be characterized by an average particle size in the range of 5 to 15 microns, or 3 to 5 microns, or 30 to 60 microns.Ethyl cellulose products can be purchased, for example, from Dow Chemical under the trade name Ethocel and grades 4 Premium, 7 Premium, 7FP Premium, 10 Premium, 10FP Premium, 20 Premium, 45 Premium, 100 Premium, and 100FP premium. In one embodiment according to the present disclosure, the amount of EC is in the range of, for example, about 5 wt% to about 60 wt%. In one extrusion-spheronization type formulation embodiment according to the present disclosure, the amount of EC is in the range of, for example, about 5 wt% to about 60 wt%. Other expected ranges include about 1 wt% to about 20 wt%, or about 1 wt% to about 10 wt%, or about 2 wt% to about 10 wt%. These or other EC-based formulations can include lactose monohydrate in a weight percentage of about 20 wt% to 50 wt%. Such components can be used in an aqueous wet-extrudable material that forms granules, which are then spheronized to form pellets.

[0053] In another aspect, low-substituted hydroxypropyl cellulose (L-HPC) polymers are expected to be used for water-insoluble polymer materials. L-HPC is a low-substituted hydroxypropyl ether of cellulose, where a small fraction of the hydroxypropyl groups substitute the hydroxyl groups in the glucose units. Although hydroxypropyl cellulose (molar substitution degree of about 3) is soluble in water and alcohol, L-HPC (molar substitution degree of about 0.2 - 0.4) only swells in water and is insoluble. The substitution degree can alternatively be characterized by the hydroxypropyl content in the polymer. For example, the hydroxypropyl content can be in the range of about 5% to about 15%, or about 8% to about 14%, or about 10% to 12%, or 11%. Similar to EC, the particle size is not particularly limited, and 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 expected. In another aspect, the particle size D90 value can be in the range of about 50 microns to about 200 microns, or about 50 microns to about 135 microns, or about 50 microns to about 125 microns, or about 50 microns to about 100 microns, or about 60 microns to about 80 microns, or about 70 microns, or less than 100 microns. For example, the hydroxypropyl content of L-HPC can be about 11%, the average particle size can be about 20 microns, and the particle size D90 is about 70 microns. Suitable L-HPC is commercially available under the trade name L-HPC LH-31.

[0054] In another aspect, polyvinyl acetate polymer (PVA, CAS No. 9003-20-7) is contemplated for use in water-insoluble polymeric materials. This polymer is also used as an extended-release component in aqueous wet-extrudable substances, which form granules and can be used to form spheronized pellets. In one type of embodiment, the insoluble polyvinyl acetate is blended with polyvinylpyrrolidone (PVP, CAS No. 9003-39-8), for example, such blends are commercially available under the trade name Kollidon SR. For example, for water-soluble PVP, the PVP leaches out of the composition, leaving pores in the PVA component. For example, PVP is characterized by a 1% solution viscosity at 25 °C in the range of about 20 cP to about 40 cP, or about 25 cP to about 35 cP. In an alternative, the weight-average molecular weight of PVP (e.g., measured by light scattering) can be in the range of about 7,000 to about 100,000, or about 25,000 to about 60,000, or 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 about 10:1 to about 1:1, or about 10:1 to about 2:1, or about 8:1 to about 2:1, or about 6:1 to about 2:1, or about 5:1 to about 3:1, for example, about 4:1. Although the particle size is not particularly limited, for one type of embodiment, an average particle size in the range of about 50 microns to about 250 microns is contemplated. Optionally, the PVA / PVP blend can include small amounts of sodium lauryl sulfate (SLS, e.g., 0.8 wt%) and colloidal silica (e.g., 0.2 wt%) as stabilizers, for example, in the form of KOLLIDON SR.

[0055] Drug release from insoluble polymer-based formulations is controlled by erosion and concentration-dependent diffusion mechanisms (Fickian or non-Fickian) through channels or capillaries in the polymer formulation in the dissolution medium - (e.g., channel / porogen agents such as lactose containing EC and hydrophilic HPMC containing Eudragit polymers). As part of the release mechanism, there are different processes: wetting of the polymer formulation with the medium; penetration of the medium into the polymer formulation; phase change 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, these insoluble polymer formulations ideally remain intact during the drug release process. However, the medium penetrates the pellets such that the active pharmaceutical ingredient (API) molecules can diffuse out via the polymer network. In the case of swellable polymers, the size of the polymer formulation also increases with dissolution time, while for non-swellable polymers it generally remains the same. The size of the polymer formulation, the distribution of the drug within the polymer formulation, and the content and properties of the polymer formulation (such as wettability and solubility) are key parameters affecting the process of controlled drug release. Sparingly soluble and slightly soluble active ingredients (e.g., calcifediol) result in delayed release due to their low dissolution rate.

[0056] In yet another aspect, additives such as glyceryl behenate can be used as extended release agents. Such compounds are used as thickening or gelling agents and are suitable as extended release agents and include, for example, glyceryl behenate (e.g., Compritol 888 ATO). It can be added in a weight percentage between 5 wt% and 25 wt%, or between 5 wt% and 40 wt% in a wet granulation aqueous blend. For example, higher concentrations are particularly covered when glyceryl behenate is the primary or sole extended release agent.

[0057] The present inventors demonstrate polymer-based pellet formulations using extrusion and spheronization techniques to provide improved extended release formulations of 25-hydroxyvitamin D. Such formulations meet all the criteria necessary for use in children, but additionally, based on in vitro dissolution data, are also suitable for use in adults. Examples of the extrusion-spheronization process can provide one or more advantages over other methods, including (1) being more cost-effective relative to manufacturing coated beads or pellets; (2) being able to provide formulations bioequivalent to approved extended release calcifediol capsules without a coating step; (3) providing formulations with consistent and reproducible properties between unit doses; and (4) providing a formulation that has consistent and reproducible in vitro release characteristics on a unit dose basis and / or batch basis (e.g., as measured from six sample sizes at dissolution time points of 2, 4, 6, 10, and 12 hours, with an RSD between dosage forms of less than about 16, or about 10 or less, or about 8 or less, or about 7 or less, or about 6 or less, or about 5 or less).

[0058] For example, by providing an average AUC 0-inf , and then orally administering to a human in a fasting state that is 80% to 125% of the average AUC 0-inf , and then orally administering in a fasting state of an approved extended-release calcifediol product, the formulation can be bioequivalent to the approved extended-release calcifediol (e.g., ). In another embodiment, by providing an average AUC 0-inf , and then orally administering to a human in a fasting state that is 80% to 120% of the average AUC 0-inf , and then orally administering in a fasting state of an approved extended-release calcifediol product, the formulation can be bioequivalent to the approved extended-release calcifediol. In another aspect, by providing an average Cmax, and then orally administering to a human in a fasting state that is 80% to 125% of the average Cmax, and then orally administering in a fasting state of an approved extended-release calcifediol product, the formulation can be bioequivalent to the approved extended-release calcifediol. In another embodiment, by providing an average Cmax, and then orally administering to a human in a fasting state that is 80% to 120% of the average Cmax, and then orally administering in a fasting state of an approved extended-release calcifediol product, the formulation can be bioequivalent to the approved extended-release calcifediol. In one aspect, the fasting state can be defined by fasting for at least 10 hours.

[0059] For example, when administered as a single dose of 900 μg to a healthy adult in a fasting state and measured over a 650-hour period, the formulation according to the present disclosure can be formulated to provide an average baseline-adjusted value within 80% to 125%, or 80% to 120%, of one or more of the values set forth in Table 1 below.

[0060] Table 1

[0061] Parameter Value <![CDATA[Serum 25-hydroxyvitamin D3 AUC 0-inf (h*ng / mL)]]> 8879.83 <![CDATA[Serum 25-hydroxyvitamin D3 AUC 0-650hr (h*ng / mL)]]> 6395.80 <![CDATA[Serum 25-hydroxyvitamin D3 Cmax (ng / mL)]]> 22.79 <![CDATA[T 1 / 2el (hours)]]> 325.74 <![CDATA[T max (hour)]]> 24.78

[0062] In another aspect, when administered as a dose of 30 μg to a healthy adult in a fasting state and measured over a 650-hour period, the formulation according to the present disclosure can be formulated to provide an average baseline-adjusted value within 80% to 125%, or 80% to 120%, of one or more of the values set forth in Table 2 below.

[0063] Table 2

[0064] Parameter Value <![CDATA[Serum 25-hydroxyvitamin D3 AUC 0-inf (h*ng / mL)]]> 295.99 <![CDATA[Serum 25-hydroxyvitamin D3 AUC 0-650hr (h*ng / mL)]]> 213.19 <![CDATA[Serum 25-hydroxyvitamin D3 Cmax (ng / mL)]]> 0.76 <![CDATA[T 1 / 2el (hours)]]> 325.74 <![CDATA[T max (hours)]]> 24.78

[0065] In another aspect, the administration as described in the table is administered to stage 3 or 4 CKD patients in a fasting state, and when measured after a six-week period following the start of administration, the formulation according to the present disclosure can be formulated to provide an average baseline-adjusted value within 80% to 125%, or 80% to 120% of one or more of the values described in Table 3 below.

[0066] Table 3

[0067]

[0068] Such spheronized pellets produced by the aqueous wet granulation method described herein may also have other components in the granulation mixture, including absorption enhancers, diluents, and spheronization aids, pore formers, binders, additional extended-release agents, adhesion aids, fillers, and water.

[0069] In another type of embodiment, one or more fatty acid glycerides (such as glyceryl behenate) are contemplated for water-insoluble materials. Glyceryl behenate is a mixture of fatty acid glycerides, mainly behenic acid (such as at least 50% or at least 80% behenic acid). In one type of embodiment, the content of 1-monoacylglycerol can be limited to the range of 12.0 - 18.0%. In another type of embodiment, the glyceride can be characterized as a hydrophobic mixture of monobehenate (12 to 18% w / w), dibehenate (45 to 54% w / w), and tribehenate (28 to 32% w / w) of glycerol with a melting point in the range of 69 to 74 °C and a hydrophilic-lipophilic balance (HLB) of about 2. In another embodiment, the glyceride can be characterized as a mixture of diacylglycerol (40 to 60% w / w), monoacylglycerol (13 to 21% w / w), and triacylglycerol (21 to 35% w / w). Suitable glyceryl behenate is commercially available under the trade name Compritol 888ATO.

[0070] In another aspect, the water-insoluble formulation can be based on one or more water-insoluble polymeric materials and optionally include a lesser amount of fatty acid glycerides. In another aspect, the water-insoluble formulation can be based on fatty acid glycerides and include a lesser amount of one or more water-insoluble polymeric materials.

[0071] In one type of embodiment, the water-insoluble polymeric material is the main material in the formulation, for example, present in an amount of at least 40 wt%, or at least 50 wt%, or from 40 wt% to 90 wt%, or from about 40 wt% to about 80 wt%, or from about 40 wt% to about 70 wt%, or from about 40 wt% to about 60 wt%, or from about 40 wt% to about 50 wt%. For example, a polymer formulation may include from about 50 wt% to about 60 wt%, or about 55 wt% of 1:2:0.2 poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) (e.g., Eudragit RL). As another example, the formulation may include a blend that includes from about 40 wt% to about 50 wt% of the Eudragit RL polymer and a small amount (e.g., 1 wt% to about 10 wt%) of one or more other water-insoluble polymeric materials, such as L-HPC as described herein or EC as described herein or a combination thereof.

[0072] In another type of embodiment, the water-insoluble polymeric material is not the main material in the composition, for example, when the permeability of the water-insoluble polymer is relatively low. For example, the water-insoluble polymeric material may be included in an amount of 1 wt% to about 40 wt%, or about 1 wt% to about 30 wt%, or 1 wt% to about 20 wt%, or about 1 wt% to about 10 wt%, or about 2 wt% to about 10 wt%, or about 3 wt% to about 8 wt%, or about 5 wt%. The composition may further include a release regulator, such as a pore former.

[0073] The formulation may optionally include one or more additional functional additives, including but not limited to release regulators (including pore formers), absorption enhancers, fillers (also referred to as diluents), binders (including dry binders), spheronization aids, flavorants, and lubricants.

[0074] For example, excipients suitable for spheronized pellets as 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 / extended release agents such as glyceryl behenate (Compritol 888 ATO, melting point in the range of 65 °C to 77 °C and HLB of 2); extended release matrix formers / extrusion and spheronization aids such as low-substituted hydroxypropyl cellulose (L-HPC LH-31); adhesion aids such as Methocel K3 Premium LV; lubricants such as talc powder or glyceryl behenate; flavorants such as caramel; and purified water as a process diluent (e.g., to dissolve the binder). The diluent and / or spheronization aid may be present at a concentration of about 30 wt% to about 90 wt%. The absorption enhancer may be present at a concentration of about 3 wt% to about 10 wt%. The adhesion aid such as Methocel K3 may be present at a concentration of about 5 wt% to about 10 wt%. The lubricant such as talc may be present at a weight concentration of about 1 wt% to about 2 wt%. The concentration of the extended release matrix former / extrudate and spheronization aid (e.g., L-HPC LH-31) may be in the range of about 5 wt% to 25 wt%.

[0075] Release regulators 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 one type of embodiment, EC may be used as a water-insoluble polymer (e.g., 1 to 10 wt%, or 5 wt%), and the pore former may be used in a relatively high amount (e.g., 20 wt% to 40 wt%), such as lactose monohydrate. Other examples include about 25 wt%, about 30 wt%, and about 35 wt%.

[0076] The composition may optionally include an absorption enhancer. Examples of suitable absorption enhancers include, but are not limited to, polyethylene glycol glyceryl caprylocaprate, such as polyethylene glycolylated glyceryl esters, also known as polyglycolized glycerides or PEGylated glycerides. Polyethylene glycolylated glycerides that can be used in the composition include, but are not limited to, monoglycerides, diglycerides, and triglycerides and monoesters and diesters of polyethylene glycol, polyethylene glycolylated almond glycerides, polyethylene glycolylated corn glycerides, and polyethylene glycolylated caprylic / capric triglycerides. The HLB value of the absorption enhancer can be 11 to 18, or 13 to 18, or 13 to 16, or 13 to 15, or 11 - 12.

[0077] A preferred absorption enhancer is known under the trade name GELUCIRE (Gattefossé Corporation, Paramus, New Jersey, USA). GELUCIRE is a well-known excipient that belongs to the fatty acid ester family of glycerol and PEG esters, also known as polyethylene glycolated glycerol esters. GELUCIRE is used in various applications, including the preparation of extended-release pharmaceutical compositions. GELUCIRE compounds are inert semi-solid waxy materials that are amphiphilic and can obtain different physical characteristics (such as melting point, HLB, and solubility) in different solvents. It is actually surface-active and disperses or dissolves in an aqueous medium to form micelles, microspheres, or vesicles. It is identified by its melting point / HLB value. The melting point is expressed in degrees Celsius. One or a mixture of different grades of GELUCIRE excipients can be selected to obtain the desired melting point and / or HLB value characteristics. One GELUCIRE composition is a mixture of GELUCIRE 44 / 14, polyethylene glycol glycerol laurate, and polyoxyglycerol laurate, which has 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 the PEG 32 monoester and diester of stearic acid and palmitic acid, with a nominal melting point of 48 °C (in the range of 46 °C to 50 °C) and an HLB of 12. Another polyethylene glycolated glycerol ester absorption enhancer is polyethylene glycol-8-glyceryl caprylocaprate (CAS numbers 85536-07-8 and 84963-88-2). This is a monoester, diester, and triester of glycerol with medium-chain fatty acids and monoester, diester, and triester of PEG400 (C8-C10), which is sold, for example, by Gattefossé Corporation, Paramus, New Jersey, USA under the trade name LABRASOL. LABRASOL has an HLB value of 14 and has the following composition by weight: approximately 4% monoglyceride of C8-C10; approximately 17% diglyceride of C8-C10; approximately 6% triglyceride of C8-C10; approximately 14% monoesters of C8-C10 of PEG 400; approximately 36% diesters of C8-C10 of PEG 400; approximately 20% free PEG 400; approximately 3% free glycerol. Another type of absorption enhancer is triglyceride, such as medium-chain triglyceride. For example, a mixture of C8-C10 triglycerides can be used. In one type of embodiment, the C8-C10 triglyceride can include about 50 to 65% by weight of caprylic triglyceride and about 30 to 45% by weight of capric triglyceride. Suitable triglycerides are commercially available under the trade name Miglyol 812N.The absorption enhancer can be present in any suitable amount, such as from about 1% to about 20% by weight, or from about 1% to about 15% by weight, or from about 1% to about 10% by weight, or from about 3% to about 10% by weight, or from about 5% to about 10% by weight, or from 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 having an HLB greater than 10, such as in the range of 11 to 18, or 13 to 18, for example a release aid, then it also includes a lipophilic excipient, such as an excipient having an HLB less than 10, such as 1 to 6, or 1 to 3, or 3 to 6.

[0078] The formulation may also include one or more fillers, also known as diluents. Fillers include but are not limited to, for example, lactose, sucrose, glucose, starch, microcrystalline cellulose (MCC), microfine cellulose, mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate, amorphous silica, sodium chloride, starch, and calcium hydrogen phosphate dihydrate. In one type of embodiment, the filler is not water-soluble, although it may absorb water. As described above, when mixed with other components (such as a water-insoluble polymer), the filler can act as a pore former. In one type of embodiment, the filler is a spheronization aid. The spheronization aid may include, for example, one or more of crospovidone, carrageenan, polyglucosamine, 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. MCC can have any suitable particle size, such as an average particle size in the range of, for example, about 10 microns to about 200 microns, or about 20 microns to about 100 microns, or about 20 microns, or about 50 microns, or about 100 microns. MCC can be characterized by a crystallinity in the range of, for example, about 60% to about 80%. Suitable commercially available MCC can be obtained under the trade name AVICEL, such as PH grades 101, 102, 104, 105, 112, 113, 200, 200LM, 301, and 302. In one embodiment, the MCC is AVICEL PH 101; in another embodiment, the MCC is AVICEL PH 201.

[0079] The amount of the filler is not particularly limited and can be, for example, at least about 1 wt%, or 5 wt%, or 10 wt%, or 20 wt%, or 30 wt%, or 40 wt%, or 50 wt%, or 60 wt%, or 70 wt%, or 80 wt% and at most about 95 wt%, or about 90 wt%, or about 80 wt%, or about 70 wt%, or about 60 wt%, or about 50 wt%, or about 40 wt%, or about 30 wt%, or an amount within a range formed by any of the foregoing values. For example, the filler can be, for example, in the range of about 1 wt% to about 95 wt%, or about 30 wt% to about 85 wt%, or about 70 wt% to about 90 wt%. The spheronizing aid can be included within such ranges or can be in an amount such as about 35 wt% to about 60 wt%, or about 35 wt% to about 40 wt%, or about 40 wt% to about 60 wt%.

[0080] The formulation can include one or more binders, including dry binders. The binders include, for example, relatively low viscosity hydrophilic cellulose ethers and PVP. In other embodiments, the binder can include carboxymethyl cellulose, starch, pregelatinized starch, gum arabic, tragacanth, gelatin, sodium alginate, low-substituted hydroxypropyl cellulose, and the lowest viscosity grade of hydroxypropyl methylcellulose (HPMC). For example, the binder can be selected from low viscosity hypromellose, such as low viscosity hypromellose having a 2% aqueous viscosity of 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. Suitable low viscosity hydroxypropyl methylcellulose is commercially available under the trade name Methocel K3 Premium LV. For example, the methoxy % of the hypromellose can be in the range of 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 hydroxypropyl % of the hypromellose can be about 5 to about 15, or about 7 to about 12.

[0081] Pharmaceutically acceptable lubricants are known in the art and can include, but are not limited to, stearic acid, magnesium stearate, calcium stearate, aluminum stearate, talc, and silicified talc. In one type of embodiment, the lubricant is talc. Usually a small amount of lubricant can be used, for example, in the range of about 0.1 wt% to about 5 wt%, or about 0.5 wt% to about 3 wt%, such as 0.5 wt%, 0.7 wt%, 1 wt%, 1.5 wt% or 2 wt%.

[0082] The formulation may optionally include a top coat or outer coating to modify the release characteristics. For example, the top coat can be used to delay or slow the release during the initial few hours after administration, e.g., to counteract an initial burst release, or otherwise slow an initial release that is faster than desired. Suitable top coat materials include, for example, film-forming polymers. The top coat material can be water-soluble, such as the water-soluble polymers described herein (e.g., hypromellose, PVP), or water-swellable polymers, which further include a pore former (e.g., EC as described herein and a pore former such as hypromellose). The top coat may optionally include a lubricant, such as talc. A suitable EC top coat material is commercially available under the trade name SURELEASE, sold as an aqueous emulsion dispersion of plasticized EC. A suitable hypromellose pore former can have a 2% solution viscosity at 20 °C of about 3 cP, with the methoxy % in the range of about 19 to about 30, or about 19 to about 24, or about 25 to about 35, or about 28 to 30, and the hydroxypropyl % of about 5 to about 15, or about 7 to about 12. For example, hypromellose can be one commercially available as PHARMACOAT 603. The ratio of the top coat material (e.g., EC) to the pore former (e.g., hypromellose) can be adjusted to obtain the desired release characteristics, and can be, for example, in the range of 80:20 to 20:80, or for example 70:30 to 30:70, or 60:40 to 40:60, such as 65:45, or 60:40, or 55:45, or 50:50. Similarly, the amount of the top coat can be adjusted to obtain the desired release characteristics. The amount of the coated top coat material can be measured as an increase in the weight of the formulation particles, e.g., when the top coat is sprayed onto the particles. For example, the amount of the top coat on the formulation particles can be in the range of about 1 wt% to about 40 wt%, or 1 wt% to about 30 wt%, or about 5 wt% to about 25 wt%, such as 10 wt%, or 15 wt%, 20 wt%, or 25 wt%. Alternative coating materials for achieving delayed release include enteric coating materials, such as those that release based on the pH of the GI medium. Examples of such materials include shellac (aleuritic acid esters), cellulose acetate phthalate, poly(methacrylic acid-co-methyl methacrylate), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), and hydroxypropyl methylcellulose phthalate (HPMCP).

[0083] An alternative method of manufacturing a pediatric formulation according to the present invention involves preparing and using nano / microparticles. The nano / microparticles are colloidal carriers that exhibit great potential in providing each oral drug administration. In this type of embodiment, a vitamin D compound (e.g., calcifediol) can be encapsulated in a liquid oily core surrounded by a solid shell material of an extended release polymer.

[0084] The emulsion-diffusion-spray drying / freeze drying technique can be used to prepare extended-release nano / microparticles. For APIs with poor water solubility (e.g., calcifediol), the single emulsion technique is more desirable.

[0085] The emulsion can be converted into a powder formulation using freeze drying or spray drying techniques. The solvent blend used for homogenization to form the emulsion can include a discontinuous phase solvent such as ethyl acetate and a continuous solvent such as water. The final formulation of the extended-release particles can be in the form of an aqueous suspension, a non-aqueous suspension (e.g., having triglycerides such as fatty acid triglycerides), or can be presented in a spray form in a capsule.

[0086] For example, Eudragit RL PO can be used as an extended-release polymer, and poly(vinyl alcohol) can be used as an emulsion stabilizer. For example, the amount of Eudragit and the stabilizer can be in a weight ratio range of, 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 extended-release polymer can widely range from 0.5 wt% to 98 wt%, and in some embodiments, for example, it can be in the range of 75 wt% to about 98 wt%. The amount of the polymer (e.g., Eudragit and poly(vinyl alcohol)) and the API can be in a weight ratio range of, 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. In an alternative, EC or other extended-release polymers described herein can be used as a solid shell material. The release characteristics can be adjusted by varying the extended-release polymer type and the polymer ratio, for example, to form a slow-release characteristic comparable to the target characteristic, such as the previous wax-based calcifediol system. Various exemplary formulation methods are shown in Table 4 below.

[0087] Table 4

[0088]

[0089] An exemplary method of the manufacturing process is described in Table 5 below. Those skilled in the art will understand that this sequence is representative and not restrictive.

[0090] Table 5

[0091]

[0092] The processing and product parameters can vary and include inlet temperature, draw percentage, column air flow, cyclone size, homogenization speed and conditions, polymer solvent concentration, discontinuous to continuous phase ratio, to provide an acceptable product yield.

[0093] In addition to the dehumidifying granulation / pelletization and spray drying of emulsions, spray congealing is an alternative process for producing formulations according to the present disclosure, including extended release formulations of vitamin D compounds such as calcidiol. If desired, the process can be solvent-free. The hot melt process can include spray cooling / congealing, for example to produce small particle sizes. Spray cooling, also known as spray congealing or spray freezing, is the process of transforming a melt into well-defined spherical particles, for example. This process uses spray drying technology and rapid freezing processes. For example, it can produce free-flowing lipid microparticles in the size range of about 10 microns to 1000 microns. For example, cold nitrogen gas can be circulated through a column or other vessel while a hot melt mixture of lipid, API (e.g., calcidiol), and optionally a surfactant is sprayed into the column to form a fine particle mist. The particles can optionally be coated with a top coat of extended release polymer and pore former.

[0094] Lipids that are solid or semi-solid at room temperature can be used as extended release aids, and surfactants can be used to assist in the solubility and complete release of the API. Such lipids include, but are not limited to, one or more of paraffin, glyceryl 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 point in the range of 50°C to 60°C, and HLB of 2), and glyceryl dibehenate (e.g., Compritol 888ATO). 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 modulate drug release for oral delivery. Other lipids can be selected from mixtures of monoacylglycerols, diacylglycerols, and triacylglycerols of fatty acids selected from palmitic acid, tallowic acid, stearic acid, oleic acid, linoleic acid, linolenic 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 of PEG (e.g., PEG6000) and Tween (e.g., Tween 80).

[0095] Spray congealing can be carried out using a suitable spray congealing unit in a closed-loop device (e.g., supplied by Büchi, Flawil, Switzerland, GEA Group, Düsseldorf, Germany or ProCepT N.V., Zelzate, Belgium). A cooler can be used to cool the gas in the column. Nitrogen can be used through the system in order to obtain a temperature below 0 °C in the system. The melt temperature can be kept as low as possible. The melt can be sprayed through a heated two-fluid nozzle. The product can be dosed through a pressure vessel. Exemplary process parameters are described in Table 6 below.

[0096] Table 6

[0097] Heating bath nozzle (°C) 70 to 90 Product temperature (°C) 60 to 90 Chiller temperature (°C) -30 Internal temperature (°C) -20 Temperature outside the chamber (°C) 0 to - 2.5 Temperature before cyclone (°C) 0 to - 2.5 Cyclone pressure drop (mbar) 10 to 13 <![CDATA[Internal air flow (m 3 / min)]]> 0.7 Two - fluid nozzle (mm) 1 Nozzle gas (l / min) 4 Pressure on the barrel (bar) 0.4 to 1 Dosing rate (g / min) 20 to 70 Cyclone size used Large

[0098] Formulations containing an active agent can be prepared in any suitable form. A pharmaceutical formulation can constitute the entire dosage form, or it can be a region of the dosage form, such as a core or a coating (e.g., on an inert seed core, such as a blank pellet). In one type of embodiment, the formulation is in particulate form and is optionally top-coated. The particles can be of any size or shape, such as pellets or mini-tablets. In another type of embodiment, particles containing the active agent are manufactured and subsequently compressed, for example, into the form of tablets, lozenges or dragees. In another type of embodiment, the particles containing the active agent (optionally coated) are filled into a capsule shell, sachet or cartridge, resulting in a multi-particle dosage form. Compared to a monolithic matrix tablet, multi-particles (a dosage form made up of multiple particle units, such as pellets or mini-tablets) provide an increased surface area, allowing for preferred release characteristics and bioavailability. Unlike monolithic matrix tablets, multi-particles are evenly dispersed throughout the GI tract. Multi-particles are less sensitive to dose dumping and their therapeutic effect is more predictable and reproducible than that of monolithic reservoir-type (matrix) formulations. Compared to matrix tablets, pellets reduce the likelihood of a burst effect and minimize inter- and intra-individual variability within the GI tract. Compared to a single-unit matrix tablet, multi-particles have a lower risk of local irritation due to their carrying of trace amounts of drug. In the case of a monolithic matrix tablet, the GI transit rate depends largely on the gastric emptying rate and GI motility, but multi-particles (e.g., pellets) have a highly reproducible GI transit rate due to their relatively small size, and thus the inter- and intra-individual variability is minimal compared to single-unit formulations. Other advantages of multi-particles (e.g., pellets) over monolithic matrix tablets include: providing excellent flow properties, a high encapsulation rate, low brittleness, providing flexibility for different drug substances requiring different release patterns, can be combined with a single dose unit, and, unlike monolithic matrix tablets, having the flexibility to adjust the dose by using a higher or lower amount of pellets.

[0099] The capsule should optionally be an HMPC shell or a hard gelatin shell. In another type of embodiment, the fine granules prepared by aqueous wet granulation can be directly compressed into tablets or microtablets or minitablets, which may or may not be coated.

[0100] In one type of particulate form, the particle size (diameter) is in the range of 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. By way of example, the target particle size can reach 2.5 mm, with a variation of no more than 10% at this size and 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 foregoing ranges or amounts. When the particle size becomes too large, the particles are too large to be used in pharmaceuticals labeled for administration by spraying on a substrate (e.g., on 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 related method of administration, the multi-particles according to the present disclosure can be dispersed in a suspension matrix and administered in the form of a powder for oral suspension. By way of example, the suspension matrix can include, for example, purified water and optionally together with one or more excipients. The suspension matrix can, for example, include at least 50% by weight of water, more than about 50% by weight of water, at least about 80% by weight of water, at least about 90% by weight of water, at least about 95% by weight of water, at least about 99% by weight of water, or 100% by weight of water. By way of example, the suspension matrix can be a sugar-based syrup. The suspension matrix can optionally include a suspending agent or a thickening agent. Suitable suspending agents and thickening agents include, for example, methylcellulose, starch, xanthan gum, and glycerol. In another embodiment, the suspension matrix is non-aqueous, for example containing or consisting of triglycerides.

[0101] In the case of the spray-type dosage form, a narrow particle size distribution with a desired size less than 1.0 mm, optionally less than 0.5 mm, is desired to avoid a gritty feeling and an unpleasant taste in infants. Sugar spheres are preferred over MCC spheres because the sweetness of the sugar can also be used as a taste masking aid.

[0102] As another alternative, layered formulations are contemplated. Formulations of this type include a starter seed (e.g., a blank core) having a layer of a vitamin D compound, which further has a sealing coat (e.g., a low viscosity hydroxypropylmethylcellulose) to smooth the seed surface after API layering / coating and also to enable a uniform coat in subsequent stages. Above the sealing coat is an extended release polymer coat (e.g., a water-insoluble polymer such as the polymers with pore formers described herein). If desired, this embodiment can further include an optional taste masking coat and another optional sealing coat over the extended release polymer coat and under the taste masking coat.

[0103] In one type of method, for example, seeds (also referred to as pellets or spheres) can be prepared by one or more methods including spheronization extrusion, rotary fluid bed processing, and spray congealing. The seeds can optionally have an API within the seed itself, e.g., in the range of 0.01 wt% to 10 wt% of the seed. These seeds are coated with one or more coats, e.g., using fluid bed processing with the Wurster coating technique. For example, the first sealing coat of the seeds can be in the range of 1 wt% to 5 wt% based on the weight of the seeds, and the functional release coat is in the range of 3 wt% to 50 wt% based on the weight of the seeds. An optional second sealing coat can be present, e.g., in the range of 1 wt% to 5 wt% based on the weight of the seeds; and a second functional release coat, e.g., in the range of 3 wt% to 50 wt% based on the weight of the seeds. After the optional second functional release coat, a third optional sealing coat can be present, e.g., in the range of 1 wt% to 5 wt% based on the weight of the seeds. The formulation can also include an aesthetic (non-functional) coat, e.g., in the range of 1 wt% to 5 wt% based on the weight of the seeds.

[0104] In another type of method, inert blank cores can be used and coated with different layers to obtain the desired release characteristics, for example using fluid bed processing with the Wurster coating technique. In this method, inert blank cores having a specific average size or range (e.g., in the range of 150 μm to 1000 μm) can be selected. A drug-loaded layer is fabricated on the seeds, for example with a loading of 0.01 wt% to 10 wt% of the seeds. These seeds are coated with one or more coatings, for example using fluid bed processing with the Wurster coating technique. For example, the first sealing coating of the drug-coated seeds can be in the range of 1 wt% to 5 wt% based on the weight of the seeds, and the functional release coating is in the range of 3 wt% to 50 wt% based on the weight of the seeds. An optional second sealing coating can be present, for example in the range of 1 wt% to 5 wt% based on the weight of the seeds; and a second functional release coating, for example in the range of 3 wt% to 50 wt% based on the weight of the seeds. After the optional second functional release coating, a third optional sealing coating can be present, for example in the range of 1 wt% to 5 wt% based on the weight of the seeds. The formulation can also include an aesthetic (non-functional) coating, for example in the range of 1 wt% to 5 wt% based on the weight of the seeds.

[0105] The excipients of the seeds and coating materials can be selected from those known in the art, including those described herein. For example, the blank core material can be selected from microcrystalline cellulose, silica, mannitol, other sugars, and combinations thereof. The functional coating excipients can be selected from cellulose, HPMC, ethyl cellulose, waxes, glyceryl monostearate, acrylic polymers (including Eudragit), and combinations thereof. The sealing coating excipients can be selected from cellulose, such as HMPC. The pore formers can be selected from cellulose, HMPC, and lactose. Plasticizers can be used for the functional and aesthetic coatings, and can be selected from, for example, dibutyl sebacate, triethyl citrate, and PEG. The aesthetic coating materials can be selected from hydroxypropyl methylcellulose, polyvinyl alcohol, and commercial coating products, such as coatings. The coatings can be applied in the form of aqueous or non-aqueous solutions.

[0106] The final dosage form can have any desired amount of vitamin D compound per unit dose. For example, the capsule shell can be filled with sufficient formulation material, such as fines, granules, or pellets, to produce a dosage form having an amount of calcifediol in the range of 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, such as 30 μg, or about 60 μg, or about 90 μg. Dosage forms other than capsules, such as sachets, pills, or lozenges, can have the same or similar strength. Dosage forms, including fines, pellets, sachets, capsules, etc., can be stored with a desiccant.

[0107] As described below in connection with examples, various exemplary dosage forms (e.g., EC-based formulations) exhibit in vivo exposure characteristics that are different from currently approved extended-release calcifediol capsule products. Administration of such products is expected to be adjusted proportionally based on their in vivo exposure characteristics (e.g., compared to an extended-release capsule, based on AUC(0-inf), or compared to an extended-release capsule, based on AUC(0-t)). For example, the pellets of Example 9 can have 60 mcg of calcifediol instead of 30 mcg of an extended-release capsule.

[0108] In principle, the formulations described herein can be characterized by any extended-release feature.

[0109] In one type of embodiment, the target dissolution characteristics of the formulations according to the present disclosure can be within the specification limits of the in vitro dissolution characteristics of an extended-release 25-hydroxyvitamin D capsule (30 mg) in a lipophilic wax matrix formulation (Table 7) (e.g., ). Specification limits can be applied based on the dissolution of individual units. For example, ≤30% of the labeled value dissolves in 2 hours; 53 - 78% of the labeled value dissolves within 6 hours, and ≥80% of the labeled value dissolves in 12 hours. For example, the following dissolution method can be used to measure dissolution.

[0110] USP equipment II (paddle with settling flakes) RPM 75 Medium 5 mM monosodium dihydrogen phosphate monohydrate containing 0.5% SDS, pH 6.8, 37 ± 0.5 °C Volume (mL) 500

[0111] Figure 1 Comparative in vitro dissolution release characteristics of such 30 μg dosage forms are shown, representing 52 commercial batches. The results are classified as relatively "slow", "medium", and "fast" release characteristics. Relative standard deviation is evaluated among all dissolution release characteristics.

[0112] Table 7

[0113]

[0114] The difference (Δ) between A and C at a given time point is approximately 3% at the 2-hour time point; 11% at the 4-hour time point; 15% at the 6-hour time point; 13% at the 8-hour time point; 8% at the 10-hour time point; and 3% at the 12-hour time point. The formulations of the present invention can be designed to substantially match any one or a combination thereof (e.g., the average of any two or the average of all three A, B, and C) of formulations A, B, or C. For example, the formulation can be characterized by in vitro dissolution release values: 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, such as the dissolution release characteristics being 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% active release at 2 hours; 35% to 45% at 4 hours; 55% to 80% at 6 hours; 65% to 85% at 8 hours; 85% to at least 100% at 10 hours; and 90% or more (e.g., 90% to 110%) at 12 hours. In another embodiment, the formulation is characterized by an in vitro dissolution release profile with 14 to 18% release at 2 hours; 36% to 45% at 4 hours; 55% to 69% at 6 hours; 74% to 88% at 8 hours; 89% to at least 100% at 10 hours; 97% or more (e.g., 97% to 110%) at 12 hours.

[0115] In an alternative, formulations according to the present disclosure can be manufactured to form unique or customized extended release dissolution profiles. Formulations according to the present disclosure can also have consistent in vitro dissolution profiles between unit doses with limited variability within a batch or between batches. For example, the dissolution profile can be measured at 75 RPM using USP Apparatus II (paddle with a sinker), where the medium is 5 mM monosodium dihydrogen phosphate containing 0.5% SDS, pH 6.8, 37 ± 0.5 °C, and a volume of 500 mL. In one embodiment, as measured from six dosage forms, the variability can be expressed as the RSD (%) at any dissolution time point of 2 hours or more. For example, the RSD can be at the dissolution points of 2, 4, 6, 8, 10, and 12 hours. In another embodiment, the RSD can be at the dissolution points of 4, 6, 8, 10, and 12 hours. In another embodiment, the RSD can be at the dissolution points of 2, 6, and 12 hours. For example, as demonstrated in the following examples, such RSD values can be less than 16%, or 10% or less, or 8% or less, or 6% or less, or 5% or less.

[0116] Methods for preparing formulations and final dosage forms in accordance with the present disclosure are also contemplated. Formulations comprising a vitamin D compound can be manufactured by any suitable method, including but not limited to direct compression, granulation, extrusion, fluid bed coating, or any combination thereof.

[0117] Such methods include aqueous extrusion / spheronization to produce fine granules / pellets suitable for extended release formulations containing vitamin D compounds such as 25-hydroxyvitamin D or calcidiol, coating methods for coating seeds or fine granules containing the active agent, and methods for manufacturing vitamin D extended release formulations from nano- or micro-particles. An example of a method for preparing a suitable pediatric vitamin D formulation in which the active agent is 25-hydroxyvitamin D or calcidiol includes aqueous extrusion / spheronization to form multi-particle fine granules / pellets, which may be uncoated or coated. Controlled release polymers suitable for preparing such fine granules may be selected from, for example, Eudragit RL PO, Eudragit RS PO, EC, L-HPC, LH-31, Compritol 888ATO, and Kollidon SR. In one embodiment, other excipients including binders and / or absorption enhancers, lipid agents, diluents, spheronization aids, flavorants, and pore formers may be used in the aqueous extrusion fine granule formulation. In one embodiment, the pellets are readily made from an extrudable aqueous formulation without the need for an additional coating to achieve the desired extended release in vitro and in vivo. Such methods may include (1) forming an aqueous extrudable material comprising active and inactive excipients; (2) extruding such material to form fine granules containing the active agent; (3) spheronizing the fine granules to form pellets; and (4) drying the pellets. The dried pellets may optionally be coated with a lubricant and / or flavorant such as talc and flavorant. More specifically, the method may include wetting a powder mixture of the API and excipients, forming an extrudate by extrusion, breaking and rounding the extrudate into round pellets by spheronization, and drying the finished pellets. For example, the diameter size of the pellets may range from 200 μm to 2 mm. The aqueous formulation for forming the wet extrudable material may include a substantial percentage of water (wt / wt). The percentage of water may range from 10 wt% to 90 wt%, or at least 50 wt%. The fine granules (aqueous and non-aqueous) produced by this method have the necessary strength and integrity to provide processable, extrudable, and functional spheronized pellets. The pellets may also be referred to as beads or spheres. The enhanced properties may include one or more properties including most preferably flow characteristics; reproducibly providing into capsules or other drug delivery vehicles; most preferably density / hardness characteristics for handling and coating if desired; increased hardness and brittleness (e.g., not exceeding 1.0%); and more consistent inter-batch in vitro and in vivo drug delivery and release characteristics. The pellets may provide one or more benefits including: free dispersion in the GI tract, thereby improving drug absorption, minimizing dose dumping, reducing peak plasma fluctuations, and minimizing side effects; avoiding high local concentrations of the API in the GI tract; reducing processing steps, e.g., by avoiding the use of coatings; improving flow characteristics, e.g., for capsule or sachet filling; providing a narrow particle size distribution; and providing uniform encapsulation characteristics.

[0118] In one embodiment, a formulation is formed by granulating a mixture of a vitamin D compound with a material (such as a water-insoluble polymer) and one or more other optional excipients, and optionally adjusting the formulation method to a desired particle size range, for example via extrusion parameters and / or optionally in combination with one or more steps including screening, fractionating screening, and milling. In another embodiment, a formulation can be formed by extruding and spheronizing a mixture of a vitamin D compound with a material (such as a water-insoluble polymer) and one or more other optional excipients as described herein. For example, an extruder can be equipped with an extrusion screen of a desired size (such as 0.1 mm to 5 mm, or 0.5 mm to 2 mm). Additionally or alternatively, a spheronizer can be equipped with plates of a desired size and configuration, such as a cross-hatched plate of 0.1 to 5 mm, or a cross-hatched plate of 0.5 to 2 mm. Granulation methods can include, for example, fluidized bed granulation, wet granulation, hot melt granulation, and spray congealing. Other methods include tableting and roller compaction. As is generally known in the art, the mixture to be granulated can be dry-blended first. Before extrusion, the dry-blended dry components can be mixed with water.

[0119] For example, in one embodiment of a method for producing spheronized pellets, the dry components are combined, blended, and mixed with about 50 wt% to 80 wt% water and wet granulated to form a wettable extrudable mass. The blend, extrusion, spheronization, and drying of the extrudable mass of the combined components in weight ratios selected depending on the extended release polymer and excipients are carried out to form the desired pellets for pediatric or adult formulations. For example, a mixture of calcifediol and triglyceride can be added to a blend of pre-mixed dry excipients, and then a binder solution can be added to prepare a wet mass for extrusion. Drying can be accomplished, for example, by tray drying, vacuum drying, or fluidized bed drying.

[0120] The sequential method of the manufacturing method is described in Table 8 below. Those skilled in the art will understand that this sequence is representative and not restrictive.

[0121] Table 8

[0122]

[0123] It has been found that the extrusion and spheronization of a mixture of a vitamin D compound with an extended release component (such as a water-insoluble polymer) as described herein can provide desired vitamin D-containing polymer particles (such as containing calcifediol) having dissolution and release characteristics similar to or equivalent to those of a commercially available extended release wax matrix formulation of calcifediol (such as ) type formulations can fill the following compositions into soft In the phyto-polysaccharide shell: 0.02% of calcifediol by weight of the capsule filling, 20.0% of paraffin by weight of the capsule filling, 35.34% of mineral oil by weight of the capsule filling, 10.0% of hypromellose by weight of the capsule filling, 22.56% of monoglycerides and diglycerides by weight of the capsule filling, 9.75% of polyoxylglyceryl laurate by weight of the capsule filling, 2.32% of absolute alcohol by weight of the capsule filling, and 0.02% of BHT by weight of the capsule filling.

[0124] The formulations described herein can be processed directly as a finished dosage form or they can be further processed to make a finished dosage form. For example, the formulation can be top-coated. Coating can be done by fluidized bed coating, for example, with a top, tangential, or bottom spray configuration. As another example, the formulation can be compressed into the form of, for example, pills or lozenges. In another type of embodiment, the granules (optionally coated) of the formulations described herein are filled into a capsule shell or can be in the form of a cachet or can be provided with a suspension as a vehicle to suspend these pellets prior to administration.

[0125] The dissolution characteristics of an extruded / spheronized calcifediol pill batch described in the following examples and employing Compritol 888 ATO were shown to decline with accelerated storage stability testing. The lipid-containing formulations described herein (e.g., formulations containing Gelucire or Compritol components) can be thermally cured to stabilize the formulation against structural changes during long-term storage. In the absence of thermal curing, the lipid components can migrate over time during storage, blocking hydrophilic sites or pores and thus altering the dissolution release characteristics compared to the formulation at time zero. Further optionally, formulations described herein having a higher melting point lipid can be admixed with a lower melting point lipid such that the formulation can be thermally cured at a lower temperature. For example, a formulation containing glyceryl behenate (e.g., Compritol 888 ATO) having a melting point in the range of 65°C to 77°C and an HLB of 2 can be admixed with or partially replaced by diglyceryl stearate / palmitostearate (e.g., Precirol ATO 5) having a melting point in the range of 50°C to 60°C (e.g., 54°C) and an HLB of 2 such that thermal curing can be carried out at about 60°C and below 65°C (relative to glyceryl behenate), thereby avoiding degradation of calcifediol. Optionally, thermal curing can be carried out over a period of minutes to weeks, such as 1 hour to 1 week, or 1 to 24 hours, such as 2 hours, 3 hours, 4 hours, 6 hours, 12 hours, or 24 hours, or 48 hours, or 72 hours, or 96 hours, or one week.

[0126] Administration of the dosage forms according to the present disclosure can be based on the weight of the active ingredient in the formulation. For example, administration of a formulation containing calcifediol can be in an amount of 1 μg of calcifediol to about 1 g of calcifediol. The dosage form can be administered orally to a patient suffering from a condition of a designated vitamin D compound, the conditions including but not limited to vitamin D deficiency, vitamin D insufficiency, secondary hyperparathyroidism associated with CKD (such as any one of stages 1 to 5 of CKD, including stage 3, stage 4, stage 5, or stage 3 - 5 or stage 3 - 3). In any method or use described herein, treatment of humans is contemplated. In any method or use described herein, treatment of mammals is contemplated. In any formulation, dosage form, use, and method 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 designated diseases and conditions.

[0127] Additionally or alternatively, the formulations described herein can be used to prepare a medicament for treating vitamin D-responsive conditions or diseases.

[0128] The compositions and methods described herein are applicable for the prophylactic or therapeutic treatment of vitamin D-responsive diseases, i.e., diseases in which 25-hydroxyvitamin D or active vitamin D (e.g., 1,25-dihydroxyvitamin D) prevents the onset or progression of the disease or reduces the signs and symptoms of the disease. Such vitamin D-responsive diseases include hyperparathyroidism, secondary hyperparathyroidism due to CKD (e.g., independently or within any one of stages 1, 2, 3, 4, or 5), secondary hyperparathyroidism due 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). It has been observed that active vitamin D (e.g., calcitriol) induces cell differentiation and / or inhibits the in vitro cell proliferation of many cells. Vitamin D-responsive diseases also include autoimmune diseases, such as type I diabetes, multiple sclerosis, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma, fibrosis, Grave's disease, Hashimoto's disease, acute or chronic transplant rejection, acute or chronic graft-versus-host disease, inflammatory bowel disease, Crohn's disease, systemic lupus erythematosus, Sjogren's Syndrome, eczema and psoriasis, dermatitis (including atopic dermatitis, contact dermatitis, allergic dermatitis, and / or chronic dermatitis). 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 ovary syndrome, pancreatitis, nephritis, hepatitis, and / or infection. It has also been reported that vitamin D-responsive diseases include hypertension and cardiovascular diseases. Thus, the methods encompass the prophylactic or therapeutic treatment of individuals at risk of developing cardiovascular diseases, such as individuals with 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 related diabetic dyslipidemia and mixed dyslipidemia, hypoalphalipoproteinemia, hypertriglyceridemia, hypercholesterolemia, and low HDL (high density lipoprotein)), metabolic disorders (e.g., metabolic syndrome, type II diabetes, type I diabetes, hyperinsulinemia, impaired glucose tolerance, insulin resistance, diabetic complications (including neuropathy, nephropathy, retinopathy, diabetic foot ulcers, and cataracts)), and / or thrombosis. It is contemplated that any formulation described herein, including Extended-release capsules for treating or preventing such diseases, e.g., preventing the onset or worsening of a disease, or reducing the signs and symptoms of a disease.

[0129] Patients in need of vitamin D supplementation include healthy individuals and individuals at risk of vitamin D insufficiency or deficiency, such as individuals with stage 1, 2, 3, 4, or 5 CKD; infants, children, and adults who do not drink vitamin D-fortified milk (e.g., lactose-intolerant individuals, individuals with milk allergies, vegetarians who do not consume milk, and breastfed infants); individuals with rickets; individuals with dark skin (e.g., in the United States, 42% of African American women between 15 and 49 years of age are vitamin D deficient compared to 4% of Caucasian women); the elderly (the elderly have a reduced ability to synthesize vitamin D in the skin during sun exposure and are also more likely to stay indoors); adults living in institutions long-term (adults who are likely to stay indoors, including individuals with Alzheimer's disease or mental illness); individuals who cover all exposed skin (e.g., members of certain religions or cultures); individuals who always use sunscreen (e.g., the application of sunscreen with a sun protection factor (SPF) of 8 reduces vitamin D production by 95%, and higher SPF can further reduce skin vitamin D production); individuals with fat malabsorption syndromes (including but not limited to cystic fibrosis, cholestatic liver disease, other liver diseases, gallbladder disease, pancreatic enzyme deficiency, Crohn's disease, inflammatory bowel disease, sprue or celiac disease, or surgical removal and / or bypass of the small intestine or part or all of the stomach and / or intestine); individuals with inflammatory bowel disease; individuals with Crohn's disease; individuals with small bowel resection; individuals with gum disease; individuals taking drugs that increase the catabolism of vitamin D (including phenytoin, fosphenytoin, phenobarbital, carbamazepine, and rifampin); individuals taking drugs that reduce the absorption of vitamin D (including cholestyramine, colestipol, orlistat, mineral oil, and fat substitutes); individuals taking drugs that inhibit the activation of vitamin D (including ketoconazole); individuals taking drugs that reduce calcium absorption (including corticosteroids); individuals with obesity (vitamin D deposited in body fat stores has lower bioavailability); individuals with osteoporosis and / or postmenopausal women.According to the Institute of Medicine's report on the Dietary Reference Intakes for vitamin D, food consumption data indicate that median intakes of vitamin D in younger and older women are below current recommendations; data indicate that over 50% of younger and older women do not consume the recommended amount of vitamin D. Optionally, the method excludes therapeutic treatment of individuals suffering from renal osteodystrophy, including osteomalacia and bone cysts. Administration of any of the formulations described herein (including. extended release capsules) is contemplated to such individuals.

[0130] Formulations described herein with 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 spraying (e.g., on applesauce or other soft foods such as jelly) such that they can be swallowed without chewing. In an alternative, such formulations can be administered via an enteral feeding tube. In these embodiments, capsules containing the particles, or packets or sachets containing the particles, can be opened prior to spraying. For example, easy-open hard gelatin capsules are available from Capsugel under the trade name CONISNAP.

[0131] The formulations can be administered to adult patients or pediatric patients. In an embodiment, a pediatric patient can be, for example, 8 to 17 years old, 12 to 17 years old, 8 to 11 years old, 1 month to 7 years old, 6 months to 8 years old, or 6 years old or younger, or 4 years old or younger, or 2 years old or younger.

[0132] Formulations with a particle size limit of 2.8 mm or less can be encapsulated with instructions for spraying the particles on a soft food (e.g., apple puree) and optionally also swallowing the particles and food without chewing.

[0133] Formulations with a particle size limit of 2.8 mm or less can be encapsulated with instructions for enteral feeding tube administration.

[0134] The formulation can be used with a dosing regimen that includes dose reduction. The dose can be reduced once a week (e.g., a single 30 mcg dose) as needed and no more frequently than once every two weeks if any one of the following four criteria is met: confirmed plasma iPTH < 35 pg / mL (for individuals with stage 3 CKD) or < 70 pg / mL (for individuals with stage 4 CKD), confirmed serum calcium (corrected) > 10.3 mg / dL, confirmed serum total 25-hydroxyvitamin D > 100 ng / mL, or confirmed serum phosphorus > 5.5 mg / dL (12 years to < 18 years) or > 6.0 mg / dL (8 years to < 12 years), provided that the increase in serum phosphorus is associated with calcifediol administration and appropriate and ongoing measures have been taken to control serum phosphorus by initiating or adjusting any phosphate binder therapy.

[0135] Dose reduction can be achieved by consistently omitting the dose on a specific day of the week, e.g., as follows:

[0136] · First dose reduction: On one day of the week, e.g., all Mondays (M), dosing is omitted;

[0137] · Second dose reduction: On two non-consecutive days of the week, e.g., on all M and Wednesdays (W), dosing is omitted;

[0138] · Third dose reduction: On three non-consecutive days of the week, e.g., on all M, W, and Fridays (F), dosing is omitted;

[0139] · On four days of the week, where at least two or three days are non-consecutive, e.g., on all M, W, F, and Sundays (S), dosing is omitted;

[0140] · Any individual requiring further dose reduction discontinues dosing.

[0141] As described above, non-consecutive days of the week can consist of or include alternate days of the week, e.g., M, W, F.

[0142] Examples

[0143] The following examples are provided for illustration and are not intended to limit the scope of the invention.

[0144] Example 1 - Eudragit Polymer Formulation

[0145] Examples 1.1 to 1.4 containing Eudragit-based polymer pellets were manufactured by extrusion-spheronization using the excipients identified in Table 9 below. Calcifediol was dissolved in ethanol. The wet-extrudable mass was prepared, extruded, and spheronized. The extrusion / spheronization process followed the general sequence described in Table 8 above. The extruder was a Caleva bench screen extruder 20 with a screen size of 1 mm and operating at a speed of approximately 30 - 35 RPM. The spheronizer was a Caleva MultiBowl Spheronizer / mbs 250 operating at approximately 1000 - 2500 RPM. The sieves used for sizing were 1.4 mm, 1.0 mm, 850 μm, 500 μm, and 250 μm. The pellets selected in the final different batches were: 500 μm, 850 μm, and 1.0 mm. The average diameter of the pellets of formulation 1.2 was approximately 500 μm, and the average diameter of the pellets of formulations 1.1, 1.3, and 1.4 was approximately 1.0 mm. All particles were analyzed for at least 94% of the intended API and exhibited satisfactory flow properties, friability, and acceptable levels of related substance impurities. By Karl Fischer titration, the pellets contained approximately 4 to 6 wt% or less water.

[0146] Table 9

[0147]

[0148] The dissolution release characteristics of the pellets were measured and compared to the dissolution release of a representative batch of calcifediol extended release wax-matrix extended release soft capsules. 50 mg pellets were filled into hard capsule shells and dissolution release was carried out at 75 RPM using USP apparatus II (paddle with sinker), where the medium was 5 mM monosodium dihydrogen phosphate monohydrate containing 0.5% SDS, pH 6.8, 37 ± 0.5 °C, and volume 500 mL. The dissolution results are as Figure 1 shown and tabulated in Table 10 below for Examples 1.1 to 1.4. The average dissolution time and relative standard deviation (RSD) values were derived from dissolution tests on six capsules.

[0149] Table 10

[0150]

[0151] Example 2 - EC Polymer Formulations

[0152] Examples 2.1 to 2.4 containing EC-based polymer pellets were manufactured by an extrusion-spheronization method using the excipients identified in Table 11 below. The wet-extrudable mass was prepared, extruded, and spheronized. The extrusion / spheronization process followed the general sequence described in Table 8 above. The extruder was a Caleva benchtop screen extruder 20 with a screen size of 1 mm and operating at a speed of approximately 30 - 35 RPM. The spheronizer was a Caleva MultiBowl Spheronizer / mbs 250 operating at approximately 1000 - 2500 RPM. The average diameter of the pellets of Formulations 2.1 and 2.2 was approximately 500 μm. The average diameter of the pellets of Formulation 2.3 was approximately 850 μm. Prior to coating, the average diameter of the pellets of Formulation 2.4 was approximately 850 μm. Example 2.4 included a top coat containing a 60:40 weight ratio mixture of Surelease extended-release polymer and Pharmacoat 603 pore former, coated in an amount of 25% weight gain using purified water as the dispersion medium, and then dried. All pellets were analyzed to at least 93% of the expected API and demonstrated satisfactory flow properties, friability, and related substance impurities at an acceptable level. By Karl Fischer titration, the pellets contained approximately 5.5% weight or less of water.

[0153] Table 11

[0154]

[0155] The dissolution release characteristics of the pellets were measured and compared with those of a representative batch of calcifediol extended-release wax-matrix extended-release soft capsules. 50 mg pellets were filled into hard capsule shells and dissolution release was carried out at 75 RPM using USP Apparatus II (paddle with sinker), where the medium was 5 mM monosodium dihydrogen phosphate containing 0.5% SDS, pH 6.8, 37 ± 0.5 °C, and the volume was 500 mL. The dissolution results are shown in Figure 2 and tabulated in Table 12 below for Examples 2.1 to 2.4. The average dissolution time and relative standard deviation (RSD) values were derived from dissolution tests on six capsules.

[0156] Table 12

[0157]

[0158] Example 3 - Nano / Micron Particles

[0159] A nano / microparticle formulation having 1 part by weight of calcifediol, 25 parts by weight of Eudragit RLPO and 1 part by weight of poly(vinyl alcohol) is prepared by an emulsion-diffusion-spray drying technique. An emulsion is formed with an API and excipients, using ethyl acetate as the discontinuous phase solvent and water as the continuous phase solvent. The emulsion is homogenized and spray dried via a cyclone using a Buchi Mini Spray Dryer B-191, and the general procedure and parameters are described in Table 5 above. The product powder is produced in a satisfactory yield, with particle sizes in the range of about 900 nm to about 10 microns, including spherical to toroidal particles.

[0160] Table 13 below describes the formulated compositions analyzed for dissolution.

[0161] Table 13

[0162] Composition Ratio (w.r.t. API) Calcifediol 1.00 Eudragit RL PO 25.00 Polyvinyl alcohol 1.00

[0163] The batch produced from the above composition yields a fine spray dried powder with a product yield of 53%. Figure 3 An initial comparison is provided in Table 13 of the spray dried formulation compared to extended release 25-hydroxyvitamin D3 capsules of various slow, medium and fast wax-based batches.

[0164] Additional batches of the nano / microparticle formulation are manufactured by the same method, where the formulation differences are according to Table 14 below, to target the release characteristics of the slow and medium soft capsule wax-based formulations as described above. The release characteristics will be as Figure 5 shown.

[0165] Table 14

[0166]

[0167] Example 4 - Spray Congealing

[0168] Batches 4.1 - 4.13 of lipid particles containing calcifediol with one or more lipids and optional surfactants as shown in Tables 15 and 16 below are manufactured by spray congealing. A ProCepT spray congealing unit is used to manufacture the spray congealate in a closed loop apparatus. A chiller is used to cool the gas in the column. Nitrogen is used through the system to obtain a temperature in the system below 0 °C. The temperature of the melt is kept as low as possible. The melt is sprayed using a heated two-fluid nozzle. The product is dosed from a pressure vessel. The process parameters used are described in Table 6 above.

[0169] The product obtained is free flowing and has a size range (d 50) ranges from 100 to 700 μm. Analyzing the calcifediol content and related substances of Examples 4.1 to 4.9 yields at least 86% of the expected amount of calcifediol. The water content of Examples 4.1 to 4.9 is also analyzed by Karl Fischer titration and shows about 0.3 wt% or less water.

[0170] Table 15

[0171]

[0172] Table 16

[0173]

[0174] Figure 4 Shows the release characteristics of various test formulations relative to slow, medium, and fast soft capsule 25-hydroxyvitamin D3 batches. As Figure 4 shown, these examples provide a range of release characteristics with different in vitro dissolution characteristics, demonstrating that the specific formulations used in the method can be varied to provide the desired dissolution release characteristics.

[0175] Example 5 - Batch - to - batch reproducibility

[0176] Two batches related to the formulations of Examples 1.1, 1.2, and 1.4 above are prepared. The batches are consistent except that each comparative batch omits the flavorant (0.5 wt%) and offsets it by including an equivalent increase in the MCC content. Dissolution characteristics are measured at 75 RPM using USP Apparatus II (paddle with sinker), where the medium is 5 mM sodium dihydrogen phosphate monohydrate containing 0.5% SDS, pH 6.8, 37 ± 0.5 °C, and volume of 500 mL. Comparative dissolution release characteristics are shown in Figures 6 to 8 , where the batches without flavorant are designated 1.1a, 1.2a, and 1.4a. The results show that the formulations demonstrate good batch - to - batch consistency.

[0177] Example 6 - Friability test

[0178] Weigh out 10 grams of dust - free pellets from Examples 1.1 and 2.1 and record as the weight before testing (B wt ). Place these pellets together with 200 3 - mm solid glass beads in a friabilator. Rotate the pellets and beads at 25 RPM for 10 minutes. Collect the pellets from the friabilator and gently screen - dust them through a 250 - μm sieve. The weight of the pellet fraction retained on the 250 - μm sieve is recorded as the weight after testing (A wt ). Calculate through the formula ((B wt - A wt ) / B wt) Calculate the crispness % by ×100. The results are shown in Table 17 below (three replicates), demonstrating the good crispness of the formulations according to the present disclosure.

[0179] Table 17

[0180]

[0181] Example 7 - In Vivo Pharmacokinetics in Miniature Swine

[0182] The formulations of Examples 1.1 to 1.4 and 2.1 to 2.4 were used in a single - oral - dose pharmacokinetic study, which was conducted in local male Yucatan minipigs ( Male Yucatan Minipig) weighing approximately 8 to 12 kg on Day 1. Two control arms of wax - matrix - based soft gelatin capsules ( type formulations) and immediate - release oral products were used as control groups. The animals were acclimated for at least 21 days to a 12 - hour light / 12 - hour dark cycle to stabilize their baseline calcidiol 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 sufficient to achieve the study objectives. The animals' food was fasted overnight for at least 10 hours and not fed for at least 4 hours before and after dosing. The animals were also water - deprived for one hour after dosing. Multiple baseline and post - dosing blood samples were collected up to 120 hours after administration of the test article. The concentration of 25 - hydroxyvitamin D3 (calcidiol) in serum was measured using a validated method. The following pharmacokinetic parameters of calcidiol were calculated by a standard non - compartmental method: AUC 0-t : Area under the concentration - time curve from the measured time zero to the last non - zero concentration; C max : Maximum observed concentration; Tmax: Time of observed C max .

[0183] The study was conducted to evaluate the absorption phase of the pharmacokinetic (PK) characteristics of various modified - release calcidiol multiparticulate capsule formulations after a single oral dose of 270 μg, compared to a wax - matrix - based modified - release soft gelatin capsule and an immediate - release calcidiol product administered at oral doses of 270 μg and 266 μg, respectively.

[0184] PK studies showed the prospects of the pellet formulation concept in prolonging the in vivo release of calcifediol. Compared to the formulations containing Eudragit (1.1 to 1.4), a greater extent of absorption (AUC0-t) was observed for the formulations containing ethylcellulose (EC), especially 2.1, 2.2, and 2.3. For all multi-particle formulations, the median time to reach the maximum concentration (Tmax) was in the range between 8 and 16 hours after dosing, while for the wax matrix-based modified release soft capsules of 270 μg and immediate release calcifediol of 266 μg, the median observed Tmax was approximately 24 hours and 4 hours, respectively. See Figure 9 and Table 18.

[0185] Table 18: PK parameters of baseline-corrected (BC) serum calcifediol in local male Yucatan minipigs

[0186]

[0187] Formulations containing Eudragit prolonged the in vivo release of calcifediol (Tmax), although these specific formulations showed relatively lower absorption rates and extents compared to non-Eudragit formulations. Formulations 2.2 and 2.3 showed generally higher absorption profiles, with the Tmax of 2.2 being greater than that of 2.3. Without wishing to be bound by any particular theory, it is believed that the enhanced absorption profiles of the ethylcellulose formulations 2.1 to 2.4 compared to the Eudragit-containing formulations 1.1 to 1.4 can be attributed to absorption-enhancing excipients (such as Miglyol) and soluble excipients (such as lactose and HPMC).

[0188] These formulations demonstrated pellet / multi-particle dosage forms for prolonging the in vivo release of calcifediol.

[0189] Example 8 - Additional EC polymer formulations

[0190] After the study in Example 7, another formulation development session was conducted to explore the dissolution and human pharmacokinetic characteristics of polymer-based pellets produced by the extrusion-spheronization method. In this work, formulation 2.2 was selected as the main formulation, and the development trials were based on this composition.

[0191] Learning from the pig PK data in Example 7, the Eudragit formulations showed relatively lower absorption rates and extents. Without wishing to be bound by any particular theory, it is believed that this may be due to the lower concentration of Miglyol and the higher concentration of the hydrophobic Eudragit polymer. Since the formed Eudragit matrix is hydrophobic, this may prevent the release of hydrophobic calcifediol. However, the hydrophobic matrix helps to prolong the release of calcifediol and thus contributes to the in vivo release of Tmax.

[0192] In contrast, the EC formulation exhibited a higher rate and extent of absorption. Without wishing to be bound by any particular theory, it is believed that the higher rate and extent of absorption in the EC-based formulation can be attributed to the presence of higher concentrations of soluble excipients such as Miglyol, lactose, and HPMC. The presence of such soluble excipients contributes to making the matrix more hydrophilic, and it is possible that this calcifediol is preferably absorbed near this matrix due to this.

[0193] Considering these results, the focus of the research and development was to incorporate soluble excipients into the matrix to promote the solubility / absorption / bioavailability of calcifediol, and at the same time prevent the rapid release of this dissolved calcifediol by using an extended-release matrix former. Additionally, it was also envisioned that since calcifediol is a BCS class IV compound, this formulation system could benefit from an appropriate hydrophilic-lipophilic balance value (HLB), and thus, work was incorporated to meet this hypothesis with a suitable lipid reagent.

[0194] To balance the HLB and prevent the matrix from being hydrophobic, Gelucire was used as a hydrophilic agent with an HLB of 11 to 12, and glyceryl behenate (Compritol 888ATO) was used as a lipophilic agent with an HLB of 2. In view of obtaining a hydrophilic extended-release matrix containing calcifediol, other hydrophilic extended-release agents such as Methocel E50 Premium LV and Methocel K4M Premium CR were also evaluated. Gelucire was also used as a bioavailability enhancer. The Gelucire 48 / 16 grade (PEG-32-stearate, also known as the PEG 32 monoester and diester of stearic acid and palmitic acid, with an HLB of 12 and a CMC of 153 ± 31 mg / L, which helps to improve the solubility of hydrophobic and lipophobic molecules. Based on its physical properties and adaptability to the extrusion and spheronization processes, it is solid at ambient temperature and has a melting point of 48 °C. Compritol 888ATO was used as a lipid extended-release matrix agent, which has a dual purpose, one for the lipophilic part to balance the HLB, i.e., its HLB is 2, and the other for providing extended release with a non-hydrophobic matrix, since Compritol itself is an extended-release agent.

[0195] Examples 8.1 to 8.28 were manufactured by the extrusion-spheronization method using the excipients identified in Table 19 below. The wet-extrudable mass was prepared, extruded, and spheronized. The extrusion / spheronization process followed the general sequence described in Table 8 above, with Comprtol 888ATO incorporated into the DR mixture and Gelucire incorporated into the binder solution with appropriate modifications. The extruder was a Caleva benchtop screen extruder 20 with a screen size of 1 mm and operating at a speed of approximately 30 - 35 RPM. The spheronizer was a Caleva MultiBowl Spheronizer / mbs250 operating at approximately 1000 - 2500 RPM. The average diameter of the pellets was approximately 500 μm. All pellets demonstrated satisfactory flow characteristics, friability, and acceptable levels of related substance impurities. By Karl Fischer titration, the pellets contained approximately 5.5 wt% or less water. Table 19 below also includes the initial analytical results for the calcifediol content upon receipt.

[0196] Table 19

[0197]

[0198]

[0199] Table 19 (continued)

[0200]

[0201]

[0202] Table 19 (continued)

[0203]

[0204]

[0205] *Stored at room temperature for five months

[0206] Typically, 100 mg of the pellets were filled into hard gelatin capsule shells and dissolution release was carried out at 75 RPM using USP Apparatus II (paddle with sinker), where the medium was 5 mM sodium dihydrogen phosphate monohydrate containing 0.5% SDS, pH 6.8, 37 ± 0.5 °C, and a volume of 500 mL. Example 8.16 had a higher concentration of calcifediol and a fill weight of 50 mg. Dissolution results are listed in Table 20 below when available. The average dissolution time values were derived from dissolution tests of six capsules; a comparison with soft gelatin capsules is provided.

[0207] Table 20

[0208]

[0209]

[0210] Table 20 (continued)

[0211]

[0212] Table 20 (continued)

[0213]

[0214] *Stored at room temperature for five months

[0215] Initially, compared to the formulations of Examples 1 and 2, Gelucire 48 / 16 was added to the binder solution and Methocel K3 Premium LV from the binder solution was replaced and added to the dry blend as a dry binder (Examples 8.1 to 8.12). The R&D associated with this process produced more burst effects, releasing 53%-86% calcifediol within 2 hours. Those trials using Gelucire 48 / 16 demonstrated high solubility and rapid release of calcifediol, although the release characteristics could not be fully controlled as desired. These results favored the use of Gelucire as a bioavailability enhancer. These pellets were observed to be relatively soft pellets, and without wishing to be bound by any particular theory, it is believed that the softness of the pellets may be the reason behind the sudden release.

[0216] In view of the foregoing results, in subsequent trials (Examples 8.13 to 8.28) Methocel K3 Premium LV was added to the binder solution and removed from the dry blend. Further R&D of Gelucire 48 / 16 together with Methocel K3 in the binder solution was well suited to the method and also effectively restored the sudden release to <40% within 2 hours. The pellets were also observed to be harder than those in which HMPC was added to the dry blend.

[0217] To compensate for the enhanced solubility provided by Gelucire, further trials were conducted using Compritol and EC as extended release agents to effectively control the release characteristics and provide extended release properties for calcifediol. Some trials were also in the lower content of lactose and lactose without providing slower release. As a general trend of these matrix formulations tested, it was observed that reducing the initial release also reduced the total release. Thus, the formulations were mainly optimized with 20% EC and 20% Compritol as extended release agents and 5% concentration of Gelucire 48 / 16 as a bioavailability enhancer.

[0218] In addition to the development of this release feature, BHT antioxidant was also added to the formulation to provide API stability to the formulation, resulting in a significant decrease in related substances as shown in Table 21.

[0219] To complete the second-phase development work, formulation 8.21 was selected as the second prototype formulation for human clinical studies (Example 9 below). The PK study involved a total of two formulation prototypes. One formulation was based on a conservative approach - i.e., porcine data (the formulation was the same as Example 2.2; new Example 8.27), and the other formulation was an improved formulation of Example 2.2, which was a batch of Examples 8.21 and 8.28.

[0220] Table 21: Effect of BHT on ethylcellulose formulations

[0221]

[0222] *Examples 2.2, 8.2, and 8.4 were manufactured and analyzed under similar conditions and at the same level, so the results were comparable. Example 8.27 was manufactured and analyzed under different conditions, and therefore the related substance results were considered not comparable to those of Examples 2.2, 8.2, and 8.4.

[0223] Example 9: Single-dose oral pharmacokinetic study of two colecalciferol 30 mcg pellet formulations in healthy adult individuals under fasting conditions

[0224] The purpose of this study was to evaluate the pharmacokinetics of two colecalciferol 30 mcg pellet formulations after a single oral dose administration to humans under fasting conditions. This single-dose study was designed according to EMA and FDA regulatory guidelines with the aim of characterizing the bioavailability and PK of colecalciferol in two new formulations in healthy individuals. The primary study endpoint evaluated the baseline-adjusted PK parameters Cmax and AUC 0-T . The purpose of this study was to quantify the rate and extent of absorption from the formulation.

[0225] After a single oral dose administration under fasting conditions, the baseline-adjusted mean peak concentration and exposure of colecalciferol in the formulation of Example 8.27 were slightly higher compared to Example 8.28. For the formulations of Example 8.27 and Example 8.28, the mean Cmax values were 25.65 ng / mL and 22.01 ng / mL, respectively, and the extent of absorption (AUC 0-T) They were 2390.05 ng·h / mL and 2059.61 ng·h / mL, respectively. The time to reach peak concentration (Tmax) between the two formulations was similar. The median Tmax of the formulations of Example 8.27 and Example 8.28 was 6.00 and 6.05 hours, respectively. For unadjusted calcifediol, the trends in mean peak concentration and exposure were the same. However, the magnitude of the difference was smaller compared to the results of baseline-adjusted calcifediol. In summary, the tested formulations were generally safe and well tolerated by the individuals included in this study (see Figure 10 and Table 22).

[0226] Table 22: Summary of Baseline-Adjusted Pharmacokinetic Parameters

[0227]

[0228] a Median (Range)

[0229] b For AUC 0-∞_FDA 、AUC 0-T / ∞ 、AUC 0-∞_EMA and remaining area, n = 8

[0230] c For AUC 0-T ,n = 14

[0231] d For AUC 0-∞_FDA 、AUC 0-T / ∞ 、AUC 0-∞_EMA and remaining area, n = 7

[0232] Example 10: Thermally Cured Formulations for Storage Stability

[0233] Previous batches of Example 8 using Compritol as the matrix agent showed a decline in dissolution characteristics after 3 months of accelerated stability testing at 40 °C and 75% RH. Without wishing to be bound by any particular theory, the change in drug release (decrease) observed after storage under accelerated conditions may be due to an altered distribution of lipid components within the matrix structure; lipids can migrate within the matrix structure and increase the hydrophobicity of the pellet matrix in the absence of appropriate stabilization. The hydrophobicity of the matrix in turn reduces the rate of water diffusion into the matrix and drug diffusion out of the matrix. This can result in slower release kinetics in terms of stability. To reduce the decline in dissolution under these conditions, a curing / sintering step can be used. This additional step will stabilize the lipids in the matrix at the initial stage of formulation manufacture.

[0234] However, high melting point lipids (e.g., glyceryl behenate, Compritol 888 ATO, melting point range 65 - 77 °C) need to be solidified at higher temperatures and thus solidification above this temperature can degrade the API (e.g., calcidiol). Thus, in addition to or partially or fully replacing the relatively high melting point components, relatively low melting point components with similar functional groups can be used. For example, glyceryl distearate / stearyl palmitate (e.g., Precirol ATO 5) is a lipid that is functionally similar to glyceryl behenate while having a lower melting point of 54 °C. Solidification at 60 °C can melt the Precirol in the matrix and provide a cement-like network that will help strengthen and stabilize the Compritol network to prevent further changes during storage, such as during accelerated stability testing.

[0235] The formulation of Example 8.28 described above was altered by adding glyceryl distearate / stearyl palmitate and compensating for changes in other formulation ingredients to prepare formulation Examples 10.1 to 10.5, as described in Table 23 below. The preparation of pellets was generally described in Example 8 above. The Precirol component was added to the dry blend for processing.

[0236] Table 23

[0237]

[0238]

[0239] The resulting pellets of Formulation Examples 10.1 and 10.2 were tested for dissolution characteristics as described in Example 8 above, either in their uncured state or after curing at 60 °C for a certain time, and the initial dissolution results are listed in Table 24 below.

[0240] Table 24

[0241]

[0242] As shown in Table 24, although curing showed some reduction in release, curing generally did not change the initial release characteristics of the formulation.

[0243] Under accelerated stability conditions, i.e., after storage at 40 °C and 75% RH, the cured formulation will exhibit release characteristics more similar to the initial release characteristics, while the uncured formulation will exhibit reduced release characteristics due to the presence of unstable lipids in the formulation.

[0244] Example 11: Pediatric Study

[0245] Phase 3, multicenter, randomized, double-blind, placebo-controlled study conducted primarily or entirely within the United States (US). The study involved approximately 108 eligible individuals, balanced for gender and CKD stage, aged 8 to <18 years, with secondary hyperparathyroidism (SHPT), stage 3 or 4 CKD, and vitamin D insufficiency (VDI). Approximately 72 individuals aged 12 to <18 years (cohort 1) were initially recruited, and an additional approximately 36 individuals aged 8 to <12 years (cohort 2) were recruited. Individuals in both cohorts were randomly assigned to two treatment groups in a 2:1 ratio to receive a daily bedtime dose of (a) the calcifediol extended-release formulation described herein, or (b) a matching placebo for 26 weeks. Individuals assigned to treatment with the calcifediol formulation in group 1 were initiated on 30 micrograms per day and, at the end of 12 weeks of treatment, were up-titrated to 60 mcg per day if (a) plasma iPTH had not decreased by at least 30% from the pre-treatment baseline, (b) serum calcium (corrected for albumin) <9.8 mg / dL, (c) serum phosphorus ≤5.5 mg / dL, and (d) serum total 25-hydroxyvitamin D ≤65 ng / mL. The initial dose in group 2 was determined based on a mid-analysis of the data obtained from cohort 1, as described below. The efficacy of the calcifediol formulation in the treatment of SHPT was evaluated by multiple plasma iPTH and serum 25-hydroxyvitamin D measurements obtained during the efficacy assessment period (EAP), defined as the last 6 weeks of the 26-week treatment period.

[0246] An interactive response system (IRS) provided study treatment group assignment (using a computer-generated randomization code provided by the IRS vendor) and dosing adjustments. An independent, unblinded data safety monitoring board (DSMB) was established to oversee the IRS and verify the appropriateness of all dosing adjustments, and to regularly monitor individual safety and the effectiveness of the calcifediol formulation.

[0247] DSMB members also conducted periodic reviews of study conduct to verify that all required data were retrieved at a high enough level (>95%) and within a specified time frame (usually within 5 days) and to prompt appropriate corrective action to address any noted deficiencies, with the goal of minimizing missing data. The specific responsibilities and activities of the DSMB were defined in a charter approved at a pre-study organizing meeting. These responsibilities included completion of a mid-analysis of the data obtained from group 1 to demonstrate the starting dose for group 2, and a mid-analysis of the data obtained from group 2 to demonstrate the starting dose for a separate phase 2 study in individuals aged 1 month to <8 years.

[0248] Individuals who had received treatment with calcitriol or another 1α-hydroxylated vitamin D analogue prior to study participation, or who had received a calcium mimetic prior to study participation, were further dosed with these agents for the duration of the study and completed an 8-week washout period prior to baseline assessment.

[0249] If serum total 25-hydroxyvitamin D ≥ 30 ng / mL, then individuals who were receiving vitamin D supplementation at a rate higher than 1,700 IU / day or 50,000 IU (1,250 mcg) per month prior to study participation will have their dose reduced to ≤ 1,700 IU / day to maintain the study duration and have an 8-week washout period prior to baseline assessment. If serum total 25-hydroxyvitamin D < 30 ng / mL, then no washout period is required. Individuals complete a 6-week follow-up (FU) period after completion of the 26-week treatment period or early termination (ET).

[0250] Blood samples are collected weekly, bi-weekly, or monthly during the 10-week pre-treatment screening / baseline period, 26-week treatment period, and 6-week post-treatment FU period. Sparse PK samples are collected from all individuals at 0 (before dosing), 6, 12, 24 hours (day 84 before dosing), and 48 hours (day 85 before dosing) on day 83. During the last 3 days of 12-week treatment (before dose titration), additional PK blood samples are collected in a subset of 10 individuals treated with the calcifediol formulation and 5 individuals treated with placebo in groups 1 and 2. Additional PK samples are collected as follows: Day 83: -2, 2, 4, and 8 hours. At the end of the study, study PK blood samples are collected in another subset of approximately 20 individuals (20 individuals from each cohort) during the post-treatment FU period. In each cohort, an attempt is made to collect PK samples from 10 individuals at each of the end-of-day dose levels (30 or 60 mcg) of the calcifediol formulation in order to establish the half-life (t1 / 2) of terminal elimination of 25-hydroxyvitamin D3 at each of these dose levels.

[0251] All individuals, investigators, and sponsors are blinded to the treatment administered and plasma iPTH, serum total 25-hydroxyvitamin D, and serum 25-hydroxyvitamin D3 data until the last individual has completed 26 weeks of treatment. Unblinded data are provided to all study sites in the final clinical study report.

[0252] A mid-term analysis of data obtained from 15 individuals in group 1 who provided intensive PK samples during the last three days of 12-week treatment is conducted by the DSMB to determine the appropriate starting dose for group 2. A second mid-term analysis of data obtained from 15 individuals in group 2 who provided intensive PK samples during the last three days of 12-week treatment is conducted by the DSMB to determine the appropriate starting dose for a separate phase 2 study in individuals aged 1 month to < 8 years.

[0253] Each individual participates in the study for up to approximately 42 weeks (2-week screening / baseline, 8-week washout if necessary, 26-week treatment with the calcifediol formulation or matching placebo, and 6-week FU assessment).

[0254] Key parameters that were monitored regularly during the study included: 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) were monitored at each study visit. Other parameters that were monitored less frequently included brief physical examination (PE), clinical laboratory tests (hematology and clinical and urinary chemistry), and patient-reported palatability and acceptability. Twelve frontal electrocardiograms (ECGs) were obtained at baseline and at the end of treatment or ET. Additional exploratory parameters were monitored at specified intervals, 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), procollagen type 1 N-terminal propeptide (P1NP), and tartrate-resistant acid phosphatase 5b (TRAP 5b)).

[0255] Individuals in Group 1 received two unit doses (e.g., capsules) and / or matching placebo unit doses daily at bedtime to achieve a targeted initial daily dose of 30 mcg calcifediol (one calcifediol formulation plus one placebo formulation) or 0 mcg calcifediol (two placebo unit doses). Any food intake within 60 minutes of drug administration was recorded. At the end of 12 weeks of treatment, individuals assigned to active treatment were titrated upward to 60 mcg (two calcifediol unit doses) daily, provided that (a) plasma iPTH had not decreased by at least 30% from the pre-treatment baseline, (b) corrected serum calcium < 9.8 mg / dL, (c) serum phosphorus ≤ 5.5 mg / dL, and (d) serum total 25-hydroxyvitamin D ≤ 65 ng / mL. Based on a mid-analysis of the data obtained in Group 1, individuals in Group 2 received an initial daily bedtime dose and were titrated upward to a new daily dose that was twice as high as the starting dose at the end of 12 weeks of treatment, provided that (a) plasma iPTH had not decreased by at least 30% from the pre-treatment baseline, (b) corrected serum calcium < 9.8 mg / dL, (c) serum phosphorus > 6.0 mg / dL, and (d) serum total 25-hydroxyvitamin D ≤ 65 ng / mL.

[0256] When any of the following four criteria are met, the dose may be reduced by one capsule per week as needed, and the frequency should not exceed once every two weeks: confirmed plasma iPTH < 35 pg / mL (for individuals with stage 3 CKD) or < 70 pg / mL (for individuals with stage 4 CKD), confirmed serum calcium (corrected) > 10.3 mg / dL, confirmed serum total 25-hydroxyvitamin D > 100 ng / mL, or confirmed serum phosphorus > 5.5 mg / dL (for ages 12 to < 18 years) or > 6.0 mg / dL (for ages 8 to < 12 years), provided that the investigator considers the increase in serum phosphorus to be related to the administration of the study drug and has taken appropriate and continuous measures to control serum phosphorus by initiating or adjusting any phosphate binder therapy.

[0257] Dose reduction can be achieved by consistently omitting the dose on a specific day of the week as follows:

[0258] First dose reduction: Omit dosing on Monday (M).

[0259] Second dose reduction: Omit dosing on all M and Wednesday (W).

[0260] Third dose reduction: Omit dosing on all M, W, and Friday (F).

[0261] Fourth dose reduction: Omit dosing on all M, W, F, and Sunday (S).

[0262] Any individual requiring further dose reduction discontinues administration of the study drug and immediately begins a 6-week FU period.

[0263] If the investigator deems it appropriate, individuals with dose reduction are allowed unscheduled safety visits with FU blood sampling within 48 hours of any dose reduction.

[0264] After each of the four possible dose reductions occurs as shown in Table 23 below, an overview of the initial and reduced weekly dose amounts in mcg units:

[0265] Table 23

[0266]

[0267] If plasma iPTH remains < 30 pg / mL (for three consecutive visits) or confirmed serum calcium (corrected) > 11.0 mg / dL, the individual pauses dosing and resumes when iPTH ≥ 35 pg / mL and serum calcium < 9.8 mg / dL at the next lower dose amount.

[0268] The primary factor was a reduction in mean plasma iPTH of at least 30% from the pre-treatment baseline. The primary efficacy endpoint was the proportion of individuals in the intent-to-treat (ITT) population (aged 8 to <18 years) who had a mean reduction in plasma iPTH of at least 30% from the pre-treatment baseline during the EAP compared to placebo.

[0269] Safety and tolerability were evaluated in the safety population by AE, PE, VS, hematology and clinical chemistry substances, and ECG.

[0270] For the interim analysis, repeated-dose (steady-state) PK determinations were performed in subsets of individuals in Groups 1 and 2 by analyzing the recorded serum 25-hydroxyvitamin D3 concentrations relative to time during the last three days of treatment at Week 12, during administration of the calcifediol formulation (n = 10) or placebo (n = 5).

[0271] For the final analysis, repeated-dose (steady-state) PK determinations were performed in Groups 1 and 2 by (a) analyzing the recorded serum 25-hydroxyvitamin D3 concentrations relative to time during the last three days of treatment at Week 12, during administration of the calcifediol formulation or placebo, and (b) after the last administered dose in each active treatment group.

[0272] If feasible, the following PK parameters were calculated using the observed and baseline-adjusted 25-hydroxyvitamin D3 concentrations: (a) area under the concentration curve (AUC), maximum concentration (Cmax), time to reach maximum concentration (tmax), and steady-state concentration (Css); and (b) t1 / 2, clearance (CL / F), and volume of distribution (Vd / F). Relative exposure and dose ratios were examined.

[0273] Secondary efficacy endpoints included the proportion of individuals in the per-protocol (PP) population who achieved a mean reduction in plasma iPTH of at least 30% from the pre-treatment baseline during the EAP, and the proportion of individuals in the ITT and PP populations who achieved a mean serum total 25-hydroxyvitamin D of at least 30 ng / mL overall and by the mean weekly study dose during the EAP. Other secondary endpoints included the time course of the mean absolute change from the pre-treatment baseline in serum total 25-hydroxyvitamin D and plasma iPTH; the effect of PD on mean serum calcium (corrected), serum phosphorus, serum CaxP product, and urinary calcium:creatinine ratio; the proportion of individuals with hypercalciuria (>200 mg calcium / g creatinine), hypercalcemia (serum calcium > 10.3 mg / dL at two consecutive visits), or hyperphosphatemia (serum phosphorus > 5.5 mg / dL (aged 12 to <18 years) or > 6.0 mg / dL (aged 8 to <12 years) at two consecutive visits, considered related to the study drug); and the proportion of individuals who achieved two consecutive plasma iPTH values ≤ 70 pg / mL.

[0274] Exploratory endpoints included relevant changes in serum FGF23, serum BAP, serum CTx, serum P1NP, serum 1,25-dihydroxyvitamin D3, serum 24,25-dihydroxyvitamin D, and serum TRAP 5b.

[0275] The foregoing description is given for clarity of understanding only, and should not be understood as an unnecessary limitation, since modifications within the scope of the present invention may be apparent to those of ordinary skill in the art.

[0276] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise” and variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0277] Throughout this specification, unless otherwise described, when a composition is described as including components or substances, it is contemplated that the composition may also consist essentially of or consist of any combination of the components or substances. Similarly, unless otherwise described, when a method is described as including specific steps, it is contemplated that the method may also consist essentially of or consist of any combination of the steps. The invention disclosed illustratively herein may be practiced appropriately in the absence of any element or step not specifically disclosed herein.

[0278] The practice of the methods and their individual steps disclosed herein may be performed manually and / or with the aid of or by automation provided by an electronic device. Although the processes have been described with reference to specific embodiments, those of ordinary skill in the art will readily appreciate that other ways of performing the acts associated with the methods may be used. For example, unless otherwise described, the order of the various steps may be changed without departing from the scope or spirit of the method. Additionally, some of the individual steps may be combined, omitted, or further subdivided into other steps.

[0279] 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 spheronized pellet formulation comprising 25-hydroxyvitamin D and a pharmaceutically acceptable excipient.

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

3. A nano / microparticle formulation comprising 25-hydroxyvitamin D and a pharmaceutically acceptable excipient.

4. A lipid microparticle formulation comprising 25-hydroxyvitamin D, optionally calcifediol, and a pharmaceutically acceptable lipid.

5. A blank core formulation comprising 25-hydroxyvitamin D and a pharmaceutically acceptable excipient.

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

7. A pharmaceutical composition comprising 25-hydroxyvitamin D, optionally calcifediol, and a pharmaceutically acceptable excipient selected from one or more of the group of excipients: absorption enhancer, spheronization aid, water-insoluble polymer, and binder.

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

9. An extruded spheronized sustained release vitamin D formulation comprising a mixture of: about 0.01 to about 0.1 wt% calcifediol, about 40 wt% to about 60 wt% of a 1:2:0.2 poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) sustained release polymer, about 1 wt% to about 5 wt% triglyceride, about 30 wt% to about 50 wt% microcrystalline cellulose spheronization aid, further optionally comprising about 1 wt% to about 20 wt% ethyl cellulose, and further optionally comprising about 1 wt% to about 10 wt% additional binder, optionally low-substituted hydroxypropyl cellulose or methyl cellulose, wherein the formulation is free of hydrocarbon wax and hydrocarbon oil.

10. An extruded spheronized sustained release vitamin D formulation comprising a mixture of: about 0.01 to about 0.1 wt% calcifediol, about 1 wt% to about 10 wt% ethyl cellulose sustained release polymer, about 20 wt% to about 40 wt% filler, optionally lactose, about 40 wt% to about 60 wt% microcrystalline cellulose spheronization aid, about 1 wt% to about 15 wt% triglyceride, further optionally comprising about 1 wt% to about 10 wt% ethyl cellulose, and further optionally comprising about 1 wt% to about 15 wt% additional binder, optionally methyl cellulose or low-substituted hydroxypropyl cellulose, wherein the formulation is free of hydrocarbon wax and hydrocarbon oil.

11. A pharmaceutical batch of a dosage form comprising a formulation according to any one of the preceding claims, characterized in that The between-formulation variation in in vitro dissolution release at 2, 4, 6, 8, 10, and 12 hour time points (USP Apparatus II (paddle with sinker) at 75 RPM, medium being 5 mM sodium dihydrogen phosphate monohydrate containing 0.5% SDS, pH 6.8, 37 ± 0.5 °C, volume 500 mL), as determined by measuring six dosage forms, is less than 15% RSD, or less than 10% RSD.

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

13. An oral dosage form comprising a formulation according to any one of the preceding claims.

14. A method of treating a vitamin D-responsive disease or condition, the method comprising administering to a patient in need thereof a formulation or dosage form according to any one of the preceding claims.

15. A method for improving between-batch consistency of the in vitro release characteristics of an extended-release vitamin D compound formulation, which comprises admixing the vitamin D compound with a water-insoluble polymeric material and optionally one or more additional excipients.

16. A method of manufacturing an extended-release pharmaceutical formulation, which formulation is optionally a formulation according to any one of the preceding formulation claims, the method comprising admixing a vitamin D compound with a water-insoluble polymer and optionally further with one or more pharmaceutically acceptable excipients selected from the group consisting of diluents, absorption enhancers, and binders.

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