Pediatric dosage forms, methods of manufacture and use

Abstract

Disclosed are pediatric and modified release dosage forms of vitamin D compounds and methods of making and using the same.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This article claims the benefit of U.S. Provisional Patent Application Serial No. 62 / 725,940, filed on August 31, 2018, under 35 U.S.C. §119(e), and the disclosure of which is incorporated herein by reference. Technical Field

[0003] The present disclosure relates generally to dosage forms of vitamin D compounds, such as calcifediol, including forms suitable for use by children, and methods of making and using the same. Background Art

[0004] Traditionally, vitamin D compounds have been administered in the form of immediate release formulations. Recently, some modified release dosage forms of vitamin D compounds have been described, for example in a wax matrix. The present disclosure relates to vitamin D formulations, including extended release formulations and formulations suitable for pediatric patient populations. Formulations for delivering active vitamin D, its analogs and prohormones, including some extended release formulations, have been disclosed. One such formulation is marketed in the United States under the trade name (calcifediol), a product approved to treat secondary hyperparathyroidism in patients with stage 3 and 4 chronic kidney disease (CKD). The prescribing information for this drug states that it is used The sustained release formulation of is a wax-based extended release formulation of 25-hydroxyvitamin D3. Summary of the invention

[0005] One aspect of the disclosure is a vitamin D formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol dispersed in a polymer composition. In embodiments, the formulation can be an extended release formulation, for example for oral use.

[0006] Another aspect of the disclosure is a vitamin D formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D, or calcifediol, embedded in a polymer network. The polymer may be water-insoluble and optionally swellable. In an embodiment, the formulation may be an extended release formulation, for example, for oral use.

[0007] Another aspect of the 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 an extended release formulation, for example, for oral use.

[0008] Another aspect of the disclosure is a vitamin D formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol dispersed in a fatty acid glyceride mixture. In embodiments, the formulation can be an extended release formulation, for example, for oral use.

[0009] Another aspect of the disclosure is a nano / micro particle formulation comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, and a pharmaceutically acceptable excipient. In embodiments, the nano / micro particle formulation can provide extended release of the vitamin D compound, for example, by using an extended release polymer as an excipient.

[0010] Another aspect of the 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 an extended release formulation, for example, for oral use.

[0011] Another aspect of the disclosure is a blank pellet 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.

[0012] Another aspect of the disclosure is a pharmaceutical composition comprising a vitamin D compound, optionally 25-hydroxyvitamin D or calcifediol, and a pharmaceutically acceptable excipient selected from one or more of the following groups: an absorption enhancer, a spheroidizing aid, a water-insoluble polymer, and a binder. In an embodiment, the formulation can be an extended release formulation, for example, for oral use.

[0013] Another aspect of the 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 an extended release formulation, for example, for oral use.

[0014] Another aspect of the disclosure is a pharmaceutical batch of dosage forms comprising a formulation according to the disclosure and further characterized by low dosage form-to-dosage form variation in in vitro dissolution release. In an embodiment, the dosage form can be an extended release dosage form, for example, for oral use.

[0015] Another aspect of the disclosure is a pharmaceutical batch of dosage forms comprising a formulation according to the disclosure and further characterized by low batch-to-batch variation in in vitro dissolution release. In an embodiment, the dosage form can be an extended release dosage form, for example, for oral use.

[0016] Another aspect of the present disclosure is a method of making a pharmaceutical formulation and dosage form. In an embodiment, the method can be a method of making an extended release pharmaceutical formulation, comprising compounding a vitamin D compound with a water-insoluble polymer, and optionally further compounding with at least one pharmaceutically acceptable excipient selected from one or more of a diluent, an absorption enhancer, and a binder.

[0017] Another aspect of the disclosure is a method for improving batch-to-batch consistency in the in vitro release profile of an extended release vitamin D compound formulation, the method comprising compounding the vitamin D compound with a water-insoluble polymer material and optionally one or more additional excipients.

[0018] Another aspect of the disclosure is a method of treating a vitamin D responsive disease or condition comprising administering a formulation or dosage form according to the disclosure to a patient in need thereof.

[0019] For the compositions and methods described herein, optional features including but not limited to components, composition ranges thereof, substitutions, conditions, and steps are contemplated to be selected from the various aspects, embodiments, and examples provided herein.

[0020] A review of the following embodiments in conjunction with the drawings 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 embodiment, the following description includes specific embodiments, with the understanding that the disclosure is illustrative and is not intended to limit the invention to the specific embodiments described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] In order to further facilitate the understanding of the present invention, four drawings are attached herewith.

[0022] Figure 1 The dissolution release profile of calcifediol loaded Eudragit-based pellets according to the present disclosure is shown in comparison to the dissolution release profile of a wax matrix-based soft gelatin capsule formulation.

[0023] Figure 2 The dissolution release profile of calcifediol loaded ethylcellulose (EC) based pellets according to the present disclosure is shown in comparison to the dissolution release profile of a wax matrix based soft gel capsule formulation.

[0024] Figure 3 The dissolution release profile of a spray-dried nano / microparticle formulation comprising calcifediol according to the present disclosure is shown in comparison to the dissolution release profile of a wax matrix-based soft gelatin capsule formulation.

[0025] Figure 4 The dissolution release profile of a spray-congealed lipid-based formulation comprising calcifediol according to the present disclosure is shown in comparison to the dissolution release profile of a wax matrix-based soft gelatin capsule formulation.

[0026] Figure 5 The dissolution release profiles of the softgel wax-based calcifediol formulation and the nano / microparticle formulation as described in Example 3 are presented.

[0027] Figures 6 to 8 Each shows the dissolution release profile of comparable batches of Eudragit-based pellet formulations according to the present disclosure, demonstrating batch-to-batch consistency.

[0028] Fig. 9 Baseline and dose-corrected mean serum calcifediol concentration-time profiles for the extended release formulations tested in minipigs according to Examples 1, 2, and 7 are shown.

[0029] Fig.10 Baseline-corrected serum calcifediol concentration-time curves for the extended release formulations tested in humans according to Example 9 are shown. DETAILED DESCRIPTION

[0030] There is a need for improved formulations for safely delivering vitamin D compounds, including calcifediol, including extended release formulations and similar improved formulations suitable for delivery to pediatric patients. Embodiments of the present invention can meet these needs and provide a series of extended release dosage forms and improved methods for making such formulations and dosage forms. These formulations can be bioequivalent to commercially approved wax-based systems, but can also provide different in vitro extended release dissolution characteristics and in vivo bioavailability. It can be made suitable for pediatric patient populations as well as adult patient populations, and it can be used, for example, to increase serum 25-hydroxyvitamin D levels, and thus treat vitamin D insufficiency and other conditions, including kidney diseases and conditions.

[0031] The need to develop a 25-hydroxyvitamin D formulation for children has led to research and development work that has examined several different strategies to achieve a palatable, bioavailable, extended-release oral dosage form that is easy to swallow. These strategies include pellets made using fluidized bed (Wurster) technology, nano / micro particle technology in the presence and absence of coatings, coated inert seeds (e.g., blank pellet cores) using extrusion spheronization technology, and lipid microparticles made by spray congealing / spray freezing / spray cooling.

[0032] The work of making age-appropriate extended release oral formulations has produced some surprising and unexpected results. For example, although several attempts to spray-congeal wax-based mixtures produced extended release dissolution release characteristics, none of them fully matched the target dissolution release characteristics of previous wax-based matrix formulations; on the contrary, water-based polymer pellet formulations using extrusion and spheronization technology produced improved 25-hydroxyvitamin D extended release formulations. Such formulations meet all the criteria required for children's use, and in addition, based on in vitro dissolution data, are also suitable for adult use. In an embodiment, the water-based polymer pellet formulation can eliminate any need for coatings to obtain bioequivalent products, and provide consistent and reproducible properties and consistent and reproducible in vitro release characteristics on a unit dose-to-unit basis and on a batch-to-batch basis.

[0033] Disclosed and described herein are extended release vitamin D formulations, including formulations suitable for delivery to children in need of its treatment. Such formulations may also be applicable to adults in need of its treatment, such as for vitamin D deficiency and for secondary hyperparathyroidism and other vitamin D related diseases and conditions of CKD. Formulations and formulation strategies described herein may be used to provide formulations in a form that is bioequivalent to commercially approved calcifediol extended release formulations but can be delivered to children. Such forms include conventional capsules, "easy to open" capsules or sachets, which can be applied by emptying all contents into a small amount of liquid or on a small amount of soft food. In addition to developing a variety of suitable formulations for children, the present invention also produces 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 release characteristics.

[0034] In one aspect, the extended release formulation comprises a vitamin D compound and an extended release component. In another aspect, this type of extended release formulation is in the form of a spherical pellet or multi-particle. In one aspect, the formulation comprises a spherical pellet, which comprises an extended release component selected from a polymer and / or a lipid component. The polymer is selected from a water-insoluble polymer, and optionally includes a water-soluble polymer. The active substance (e.g., calcifediol) can be embedded in a polymer network for extended release in vivo. In another aspect, the formulation can be a nano / micron particle formulation, such as manufactured by emulsion, spray drying / freeze drying (e.g., emulsion-diffusion-spray / drying freeze drying technology as described herein). In another aspect, the formulation can be a powder formulation, such as manufactured by spray condensation. In another aspect, the formulation can be a seed of extended release coating. In another aspect, the formulation can be active granules.

[0035] The formulations and / or dosage forms according to the present disclosure may be free of wax. In an embodiment, the formulations and / or dosage forms may be free of hydrocarbon wax. In an embodiment, the formulations and / or dosage forms may be free of paraffin. The formulations and / or dosage forms according to the present disclosure may be free of hydrocarbon oil. In an embodiment, the formulations and / or dosage forms may be free of mineral oil. In another aspect, the dosage form may be free of capsule shell. In an embodiment, the dosage form may be free of soft capsule shell. For example, the formulations and / or dosage forms according to the present disclosure may be free of hydrocarbon wax and hydrocarbon oil.

[0036] U.S. Patent Nos. 8,207,149 and 8,361,488 describe that previous wax-based formulations provide solid or semisolid wax pharmaceutical formulations that releasably bind and controllably release calcifediol in the gastrointestinal (GI) tract. The formulation includes a wax controlled release carrier, a lipid agent, an oily vehicle, and a calcifediol compound, which provides a formulation that is solid or semisolid at room temperature and semisolid or liquid at body temperature. U.S. Patent No. 9,861,644 describes a wax-based formulation that is suitable for use 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 can provide one or more preferred functions, such as forming a microemulsion of an oily vehicle in GI fluids; providing long-term gastric retention, such as by bioadhesive properties so that the formulation interacts with the mucus layer of the stomach and / or intestines; and enhancing the absorption of calcifediol compounds.

[0037] Hard paraffin is used as a controlled release agent, which produces a solid to semisolid lipid system at body temperature and produces a formulation that gradually releases the active ingredient through an erosion process. This wax is used as a rate control agent and is primarily responsible for the mechanical erosion mechanism. The GI medium penetrates into the wax and subsequently promotes the slow release of calcifediol. Mineral oil is a mixture of refined liquid saturated aliphatic and cyclic hydrocarbons obtained from petroleum. Mineral oil is used as a vehicle in previous formulations and can also affect calcifediol absorption. Hydroxypropyl methylcellulose in previous formulations is used as a release stabilizer, which helps stabilize the release of calcifediol on standing / stability. Hydroxypropyl methylcellulose stabilizes the release characteristics of previous wax formulations over the expected shelf life of the product. Glyceryl monostearate 40·55 (Type I) is an amphiphilic surfactant that forms mixed micelles with lauroyl polyethylene glycol-32 glyceride (Gelucire 44 / 14). Gelucire is formed by an esterification reaction between polar polyethylene glycol (PEG) and non-polar vegetable oils or fatty acids. 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 that dissolve and increase the oral bioavailability of hydrophobic APIs, such as vitamin D compounds (e.g., calcifediol). Gelucire has a unique surfactant feature that enhances the solubility and wettability of APIs, such as calcifediol, both in vitro and in vivo. Improved in vivo drug solubility promotes absorption and, therefore, oral bioavailability. Gelucire is used as an emulsifier / solubilizer that promotes the dissolution of insoluble calcifediol through emulsification and dissolution mechanisms and, therefore, improves the bioavailability of calcifediol. These lipid agents also have one or more functions, such as forming microemulsions of oily vehicles in GI fluids; providing longer gastric retention, such as through bioadhesive properties, so that the formulation interacts with the mucus layer of the stomach and / or intestines; and enhancing the absorption of calcifediol compounds. Wax formulations are gradually released by mechanical erosion and / or gradual disintegration of waxy compositions. Waxes and emulsifiers can aid absorption and can also provide bioadhesive properties to calcifediol. This can enhance retention of calcifediol in the GI tract and allow for absorption over a longer period of time and in a more systemic manner, thereby enhancing biopharmaceutical parameters.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] As used herein, the term "comprising" indicates that other reagents, elements, steps or features may be included in addition to those specified.

[0042] 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.

[0043] 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.

[0044] 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. It is specifically contemplated that in any 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, it is specifically contemplated that in any embodiments described herein, 25-hydroxyvitamin D may consist of or include 25-hydroxyvitamin D3. Unless a specific 25-hydroxyvitamin D form is mentioned, serum total 25-hydroxyvitamin D refers to the sum of all such 25-hydroxyvitamin D forms measured by the assay.

[0045] 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 embodiment 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, it is specifically contemplated that in any embodiment 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, serum total 1,25-dihydroxyvitamin D should be understood to refer to the sum of all such 1,25-dihydroxyvitamin D forms assayed.

[0046] Whether natural or synthetic, the vitamin D compound may include one or more of any desired vitamin D compound. In one type of embodiment, the vitamin D compound will include a 25-hydroxyvitamin 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 may include an active vitamin D compound or analog, such as 1,25-dihydroxyvitamin D2, 1,25-dihydroxyvitamin D3, 1α-hydroxyvitamin D2 (doxercalciferol), paricalcitol, 22-oxalcitriol, dihydrotachysterol, or 26,26,26,27,27,27-hexafluorocalcitriol (falecalcitriol).

[0047] The vitamin D compound is mixed (eg, via dissolution, mixing, emulsification, or any combination thereof) with one or more excipients to form a vitamin D formulation as described below.

[0048] 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 comprising a water-insoluble polymer as an extended release reservoir), the concentration of calcifediol 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 %, for example 0.03 wt %, or 0.06 wt %, or about 0.09 wt %.

[0049] In one aspect, it is contemplated that poly (meth) acrylate polymers including Eudragit polymers are used for water-insoluble swellable polymer components. These polymers serve as extended release excipients that form extended release characteristics. Two main mechanisms may be used for drug release via Eudragit polymers: it is possible to release the drug by corrosion or via diffusion. Eudragit polymers are copolymers derived from acrylates and methacrylates, and their physicochemical properties are optionally affected by functional groups. It is generally provided in different physical forms, such as aqueous dispersions, organic solutions, granules and powders. Eudragit RL and Eudragit RS (CAS number 33434-24-1) are cationic copolymers of ethyl acrylate, methyl methacrylate and low-content methacrylates with quaternary ammonium groups. The copolymers are water-insoluble, but include ammonium groups present in salt form to make the polymer permeable to water. Eudragit RS has relatively fewer ammonium groups and has lower permeability (1:2:0.1 poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate)), while Eudragit RL has relatively more ammonium groups and higher permeability (1:2:0.2 poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride)). 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. Powder forms of Eudragit RS and RL can be used, and in alternatives, granular forms, aqueous dispersion liquids, and organic solutions (e.g. in acetone and / or alcohol) are available. Other suitable poly(meth)acrylate polymers include Eudragit NE and Eudragit NM (CAS No. 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 extrusion-spheronization type formulation embodiment according to the present invention, the amount of Eudragit RL PO ranges, for example, from about 20 wt % to about 80 wt %, or at least 70 wt %. In one embodiment, the weight percentage ranges from 40 wt % to 60 wt % of Eudragit RL PO in the formulation. Such components are preferably used in aqueous wet extrudable masses, which are formed into granules, which are subsequently spheronized to form pellets.

[0050] In another aspect, EC polymers are expected to act as non-swellable water-insoluble polymer materials. These polymers also act as extended release components that slowly release or promote duplication of target extended release characteristics or form unique extended release characteristics. Two main mechanisms may be used for drug release via EC polymers: diffusion (concentration-dependent) and corrosion. EC is a derivative of cellulose in which some hydroxyl groups on repeating anhydroglucose units are modified to ether groups. The physical and drug release properties of EC can be affected by its molecular weight (for example, indirectly specified by its viscosity), its degree of substitution (ethoxy content) and particle size. For example, EC is commercially available in three types of ethoxy contents called K, N and T types, 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 so-called "medium" grades 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%. EC viscosity is measured at 25°C in a solvent consisting of 80% toluene and 20% ethanol as a 5% solution. The EC viscosity for the compositions described herein can be, for example, in the range of about 3cP to about 50cP, or about 3cP to about 22cP, or about 3cP to about 15.4cP, or about 6cP to about 15.4cP, or about 6cP to about 11cP, or about 9cP to about 15.4cP, or about 9cP to about 11cP. In other embodiments, the EC viscosity for the compositions described herein can be, for example, in the range of about 18cP to about 110cP, or 18cP to 22cP, or 41cP to 49cP, or 90cP to 110cP, or 18cP to 49cP, or 41cP to 110cP. Typically, smaller particle sizes can be more effectively consolidated and result in slower release rates, and porosity modifiers can offset this effect. Although the particle size is not particularly limited, in one type of embodiment, it is contemplated to use an average particle size greater than 40 microns, or between about 40 microns and about 500 microns, or between about 250 and 500 microns, or between about 100 microns and about 400 microns, or between about 200 microns and about 300 microns. Optionally, the particle size may include particles greater than 100 microns, or greater than 140 microns, or greater than 150 microns. For example, EC may 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. Suitable EC is commercially available under the trade name Ethocel Standard 10 Premium. In other embodiments, the particle size of the ethylcellulose may be characterized by a maximum of 150 microns, or 140 microns, or 100 microns; optionally, the minimum particle size may be 3 microns, or 5 microns, or 30 microns. In additional embodiments, the ethylcellulose may be characterized by an average particle size in a range of 5 to 15 microns, or 3 to 5 microns, or 30 to 60 microns.Ethylcellulose products can be purchased from Dow Chemical, for example, under the trade name Ethocel and in grades of 4 Premium, 7 Premium, 7 FP Premium, 10 Premium, 10 FP Premium, 20 Premium, 45 Premium, 100 Premium, and 100 FP premium. In one embodiment according to the disclosure, the amount of EC is, for example, in the range of about 5 wt % to about 60 wt %. In an extrusion-spheroidization type formulation embodiment according to the disclosure, the amount of EC is, for example, in the range of 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 monohydrated lactose in a weight percentage of about 20 wt % to 50 wt %. Such components can be used in aqueous wet extrudable materials, which form particles and are subsequently spheroidized to form particles.

[0051] In another aspect, it is expected that low-substituted hydroxypropyl cellulose (L-HPC) polymers are used for water-insoluble polymer materials. L-HPC is a low-substituted hydroxypropyl ether of cellulose, in which a small portion of hydroxypropyl replaces the hydroxyl group in the glucose unit. Although hydroxypropyl cellulose (molar substitution of about 3) is soluble in water and alcohol, L-HPC (molar substitution of about 0.2-0.4) only swells in water and is insoluble. The degree of substitution 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, particle size is not subject to specific restrictions, and the expected average particle size is, 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. 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.

[0052] In another aspect, it is contemplated that polyvinyl acetate polymers (PVA, CAS No. 9003-20-7) are used for water-insoluble polymer materials. This polymer is also used as an extended release component in an aqueous wet extrudable material, which forms particles and can be used to form spherical pellets. In one type of embodiment, insoluble polyvinyl acetate is blended with polyvinyl pyrrolidone (PVP, CAS No. 9003-39-8), such as such blends commercially available under the trade name Kollidon SR. For example, for water-soluble PVP, PVP is leached from the composition, giving the PVA component pores. For example, PVP is characterized in that 1% solution viscosity at 25° C. is in the range of about 20 cP to about 40 cP, or about 25 cP to about 35 cP. In alternatives, the weight average molecular weight of PVP (e.g., as 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 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, such as about 4:1. Although the particle size is not particularly limited, for one type of embodiment, the average particle size is expected to be in the range of about 50 microns to about 250 microns. Optionally, the PVA / PVP blend may include small amounts of sodium lauryl sulfate (SLS, eg 0.8 wt %) and colloidal silica (eg 0.2 wt %) as stabilizers, for example in the form of KOLLIDON SR.

[0053] Drug release from insoluble polymer-based formulations is controlled by corrosion and concentration-dependent diffusion mechanisms (Fickian or non-Fickian) through channels or capillaries in the polymer formulation in the dissolution medium - (e.g., channel / pore formers (e.g., lactose with EC and hydrophilic HPMC with Eudragit polymers). There are different processes as part of the release mechanism: 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; diffusion of the drug and / or excipients out of the dosage form. In some cases, formulations of these insoluble polymers Ideally, the pellets remain intact during the drug release process. However, the medium permeates the pellets so that the active pharmaceutical ingredient (API) molecules can diffuse out through the polymer network. In the case of swellable polymers, the size of the polymer formulation also increases with dissolution time, while it usually remains the same for non-swellable polymers. The size of the polymer formulation form, the distribution of the drug in the polymer formulation, and the content and properties of the polymer formulation (such as wettability and solubility) are key parameters that affect the process of controlling drug release. Sparingly soluble and slightly soluble active ingredients (e.g., calcifediol) cause delayed release due to their low dissolution rate.

[0054] In yet another aspect, additives such as glyceryl behenate can be used as extended release agents. Such compounds are used as thickeners or gelling agents and are suitable for use as extended release agents, and include, for example, glyceryl behenate (e.g., Compritol 888 ATO). It can be added in a weight percentage of between 5% to 25% by weight, or between 5% to 40% by weight in the wet granulation aqueous blend. For example, when glyceryl behenate is the primary or sole extended release agent, higher concentrations are particularly contemplated.

[0055] The inventors present polymer-based pellet formulations using extrusion and spheronization techniques to provide improved extended release formulations of 25-hydroxyvitamin D. Such formulations meet all criteria necessary for use in children, but are also suitable for use in adults based on in vitro dissolution data. Embodiments of the extrusion-spheronization process may provide one or more advantages over other methods, including (1) being more cost-effective relative to manufacturing coated beads or pellets; (2) providing formulations that are bioequivalent to approved extended release calcifediol capsules without the need for a coating step; (3) providing formulations with consistent and reproducible properties from unit dose to unit dose; and (4) providing a formulation that has consistent and reproducible in vitro release characteristics on a unit dose to unit dose basis and / or batch to batch basis (e.g., as measured from six sample size analyses at 2, 4, 6, 10, and 12 hour dissolution time points, the RSD between dosage forms is 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).

[0056] For example, by providing the average AUC 0-inf , and then the average AUC 0-inf The invention relates to oral administration to humans in the fasting state at 80% to 125% of the amount of calcifediol, followed by oral administration in the fasting state of an approved extended-release calcifediol product, the formulation can be combined with an approved extended-release calcifediol (e.g., ) bioequivalence. In another embodiment, by providing the mean AUC 0-inf , and then the average AUC 0-inf The formulation may be bioequivalent to an approved extended release calcifediol by oral administration to humans in a fasting state of 80% to 120% of the average Cmax, followed by oral administration in a fasting state of an approved extended release calcifediol product. In another aspect, the formulation may be bioequivalent to an approved extended release calcifediol by providing an average Cmax, followed by oral administration to humans in a fasting state of 80% to 125% of the average Cmax, followed by oral administration in a fasting state of an approved extended release calcifediol product. In another embodiment, the formulation may be bioequivalent to an approved extended release calcifediol by providing an average Cmax, followed by oral administration to humans in a fasting state of 80% to 120% of the average Cmax, followed by oral administration in a fasting state of an approved extended release calcifediol product. In one aspect, the fasting state may be defined by fasting for at least 10 hours.

[0057] For example, a single dose of 900 μg administered to healthy adults in the fasting state and measured over a 650 hour period can be formulated to provide a mean baseline-adjusted value within 80% to 125%, or 80% to 120% of one or more of the values ​​described in Table 1 below.

[0058] Table 1

[0059] 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 (Hours)]]> 24.78

[0060] In another aspect, a formulation according to the present disclosure may be formulated to provide a mean baseline-adjusted value within 80% to 125%, or 80% to 120%, of one or more of the values ​​described in Table 2 below, when administered at a dose of 30 μg to healthy adults in the fasting state and measured over a 650 hour period.

[0061] Table 2

[0062] 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

[0063] In another aspect, the formulations according to the present disclosure are administered to stage 3 or stage 4 CKD patients in the fasting state according to the dosing described in the table, and when measured after a six week period after the start of dosing, can be formulated to provide a mean baseline-adjusted value within 80% to 125%, or 80% to 120% of one or more of the values ​​described in Table 3 below.

[0064] Table 3

[0065]

[0066] Such spheronized pellets produced by the aqueous wet granulation process 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.

[0067] In another type of embodiment, it is contemplated that one or more fatty acid glycerides (e.g., glyceryl behenate) are used for the water-insoluble material. Glyceryl behenate is a mixture of fatty acid glycerides, primarily behenic acid (e.g., at least 50% or at least 80% behenic acid). In one type of embodiment, the content of 1-monoglyceride 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 tripheinate (28 to 32% w / w) of glycerol having a melting point in the range of 69 to 74° C. and a hydrophilic-lipophilic balance (HLB) of about 2. In another embodiment, the glycerides may be characterized as a mixture of diacylglycerols (40 to 60% w / w), monoacylglycerols (13 to 21% w / w), and triacylglycerols (21 to 35% w / w). Suitable behenylglycerol is commercially available under the trade name Compritol 888 ATO.

[0068] In another aspect, the water-insoluble formulation may be based on one or more water-insoluble polymer materials and optionally include minor amounts of fatty acid glycerides. In another aspect, the water-insoluble formulation may be based on fatty acid glycerides and include minor amounts of one or more water-insoluble polymer materials.

[0069] In one type of embodiment, the water-insoluble polymer 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 40 wt% to 90 wt%, or about 40 wt% to about 80 wt%, or about 40 wt% to about 70 wt%, or about 40 wt% to about 60 wt%, or about 40 wt% to about 50 wt%. For example, a polymer formulation may include 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 including about 40 wt% to about 50 wt% of Eudragit RL polymer and a small amount (e.g., 1 wt% to about 10 wt%) of one or more other water-insoluble polymer materials, such as L-HPC described herein or EC as described herein, or a combination thereof.

[0070] In another type of embodiment, the water-insoluble polymer material is not the main material in the composition, such as when the permeability of the water-insoluble polymer is relatively low. For example, the water-insoluble polymer material can be included in an amount of 1% to about 40% by weight, or about 1% to about 30% by weight, or 1% to about 20% by weight, or about 1% to about 10% by weight, or about 2% to about 10% by weight, or about 3% to about 8% by weight, or about 5% by weight. The composition may further include a release modifier, such as a pore former.

[0071] The formulation may optionally include one or more additional functional additives including, but not limited to, release modifiers (including pore formers), absorption enhancers, fillers (also known as diluents), binders (including dry binders), spheronization aids, flavoring agents, and lubricants.

[0072] For example, excipients suitable for spheroidizing pellets as described herein include absorption enhancers, such as Miglyol 812N; diluents and spheroidizing aids, such as MCC (Avicel PH 101); diluents and pore formers, such as lactose monohydrate or HPMC; compression agents / gelling agents / 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 spheroidizing aids, such as low-substituted hydroxypropyl cellulose (L-HPC LH-31); binding aids, such as Methocel K3 Premium LV; lubricants, such as talc or glyceryl behenate; flavoring agents, such as caramel; and purified water as a process diluent (e.g., to dissolve the binder). The diluent and / or spheroidizing aid may be present in a concentration of about 30% by weight to about 90% by weight. Absorption enhancer can exist at a concentration of about 3 % by weight to about 10 % by weight. For example, the adhesion aid of Methocel K3 can exist at a concentration of about 5 % by weight to about 10 % by weight. For example, the lubricant of talcum can exist at a weight concentration of about 1 % by weight to about 2 % by weight. The concentration of extended release matrix forming agent / extrudate and spheroidization auxiliary agent (for example L-HPC LH-31) can be in the scope of about 5 % by weight to 25 % by weight.

[0073] Release modifiers may include hydrophilic colloids, 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 can be used as a water-insoluble polymer (e.g., 1 to 10 wt %, or 5 wt %), and pore formers can be used in relatively high amounts (e.g., 20 wt % to 40 wt %), such as monohydrated lactose. Other examples include about 25 wt %, about 30 wt %, and about 35 wt %.

[0074] Compositions can optionally include absorption enhancers. Examples of suitable absorption enhancers include, but are not limited to, polyethylene glycol glycerol capryloyl caproyl esters, such as polyethylene glycosylated glycerides, also referred to as polyglycolized (polyglycolized) glycerides or polyglycolized (PEGylated) glycerides. The polyglycolized glycerides that can be used in the compositions include, but are not limited to, monoglycerides, diglycerides and triglycerides and polyethylene glycol, polyethylene glycosylated almond glycerides, polyethylene glycosylated corn glycerides and polyethylene glycosylated caprylic acid / capric triglyceride monoesters and diesters. 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.

[0075] A preferred absorption enhancer is known by the trade name GELUCIRE (Gattefossé Corporation, Paramus, New Jersey, USA). GELUCIRE is a well-known excipient, which belongs to the fatty acid ester family of glycerol and PEG ester, also referred to as polyethylene glycol glyceride. GELUCIRE is used for various applications, including the preparation of extended release pharmaceutical compositions. The GELUCIRE compound is an inert semisolid waxy material, which is amphiphilic and can obtain different physical characteristics (such as melting point, HLB and solubility) in different solvents. It actually has surface activity and disperses or dissolves in aqueous media to form micelles, microscopic spheres or vesicles. It is identified by its melting point / HLB value. Melting point is expressed in degrees Celsius. One or a mixture of GELUCIRE excipients of different grades can be selected to obtain desired melting point and / or HLB value characteristics. One GELUCIRE composition is GELUCIRE 44 / 14, a mixture of polyethylene glycol glyceryl lauroyl ester and polyoxyglyceryl lauroyl ester, having a melting point of 44°C and an HLB of 11. Another GELUCIRE composition is GELUCIRE 48 / 16, also known as PEG-32-stearate, also known as PEG 32 mono- and diesters of stearic and palmitic acid, having a nominal melting point of 48°C (within a range of 46°C to 50°C) and an HLB of 12. Another polyglycolyzed glyceride absorption enhancer is polyethylene glycol-8-glyceryl caprylocaproyl ester (CAS Nos. 85536-07-8 and 84963-88-2). This is monoesters, diesters and triesters of glycerol and PEG 400 (C8-C10) with medium-chain fatty acids, which are sold, for example, under the trade name LABRASOL by Gattefossé Corporation, Paramus, New Jersey, USA. LABRASOL has an HLB value of 14 and has the following composition by weight: about 4% C8-C10 monoglycerides; about 17% C8-C10 diglycerides; about 6% C8-C10 triglycerides; about 14% C8-C10 monoesters of PEG 400; about 36% C8-C10 diesters of PEG 400; about 20% free PEG 400; about 3% free glycerol. Another type of absorption enhancer is a triglyceride, such as a medium-chain triglyceride. For example, a mixture of C8-C10 triglycerides can be used. In one type of embodiment, the C8-C10 triglycerides may include about 50 to 65 weight percent caprylic triglyceride and about 30 to 45 weight percent capric triglyceride. Suitable triglycerides are commercially available under the trade name Miglyol 812N.Absorption enhancers can be present in any suitable amount, for example, from about 1 wt % to about 20 wt %, or from about 1 wt % to about 15 wt %, or from about 1 wt % to about 10 wt %, or from about 3 wt % to about 10 wt %, or from about 5 wt % to about 10 wt %, or from about 3 wt % to about 5 wt %. Other examples include about 3 wt %, about 5 wt % and about 10 wt %. Optionally, when the formulation includes a hydrophilic excipient with an HLB greater than 10, such as in the range of 11 to 18, or 13 to 18, such as a release aid, then it also includes a lipophilic excipient, such as an excipient with an HLB less than 10, such as 1 to 6, or 1 to 3, or 3 to 6.

[0076] The formulation may also include one or more fillers, also referred to 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 silicon dioxide, sodium chloride, starch, and calcium hydrogen phosphate dihydrate. In one type of embodiment, the filler is not water-soluble, although it can absorb water. As described above, when mixed with other components (such as water-insoluble polymers), the filler can serve as a pore-forming agent. In one type of embodiment, the filler is a spheroidizing aid. Spheroidizing aids may include, for example, one or more of cross-linked polyvinylpyrrolidone, carrageenan, polyglucosamine, pectin, glyceride, β-CD, cellulose derivatives, MCC, powdered cellulose, polyplasdone cross-linked polyvinylpyrrolidone and polyethylene oxide. In one embodiment, filler or spheroidizing aid includes MCC. The MCC may 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. The MCC may be characterized by a crystallinity in the range of, for example, about 60% to about 80%. Suitable commercially available MCCs are available 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.

[0077] The amount of filler is not particularly limited, and for example can be 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 the amount of the range formed by any one of the aforementioned values. For example, 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 %. Spheroidization aids can be included in this type of range, or in the amount of, for example, about 35 wt % to about 60 wt %, or about 35 wt % to about 40 wt %, or about 40 wt % to about 60 wt %.

[0078] The formulation may include one or more adhesives, including dry adhesives. The adhesive includes, for example, relatively low viscosity hydrophilic cellulose ethers and PVP. In other embodiments, the adhesive may include carboxymethyl cellulose, starch, pregelatinized starch, gum arabic, gum tragacanth, gelatin, sodium alginate, low-substituted hydroxypropyl cellulose and hydroxypropyl methylcellulose (HPMC) of the lowest viscosity grade. For example, the adhesive may be selected from low viscosity hydroxypropyl methylcellulose, such as low viscosity hydroxypropyl methylcellulose 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 2% aqueous viscosity. Suitable low viscosity hydroxypropyl methylcellulose is commercially available under the trade name Methocel K3Premium LV. For example, the methoxy % of hydroxypropyl methylcellulose may 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 hypromellose can be about 5 to about 15, or about 7 to about 12.

[0079] Pharmaceutically acceptable lubricants are known in the art and may include, but are not limited to, stearic acid, magnesium stearate, calcium stearate, aluminum stearate, talc, and 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 %, for example 0.5 wt %, 0.7 wt %, 1 wt %, 1.5 wt % or 2 wt %.

[0080] The formulation may optionally include a top coating or outer coating to adjust the release characteristics. For example, the top coating can be used to delay or slow down the release within the first few hours after application, such as to offset the initial burst release, or otherwise slow down the initial release faster than expected. Suitable top coating materials include, for example, film-forming polymers. The top coating material can be water-soluble, such as a water-soluble polymer (e.g., hypromellose, PVP) or a water-swellable polymer as described herein, which further includes a pore former (e.g., EC described herein and a pore former, such as hypromellose). The top coating may optionally include a lubricant, such as talc. Suitable EC top coating materials are commercially available under the trade name SURELEASE, sold as an aqueous emulsified dispersion of plasticized EC. Suitable hypromellose pore formers may have a 2% solution viscosity at 20°C of about 3 cP, a 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 a hydroxypropyl % of about 5 to about 15, or about 7 to about 12. For example, the hypromellose may be one commercially available as PHARMACOAT 603. The ratio of the top coating material (e.g., EC) to the pore former (e.g., hypromellose) may be adjusted to obtain the desired release profile, and may 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, for example, 65:45, or 60:40, or 55:45, or 50:50. Likewise, the amount of the top coating may be adjusted to obtain the desired release profile. The amount of coated top coating material can be measured by the weight increase of formulation particles, such as when the top coating is sprayed on the particles. For example, the amount of the top coating 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 %. The alternative coating material for realizing delayed release includes enteric coating materials, such as based on GI medium pH to realize release. The example of this type of material includes shellac (aleuritic acid ester), cellulose acetate phthalate, poly (methacrylic acid-to-methyl methacrylate), cellulose acetate trimellitate (CAT), poly (vinyl acetate phthalate) (PVAP) and hydroxypropyl methylcellulose phthalate (HPMCP).

[0081] An alternative method of making a children's formulation according to the present invention includes preparing and using nano / micro particles. Nano / micro particles are colloidal carriers that show great potential for providing per oral drug administration. In this type of embodiment, the 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.

[0082] Extended release nano / micro particles can be prepared using emulsion-diffusion-spray drying / freeze drying technology. For poorly water soluble APIs (e.g., calcifediol), single emulsion technology is more desirable.

[0083] The emulsion can be converted into a powder formulation using freeze drying or spray drying techniques. The solvent blend for homogenization to form an 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 granules can be in the form of an aqueous suspension, a non-aqueous suspension (e.g., with a triglyceride, such as a fatty acid triglyceride), or can be presented as a spray in a sachet.

[0084] 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 stabilizer can be, for example, in a weight ratio range of 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 be widely in the range of 0.5 wt % to 98 wt %, and in some embodiments, for example, can be in the range of 75 wt % to about 98 wt %. The amount of polymer (e.g., Eudragit and poly(vinyl alcohol)) and API can be, for example, in a weight ratio range of 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 profile can be adjusted by varying the extended release polymer type and polymer to ratio, for example to create a slow release profile comparable to a target profile, such as the previous wax-based calcifediol system. Various exemplary formulation methods are shown in Table 4 below.

[0085] Table 4

[0086]

[0087] One sequential method of the manufacturing process is described below in Table 5. One skilled in the art will appreciate that this sequence is representative and not limiting.

[0088] Table 5

[0089]

[0090] Process and product parameters may be varied and include inlet temperature, suction percentage, column gas flow, cyclone size, homogenization speed and conditions, polymer solvent concentration, discontinuous to continuous phase ratio to provide acceptable product yields.

[0091] In addition to wet granule / pellet formation and spray-dried emulsions, spray congealing is an alternative processing method for producing formulations according to the present disclosure, including extended release formulations of vitamin D compounds, such as calcifediol. If desired, the method can be solvent-free. Hot melt processing can include spray cooling / condensation, such as to produce small particle sizes. Spray cooling, also referred to as spray congealing or spray freezing, is a process in which a melt is converted into well-defined, such as spherical particles. This process uses spray drying technology and a rapid freezing process. For example, it is possible to produce free-flowing lipid micron particles in a size range of about 10 microns to 1000 microns. For example, cold nitrogen can be circulated through a tubing column or other container while a hot melt mixture of lipids, API (e.g., calcifediol) and an optional surfactant is sprayed into the tubing column to form a fine particle mist. The particles can optionally be coated with a top coating of an extended release polymer and a pore-forming agent.

[0092] Lipids that are solid or semisolid at room temperature can be used as extended release adjuvants, and surfactants can be used to help the solubility and complete release of the API. Such lipids include, but are not limited to, paraffin, glyceryl monostearate (Geleol 40-55), Gelucire (e.g., grade 44 / 14, 43 / 01 (CAS number 157710-38-8)), distearic acid glyceryl ester / palmitic acid stearate (e.g., Precirol ATO 5, melting point in the range of 50°C to 60°C, and HLB is 2) and one or more of dibehenic acid glyceryl ester (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 regulate the release of drugs delivered orally. Other lipids can be selected from the mixture of monoacylglycerol, diacylglycerol and triacylglycerol of fatty acid, and the fatty acid is selected from palmitic acid, tallow fatty acid, stearic acid, oleic acid, linolenic acid, linolenic acid, arachidic acid, behenic acid, erucic acid and its combination, such as palmitic acid and stearic acid. Surfactant includes but is not limited to one or more of PEG (such as PEG6000) and Tween (such as Tween 80).

[0093] Spray condensation can be produced in a closed loop device (e.g., supplied by Büchi, Flawil, Switzerland, GEA Group, Düsseldorf, Germany, or ProCepT NV, Zelzate, Belgium) using a suitable spray condensation unit. A freezer can be used to cool the gas in the column. Nitrogen can be used through the system 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.

[0094] Table 6

[0095] Heating bath nozzle(℃) 70 to 90 Product temperature (℃) 60 to 90 Freezer temperature (℃) -30 Internal temperature (℃) -20 Chamber outside temperature (℃) 0 to -2.5 Temperature before cyclone (℃) 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 Barrel pressure (bar) 0.4 to 1 Dosing speed (g / min) 20 to 70 Cyclone size used big

[0096] The formulation containing actives can be prepared in any suitable form. The formulation containing drugs can constitute the entire dosage form, or it can be the region of the dosage form, for example as a core or as a coating (for example on an inert seed core, for example on a blank pill core). In one type of embodiment, the formulation is in the form of particles, and optionally top-coated. The particles can be of any size or shape, such as pellets or miniature tablets. In another type of embodiment, particles containing actives are manufactured, and then, for example, compressed into the form of pills, tablets or dragees. In another type of embodiment, particles containing actives (optionally coated) are filled into capsule shells, pouches or sachets to produce multi-particle dosage forms. Compared with a single-piece matrix tablet, multi-particles (a dosage form made of a plurality of particle units, such as pellets or miniature tablets) provide an increased surface area, allowing preferred release characteristics and bioavailability. Different from a single-piece matrix tablet, multi-particles are evenly dispersed throughout the GI tract. Multi-particles are less sensitive to dose dumping, and their therapeutic effects are more predictable and reproducible than monolithic reservoir type (matrix) formulations. Compared with matrix lozenges, pellets reduce the possibility of sudden effects, and minimize the inter-individual and intra-individual variability in the GI tract. Compared with single unit matrix lozenges, multi-particles have a lower risk of local irritation due to their carrying of trace drugs. In the case of monolithic matrix lozenges, the GI transport rate depends to a large extent on gastric emptying rate and GI movement, but multi-particles (e.g., pellets) produce highly reproducible GI transport rates due to their relatively small size, so inter-individual and intra-individual variability is minimal compared to single unit formulations. Multi-particles (e.g., pellets) include other advantages relative to monolithic matrix lozenges: providing excellent flow properties, high encapsulation rate, low brittleness, providing the flexibility of different drug substances requiring different release modes, can be combined with a single dosage unit, and are different from monolithic matrix lozenges, by using a higher or lower amount of pellets to adjust the flexibility of the dose.

[0097] The capsule should optionally be a HMPC shell or a hard gelatin shell.In another type of embodiment, the granules prepared by water-based wet granulation can be compressed directly into tablets or mini-tablets or micro-tablets, which may be coated or uncoated.

[0098] In one type of granular form, the particle size (diameter) is in the range of about 0.2 mm to about 2.8 mm, or about 0.2 mm to about 2.5 mm, or about 0.2 mm to about 2.0 mm, or about 0.7 mm to about 2.5 mm, or about 0.7 mm to about 2.8 mm, or about 0.5 mm to about 2.8 mm, or about 0.8 mm to about 1.7 mm, or about 0.5 mm to about 1.2 mm, or about 0.5 mm to about 1.0 mm. For example, the target particle size can be up to 2.5 mm, with a variation of no more than 10% in this size, with a maximum size of 2.8 mm. The particles can be sorted into a desired size range by sieving according to known methods. The formulation can also be characterized by an average particle size in any of the aforementioned ranges or amounts. When the particle size becomes too large, the particles are too large to be used in a drug product labeled for administration by spraying on a substrate (e.g., on applesauce or other soft food, such as jelly) and swallowing without chewing or administration via an enteral feeding tube. In another type of dosage form and related administration method, the multiparticles according to the present disclosure can be dispersed in a suspension matrix and administered in a powder form for oral suspension. For example, the suspension matrix can include, for example, purified water, and optionally with one or more excipients. The suspension matrix can, for example, include at least 50% by weight water, more than about 50% by weight water, at least about 80% by weight water, at least about 90% by weight water, at least about 95% by weight water, at least about 99% by weight water, or 100% by weight water. For example, the suspension matrix can be a sugar-based syrup. The suspension matrix can optionally include a suspending agent or thickener. Suitable suspending agents and thickeners include, for example, methylcellulose, starch, trisaccharide and glycerol. In another embodiment, the suspension base is non-aqueous, for example containing or consisting of triglycerides.

[0099] In the case of a sprinkle dosage form, a narrow particle size distribution of less than 1.0 mm, optionally less than 0.5 mm in size is desired to avoid gritty sensation and unpleasant mouthfeel for infants. Sugar spheres are preferred over MCC spheres because the sweetness of sugar can also act as a taste masking aid.

[0100] As another alternative, layered formulations are contemplated. This type of formulation includes a starter seed (e.g., blank pellet core) having a layer of vitamin D compound, which further has a seal coat (e.g., low viscosity hypromellose) to smooth the seed surface after API layering / coating, and also to achieve a uniform coating at a subsequent stage. Above the seal coat is an extended release polymer coating (e.g., a water-insoluble polymer, such as a polymer with a pore former as described herein). If desired, this embodiment may further include an optional taste masking coating, as well as another optional seal coat on the extended release polymer coating and below the taste masking coating.

[0101] In one type of method, for example, seeds (also referred to as pellets or spheres) can be prepared using one or more methods, including extrusion with spheronization, rotary fluidized bed processing, and spray congealing. The seeds may optionally have an API in the seeds themselves, for example, in the range of 0.01% to 10% by weight of the seeds. These seeds are coated with one or more coatings, for example, using a fluidized bed process using a Wurster coating technique. For example, the first seal coating of the seeds may be in the range of 1% to 5% by weight, based on the weight of the seeds, and the functional release coating may be in the range of 3% to 50% by weight, based on the weight of the seeds. There may be an optional second seal coating, for example, in the range of 1% to 5% by weight, based on the weight of the seeds; and a second functional release coating, for example, in the range of 3% to 50% by weight, based on the weight of the seeds. After the optional second functional release coating, there may be a third optional seal coating, for example, in the range of 1% to 5% by weight, based on the weight of the seeds. The formulation may also include an aesthetic (non-functional) coating, for example in the range of 1 wt % to 5 wt % based on the weight of the seed.

[0102] In another type of method, an inert blank pellet core can be used and coated with different layers to obtain the desired release characteristics, such as using a fluidized bed process using a Wurster coating technique. In this method, an inert blank pellet core with a specific size average or range (e.g., in the range of 150 μm to 1000 μm) can be selected. A drug loading layer is made on the seed, such as a loading of 0.01% to 10% by weight of the seed. These seeds are coated with one or more coatings, such as using a fluidized bed process using a Wurster coating technique. For example, the first sealing coating of the drug-coated seed can be in the range of 1% to 5% by weight, and the functional release coating is in the range of 3% to 50% by weight, based on the weight of the seed. There may be an optional second sealing coating, such as in the range of 1% to 5% by weight, based on the weight of the seed; and a second functional release coating, such as in the range of 3% to 50% by weight, based on the weight of the seed. After the optional second functional release coating, there may be a third optional seal coating, for example in the range of 1 wt % to 5 wt % based on the weight of the seed. The formulation may also include an aesthetic (non-functional) coating, for example in the range of 1 wt % to 5 wt % based on the weight of the seed.

[0103] The excipients for the seed and coating materials may be selected from those known in the art, including those described herein. For example, the blank pellet core material may be selected from microcrystalline cellulose, silicon dioxide, mannitol, other sugars, and combinations thereof. Functional coating excipients may be selected from cellulose, HPMC, ethyl cellulose, waxes, glyceryl monostearate, acrylic polymers (including Eudragit), and combinations thereof. Sealing coating excipients may be selected from cellulose, such as HMPC. Pore formers may be selected from cellulose, HMPC, and lactose. Plasticizers may be used for sealing functional and aesthetic coatings, and may be selected from, for example, dibutyl sebacate, triethyl citrate, and PEG. Aesthetic coating materials may be selected from hydroxypropyl methylcellulose, polyvinyl alcohol, and commercial coating products, such as Coatings. Coatings can be applied as aqueous or non-aqueous solutions.

[0104] 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 enough formulation material, such as granules, particles or pellets, to produce a dosage form having calcifediol in an amount ranging from about 1 μg to about 1 g, or from about 10 μg to about 600 μg, or from about 10 μg to about 300 μg, or from about 10 μg to about 100 μg, or from 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 granules, pellets, sachets, capsules, etc., can be stored with a desiccant.

[0105] As described below in conjunction with the Examples, various exemplary dosage forms (e.g., EC-based formulations) exhibit in vivo exposure characteristics that differ from currently approved Extended-release calcifediol capsule products. It is expected that the dosing of such products can be based on their in vivo exposure characteristics (e.g. Compared with extended-release capsules, based on AUC(0-inf), or Compared to the extended release capsule, the ratio is adjusted based on AUC(0-t). For example, the pellets of Example 9 can have 60mcg calcifediol instead of 30mcg Extended-release capsules.

[0106] In principle, the formulations described herein can be characterized by any extended release profile.

[0107] In one type of embodiment, the targeted solubility profile of a formulation according to the present disclosure can be achieved in a lipophilic wax base formulation (Table 7) (e.g., ) in an in vitro dissolution profile of an extended-release 25-hydroxyvitamin D capsule (30 mg) in a 5% saturation (pH 7.0) concentration range. The specification limits may be applied based on the dissolution of each individual unit. For example, ≤30% of the labeled value is dissolved at 2 hours; 53-78% of the labeled value is dissolved at 6 hours, and ≥80% of the labeled value is dissolved at 12 hours. For example, dissolution may be measured using the following dissolution method.

[0108] USP Equipment II (paddle with sinker) RPM 75 medium 5 mM sodium dihydrogen phosphate monohydrate containing 0.5% SDS, pH 6.8, 37 ± 0.5 °C Volume (mL) 500

[0109] Figure 1 Comparative in vitro dissolution release profiles of this type of 30ug dosage form are presented, representing 52 commercial batches. Results are classified as relative "slow", "medium" and "fast" release profiles. Relative standard deviations are evaluated in all dissolution release profiles.

[0110] Table 7

[0111]

[0112] The difference (Δ) between A and C at a given time point is approximately 3% at the 2 hour point; 11% at the 4 hour point; 15% at the 6 hour point; 13% at the 8 hour point; 8% at the 10 hour point; and 3% at the 12 hour point. The formulations of the invention can be designed to substantially match any one of formulations A, B, or C or a combination thereof (e.g., an average of any two or an average of all three A, B, and C). For example, the formulation can be characterized by an in vitro dissolution release value of about 14% to about 18% at 2 hours; or about 36% to about 48% at 4 hours; or about 56% to about 73% at 6 hours; or about 74% to about 88% at 8 hours; or about 89% to about 100% at 10 hours; or about 97% to at least 100% at 12 hours, or any combination thereof, e.g., a dissolution release profile characterized by a combination of all such time points. In another embodiment, the formulation is characterized by an in vitro dissolution release profile of 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 of 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; and 97% or more (e.g., 97% to 110%) at 12 hours.

[0113] In an alternative, the formulation according to the disclosure can be manufactured to form a unique or customized extended release dissolution profile. It is also possible to make the formulation according to the disclosure have a consistent unit dose in vitro dissolution profile with limited intra-batch variability or batch-to-batch variability. For example, the dissolution profile can be measured using USP apparatus II (paddle with a sinker) at 75RPM, where the medium is 5mM sodium dihydrogen phosphate monohydrate containing 0.5% SDS, pH 6.8, 37 ± 0.5 ° C, and a volume of 500mL. In one embodiment, as measured from six dosage forms, variability can be expressed as RSD (%) at any dissolution time point of 2 hours or more. For example, RSD can be at a dissolution point of 2, 4, 6, 8, 10, and 12 hours. In another embodiment, RSD can be at a dissolution point of 4, 6, 8, 10, and 12 hours. In another embodiment, RSD can be at a dissolution point of 2, 6, and 12 hours. For example, as demonstrated in the examples below, such RSD values ​​may be less than 16%, or 10% or less, or 8% or less, or 6% or less, or 5% or less.

[0114] Also contemplated are methods of preparing formulations and final dosage forms according to the present disclosure.Formulations including vitamin D compounds may be made by any suitable method including, but not limited to, direct compression, granulation, extrusion, fluid bed coating, or any combination thereof.

[0115] Such methods include water-based extrusion / spheronization of granules / pellets suitable for extended release formulations containing vitamin D compounds (e.g., 25-hydroxyvitamin D or calcifediol), coating methods for coated seeds or granules containing active substances, and methods for making vitamin D extended release formulations from nano or micro particles. One embodiment of a method for preparing a suitable children's vitamin D formulation in which the active substance is 25-hydroxyvitamin D or calcifediol includes water-based extrusion / spheronization to form multi-particle granules / pellets, which may be uncoated or coated. Controlled release polymers suitable for preparing such 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, flavoring agents and pore formers may be used in water-based extruded granule formulations. In one embodiment, pellets are readily made from an extrudable water-based formulation without the need for additional coatings to achieve the desired extended release of in vitro and in vivo characteristics. Such methods may include (1) forming a water-based extrudable mass including active and inactive excipients; (2) extruding such mass to form granules containing the active; (3) spheronizing the granules to form pellets; and (4) drying the pellets. The dried pellets may optionally be coated with a lubricant and / or flavoring agent, such as talc and flavoring agents. 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 water-based formulation used to form the wet extrudable mass 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 granules (aqueous and non-aqueous) produced by this method have the necessary strength and integrity to provide processable, extrudable and functional spheroidized pellets. Pellets may also be referred to as beads or spheres. The enhanced properties may include one or more properties, including optimal flow characteristics; reproducible provision into capsules or other drug delivery vehicles; optimal density / hardness properties for processing and coating, if desired; improved hardness and friability (e.g., not more than 1.0%); and more consistent batch-to-batch in vitro and in vivo drug delivery and release characteristics. 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 API in the GI tract; reducing processing steps, such as by avoiding the use of coatings; improving flow characteristics, such as for capsule or sachet filling; providing a narrow particle size distribution; and providing uniform encapsulation characteristics.

[0116] In one embodiment, by granulating a mixture of a vitamin D compound and a material (e.g., 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 combined with one or more steps (including screening, graded screening, and grinding) to form a formulation. In another embodiment, a formulation can be formed by extruding and spheroidizing a mixture of a vitamin D compound and a material as described herein (e.g., a water-insoluble polymer) and one or more other optional excipients. For example, an extruder can be equipped with an extrusion screen of a desired size (e.g., 0.1 mm to 5 mm, or 0.5 mm to 2 mm). Additionally or in an alternative, a spheronizer can be equipped with a plate of a desired size and configuration, such as a cross-line plate of 0.1 to 5 mm, or a cross-line plate of 0.5 to 2 mm. Granulation methods may include, for example, fluidized bed granulation, wet granulation, hot melt granulation, and spray congealing. Other methods include tabletting and roller pressing. The mixture to be granulated may first be dry blended as is generally known in the art. Prior to extrusion, the dry blended dry ingredients may be mixed with water.

[0117] For example, in one embodiment of the method for producing spheroidized pellets, dry ingredients are combined, blended and mixed with about 50% by weight to 80% by weight of water, and wet granulation is to form a wet extrudable material. Blending, extrusion, spheroidization and drying are extrudable materials of the combined ingredients of the weight ratio selected depending on the extended release polymer and excipient to form the desired pellets for children or adults' formulations. For example, a mixture of calcifediol and triglyceride can be added to the blend of premixed dry excipients, and a binder solution can be added subsequently to prepare the wet material for extrusion. Drying can be accomplished by, for example, tray drying, vacuum drying or fluidized bed drying.

[0118] The sequential method of the manufacturing process is described below in Table 8. One skilled in the art will appreciate that this sequence is representative and not limiting.

[0119] Table 8

[0120]

[0121] It has been found that extrusion and spheronization of a mixture of a vitamin D compound and an extended release component as described herein (e.g., a water-insoluble polymer) can provide a commercially available extended release wax matrix formulation (e.g., ) of the present invention. It is contemplated to use calcifediol as the vitamin D compound in an extrusion-spheronization type formulation. The following composition can be filled into soft In the plant polysaccharide shell: calcifediol 0.02% by weight of the capsule fill, paraffin 20.0% by weight of the capsule fill, mineral oil 35.34% by weight of the capsule fill, hypromellose 10.0% by weight of the capsule fill, mono- and di-glycerides 22.56% by weight of the capsule fill, polyoxyglycerol lauroyl ester 9.75% by weight of the capsule fill, anhydrous alcohol 2.32% by weight of the capsule fill and BHT 0.02% by weight of the capsule fill.

[0122] The formulations described herein can be directly processed as finished dosage forms, or they can be further processed to make finished dosage forms. For example, the formulation can be top coated. Coating can be done by fluidized bed coating, for example, with top, tangential or bottom spray configuration configuration. As another example, the formulation can be compressed into the form of, for example, a pill or lozenge. In another type of embodiment, the particles of the formulation described herein (optionally coated) are filled into a capsule shell or can exist in a sachet form or can be provided with a suspension as a vehicle to suspend these pellets before applying it.

[0123] The extrusion / spheroidization calcidiol pellet batches described in the following examples and using Compritol 888ATO show that the dissolution characteristics decrease with the accelerated storage stability test. The formulations containing lipids as described herein (e.g., formulations containing Gelucire or Compritol components) can be heat-cured to stabilize the formulations for structural changes during long-term storage. In the absence of heat curing, the lipid components can migrate over time during storage, blocking hydrophilic sites or holes, and therefore changing the dissolution release characteristics compared to the formulations at time zero. Further optionally, the formulations with higher melting point lipids as described herein can be mixed with lipids of lower melting points so that the formulations can be heat cured at lower temperatures. 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 compounded or partially substituted with glyceryl distearate / 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, so that thermal curing can be performed at about 60°C and below 65°C (relative to glyceryl behenate) to avoid degradation of calcifediol. Optionally, thermal curing can be performed 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.

[0124] The administration of the dosage form according to the present disclosure can be based on the weight of the active ingredient in the formulation. For example, the administration of the formulation containing calcifediol can be in the amount of 1 μg calcifediol to about 1g calcifediol. The dosage form can be orally administered to patients suffering from the condition of a specified vitamin D compound, including but not limited to vitamin D deficiency, vitamin D deficiency, secondary hyperparathyroidism associated with CKD (e.g., any one of CKD in phase 1 to phase 5, including phase 3, phase 4, phase 5, or phase 3-5 or phase 3-3). In any method or use described herein, it is expected to treat humans. In any method or use described herein, it is expected to treat mammals. In any formulation, dosage form, use and method described herein, oral formulations and oral administration are expected. The composition of the present disclosure can be used in combination with other therapies useful for specified diseases and disorders.

[0125] Additionally or in the alternative, the formulations described herein may be used in the preparation of a medicament for treating a vitamin D responsive condition or disease.

[0126] The compositions and methods described herein are suitable for the preventive 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 worsening of the disease or reduces the signs and symptoms of the disease. Such vitamin D responsive diseases include hyperparathyroidism, hyperparathyroidism secondary to CKD (e.g., independently or within any one of stages 1, 2, 3, 4, or 5), hyperparathyroidism secondary to CKD in patients undergoing hemodialysis, or tertiary hyperparathyroidism. Such vitamin D responsive diseases include cancer (e.g., breast cancer, lung cancer, skin cancer, melanoma, colon cancer, colorectal cancer, rectal cancer, prostate cancer, and bone cancer). It has been observed that active vitamin D (e.g., calcitriol) induces cell differentiation and / or inhibits cell proliferation in vitro 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. Vitamin D responsive diseases have also been reported to include hypertension and cardiovascular disease. Thus, the method encompasses prophylactic or therapeutic treatment of individuals at risk of cardiovascular disease, 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 to use any of the formulations described herein, including Extended release capsules are used to treat or prevent such diseases, such as to prevent the onset or progression of the disease, or to reduce the signs and symptoms of the disease.

[0127] Patients in need of vitamin D supplementation include healthy individuals and individuals at risk for vitamin D insufficiency or deficiency, e.g., individuals with stage 1, 2, 3, 4, or 5 CKD; infants, children, and adults who do not consume milk fortified with vitamin D (e.g., lactose-intolerant individuals, individuals with milk allergies, vegetarians who do not consume milk, and breast-fed infants); individuals with rickets; individuals with dark skin (e.g., in the United States, 42% of African American women between the ages of 15 and 49 are vitamin D deficient compared to 4% of Caucasian women); the elderly (who have a reduced ability to synthesize vitamin D in the skin during exposure to sunlight and who are also more likely to stay indoors); adults living in institutions for a long time (adults who are likely to stay indoors, including those with Alzheimer's disease); 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., application of sunscreen with a sun protection factor (SPF) of 8 reduces vitamin D production by 95%, and higher SPFs can further reduce cutaneous vitamin D production); individuals with fat malabsorption syndromes (including but not limited to cystic fibrosis, cholestatic liver disease, other liver disease, gallbladder disease, pancreatic enzyme deficiency, Crohn's disease, inflammatory bowel disease, stomatitis or celiac disease, or surgery to remove and / or skip part or all of the stomach and / or intestines); individuals with inflammatory bowel disease; individuals with Crohn's disease; individuals who have had a small bowel resection; individuals with periodontitis (gum disease). disease); individuals taking medications that increase the catabolism of vitamin D (including phenytoin, fosphenytoin, phenobarbital, carbamazepine, and rifampin); individuals taking medications that reduce the absorption of vitamin D (including cholestyramine, colestipol, orlistat, mineral oil, and fat substitutes); individuals taking medications that inhibit the activation of vitamin D (including ketoconazole); individuals taking medications that reduce calcium absorption (including corticosteroids); individuals with obesity (vitamin D deposited in body fat stores has low 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 more than 50% of younger and older women do not consume the recommended amounts of vitamin D. Optionally, the method excludes therapeutic treatment of individuals suffering from renal osteodystrophy, including osteomalacia and bone cysts. It is contemplated that any of the formulations described herein, including, are administered to such individuals. extended-release capsules).

[0128] The 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 applied by spraying (e.g., on applesauce or other soft foods, such as jelly) so that they can be swallowed without chewing. In an alternative, such formulations can be administered by an enteral feeding tube. In these embodiments, the capsule containing the particles can be opened before spraying, or the bag or sachet containing the particles can be opened. For example, easy-opening hard gelatin capsules are available from Capsugel under the trade name CONISNAP.

[0129] The formulation can be administered to an adult patient or a pediatric patient. 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.

[0130] Formulations with a particle size limit of 2.8 mm or less may be packaged with instructions for sprinkling the particles on a soft food (eg, apple puree) and optionally also swallowing the particles and food without chewing.

[0131] Formulations with a particle size limit of 2.8 mm or less may be packaged with instructions for enteral feeding tube administration.

[0132] The formulation can be used with a dosing regimen that includes a dose reduction aspect. The dose can be reduced weekly (e.g., a 30 mcg unit dose) as needed, and no more frequently than once every two weeks, if any of the following four criteria are 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.

[0133] Dose reduction can be achieved by consistently omitting doses on specific days of the week, such as the following:

[0134] First dose reduction: omit dosing on one day of the week, e.g., all Mondays (M);

[0135] Second dose reduction: two non-consecutive days of the week, for example, omitting dosing on all M and Wednesday (W);

[0136] · Third dose reduction: omit dosing on three non-consecutive days of the week, for example, on all M, W, and Friday (F);

[0137] · On four days of the week, at least two or three of which are not consecutive, for example, omitting dosing on all M, W, F and Sunday (S);

[0138] Any subject requiring further dose reduction should have dosing discontinued.

[0139] As described above, non-consecutive days of the week may consist of or include alternating days of the week, eg, M, W, F.

[0140] Examples

[0141] The following examples are provided for illustration and are not intended to limit the scope of the present invention.

[0142] Example 1 - Eudragit polymer formulation

[0143] Examples 1.1 to 1.4 containing Eudragit-based polymer pellets were made by extrusion-spheronization using the excipients identified in Table 9 below. Calcifediol was dissolved in ethanol. Wet extrudable material 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 operated at a speed of about 30-35 RPM. The spheronizer was a Caleva MultiBowl Spheronizer / mbs 250 operated at about 1000-2500 RPM. The sieves used for classification were 1.4 mm, 1.0 mm, 850 μm, 500 μm and 250 μm. The pellets in the different batches finally selected were: 500 μm, 850 μm and 1.0 mm. The average diameter of the pellets of Formulation 1.2 was about 500 μm, and the average diameter of the pellets of Formulations 1.1, 1.3, and 1.4 was about 1.0 mm. All particles analyzed for at least 94% of the expected API and exhibited satisfactory flow properties, friability, and acceptable levels of related material impurities. The pellets contained about 4 to 6 wt % or less water by Karl Fischer titration.

[0144] Table 9

[0145]

[0146] The dissolution release characteristics of the pellets were measured and compared with the dissolution release of a representative batch of calcifediol extended release wax-matrix extended release soft capsules. 50 mg of the pellets were filled into hard capsule shells and the dissolution release was carried out using USP apparatus II (paddle with sinker) at 75 RPM in a medium of 5 mM sodium dihydrogen phosphate monohydrate containing 0.5% SDS, pH 6.8, 37 ± 0.5 ° C, and a volume of 500 mL. The dissolution results are shown in Table 1. Figure 1 1.4 and are tabulated in Table 10 below for Examples 1.1 to 1.4. The average dissolution times and relative standard deviation (RSD) values ​​were derived from dissolution testing of six capsules.

[0147] Table 10

[0148]

[0149] Example 2 - EC Polymer Formulations

[0150] Examples 2.1 to 2.4 containing EC-based polymer pellets were made by an extrusion-spheronization process using the excipients identified in Table 11 below. Wet extrudable materials were 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 operated at a speed of about 30-35 RPM. The spheronizer was a Caleva MultiBowl Spheronizer / mbs 250 operated at about 1000-2500 RPM. The average diameter of the pellets of Formulations 2.1 and 2.2 was about 500 μm. The average diameter of the pellets of Formulation 2.3 was about 850 μm. Before coating, the average diameter of the pellets of Formulation 2.4 was about 850 μm. Example 2.4 included a top coating comprising a mixture of Surelease extended release polymer and Pharmacoat 603 pore former in a 60:40 weight ratio, applied at 25% weight gain using purified water as a dispersion medium, and subsequently dried. All pellets analyzed to at least 93% of the expected API and exhibited satisfactory flow properties, friability, and acceptable levels of related material impurities. The pellets contained about 5.5% by weight or less water by Karl Fischer titration.

[0151] Table 11

[0152]

[0153] The dissolution release characteristics of the pellets were measured and compared with the dissolution release of a representative batch of calcifediol extended release wax-matrix extended release soft capsules. 50 mg of the pellets were filled into hard capsule shells and the dissolution release was carried out using USP apparatus II (paddle with sinker) at 75 RPM in a medium of 5 mM sodium dihydrogen phosphate monohydrate containing 0.5% SDS, pH 6.8, 37 ± 0.5 ° C, and a volume of 500 mL. The dissolution results are shown in Figure 2 2.1 to 2.4 are tabulated in Table 12 below. The average dissolution time and relative standard deviation (RSD) values ​​were derived from dissolution testing of six capsules.

[0154] Table 12

[0155]

[0156] Example 3 - Nano / Micro Particles

[0157] Preparation of nano / micro particle formulations with 1 part by weight of calcifediol, 25 parts by weight of Eudragit RLPO and 1 part by weight of poly(vinyl alcohol) by emulsion-diffusion-spray drying technology An emulsion was formed with the API and excipients, using ethyl acetate as the discontinuous phase solvent and water as the continuous phase solvent. The emulsion was homogenized and spray dried via a cyclone using a Buchi micro spray dryer B-191, and the general procedure and parameters are described in Table 5 above. The product powder was produced in satisfactory yields with particle sizes ranging from about 900 nm to about 10 microns, including spherical to annular particles.

[0158] Table 13 below describes the formulations analyzed for dissolution.

[0159] Table 13

[0160] composition ratio(wrtAPI) Calcifediol 1.00 Eudragit RL PO 25.00 Polyvinyl alcohol 1.00

[0161] The batch produced from the above composition produced a fine spray dried powder with a product yield of 53%. Figure 3 An initial comparison in Table 13 of the spray dried formulations compared to various slow, medium and fast batches of wax based extended release 25-hydroxyvitamin D3 capsules is provided.

[0162] Additional batches of nano / micro particle formulations were made by the same process with formulation differences according to Table 14 below to target the release characteristics of the slow and medium softgel wax based formulations as described above. The release characteristics will be as follows Figure 5 shown.

[0163] Table 14

[0164]

[0165] Example 4 - Spray Condensation

[0166] Batch 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 were manufactured by spray congealing. Spray congealing was manufactured in a closed loop device using a ProCepT spray congealing unit. A freezer was used to cool the gas in the column. Nitrogen was used through the system to obtain a temperature in the system below 0°C. The temperature of the melt was kept as low as possible. The melt was sprayed using a heated two-fluid nozzle. The product was dosed by a pressure vessel. The process parameters used are described in Table 6 above.

[0167] The obtained product was free flowing and had a size range (d 50) was 100 to 700 μm. The calcifediol content and related substances of Examples 4.1 to 4.9 were analyzed and yielded at least 86% of the expected amount of calcifediol. The water content of Examples 4.1 to 4.9 was also analyzed by Karl Fischer titration and showed about 0.3 wt % or less of water.

[0168] Table 15

[0169]

[0170] Table 16

[0171]

[0172] Figure 4 The release characteristics of various test formulations relative to slow, medium and fast soft gel capsule 25-hydroxyvitamin D3 batches are shown. Figure 4 As shown, these examples provide a range of release profiles having different in vitro dissolution profiles, illustrating that the specific formulation used in the methods can be varied to provide a desired dissolution release profile.

[0173] Example 5 - Batch-to-Batch Reproducibility

[0174] Two batches were prepared related to the formulations of Examples 1.1, 1.2 and 1.4 above. The batches were identical except that the flavoring (0.5 wt%) was omitted from each comparative batch and was offset by including an equivalent increase in MCC content. Dissolution properties were measured at 75 RPM using USP Apparatus II (paddle with sinker) with the medium being 5 mM sodium dihydrogen phosphate monohydrate with 0.5% SDS, pH 6.8, 37 ± 0.5 °C, and a volume of 500 mL. Comparative dissolution release profiles are shown in Figures 6 to 8 The batches without flavoring were designated 1.1a, 1.2a, and 1.4a. The results show that the formulations demonstrated good batch-to-batch consistency.

[0175] Example 6 - Brittleness Test

[0176] Weigh out 10 grams of dust-free pellets from Examples 1.1 and 2.1 and record as the pre-test weight (B wt ). These pellets were placed in an embrittler along with 200 3 mm solid glass beads. The pellets and beads were rotated at 25 RPM for 10 minutes. The pellets were collected from the embrittler and dusted by gently sieving through a 250 μm sieve. The weight of the pellet fraction retained on the 250 μm sieve was recorded as the post-test weight (A wt ). Through the formula ((B wt -A wt ) / B wt)×100 to calculate the crispness %. The results are shown in Table 17 below (three replicates), demonstrating the good crispness of the formulations according to the present disclosure.

[0177] Table 17

[0178]

[0179] Example 7 - In vivo pharmacokinetics in minipigs

[0180] The formulations of Examples 1.1 to 1.4 and 2.1 to 2.4 were used in a single oral dose pharmacokinetic study in local male Yucatan miniature pigs ( Male Yucatan Minipig. Administer wax matrix soft capsule ( The two control arms of the oral product (type formulation) and the immediate release oral product served as the control group. The animals were adapted for at least 21 days to a 12-hour light cycle / 12-hour dark cycle to stabilize their baseline calcifediol blood content. From the beginning of acclimatization to the end of the study, all animals were kept on a standardized diet. It was determined that the sample size of 5 animals for each formulation was sufficient to achieve the research objectives. The animals were fasted from food overnight for at least 10 hours and were not fed for at least 4 hours before and after dosing. The animals were also deprived of water for one hour after dosing. Multiple baseline and post-dose blood samples were collected up to 120 hours after administration of the test article. The concentration of 25-hydroxyvitamin D3 (calcifediol) in serum was determined using a qualified method. The following pharmacokinetic parameters of calcifediol were calculated by the standard non-compartmental method: AUC 0-t : The area under the concentration-time curve from time zero to the last non-zero concentration measured; C max Tmax: observed maximum concentration; max time.

[0181] The study was conducted to evaluate the absorption phase of the pharmacokinetic (PK) profile of various modified release calcifediol multiparticulate capsule formulations after a single oral dose of 270 μg compared to wax matrix based modified release softgels and immediate release calcifediol products administered at oral doses of 270 μg and 266 μg, respectively.

[0182] PK studies have shown the promise of the pellet formulation concept in terms of prolonged in vivo release of calcifediol. A greater extent of absorption (AUC0-t) was observed for the ethylcellulose (EC) containing formulations, especially 2.1, 2.2 and 2.3, compared to the Eudragit containing formulations (1.1 to 1.4). For all multiparticulate formulations, the median time to reach maximum concentration (Tmax) ranged between 8 and 16 hours after administration, while the median observed Tmax was approximately 24 hours and 4 hours for the wax matrix based modified release softgel capsules 270 μg and immediate release calcifediol 266 μg, respectively. See Fig. 9 and Table 18.

[0183] Table 18: PK Parameters of Baseline Corrected (BC) Serum Calcifediol in Local Male Yucatan Minipigs

[0184]

[0185] The Eudragit-containing formulations extended the in vivo release of calcifediol (Tmax), although these particular formulations exhibited relatively lower rates and extents of absorption compared to non-Eudragit formulations. Formulations 2.2 and 2.3 exhibited overall higher absorption profiles, with 2.2 having a Tmax greater than 2.3. Without wishing to be bound by any particular theory, it is believed that the enhanced absorption profiles of the 2.1 to 2.4 ethylcellulose formulations compared to the 1.1 to 1.4 Eudragit-containing formulations can be attributed to absorption enhancing excipients (such as Miglyol) and soluble excipients (such as lactose and HPMC).

[0186] These formulations are indicated as pellet / multiparticulate dosage forms for prolonged release of calcifediol in vivo.

[0187] Example 8 - Additional EC Polymer Formulations

[0188] Following the study of Example 7, another formulation development session was conducted to explore the dissolution and human pharmacokinetic profile of polymer-based pellets produced by the extrusion-spheronization process. In this work, Formulation 2.2 was selected as the lead formulation and development trials were based on this composition.

[0189] Learning from the porcine PK data in Example 7, the Eudragit formulation exhibited a relatively low absorption rate and extent. 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 hydrophobic Eudragit polymer. Since the Eudragit matrix formed is hydrophobic, this may prevent the release of hydrophobic calcifediol. However, the hydrophobic matrix helps to prolong the release of calcifediol and therefore helps the release of Tmax in vivo.

[0190] In contrast, the EC formulations 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 formulations can be attributed to the presence of higher concentrations of soluble excipients such as Miglyol, lactose, and HPMC, the presence of such soluble excipients contributing to the matrix being more hydrophilic and since calcifediol may be absorbed more preferentially in the vicinity of this matrix.

[0191] In view of these results, the focus of research and development is to incorporate soluble excipients into the matrix to promote the solubility / absorption / bioavailability of calcifediol and at the same time prevent the too rapid release of this dissolved calcifediol by using extended release matrix forming agents. In addition, it is also envisioned that since calcifediol is a BCS class IV compound, this formulation system can benefit from an appropriate hydrophilic-lipophilic balance (HLB), and therefore, work is made to incorporate suitable lipid agents that meet this assumption.

[0192] In order 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. Gelucire 48 / 16 grade (PEG-32-stearate, also known as PEG 32 mono- and diesters of stearic and palmitic acid, HLB of 12 and CMC of 153 ± 31 mg / L, which helps to improve the solubility of hydrophobic and lipophobic molecules, was used based on its physical properties and suitability for extrusion and spheronization processes, being solid at ambient temperature with a melting point of 48°C. Compritol 888ATO was used as a lipid extended release matrix agent, which has a dual purpose, one for balancing the lipophilic part of 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.

[0193] Example 8.1 to 8.28 is manufactured by extrusion-spheronization using the excipients identified in Table 19 below.Preparation, extrusion and spheronization wet extrudable materials.Extrusion / spheronization process follows the general order described in Table 8 above, and Comprtol 888ATO is incorporated into the DR mixture and Gelucire is incorporated into the binder solution by suitable modification.The extruder is a Caleva bench screen extruder 20 with a screen size of 1mm and operating at a speed of about 30-35RPM.The spheronizer is a Caleva MultiBowl Spheronizer / mbs250 operating at about 1000-2500RPM.The average diameter of the pellets is about 500 μm.All pellets show satisfactory flow characteristics, brittleness and acceptable content of related material impurities.By Karl Fischer titration, the pellets contain about 5.5% by weight or less water.Table 19 below also includes the initial analysis results of calcifediol content when obtained.

[0194] Table 19

[0195]

[0196]

[0197] Table 19 (Continued)

[0198]

[0199]

[0200] Table 19 (Continued)

[0201]

[0202]

[0203] *Store at room temperature for five months

[0204] Typically, 100 mg of pellets were filled into hard gelatin capsule shells and dissolution release was performed using USP Apparatus II (paddle with sinker) at 75 RPM in a medium of 5 mM sodium dihydrogen phosphate monohydrate with 0.5% SDS, pH 6.8, 37 ± 0.5 °C, in a volume of 500 mL. Example 8.16 has a higher concentration of calcifediol and a fill weight of 50 mg. Dissolution results are listed in Table 20 below when available. Average dissolution time values ​​are derived from dissolution testing of six capsules; Comparison of softgel capsules.

[0205] Table 20

[0206]

[0207]

[0208] Table 20 (Continued)

[0209]

[0210] Table 20 (Continued)

[0211]

[0212] *Store at room temperature for five months

[0213] Initially, compared with 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 research and development associated with this process produced more sudden effects, releasing 53%-86% calcifediol within 2 hours. Those trials using Gelucire 48 / 16 demonstrated the high solubility and rapid release of calcifediol, although the release characteristics could not be fully controlled as desired. These results are conducive to using Gelucire as a bioavailability enhancer. It was observed that these pellets were 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.

[0214] In view of the foregoing results, Methocel K3 Premium LV was added to the binder solution in subsequent trials (Examples 8.13 to 8.28) and removed from the dry blend. Further development of Gelucire 48 / 16 in binder solution together with Methocel K3 was well suited to the process and was also effective in restoring the burst release to <40% within 2 hours. It was also observed that the pellets were harder than those in which HMPC was added to the dry blend.

[0215] In order to compensate for the enhanced solubility provided by Gelucire, further tests were performed using Compritol and EC as extended release agents to effectively control the release profile and provide extended release characteristics for calcifediol. The range of some tests was also within a lower content of lactose, and there was no lactose providing a slower release. As a general trend of these matrix formulations tested, it was observed that reducing initial release also reduced total release. Therefore, formulations were mainly optimized as bioavailability enhancers with 20% EC and 20% Compritol as extended release agents and 5% concentration of Gelucire 48 / 16.

[0216] In addition to the development of this release profile, 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.

[0217] To complete the second phase of 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., pig data (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.

[0218] Table 21: Effect of BHT on Ethylcellulose Formulations

[0219]

[0220] *Examples 2.2, 8.2, and 8.4 were made and analyzed under similar conditions and at the same scale, so the results are comparable. Example 8.27 was made and analyzed under different conditions, and so the related material results are not considered comparable to Examples 2.2, 8.2, and 8.4.

[0221] Example 9: Single-dose oral pharmacokinetics study of two calcifediol 30mcg pellet formulations in healthy adult subjects under fasting conditions

[0222] The objective of this study was to evaluate the pharmacokinetics of two calcifediol 30mcg 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 to characterize the bioavailability and PK of calcifediol in two new formulations in healthy subjects. The primary study endpoints evaluated the baseline adjusted PK parameters Cmax and AUC of calcifediol 0-T The purpose of this study was to quantify the rate and extent of absorption from the formulation.

[0223] After a single oral dose under fasting conditions, the baseline adjusted mean peak concentration and exposure of calcifediol were slightly higher for the formulation of Example 8.27 compared to Example 8.28. The mean Cmax was 25.65 ng / mL and 22.01 ng / mL for the formulations of Example 8.27 and Example 8.28, respectively, and the extent of absorption (AUC 0-T) were 2390.05 ng·h / mL and 2059.61 ng·h / mL, respectively. The time to peak concentration (Tmax) was similar between the two formulations, with median Tmax of 6.00 and 6.05 hours for the formulations of Example 8.27 and Example 8.28, respectively. For unadjusted calcifediol, the same trend in mean peak concentration and exposure was observed, however, the magnitude of the difference was smaller compared to the results for baseline-adjusted calcifediol. In summary, the formulations tested were generally safe and well tolerated by the subjects included in this study (see Fig.10 and Table 22).

[0224] Table 22: Summary of Baseline-Adjusted Pharmacokinetic Parameters

[0225]

[0226] a Median (range)

[0227] b For AUC 0-∞_FDA , AUC 0-T / ∞ , AUC 0-∞_EMA and the remaining area, n = 8

[0228] c For AUC 0-T , n = 14

[0229] d For AUC 0-∞_FDA , AUC 0-T / ∞ , AUC 0-∞_EMA and the remaining area, n = 7

[0230] Example 10: Thermally Cured Formulation for Storage Stability

[0231] The previous batch of Example 8 using Compritol as a matrix agent shows a drop in dissolution characteristics after accelerated stability testing for 3 months at 40°C and 75%RH. Without wishing to be bound by any particular theory, the change in drug release (reduction) observed after storage under accelerated conditions may be due to the distribution change of lipid components in the matrix structure; lipids can migrate in 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 speed at which water diffuses into the matrix and the drug diffuses out from the matrix. This can result in slower release kinetics on stability. In order to reduce the drop in dissolution under these conditions, a solidification / sintering step can be used. This additional step will stabilize the lipids in the matrix in the initial stage of formulation manufacturing.

[0232] However, high melting point lipids (e.g., glyceryl behenate, Compritol 888ATO, with a melting point range of 65-77°C) require curing at higher temperatures, and thus curing of degradable APIs (e.g., calcifediol) above this temperature. Therefore, relatively low melting point components with similar functional groups can be used in addition to or in partial or complete replacement of relatively high melting point components. For example, distearin / palmitostearin (e.g., Precirol ATO5) is a lipid similar in function to glyceryl behenate, but has a lower melting point of 54°C. Curing 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.

[0233] The formulation of Example 8.28 described above was modified by adding glyceryl distearate / palmitostearate and compensating for changes in other formulation ingredients to prepare Formulation Examples 10.1 to 10.5 as described below in Table 23. Pellets were prepared as generally described in Example 8 described above. The Precirol component was added to the dry blend for processing.

[0234] Table 23

[0235]

[0236]

[0237] The resulting pellets of Examples 10.1 and 10.2 were tested for dissolution characteristics as described above in Example 8, either in their uncured state or after curing at 60°C for a certain period of time, as shown in the initial dissolution results listed in Table 24 below.

[0238] Table 24

[0239]

[0240] As shown in Table 24, although curing showed some reduction in release, curing did not substantially change the initial release characteristics of the formulations.

[0241] After storage under accelerated stability conditions, ie, 40°C and 75% RH, the solidified formulation will exhibit a release profile more similar to the initial release profile, whereas the unsolidified formulation will exhibit a reduced release profile due to the presence of unstabilized lipids in the formulation.

[0242] Example 11: Children's Research

[0243] Phase 3, multicenter, randomized, double-blind, placebo-controlled studies were conducted primarily or entirely in the United States (US). The study involved approximately 108 eligible individuals, balanced for gender and CKD stage, aged 8 to <18 years old, secondary hyperparathyroidism (SHPT), 3 or 4 CKD and vitamin D insufficiency (VDI). Initially, approximately 72 individuals aged 12 to <18 years old (Group 1) were recruited, and approximately 36 additional individuals aged 8 to <12 years old (Group 2) were recruited. Individuals in the two groups were randomly divided into two treatment groups at a ratio of 2: 1 to receive daily bedtime doses of (a) the extended release formulation of calcifediol described herein, or (b) matching placebo for 26 weeks. Individuals assigned to treatment with the calcifediol formulation in Group 1 were initially dosed at 30 micrograms / day and, at the end of 12 weeks of treatment, were titrated upward to 60 mcg per day, provided that (a) plasma iPTH had not decreased by at least 30% from 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 an interim analysis of data obtained from Cohort 1, as described below. The efficacy of the calcifediol formulation in the treatment of SHPT was assessed by multiple plasma iPTH and serum 25-hydroxyvitamin D levels obtained during the efficacy assessment period (EAP), which was defined as the last 6 weeks of the 26-week treatment period.

[0244] An interactive response system (IRS) provided study treatment group assignment (using computer-generated randomization codes 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.

[0245] DSMB members also conduct periodic reviews of study conduct to verify that all required data are retrieved to a sufficient degree (>95%) and within a specified time frame (usually within 5 days) and to prompt appropriate corrective actions to address any noted deficiencies, with an effort to minimize missing data. The specific responsibilities and activities of the DSMB are defined in a charter approved at the pre-study organizational meeting. These responsibilities include completing an interim analysis of data obtained from Group 1 to justify the starting dose for Group 2, and an interim analysis of data obtained from Group 2 to justify the starting dose for a separate Phase 2 study in subjects aged 1 month to <8 years.

[0246] Subjects who were treated with calcitriol or another 1α-hydroxylated vitamin D analog prior to study participation, or who were receiving a calcimimetic 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 the baseline assessment.

[0247] Subjects receiving vitamin D supplementation at a rate greater than 1,700 IU / day or 50,000 IU (1,250 mcg) per month prior to study participation had their dose reduced to ≤1,700 IU / day for the duration of the study and an 8-week washout period prior to baseline assessment if serum total 25-hydroxyvitamin D was ≥30 ng / mL. No washout period was required if serum total 25-hydroxyvitamin D was <30 ng / mL. Subjects completed a 6-week follow-up (FU) period after completing the 26-week treatment period or after early termination (ET).

[0248] Blood samples were collected weekly, biweekly or monthly during the 10-week pre-treatment screening / baseline phase, the 26-week treatment phase and the 6-week post-treatment FU phase. Sparse PK samples were collected from all individuals at 0 (pre-dose), 6, 12, 24 hours (pre-dose 84th day) and 48 hours (pre-dose 85th day) on the 83rd day. During the last 3 days of treatment for 12 weeks (before dose titration), additional PK blood samples were collected in a subset of 10 individuals treated with calcifediol formulations and 5 individuals treated with placebo in Groups 1 and 2. Additional PK samples were collected as follows: Day 83: -2, 2, 4 and 8 hours. The study was terminated and study PK blood samples were collected in other subsets of approximately 20 individuals (20 individuals from each group) during the post-treatment FU phase. In each cohort, PK samples were collected from 10 subjects at each final daily dose level (30 or 60 mcg) of the calcifediol formulation in an attempt to establish the terminal elimination half-life (t1 / 2) of 25-hydroxyvitamin D3 at each of these dose levels.

[0249] All subjects, investigators, and sponsors were blinded to the treatment administered and plasma iPTH, serum total 25-hydroxyvitamin D, and serum 25-hydroxyvitamin D3 data until the last subject completed 26 weeks of treatment. Unblinded data were provided to all study sites in the final clinical study report.

[0250] An interim analysis of data obtained from 15 subjects in Cohort 1 who provided intensive PK samples during the last three days of treatment Week 12 was conducted by DSMB to determine the appropriate starting dose for Cohort 2. A second interim analysis of data obtained from 15 subjects in Cohort 2 who provided intensive PK samples during the last three days of treatment Week 12 was conducted by DSMB to determine the appropriate starting dose for a separate Phase 2 study in subjects aged 1 month to <8 years.

[0251] Each subject participated in the study for up to approximately 42 weeks (2-week screening / baseline, 8-week washout if necessary, 26 weeks of treatment with calcifediol formulation or matching placebo, and 6-week FU assessments).

[0252] Key parameters 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 urine calcium: creatinine ratio. Vital signs (VS) and adverse events (AEs) were monitored at each study visit. Other parameters monitored less frequently included brief physical examinations (PE), clinical laboratory tests (hematology and clinical and urine chemistry), and palatability and acceptability reported by patients. Twelve front-end electrocardiograms (ECGs) were obtained at baseline and at the end of treatment or ET. Additional exploratory parameters were monitored at designated 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), N-terminal propeptide of procollagen type 1 (P1NP), and tartrate-resistant acid phosphatase 5b (TRAP 5b)).

[0253] 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 the 12-week treatment, individuals assigned to active treatment underwent an upward dose titration to 60 mcg (two calcifediol unit doses) daily, provided that (a) plasma iPTH had not decreased by at least 30% from 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 determinations from an interim analysis of data obtained in Group 1, subjects in Group 2 received an initial daily bedtime dose and underwent an upward dose titration to a new daily dose that was two times higher than 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 pretreatment 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.

[0254] The dose may be reduced by one capsule per week, as needed, and no more frequently than every two weeks, if any of the following four criteria are 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 investigator considers the increase in serum phosphorus to be related to study drug administration and that appropriate and ongoing measures have been taken to control serum phosphorus by initiating or adjusting any phosphate binder therapy.

[0255] Dose reduction can be achieved by consistently omitting doses on specific days of the week, as follows:

[0256] First dose reduction: Omit dose on Monday (M).

[0257] Second dose reduction: Omit doses on all M and Wednesday (W) days

[0258] Third dose reduction: Omit dose on all M, W, and Friday (F) days

[0259] Fourth dose reduction: Omit the dose on all M, W, F, and Sunday (S)

[0260] Any subject requiring further dose reduction discontinued dosing with study drug and immediately began the 6-week FU period.

[0261] Subjects undergoing dose reductions were permitted unscheduled safety visits with FU blood sampling within 48 hours of any dose reduction if deemed appropriate by the investigator.

[0262] A summary of the initial and reduced weekly dosage levels in mcg units following each of the four possible dose reductions appears in Table 23 below:

[0263] Table 23

[0264]

[0265] Subjects had dosing withheld if plasma iPTH remained <30 pg / mL (three consecutive visits) or serum calcium (corrected) >11.0 mg / dL was confirmed and resumed when iPTH ≥35 pg / mL and serum calcium <9.8 mg / dL at the next lower dose level.

[0266] The primary factor was a mean plasma iPTH reduction of at least 30% from pre-treatment baseline.The primary efficacy endpoint was the proportion of subjects in the intensive treatment (ITT) population (ages 8 to <18 years) with at least 30% mean reduction in plasma iPTH from pre-treatment baseline during EAP compared with placebo.

[0267] Safety and tolerability were assessed in the safety population by AEs, PE, VS, hematology and clinical chemistry, and ECG.

[0268] For the interim analysis, a repeated-dose (steady-state) PK assay was performed in a subset of subjects in Groups 1 and 2 by analyzing recorded serum 25-hydroxyvitamin D3 concentrations versus time during dosing with the calcifediol formulation (n=10) or placebo (n=5) during the last three days of treatment at Week 12.

[0269] For the final analysis, a repeated dose (steady-state) PK assay was performed in Groups 1 and 2 by analyzing recorded serum 25-hydroxyvitamin D3 concentrations versus time (a) during dosing with the calcifediol formulation or placebo during the last three days of treatment at Week 12, and (b) after the last dose administered in each active treatment group.

[0270] The following PK parameters were calculated using observed and baseline-adjusted 25-hydroxyvitamin D3 concentrations, as applicable: (a) area under the concentration curve (AUC), maximum concentration (Cmax), time to 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.

[0271] Secondary efficacy endpoints included the proportion of subjects achieving a mean reduction in plasma iPTH of at least 30% from pretreatment baseline during the EAP in the per-protocol (PP) population, and the proportion of subjects achieving mean serum total 25-hydroxyvitamin D of at least 30 ng / mL in both the ITT and PP populations, total and by mean weekly study dose in the EAP. Other secondary endpoints included the time course of mean absolute changes from pretreatment baseline in serum total 25-hydroxyvitamin D and plasma iPTH; the effect of PD on mean serum calcium (corrected), serum phosphorus, serum CaxP product, and urine calcium:creatinine ratio; the proportion of subjects with hypercalciuria (>200 mg calcium / g creatinine), hypercalcemia (serum calcium >10.3 mg / dL for 2 consecutive visits), or hyperphosphatemia (serum phosphorus >5.5 mg / dL (age 12 to <18 years) or >6.0 mg / dL (age 8 to <12 years) for 2 consecutive visits, considered related to study drug); and the proportion of subjects achieving 2 consecutive plasma iPTH values ​​≤70 pg / mL.

[0272] Exploratory endpoints included treatment-related changes in serum FGF23, serum BAP, serum CTx, serum P1NP, serum 1,25-dihydroxyvitamin D3, serum 24,25-dihydroxyvitamin D, and serum TRAP 5b.

[0273] The foregoing description has been given for clearness of understanding only, and no unnecessary limitations are to be understood therefrom, since modifications within the scope of the invention may be apparent to one skilled in the art.

[0274] Throughout this specification and the claims that follow, unless otherwise indicated herein, the word "comprise" and variations (e.g., "comprises" and "comprising") will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or any other group of integers or steps.

[0275] Throughout this specification, unless otherwise described, when a composition is described as comprising a component or substance, 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 comprising specific steps, it is contemplated that the method may also consist essentially of or consist of any combination of the steps. The invention illustratively disclosed herein may suitably be practiced in the absence of any element or step not specifically disclosed herein.

[0276] The practice of the methods disclosed herein and their individual steps may be performed manually and / or with the aid of an electronic device or automation provided by an electronic device. Although the processes have been described with reference to specific embodiments, it will be readily appreciated by those of ordinary skill in the art that other executions of the behaviors 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 methods. In addition, some of the individual steps may be combined, omitted, or further subdivided into other steps.

[0277] All patents, publications, and references cited herein are hereby incorporated by reference in their entirety. In the event of a conflict between the present disclosure and the incorporated patents, publications, and references, the present disclosure shall control.

Claims

1. An extended release oral spheroidized pellet vitamin D formulation comprising a vitamin D compound comprising 0.01 wt % to 1 wt % 25-hydroxyvitamin D and / or 25-hydroxyvitamin D3 dispersed in a polymer composition, the polymer composition being water-insoluble and water-permeable, comprising 1 wt % to 20 wt % ethylcellulose, 30 wt % to 50 wt % of a spheroidizing aid comprising microcrystalline cellulose, 1 wt % to 20 wt % of an absorption enhancer comprising medium chain C8-C10 triglycerides, and 1 wt % to 15 wt % of a binder being hydroxypropyl methylcellulose, wherein the formulation is free of hydrocarbon waxes, including paraffin wax, wherein the spheroidized pellet vitamin D formulation has a particle size in the range of 500 nm to 2.8 mm, and wherein the pellets are uncoated.

2. The formulation of claim 1, wherein the vitamin D compound is 25-hydroxyvitamin D3.

3. The formulation according to claim 1, wherein the particle size is in the range of 250 μm to 2.8 mm.

4. The formulation according to claim 2, wherein the particle size is in the range of 250 μm to 2 mm.

5. The formulation of claim 1, wherein the formulation is free of hydrocarbon oils, including mineral oils.

6. An oral extended release pharmaceutical composition comprising 25-hydroxyvitamin D in an amount of 0.01 wt % to 1 wt %, medium chain C8-C10 triglycerides in an amount of 1 wt % to 15 wt %, a spheroidizing aid which is microcrystalline cellulose in an amount of 40 wt % to 60 wt %, ethyl cellulose in an amount of 1 wt % to 10 wt % and a binder which is hydroxypropyl methylcellulose in an amount of 1 wt % to 15 wt %, wherein the pharmaceutical composition does not contain hydrocarbon waxes, including paraffin wax.

7. The pharmaceutical composition according to claim 6, further comprising a lipid release regulator, wherein the lipid release regulator is one or more of monoacylglycerol, diacylglycerol and triacylglycerol of behenic acid.

8. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is an extruded spheronized extended release vitamin D formulation comprising a mixture of 0.01 wt% to 0.1 wt% calcifediol, 20 wt% to 40 wt% filler, wherein the pharmaceutical composition is free of hydrocarbon oil.

9. An oral dosage form comprising the formulation according to claim 1.

10. The oral dosage form of claim 9, comprising the formulation of claim 1 disposed in a capsule shell.

11. The oral dosage form according to claim 9, comprising the formulation according to claim 1 disposed in a sachet.

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