Multi-particle dosing form containing deutetrabenazine

Abstract

This provides a drug formulation that allows for the controlled delivery of dutetrabenazine over a long period of time. [Solution] For example, a controlled-release multiparticle dosing form containing deutetrabenazine is provided herein for use in the treatment of hyperactivity disorder. When administered orally to a subject on a once-daily basis, the dosing form provides a favorable pharmacokinetic profile.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the merits of U.S. Provisional Patent Application No. 63 / 079,786, filed on 17 September 2020, and U.S. Provisional Patent Application No. 63 / 091,064, filed on 13 October 2020, both of which are incorporated herein by reference.

[0002] Technical field This disclosure relates to a multi-particle dosage form, a method for manufacturing the multi-particle dosage form, and a method for using it to treat hyperactive movement disorders resulting from conditions including Huntington's disease, tardive dyskinesia, levodopa-induced dyskinesia, and dyskinesia in cerebral palsy. [Background technology]

[0003] background Deutetrabenazine ((RR,SS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-D3)-3-(2-methylpropyl)-2H-benzo[a]quinoridine-2-one) is a vesicular monoamine transporter type 2 (VMAT2). The biologically active metabolites formed from deutetrabenazine (alpha-dihydrodeutetrabenazine [α-deuHTBZ] and beta-dihydrodeutetrabenazine [β-deuHTBZ]) are collectively identified as "deuHTBZ" and are potent inhibitors of VMAT2 binding. Deutetrabenazine has been shown to have a longer half-life for its active metabolites compared to tetrabenazine (e.g., U.S. Patent No. 8,524,733).

[0004] Deutetrabenazine (deu-TBZ), under the brand name AUSTEDO®, is approved by the U.S. Food and Drug Administration for the treatment of chorea (involuntary muscle movements) associated with Huntington's disease (HD) and for the treatment of tardive dyskinesia (TD) in adults. The AUSTEDO® dosage form is administered orally twice daily (bid) for a total daily dose of 12 mg or more of deutetrabenazine.

[0005] Several factors influence the gastrointestinal absorption of orally administered drugs, including the solubility of the drug at various pH levels and the rate at which the drug is released from its dosage form. The drug release rate for oral dosage forms is typically measured as the in vitro dissolution rate, i.e., the amount of drug released from the dosage form per unit time in, for example, an FDA-approved system. Such systems include, for example, the United States Pharmacopeia (USP) dissolving apparatus I, II, and III. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] U.S. Patent No. 8,524,733 [Patent Document 2] U.S. Patent No. 9,296,739 [Non-patent literature]

[0007] [Non-Patent Document 1] Koziolek et al., J Pharma Sci; 104(9) 2855-63 [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] The therapeutic range of a drug is the period during which the plasma drug concentration remains within the range of therapeutically effective plasma drug concentrations. However, since plasma drug concentrations decrease over time, multiple doses of a drug administration form should be administered at appropriate intervals to ensure that the plasma drug concentration remains within the therapeutic range or increases again to that level. At the same time, it is necessary to avoid or minimize plasma drug concentrations that cause undesirable side effects.

[0009] Several dosage forms including deutetrabenazine are disclosed in U.S. Patent No. 9,296,739. A dosage form capable of delivering deutetrabenazine in a controlled manner over an extended period of time should enable a more advantageous dosing regimen, for example a dosing regimen that allows once daily ("qd") administration while maintaining the therapeutic effect currently achieved with AUSTEDO®. There is a need for such alternative dosage forms. [Means for Solving the Problems]

[0010] Summary Disclosed herein are controlled release multiparticulate dosage forms for once daily oral administration of deutetrabenazine to a subject in need thereof. The dosage forms may, for example, be packaged in capsules or pharmaceutical sachets, which are suitable for the target population.

[0011] Provided herein is a controlled release oral dosage form for once daily administration of deutetrabenazine, comprising a population of sustained release beads, wherein the sustained release beads comprise a core comprising an amount of deutetrabenazine and a pharmaceutically acceptable excipient, and further comprise a pH-independent polymer coat, a pH-dependent polymer coat, or a pH-independent polymer coat further coated with a pH-dependent polymer coat. The core may be any of several forms, for example one of: a) an immediate release granule, immediate release pellet, or immediate release tablet comprising deutetrabenazine and a pharmaceutically acceptable excipient, or b) an inert particle coated with a dispersion of deutetrabenazine and a pharmaceutically acceptable excipient. In some embodiments, the dosage form comprises a population of sustained release beads.

[0012] In another embodiment, the dosage form comprises a population of sustained-release beads and a population of immediate-release beads, wherein the population of immediate-release beads comprises a) immediate-release granules, immediate-release pellets, or immediate-release tablets comprising an amount of deutetrabenazine and a pharmaceutically acceptable excipient, or b) inert particles coated with an amount of deutetrabenazine and a pharmaceutically acceptable excipient. In some embodiments of the dosage form, the core of the sustained-release particle itself serves as the population of immediate-release beads.

[0013] Accordingly, in some embodiments, the amount of deutetrabenazine and / or pharmaceutically acceptable excipient is the same in the core of the sustained-release beads and the same in the immediate-release beads. However, the amount of deutetrabenazine and / or pharmaceutically acceptable excipient may be different in the core of the sustained-release beads and may be different in the immediate-release beads. In some embodiments, the composition of the pharmaceutically acceptable excipient may be the same or different in the core of the sustained-release beads, and may be the same or different in the immediate-release beads.

[0014] In some embodiments, the deutetrabenazine present in the core of the sustained-release beads or in the immediate-release beads is nano-sized deutetrabenazine, with a median particle size of 0.02–2.0 microns, or 0.02–0.9 microns, or 0.05–0.5 microns, or 0.1–2.0 microns, or 0.1–1.6 microns, or 0.2–1.6 microns, or 0.15–1.2 microns, or 0.15–1.0 microns. In some embodiments, the deutetrabenazine has a particle size distribution characterized by D90 of about 0.8–1.6 microns, a particle size distribution characterized by D50 of about 0.1–0.6 microns, or about 0.2–0.6 microns, and a particle size distribution characterized by D10 of about 0.1–0.2 microns. In some embodiments, deutetrabenazine has a particle size distribution characterized by D90 of about 0.8 to 1.6 microns, D50 of about 0.2 to about 0.6 microns, and D10 of about 0.1 to about 0.2 microns. In various embodiments, deutetrabenazine is present in the core of sustained-release beads or in immediate-release beads at concentrations of 5 wt% to 80 wt%, or 10 wt% to 80 wt%, or 10 wt% to 70 wt%, 20 wt% to 60 wt%, 5 wt% to 30 wt%, or 50 wt% to 80 wt%, respectively, based on the weight of the core or immediate-release beads.

[0015] Deutetrabenazine is present in the core or immediate-release beads together with a pharmaceutically acceptable excipient that independently comprises one of the following: an antioxidant, a binder, a filler, a surfactant, an antifoaming agent, or a combination thereof. In some embodiments, the pharmaceutically acceptable excipient independently comprises an antioxidant, a binder, a filler, a surfactant, and an antifoaming agent.

[0016] In some embodiments, the pharmaceutically acceptable excipients include antioxidants, which may be water-insoluble antioxidants. Water-insoluble antioxidants include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquin), nordihydroguaiaretinic acid (NDGA), sodium metabisulfite (SMB), tocopherol, or combinations thereof. In some embodiments, the water-insoluble antioxidants include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), or combinations thereof. Water-insoluble antioxidants may be present in the core or immediate-release beads at a concentration of 0.1 wt% to 1.0 wt% of the weight of the core or immediate-release beads, respectively.

[0017] In some embodiments, pharmaceutically acceptable excipients include binders. Binders may be selected from the group consisting of water-soluble binders, water-insoluble binders, and combinations thereof. In some embodiments, the binder includes water-soluble binders, such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymers, polyethers, carbohydrate polymers (natural or synthetic), or combinations thereof. In some embodiments, the binder includes water-insoluble polymers, such as crospovidone, copovidone, microcrystalline cellulose, croscarmellose sodium, starch, sodium starch glycolate, colloidal silica, silica, ethylcellulose, lactic acid polymers, copolymers of lactic acid and glutamic acid, polyvinyl acetate, or combinations thereof. In some embodiments, the binder includes polyethers, such as polyethylene glycol (PEG). The binder may be present in the core or immediate-release beads at a concentration of 0.5 wt% to 10.0 wt% of the weight of the core or immediate-release beads, respectively.

[0018] In some embodiments, pharmaceutically acceptable excipients include fillers. Fillers may be saccharides, disaccharides, polysaccharides, polyhydric alcohols, microcrystalline cellulose, natural and synthetic gums, pregelatinized starch, polyvinylpyrrolidone, cellulose derivatives, dibasic calcium phosphate, kaolin, inorganic salts, calcium carbonate, sodium bicarbonate, sodium carbonate, and combinations thereof. In some embodiments, the filler includes microcrystalline cellulose, saccharides, or combinations thereof. In some embodiments, the saccharide is lactose. The filler may be present in the core or immediate-release beads at a concentration of 5.0 wt% to 50.0 wt% by weight of the core or immediate-release beads, respectively.

[0019] In some embodiments, pharmaceutically acceptable excipients include surfactants. Possible surfactants include sodium lauryl sulfate, sodium dodecyl sulfate, sodium laureth sulfate, sodium docusate, polysorbate, tween, polyoxyethylene 15-hydroxystearate, polyoxyethylene castor oil derivatives, polyoxyethylene stearate, sorbitan fatty acid esters, polyoxyethylene alkyl ethers, polyoxyethylene nonylphenol ethers, or combinations thereof. In some embodiments, the surfactant is sodium lauryl sulfate. The surfactant may be present in the core or immediate-release beads at a concentration of 2.0 wt% to 12.0 wt% of the weight of the core or immediate-release beads, respectively.

[0020] In some embodiments, pharmaceutically acceptable excipients include antifoaming agents. Antifoaming agents may include insoluble oils, polydimethylsiloxanes and other silicones, certain alcohols, stearates, glycols, and combinations thereof, preferably simethicone, dimethicone, ticactase, or peppermint oil. The antifoaming agent may be present in the core or immediate-release beads at a concentration of 0.3 wt% to 3.0 wt% of the weight of the core or immediate-release beads, respectively.

[0021] The core of the sustained-release beads may be coated with a coating, which may be a pH-independent polymer coating and / or a pH-independent polymer coating. In some embodiments, the sustained-release beads include a pH-independent polymer coating. The pH-independent polymer coating may be cellulose acetate, a mixture of cellulose acetates, ethylcellulose, or a mixture of ethylcellulose and polyethylene glycol. In some embodiments, the pH-independent polymer coating includes ethylcellulose. In some embodiments, the pH-independent polymer coating includes cellulose acetate. In some embodiments, the pH-independent polymer coating includes a mixture of cellulose acetate NF398-10 and cellulose acetate 320S. In some embodiments, the pH-independent polymer coating includes a mixture of cellulose acetate and polyethylene glycol. The sustained-release beads may further include a pH-dependent polymer coating that coats the pH-independent polymer coating.

[0022] In some embodiments, the sustained-release beads include a pH-dependent polymer coating that coats the core. In some embodiments, the pH-dependent polymer coating is formulated to dissolve at a pH of approximately 5.0 to 7.0, for example, in the upper small intestine of a human subject. The pH-dependent polymer coating may be methacrylate-ethyl acrylate copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), alginate, carboxymethylcellulose, or a combination thereof. In some embodiments, the pH-dependent polymer coating includes methacrylate-ethyl acrylate copolymer.

[0023] In some embodiments, the pH-dependent polymer coating is formulated to dissolve at a pH greater than 7.0, for example, in the large intestine or colon of a human subject. In such cases, the pH-dependent polymer coating may be cellulose phthalate acetate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate, polyvinyl phthalate acetate, pH-sensitive methacrylic acid-methyl methacrylate copolymer, polyether, shellac, or a combination thereof. In some embodiments, the pH-dependent polymer coating includes methacrylic acid-methyl methacrylate copolymer.

[0024] The pH-independent or pH-dependent polymer coating may further contain a pharmaceutically acceptable plasticizer. The plasticizer may be triethyl citrate (TEC), triacetin, acetyl tributyl citrate, acetyl triethyl citrate, glycerin, polyethylene glycol, polyethylene glycol monomethyl ether, propylene glycol, sorbitol sorbitan solution, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, or a combination thereof. In some embodiments, the plasticizer contains triethyl citrate. In some embodiments, the pH-independent or pH-dependent polymer coating is present on the sustained-release beads at a concentration of 15.0 wt% to 50.0 wt% by weight of the sustained-release beads. The pH-independent or pH-dependent polymer coating may be present on the sustained-release beads at a concentration of 20.0 wt% to 40.0 wt% by weight of the sustained-release beads.

[0025] In some embodiments, the dosage forms disclosed herein contain a total of 6 mg to 72 mg of deutetrabenazine. In some embodiments, the dosage forms contain a total of 6 mg, or 12 mg, or 18 mg, or 24 mg, or 30 mg, or 36 mg, or 42 mg, or 48 mg of deutetrabenazine.

[0026] The drug delivery forms disclosed herein may essentially consist of a group of sustained-release beads containing a pH-independent polymer coating, or a group of sustained-release beads containing a pH-independent polymer coating further coated with a pH-dependent polymer coating. The drug delivery forms may also be capsules, sachets, etc.

[0027] In some embodiments, the drug delivery method is: a) A core comprising nano-sized deutetrabenazine and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises an antioxidant containing butylated hydroxyanisole and butylated hydroxytoluene NF, a water-soluble binder containing hydroxypropyl cellulose, an antifoaming agent containing simethicone, a filler containing lactose monohydrate and sodium bicarbonate, and a surfactant containing sodium lauryl sulfate. b) pH-independent polymer coating on the core Includes, c) Capsule shell or pharmaceutical packaging It essentially consists of a group of sustained-release beads that optionally include even more.

[0028] The core may be in the form of immediate-release granules, immediate-release pellets, or immediate-release tablets, or in the form of inert particles coated with deutetrabenazine and a pharmaceutically acceptable excipient. In some embodiments, the pH-independent polymer coating contains ethylcellulose. In some embodiments, the pH-independent polymer coating contains ethylcellulose, polyethylene glycol, and triethyl citrate, and optionally further contains povidone. In some embodiments, the pH-independent polymer coating contains a mixture of cellulose acetate NF398-10 and cellulose acetate 320S. In some embodiments, the pH-independent polymer coating contains cellulose acetate and optionally contains polyethylene glycol.

[0029] In various embodiments, the dosage form comprises a group of sustained-release beads, further comprising a group of immediate-release beads. The immediate-release beads comprise one of the following: a) immediate-release granules, immediate-release pellets, or immediate-release tablets comprising a certain amount of deutetrabenazine and a pharmaceutically acceptable excipient, or b) inert particles coated with a certain amount of deutetrabenazine and a pharmaceutically acceptable excipient. In some embodiments, the immediate-release beads comprise (b).

[0030] In some embodiments, the dosage form includes a group of immediate-release beads and a group of sustained-release beads, the sustained-release beads are a) A core comprising deutetrabenazine and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises an antioxidant containing butylated hydroxyanisole and butylated hydroxytoluene NF, a water-soluble binder containing hydroxypropyl cellulose, an antifoaming agent containing simethicone, a filler containing lactose monohydrate and sodium bicarbonate, and a surfactant containing sodium lauryl sulfate. b) A pH-dependent polymer coating that is sensitive to pH 5.5 to pH 7 and coats the core. Includes.

[0031] Possible pH-dependent polymer coatings include methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), alginate, carboxymethylcellulose, or combinations thereof. While we do not wish to be bound by any particular theory, pH-dependent polymer coatings containing methacrylic acid-ethyl acrylate copolymer, as well as triethyl citrate, are sensitive at pH approximately 5.5 to 7 and therefore target the small intestine.

[0032] In some embodiments, the drug delivery method is: a) A core comprising deutetrabenazine and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises an antioxidant containing butylated hydroxyanisole and butylated hydroxytoluene NF, a water-soluble binder containing hydroxypropyl cellulose, an antifoaming agent containing simethicone, a filler containing lactose monohydrate and sodium bicarbonate, and a surfactant containing sodium lauryl sulfate. b) A pH-dependent polymer coating that is sensitive to pH 7 to approximately pH 8 and coats the core. Includes a group of sustained-release beads.

[0033] pH-dependent polymer coatings sensitive to pH > 7.0 may be cellulose phthalate acetate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate, polyvinyl phthalate acetate, pH-sensitive methacrylic acid-methyl methacrylate copolymer, polyether, shellac, or a combination thereof. While we do not wish to be bound by any particular theory, pH-dependent polymer coatings containing methacrylic acid and methyl acrylate copolymer, as well as triethyl citrate, are sensitive to pH of about 7 to about 8 and therefore dissolve in the colon / colon.

[0034] The core of the sustained-release beads described above comprises a) immediate-release granules, immediate-release pellets, or immediate-release tablets containing deutetrabenazine and a pharmaceutically acceptable excipient, or b) inert particles coated with deutetrabenazine and a pharmaceutically acceptable excipient. In some embodiments, the core comprises (b).

[0035] In some embodiments, the drug delivery configurations disclosed herein include a group of immediate-release beads and a group of sustained-release beads, the sustained-release beads having a pH-dependent coating that dissolves at pH 5.5 to 7.

[0036] In some embodiments, the drug delivery configurations disclosed herein include a group of immediate-release beads and a group of sustained-release beads, the sustained-release beads having a pH-dependent coating that dissolves at pH > 7.

[0037] In some embodiments, the dosage form disclosed herein comprises a group of immediate-release beads and two groups of sustained-release beads, one group of sustained-release beads having a pH-dependent coating that dissolves at pH 5.5 to 7.0, and the second group of sustained-release beads having a pH-dependent coating that dissolves at pH > 7.

[0038] The dosage form disclosed herein may be in the form of a capsule comprising a capsule shell and at least one group of sustained-release beads, and optionally further comprising a group of immediate-release beads. Alternatively, the dosage form disclosed herein may be in the form of a sachet comprising a sachet and at least one group of sustained-release beads, and optionally further comprising a group of immediate-release beads.

[0039] In some embodiments, when measured with a USPIII dissolution device at pH 7.2, approximately 10 wt% to 30 wt% of deutetrabenazine is released within 1 hour from the dosage form, approximately 50 to 80 wt% of deutetrabenazine is released within 3 hours, and approximately 80 wt% or more of deutetrabenazine (NLT) is released within 5 hours.

[0040] In other embodiments, the dosage form of the Disclosure releases approximately 40-60 wt% of deutetrabenazine within 7 hours when measured using a USPII device, phthalate buffer at pH 3.0, and 75 rpm. Methods useful in treating VMAT2-mediated disorders are further provided herein. In some embodiments, a method for treating a VMAT2-mediated disorder includes orally administering the controlled-release dosage form disclosed herein to a patient in need. The VMAT2-mediated disorder may be hyperactive movement disorder. The hyperactive movement disorder may be a chronic disorder, such as Huntington's disease, tardive dyskinesia, and dyskinesia in cerebral palsy.

[0041] A method for manufacturing the core of an immediate-release bead or a sustained-release bead, a) A step of providing a dispersion of nano-sized deutetrabenazine and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises an antioxidant containing butylated hydroxyanisole and butylated hydroxytoluene NF, a water-soluble binder containing hydroxypropyl cellulose, an antifoaming agent containing simethicone, a filler containing lactose monohydrate and sodium bicarbonate, and a surfactant containing sodium lauryl sulfate. b) A step of forming immediate-release granules, immediate-release pellets, or immediate-release tablets from the dispersion of a), or a step of coating inert particles with the dispersion of a). Includes, The present specification further provides a method for generating the core of an immediate-release bead or a sustained-release bead.

[0042] A method for manufacturing sustained-release beads, a) A step of providing a deutetrabenazine dispersion comprising nano-sized deutetrabenazine and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises an antioxidant, a water-soluble binder c, an antifoaming agent, a filler, and a surfactant. b) A step of providing a core, wherein the core comprises immediate-release granules, immediate-release pellets, or immediate-release tablets containing the dispersion of a), or inert particles coated with the dispersion of a), c) A step of coating the core of b) with a pH-independent polymer coating, a pH-dependent polymer coating, or a pH-independent polymer coating and a pH-dependent polymer coating. Includes, This further provides a method for generating sustained-release beads.

[0043] In some embodiments, nano-sized duetetrabenazine is prepared by milling. In some embodiments, pharmaceutically acceptable excipients consist of antioxidants including butylated hydroxyanisole and butylated hydroxytoluene NF, water-soluble binders including hydroxypropyl cellulose, antifoaming agents including simethicone, fillers including lactose monohydrate and sodium bicarbonate, and surfactants including sodium lauryl sulfate. Nano-sized duetetrabenazine having a median particle size of about 0.02 to about 2.0 microns is further provided. In some embodiments, nano-sized duetetrabenazine has a particle size distribution characterized by D90 of about 0.8 to 1.6 microns, D50 of about 0.2 to about 0.6 microns, and D10 of about 0.1 to about 0.2 microns. Brief explanation of the drawing [Brief explanation of the drawing]

[0044] [Figure 1-1]Illustrations of bead clusters are provided. Figure 1A shows three options for the core of sustained-release or immediate-release beads. The leftmost figure represents granules, pellets, or tablets containing duetetrabenazine and excipients; the rightmost figure represents granules, pellets, or tablets containing duetetrabenazine and optionally further coated with a duetetrabenazine dispersion; and the rightmost figure represents inert particles coated with a duetetrabenazine dispersion. Figures 1B, 1C, and 1D show possible sustained-release beads based on the core / immediate-release beads in Figure 1A. Figure 1B shows a cluster of sustained-release beads with a core coated with a pH-independent polymer (black layer). Figure 1C shows a cluster of sustained-release beads with a core coated with a pH-dependent polymer (dotted layer sensitive to pH 5.5–pH 7), or coated with a pH-dependent layer (black layer) and further coated with a pH-dependent polymer (dotted layer sensitive to pH 5.5–pH 7). Figure 1D shows a collection of sustained-release beads in which the core is coated with a pH-dependent polymer (a striped layer sensitive to pH > 7), or coated with a pH-dependent layer (a black layer) and then further coated with a pH-dependent polymer (a striped layer sensitive to pH > 7). [Figure 1-2]Illustrations of bead clusters are provided. Figure 1A shows three options for the core of sustained-release or immediate-release beads. The leftmost figure represents granules, pellets, or tablets containing duetetrabenazine and excipients; the rightmost figure represents granules, pellets, or tablets containing duetetrabenazine and optionally further coated with a duetetrabenazine dispersion; and the rightmost figure represents inert particles coated with a duetetrabenazine dispersion. Figures 1B, 1C, and 1D show possible sustained-release beads based on the core / immediate-release beads in Figure 1A. Figure 1B shows a cluster of sustained-release beads with a core coated with a pH-independent polymer (black layer). Figure 1C shows a cluster of sustained-release beads with a core coated with a pH-dependent polymer (dotted layer sensitive to pH 5.5–pH 7), or coated with a pH-dependent layer (black layer) and further coated with a pH-dependent polymer (dotted layer sensitive to pH 5.5–pH 7). Figure 1D shows a collection of sustained-release beads in which the core is coated with a pH-dependent polymer (a striped layer sensitive to pH > 7), or coated with a pH-dependent layer (a black layer) and then further coated with a pH-dependent polymer (a striped layer sensitive to pH > 7). [Figure 2] A flowchart illustrating a general manufacturing method for inert particles coated with a deuterated dispersion is provided. The particles can serve as immediate-release beads or as cores for sustained-release beads. [Figure 3] The dissolution profiles of samples 1, 2, and 3 in 500 mL of phosphate buffer, pH 6.8, USPII instrument, 75 rpm are shown. Micromilled and nanomilled particles show superior dissolution profiles at pH 6.8 compared to unmilled samples. Diamonds represent the release profile of the unmilled sample, indicating poor release (approximately 30-35 wt% even after 2 hours), squares represent the release profile of micromilled deutetrabenazine, and triangles represent the release profile of nanomilled deutetrabenazine. [Figure 4]This graph shows the dissolution of two dosing regimens: immediate-release beads and sustained-release beads. One group has a coating sensitive to pH 5.5–7.0, and the other group has a coating sensitive to pH 7.0. Dissolution was performed using USPIII, 10 dpm, in 250 mL of 0.1N HCl (1 hour), pH 6.8 phosphate buffer (2 hours), and pH 7.2 phosphate buffer (3 hours). The x-axis represents time. [Figure 5] This graph shows the dissolution profiles for samples 5-10 in phthalate buffer solution at pH 3.0, USPII, and 75 rpm. [Figure 6] This graph shows the dissolution profiles for samples 11-12 in phthalate buffer solution at pH 3.0, USPII, and 75 rpm. [Figure 7] This graph shows the dissolution profiles for samples 13-16 in phthalate buffer solution at pH 3.0, USPII, and 75 rpm. [Modes for carrying out the invention]

[0045] Detailed description of the present invention The subject matter of the present invention can be more readily understood by referring to the following detailed description, which forms part of this disclosure. It should be understood that the present invention is not limited to the specific methods, conditions, or parameters described and / or shown herein, and that the technical terms used herein are intended to describe specific embodiments merely as examples and are not intended to limit the claimed invention.

[0046] Unless otherwise defined herein, scientific and technical terms used in connection with this application should have meanings that are ordinarily understood by those skilled in the art.

[0047] As used above and throughout this disclosure, the following terms and abbreviations should be understood to have the following meanings unless otherwise indicated.

[0048] The singular forms "a," "an," and "the" may refer to plural articles unless otherwise specified.

[0049] When used herein, the term "approximately" is intended to modify the numerical value it alters, indicating that such value can be changed within a range of ±10%.

[0050] When various values ​​are given, an alternative embodiment includes one specific value and / or the other specific value. Similarly, when a value is given as approximately by using the preposition “about”, it should be understood that a specific value forms an alternative embodiment. All ranges are comprehensive and combinable.

[0051] As used herein, the terms “compound,” “drug,” “pharmacological activator,” “activator,” or “pharmaceutical” are used interchangeably to refer to a compound or composition of a substance that, when administered to a subject (human or animal), induces a desired pharmacological and / or physiological effect by local and / or systemic action. The activators disclosed herein are preferably deutetrabenazine. “Dutetrabenazine” or “deu-TBZ” is a selectively deuterium-substituted, stable, non-radioactive isotope form of tetrabenazine in which six hydrogen atoms on two methyl groups linked to O are replaced by deuterium atoms (i.e., the -OCD3 moiety rather than the -OCH3 moiety).

[0052] As used herein, “drug form” refers to a drug form having multi-particle properties, where each bead cluster exhibits different properties. In some embodiments, the drug form is made from a single cluster of sustained-release beads. In some embodiments, the drug form is made from one or more clusters of sustained-release beads. In some embodiments, the drug form is made from at least one cluster of sustained-release beads and at least one cluster of immediate-release beads.

[0053] As used herein, the term "beads" refers to individual units of a pharmaceutical formulation comprising at least deutetrabenazine and a pharmaceutically acceptable excipient. In some embodiments, immediate-release beads refer to an immediate-release formulation comprising a core, which may be formed from granules, pellets, or tablets comprising deutetrabenazine and a pharmaceutically acceptable excipient. In some embodiments, immediate-release beads comprise a core, e.g., granules, pellets, or tablets, which is at least partially further coated with deutetrabenazine and a pharmaceutically acceptable excipient. In other embodiments, immediate-release beads comprise inert particles, such as microcrystalline cellulose (MCC) or sugar particles, which are at least partially coated with deutetrabenazine and a pharmaceutically acceptable excipient. Sustained-release beads disclosed herein comprise an immediate-release core or immediate-release particles (i.e., deutetrabenazine-containing granules, pellets, tablets, or coated inert particles) further coated with a pH-independent polymer and / or a pH-dependent polymer.

[0054] As used herein, the term "immediate release" (IR) refers to a pharmaceutical formulation, i.e., beads, that release an active ingredient, i.e., deutetrabenazine, within approximately one hour of administration. Such release typically occurs in the upper gastrointestinal (GI) tract, for example, in the stomach.

[0055] As used herein, the term "sustained-release" refers to a pharmaceutical formulation, i.e., beads, which release an active agent, i.e., deutetrabenazine, over an extended period, typically 1 to 12 hours or 1 to 24 hours after administration. Such release typically occurs in the gastrointestinal (GI) tract, e.g., the upper and / or lower intestinal tract and / or colon.

[0056] "Controlled release" refers to a dosage form that allows the activator to be released over a long period, for example, up to approximately 7 hours, 12 hours, 15 hours, 18 hours, 21 hours, or 24 hours. The activator is preferably deutetrabenazine as disclosed herein. Part of the activator is released in the stomach (immediate release), and part is released in the small intestine and / or lower intestine / colon (sustained release). In some embodiments, the dosage form releases approximately 10 wt% to 30 wt% of the activator in the dosage form within 1 hour, approximately 50 wt% to 80 wt% within 3 hours, and 80% or more after 5 hours, as measured by a USPIII device at pH 7.2. In other embodiments, the dosage form releases approximately 5 to 40 to 60 wt% of the activator in the dosage form within 7 hours, as measured by a USPII device, phthalate buffer at pH 3.0, at 75 rpm. In another embodiment, the drug delivery method releases approximately 50 wt% of deutetrabenazine within 7 hours, as measured by a USPII device, phthalate buffer at pH 3.0, and 75 rpm.

[0057] The drug dosage forms disclosed herein may be in the form of capsules or packaged beads. “Capsule” is a drug dosage form disclosed herein that encloses a group of beads. Capsules may be formed from gelatin (animal or plant-derived) or other pharmaceutically acceptable material.

[0058] The gastrointestinal tract, or "GI tract," extends from the mouth through the esophagus to the stomach, and then through the small intestine and colon to the anus, exhibiting different pH levels depending on the region and the state of the food. The stomach is typically the first section of the GI tract, where drug breakdown and dissolution occur. The pH of the stomach is usually 1–3. The intestinal tract is the main site of absorption for nutrients and drugs. The small intestine has three distinct regions: the duodenum, jejunum, and ileum. The entry of solid drug forms into the small intestine is accompanied by a rapid increase in pH due to the duodenum's secretion of bicarbonates. Furthermore, the literature suggests a subsequent increase in pH values ​​from approximately pH 5.5–6.8 in the duodenum to pH 6.8–8 in the terminal ileum. The pH value in the large intestine (including the colon) is slightly acidic compared to the ileum, likely due to the fermentation process of the colonic microbiota (Koziolek et al., J Pharma Sci; 104(9) 2855-63).

[0059] As used herein, the terms “treatment” or “therapy” (and their different forms) include preventive (e.g., prophylactic), curative, or mitigating treatments. As used herein, the term “to treat” includes reducing or mitigating at least one harmful or negative effect or symptom of a condition, disease, or disorder. This condition, disease, or disorder may refer to hyperactive movement disorders, such as, but not limited to, Huntington's disease, tardive dyskinesia, Tourette syndrome, dystonia, dyskinesia in cerebral palsy (DCP), and levodopa-induced dyskinesia (LID) in Parkinson’s disease.

[0060] The term "administer" means providing a patient with the pharmaceutical composition or drug form (as used herein without distinction) of the present invention.

[0061] The terms “subject,” “individual,” and “patient” are used without distinction herein and refer to a person to whom treatment, including prophylactic treatment, is provided using the drug delivery form according to the present invention.

[0062] "Pharmacologically acceptable" means a compound, material, composition, and / or excipient that, within the bounds of sound medical judgment, is suitable for contact with human tissue, free from excessive toxicity, irritation, allergic reactions, or other problematic complications, and that offers a reasonable benefit-to-risk ratio.

[0063] The terms D90, D50, and D10 are well understood in the art. For example, a D90 of 15 μm means that 90% of the particle size (volume) is 15 μm or less. A D50 of 10 μm means that 50% of the particle size (volume) is 10 μm or less. A D10 of 3 μm means that 10% of the particle size (volume) is 3 μm or less. The terms may be combined to define the particle size distribution (PSD).

[0064] The particle size distribution is determined using laser diffraction. In particular, the particle size distribution was determined using a Mastersizer 3000 from Malvern Instruments. Particle size determination may be performed using either wet or dry measurement methods, depending on the sample.

[0065] While constant-release drug delivery has proven effective for many different pharmacotherapies, no clinical situation is completely satisfactory with these methods. In some patients, the therapeutic efficacy of a drug may decline below the threshold of therapeutic efficacy before the end of the desired treatment period, even when drug release is maintained at a substantially constant level, and continuous efficacy may be expected in such cases.

[0066] It was surprisingly discovered that an oral dosing form containing deutetrabenazine can be achieved that exhibits a desirable release rate and, consequently, a desirable pharmacokinetic profile over long periods. In some embodiments, the multiparticle dosing form disclosed herein, when administered orally to a subject on a once-daily (qd) basis, provides, for example, a bioequivalent pharmacokinetic profile to that of the twice-daily (bid) AUSTEDO® dosing form.

[0067] Provided herein are controlled-release oral dosage forms for administering duetetrabenazine once daily, comprising a group of sustained-release beads, wherein the sustained-release beads comprise a core containing duetetrabenazine and a pharmaceutically acceptable excipient, and further comprising a pH-independent polymer coating, a pH-dependent polymer coating, or a pH-independent polymer coating further coated with a pH-dependent polymer coating. In some embodiments, the core comprises immediate-release granules, immediate-release pellets, or immediate-release tablets containing duetetrabenazine and a pharmaceutically acceptable excipient. The duetetrabenazine and the pharmaceutically acceptable excipient may be a duetetrabenazine dispersion. In some embodiments, the core comprises inert particles, such as crystalline microcellulose particles or sugar particles. Such particles are well known to developers of formulations in the art. In such embodiments, the core comprises inert particles coated with a duetetrabenazine dispersion.

[0068] In some embodiments, the dosage form further comprises a collection of immediate-release beads, the collection of immediate-release beads comprising a) immediate-release granules, immediate-release pellets, or immediate-release tablets comprising a certain amount of deutetrabenazine and a pharmaceutically acceptable excipient, or b) inert particles coated with a certain amount of deutetrabenazine and a pharmaceutically acceptable excipient. In some embodiments, a portion of the immediate-release granules, pellets, or tablets of the immediate-release beads, or the portion of the inert particles, serves as the core of the sustained-release beads.

[0069] When the median particle size of deutetrabenazine is 0.02–2.0 microns (μm), or 0.2–1.6 microns, or 0.15–1.2 microns, 0.15–1.0 microns, 0.5–1.6 microns, or about 0.8–about 1.6 microns, the dosage form is considered relevant to function as disclosed. The desired median particle size may be achieved, for example, by milling the drug raw material to low micrometer and nanometer sizes. In some embodiments, deutetrabenazine is about 0.8–about 1.6 microns. 90It has a particle size distribution characterized by D. 90 Preferably, about 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1.00, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1. 20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.40, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.50, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, or about 1.60 μm. In some embodiments, the deutetrabenazine is about 0.1 to about 0.6 microns or about 0.2 to about 0.6 microns. 50 It has a particle size distribution characterized by D. 50 The diameter is preferably about 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, or about 0.60 μm. In some embodiments, the deutetrabenazine is about 0.1 to about 0.2 microns of D 10 It has a particle size distribution characterized by D. 10 The diameter is preferably about 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or about 0.20 μm. In some embodiments, the deutetrabenazine is about 0.8 to 1.6 microns in diameter. 90It has a particle size distribution characterized by D50 of approximately 0.2 to 0.6 microns and D10 of approximately 0.1 to 0.2 microns.

[0070] In some embodiments, deutetrabenazine is present in the core or immediate-release beads in amounts ranging from approximately 5 wt% to 80 wt%, or 10 wt% to 80 wt%, or 10 wt% to 70 wt%, 20 wt% to 60 wt%, 5 wt% to 30 wt%, or 50 wt% to 80 wt% of the total weight of the dosage form. Deuterabenazine is present in the following amounts of core or immediate-release beads, approximately 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 1.01, 12.0, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 19.0, 20.0, 21.0, 22.0, 23.0, 24.0, 25.0, 26.0, 27.0, 28.0, 29.0, 30.0, 31.0, 32.0, 33.0, 34.0, 35.0, 36.0, 37.0, 38. It may be present in the core or immediate-release beads in amounts of 0.0, 39.0, 40.0, 41.0, 42.0, 43.0, 44.0, 45.0, 46.0, 47.0, 48.0, 49.0, 50.0, 60.0, 61.0, 62.0, 63.0, 64.0, 65.0, 66.0, 67.0, 68.0, 69.0, 70.0, 71.0, 72.0, 73.0, 74.0, 75.0, 76.0, 77.0, 78.0, 79.0, and 70.0 wt%.

[0071] pharmaceutically acceptable excipients include antioxidants, binders, fillers, surfactants, antifoamers, or combinations thereof. Typically, more than one excipient is used. In some embodiments, the excipient is an antioxidant, which is a water-insoluble antioxidant. In some embodiments, the water-insoluble antioxidant is selected from the group consisting of propyl gallate, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquin), nordihydroguaiaretinic acid (NDGA), butylated hydroxyanisole, butylated hydroxytoluene, or any mixture thereof. In one particular embodiment, the antioxidant is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and combinations thereof. The antioxidant, preferably a non-water-soluble antioxidant, is present in the dosage form in the range of 0.1 wt% to 1.0 wt%, or about 0.2 wt% to 1.0 wt%, or about 0.5 wt% to 0.8 wt%, of the weight of the core or immediate-release beads, respectively, at 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0. 45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74 It may be present in amounts of 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, or 1.0 wt%.

[0072] The excipient may include a binder. In some embodiments, the binder includes a water-soluble binder, a non-water-soluble binder, or a combination thereof. In some embodiments, the binder includes a water-soluble binder, which may be a cellulosic binder including hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymer, polyether, carbohydrate polymer (natural or synthetic), or a combination thereof. In some embodiments, the binder is a cellulosic binder selected from the group consisting of methylcellulose (MC), ethylcellulose (EC), propylcellulose (PC), hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), cellulose acetate, and combinations thereof. In some embodiments, the binder is hydroxypropyl cellulose. In some embodiments, the binder is a polyether. A suitable polyether is polyethylene glycol polymer. In further embodiments, the binder comprises a water-insoluble polymer, which includes crospovidone, copovidone, microcrystalline cellulose, croscarmellose sodium, starch, sodium starch glycolate, colloidal silica, silica, ethylcellulose, lactic acid polymer, copolymer of lactic acid and glutamic acid, polyvinyl acetate, or a combination thereof. In some embodiments, the binder is present in the core or immediate-release beads in the range of 0.5 wt% to 10.0 wt%, about 1.0 wt% to 8.0 wt%, or about 2.0 wt% to 6.0 wt% by weight of the dosage form. The binder may be present in the dosage form in an amount of 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or approximately 10.0 wt% of the weight of the core or immediate-release beads, respectively.

[0073] In some embodiments, the excipients include fillers selected from the group consisting of saccharides, disaccharides, polysaccharides, polyhydric alcohols, microcrystalline cellulose, natural and synthetic gums, gelatin, pregelatinized starch, polyvinylpyrrolidone, cellulose derivatives, dibasic calcium phosphate, kaolin, inorganic salts, calcium carbonate, sodium bicarbonate, sodium carbonate, and combinations thereof. The saccharides may be, for example, glucose, galactose, dextrose, or fructose; the disaccharides may be, for example, sucrose, lactose, lactose monohydrate, maltose, trehalose, or maltose; the polysaccharides may be starch, maltodextrin, or polyhydric alcohols may be, for example, sorbitol, xylitol, inositol, lactitol, mannitol, or spray-dried mannitol. In some embodiments, the fillers are microcrystalline cellulose, lactose monohydrate, or combinations thereof. In some embodiments, the filler is present in the dosage form in the range of 5.0–50.0 wt%, 5.0–30.0 wt%, 10.0–40.0 wt%, or 10.0–40.0 wt% of the weight of the core or immediate-release beads. In some embodiments, the excipient accounts for approximately 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 1.01, 12.0, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 19.0, 20.0, 21.0, 22.0, 23.0, 24.0, 25.0, 26.0, 27.0, 28.0, 29.0, 30.0, 31.0, 32.0, 33.0, 34.0, 35.0, 36.0, 37.0, 38.0, 39.0, 40.0, 41.0, 42.0, 43.0, 44.0, 45.0, 46.0, 47.0, 48.0, 49.0, or 50 wt% of the weight of the core or immediate-release beads, respectively.

[0074] In some embodiments of the dosage form, pharmaceutically acceptable excipients include surfactants. Surfactants may include sodium lauryl sulfate, sodium dodecyl sulfate, sodium laureth sulfate, sodium docusate, polysorbate, tween, polyoxyethylene 15-hydroxystearate, polyoxyethylene castor oil derivatives, polyoxyethylene stearate, sorbitan fatty acid esters, polyoxyethylene alkyl ethers, polyoxyethylene nonylphenol ethers, or combinations thereof. In some embodiments, the surfactant is present in the core or immediate-release beads at a concentration of 2.0 wt% to 12.0 wt% of the weight of the core or immediate-release beads. The surfactant may be present in the core or immediate-release beads in an amount of 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, or 12.0 wt% of the weight of the core or immediate-release beads, respectively.

[0075] In some embodiments, the excipients include defoaming agents, such as insoluble oils, polydimethylsiloxanes and other silicones, certain alcohols, stearates, glycols, and combinations thereof. In various embodiments, the defoaming agent is simethicone, dimethicone, reticularase, or peppermint oil. The defoaming agent may be 30% simethicone, up to about 2.0 wt% by weight of the core or immediate-release beads.

[0076] In some embodiments, the immediate-release beads disclosed herein comprise inert particles coated with a nano-sized deutetrabenazine coating having a median particle size of 0.02 to 2.0 microns (μm), and pharmaceutically acceptable excipients comprising about 0.1 wt% to 1.0 wt% of antioxidants, about 0.5 wt% to 10.0 wt% of binders, about 5.0 wt% to 50.0 wt% of fillers, about 2.0 wt% to 12.0 wt% of surfactants, and about 0.3 wt% to 3 wt% of antifoaming agents by weight of the core or immediate-release beads.

[0077] In some embodiments, the sustained-release beads include a pH-independent polymer coating that coats the core. The pH-independent polymer coating may be ethylcellulose. In some embodiments, the pH-independent polymer coating may be a mixture of cellulose acetate, cellulose acetate derivatives, ethylcellulose, or a mixture of ethylcellulose and polyethylene glycol. In some embodiments, the pH-independent polymer coating includes cellulose acetate. In some embodiments, the pH-independent polymer coating includes a mixture of cellulose acetate NF398-10 and cellulose acetate 320S. In yet another embodiment, the pH-independent polymer coating includes a mixture of cellulose acetate and polyethylene glycol.

[0078] In certain embodiments, sustained-release beads include a pH-dependent polymer coating surrounding the core. In some embodiments, sustained-release beads are coated with a pH-dependent polymer to target drug release at pH 5–7.0 and target the upper small intestine. The enteric-coated polymer is methacrylate-ethyl acrylate copolymer. In some embodiments, sustained-release beads are coated with a pH-dependent polymer to target drug release at pH > 7.0 and target the large intestine / colon. In some embodiments, the pH-dependent polymer coating targeting the large intestine / colon includes cellulose phthalate acetate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate, polyvinyl phthalate acetate, pH-sensitive methacrylate-methyl methacrylate copolymer, polyethers, shellac, and combinations thereof. In some embodiments, the pH-dependent polymer coating includes methacrylate-methyl methacrylate copolymer. In some embodiments, the pH-dependent polymer coating includes a mixture of cellulose acetate and polyethylene glycol. In some embodiments, the pH-dependent polymer coating includes a mixture of ethylcellulose and polyethylene glycol.

[0079] pH-independent or pH-dependent polymer coatings may further contain pharmaceutically acceptable plasticizers. These plasticizers may be triethyl citrate (TEC), triacetin, acetyl tributyl citrate, acetyl triethyl citrate, glycerin, polyethylene glycol, polyethylene glycol monomethyl ether, propylene glycol, sorbitol sorbitan solution, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, or combinations thereof. In some embodiments, the plasticizer includes triethyl citrate.

[0080] In some embodiments of the drug delivery system, the pH-independent or pH-dependent polymer coating is present on the sustained-release beads at a concentration of 15.0 wt% to 50.0 wt% or approximately 20.0 wt% to 40.0 wt% of the weight of the sustained-release beads.

[0081] The dosage form may contain a total of 6 mg to 72 mg of deutetrabenazine. In some embodiments, the dosage form contains a total of 6 mg, 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, or 48 mg of deutetrabenazine.

[0082] In some embodiments, the drug delivery method is: a) A core comprising deutetrabenazine and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises an antioxidant containing butylated hydroxyanisole and butylated hydroxytoluene NF, a water-soluble binder containing hydroxypropyl cellulose, an antifoaming agent containing simethicone, a filler containing lactose monohydrate and sodium bicarbonate, and a surfactant containing sodium lauryl sulfate. b) pH-independent polymer coating on the core Includes, c) Capsule shell or pharmaceutical packaging It essentially consists of a group of sustained-release beads that optionally include even more.

[0083] The core of the drug formulation comprises a) immediate-release granules, immediate-release pellets, or immediate-release tablets containing deutetrabenazine and a pharmaceutically acceptable excipient, or b) inert particles coated with deutetrabenazine and a pharmaceutically acceptable excipient.

[0084] In some embodiments, the pH-independent polymer comprises ethylcellulose, polyethylene glycol, and triacetin, and optionally further comprises povidone. In other embodiments, the pH-independent polymer coating comprises cellulose acetate, and optionally comprises polyethylene glycol (PEG). In some embodiments, the cellulose acetate comprises a mixture of cellulose acetate 398-10 and cellulose acetate 320S, and optionally further comprises PEG 3350.

[0085] In some embodiments, the dosage form comprises at least one group of sustained-release beads and one group of immediate-release beads, the immediate-release beads comprising a) immediate-release granules, immediate-release pellets, or immediate-release tablets comprising duetetrabenazine and a pharmaceutically acceptable excipient, or b) inert particles coated with duetetrabenazine and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutically acceptable excipient comprises antioxidants comprising butylated hydroxyanisole and butylated hydroxytoluene NF, water-soluble binders comprising hydroxypropyl cellulose, antifoaming agents comprising simethicone, fillers comprising lactose monohydrate and sodium bicarbonate, and surfactants comprising sodium lauryl sulfate. The sustained-release beads comprise a core, which may essentially consist of immediate-release beads, and further comprises a pH-dependent polymer coating targeting the small intestine. In some embodiments, the pH-dependent polymer coating comprises a copolymer of methacrylic acid and ethyl acrylate, and optionally comprises triethyl citrate. In other embodiments, the sustained-release beads comprise a core, which may essentially be derived from the immediate-release beads and further comprises a pH-dependent polymer coating that targets the colon / colon. In some embodiments, the pH-dependent polymer coating comprises a copolymer of methacrylic acid and methyl acrylate and optionally comprises triethyl citrate.

[0086] In some embodiments, the dosage form comprises two groups of sustained-release beads and one group of immediate-release beads, with one group of sustained-release beads targeting the small intestine and the second group of sustained-release beads targeting the large intestine / colon. The dosage form may be, for example, a capsule or a sachet of medication.

[0087] Methods useful in treating VMAT2-mediated disorders are further provided herein. In some embodiments, a method for treating a VMAT2-mediated disorder comprises orally administering a controlled-release drug form disclosed herein to a patient in need. The VMAT2-mediated disorder may be hyperactive movement disorder. The hyperactive movement disorder may be a chronic disorder, such as dystonia, dyskinesia, Huntington's disease, tardive dyskinesia, and dyskinesia in cerebral palsy. In some embodiments, the method is effective in treating chorea associated with Huntington's disease. In some embodiments, the method is effective in treating tardive dyskinesia. A subject suffering from tardive dyskinesia may be concurrently administered an antipsychotic. In some embodiments, the method is effective in treating dyskinesia in cerebral palsy.

[0088] In a particular embodiment, the multi-particle drug delivery method according to any one of the embodiments disclosed herein is administered together with food.

[0089] In a particular embodiment, the multi-particle dosing form according to any one of the embodiments disclosed herein is administered under fasting conditions.

[0090] The plasma profile of the drug formulation after administration is favorable. In one embodiment, a single dose of 6 mg of deutetrabenazine in an oral formulation provides an in vivo plasma profile for total α- and β-dihydrodutetrabenazine, including a geometric mean AUC0-inf of approximately 90,000 to 142,750 hours*pg / mL and / or a geometric mean Cmax of less than approximately 4,600 pg / mL.

[0091] In one embodiment, a single dose in an oral formulation containing 12 mg of deutetrabenazine provides an in vivo plasma profile for total α- and β-dihydrodutetrabenazine, including a geometric mean AUC0-inf of approximately 180,000 to 285,500 hours*pg / mL and / or a geometric mean Cmax of less than approximately 9,200 pg / mL.

[0092] In one embodiment, a single dose in an oral formulation containing 24 mg of duutetrabenazine provides an in vivo plasma profile for total α- and β-dihydrodutetrabenazine, including a geometric mean AUC0-inf of approximately 360,000 to 571,000 hours* pg / mL and / or a geometric mean Cmax of less than approximately 18,400 pg / mL.

[0093] In one embodiment, a single dose in an oral formulation containing 36 mg of deutetrabenazine provides an in vivo plasma profile for total α- and β-dihydrodutetrabenazine, including a geometric mean AUC0-inf of approximately 540,000 to 856,500 hours*pg / mL and / or a geometric mean Cmax of less than approximately 27,600 pg / mL.

[0094] In one embodiment, a single dose in an oral formulation containing 48 mg of duutetrabenazine provides an in vivo plasma profile for total α- and β-dihydrodutetrabenazine, including a geometric mean AUC0-inf of approximately 720,000 to 1,142,000 hours* pg / mL and / or a geometric mean Cmax of less than approximately 36,800 pg / mL.

[0095] In one embodiment, administration of an oral dosage form containing 6 mg of deutetrabenazine provides an in vivo plasma profile for total α- and β-dihydrodutetrabenazine, including a geometric mean AUC0-24 of approximately 102,500–200,000 hours*pg / mL and / or a mean Cmax of less than approximately 10,000 pg / mL at steady state.

[0096] In one embodiment, administration of an oral dosage form containing 12 mg of deutetrabenazine provides an in vivo plasma profile for total α- and β-dihydrodutetrabenazine, including a geometric mean AUC0-24 of approximately 205,000–400,000 hours*pg / mL and / or a mean Cmax of less than approximately 20,000 pg / mL at steady state.

[0097] In one embodiment, administration of an oral dosage form containing 24 mg of deutetrabenazine provides an in vivo plasma profile for total α- and β-dihydrodutetrabenazine, including a geometric mean AUC0-24 of approximately 400,000–800,000 hours*pg / mL and / or a mean Cmax of less than approximately 40,000 pg / mL at steady state.

[0098] In one embodiment, administration of an oral dosage form containing 36 mg of deutetrabenazine provides an in vivo plasma profile for total α- and β-dihydrodutetrabenazine, including a geometric mean AUC0-24 of approximately 615,000 to 1,200,000 hours*pg / mL and / or a mean Cmax of less than approximately 60,000 pg / mL at steady state.

[0099] In one embodiment, administration of an oral dosage form containing 48 mg of deutetrabenazine provides an in vivo plasma profile for total α- and β-dihydrodutetrabenazine, including a geometric mean AUC0-24 of approximately 800,000 to 1,600,000 hours*pg / mL and / or a mean Cmax of less than approximately 80,000 pg / mL at steady state.

[0100] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising the step of orally administering once daily to the subject a multiparticulate dosage form according to any one of the embodiments of the present invention, wherein single dose administration of the multiparticulate dosage form comprising deutetrabenazine microparticles in a total amount of 6 mg provides a geometric mean AUC of from about 90,000 to 142,750 h*pg / mL 0-inf for an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine.

[0101] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising the step of orally administering once daily to the subject a multiparticulate dosage form according to any one of the embodiments of the present invention, wherein single dose administration of the multiparticulate dosage form comprising deutetrabenazine microparticles in a total amount of 6 mg provides a geometric mean C of less than about 4,600 pg / mL max for an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine.

[0102] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising the step of orally administering once daily to the subject a multiparticulate dosage form according to any one of the embodiments of the present invention, wherein single dose administration of the multiparticulate dosage form comprising deutetrabenazine microparticles in a total amount of 12 mg provides a geometric mean AUC of from about 180,00 to 285,500 h*pg / mL 0-inf for an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine.

[0103] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising the step of orally administering once daily to the subject a multiparticulate dosage form according to any one of the embodiments of the present invention, wherein single dose administration of the multiparticulate dosage form comprising deutetrabenazine microparticles in a total amount of 12 mg provides a geometric mean C of less than about 9,200 pg / mL maxThis invention provides a method for obtaining in vivo plasma profiles of total α- and β-dihydrodutetrabenazine, including those related to total α- and β-dihydrodutetrabenazine.

[0104] In one embodiment, the present invention provides a method for treating hyperactive movement disorder in a subject requiring it, comprising the step of orally administering a multiparticle dosage form according to any one embodiment of the present invention to the subject once daily, wherein a single dose of a multiparticle dosage form containing 24 mg of deutetrabenazine microparticles results in a geometric mean AUC of approximately 360,000 to 571,000 hours*pg / mL. 0-inf This invention provides a method for obtaining in vivo plasma profiles of total α- and β-dihydrodutetrabenazine, including those related to total α- and β-dihydrodutetrabenazine.

[0105] In one embodiment, the present invention provides a method for treating hyperactive movement disorder in a subject requiring it, comprising the step of orally administering a multiparticle dosage form according to any one embodiment of the present invention to the subject once daily, wherein a single dose of the multiparticle dosage form containing 24 mg of deutetrabenazine microparticles results in a geometric mean C level of less than approximately 18,400 pg / mL. max This invention provides a method for obtaining in vivo plasma profiles of total α- and β-dihydrodutetrabenazine, including those related to total α- and β-dihydrodutetrabenazine.

[0106] In one embodiment, the present invention provides a method for treating hyperactive movement disorder in a subject requiring it, comprising the step of orally administering a multiparticle dosage form according to any one embodiment of the present invention to the subject once daily, wherein a single dose of a multiparticle dosage form containing 36 mg of deutetrabenazine microparticles results in a geometric mean AUC of approximately 540,000 to 856,500 hours*pg / mL. 0-inf This invention provides a method for obtaining in vivo plasma profiles of total α- and β-dihydrodutetrabenazine, including those related to total α- and β-dihydrodutetrabenazine.

[0107] In one embodiment, the present invention provides a method for treating hyperactive movement disorder in a subject requiring it, comprising the step of orally administering a multiparticle dosage form according to any one embodiment of the present invention to the subject once daily, wherein a single dose of the multiparticle dosage form containing 36 mg of deutetrabenazine microparticles results in a geometric mean C level of less than approximately 27,600 pg / mL. max This invention provides a method for obtaining in vivo plasma profiles of total α- and β-dihydrodutetrabenazine, including those related to total α- and β-dihydrodutetrabenazine.

[0108] In one embodiment, the present invention provides a method for treating hyperactive movement disorder in a subject requiring it, comprising the step of orally administering a multiparticle dosage form according to any one embodiment of the present invention to the subject once daily, wherein a single dose of a multiparticle dosage form containing 48 mg of deutetrabenazine microparticles results in a geometric mean AUC of approximately 720,000 to 1,142,000 hours*pg / mL. 0-inf This invention provides a method for obtaining in vivo plasma profiles of total α- and β-dihydrodutetrabenazine, including those related to total α- and β-dihydrodutetrabenazine.

[0109] In one embodiment, the present invention provides a method for treating hyperactive movement disorder in a subject requiring it, comprising the step of orally administering a multiparticle dosage form according to any one embodiment of the present invention to the subject once daily, wherein a single dose of the multiparticle dosage form containing 48 mg of deutetrabenazine microparticles results in a geometric mean C level of less than approximately 36,800 pg / mL. max This invention provides a method for obtaining in vivo plasma profiles of total α- and β-dihydrodutetrabenazine, including those related to total α- and β-dihydrodutetrabenazine.

[0110] In one embodiment, the present invention provides a method for treating hyperactive movement disorder in a subject requiring it, comprising the step of orally administering a multiparticle dosage form according to any one embodiment of the present invention to the subject once daily, wherein the multiparticle dosage form contains a total amount of 6 mg of deutetrabenazine microparticles, resulting in an average AUC of approximately 102,500 to 200,000 hours*pg / mL. 0-24This invention provides a method for obtaining in vivo plasma profiles of total α- and β-dihydrodutetrabenazine at steady state, including those obtained by the present invention.

[0111] In one embodiment, the present invention provides a method for treating hyperactive movement disorder in a subject requiring it, comprising the step of orally administering a multiparticle dosage form according to any one embodiment of the present invention to the subject once daily, wherein the multiparticle dosage form contains a total amount of 6 mg of deutetrabenazine microparticles, resulting in an average C2 level of less than approximately 10,000 pg / mL. max This invention provides a method for obtaining in vivo plasma profiles of total α- and β-dihydrodutetrabenazine at steady state, including those obtained by the present invention.

[0112] In one embodiment, the present invention relates to a method for treating hyperactive movement disorder in a subject requiring it, comprising the step of orally administering a multiparticle dosage form according to any one embodiment of the present invention to the subject once daily, wherein the multiparticle dosage form contains 12 mg of deutetrabenazine microparticles, resulting in an average AUC of approximately 205,000 to 400,000 hours*pg / mL. 0-24 This invention provides a method for obtaining in vivo plasma profiles of total α- and β-dihydrodutetrabenazine at steady state, including those obtained by the present invention.

[0113] In one embodiment, the present invention provides a method for treating hyperactive movement disorder in a subject requiring it, comprising the step of orally administering a multiparticle dosage form according to any one embodiment of the present invention to the subject once daily, wherein the multiparticle dosage form contains 12 mg of deutetrabenazine microparticles, resulting in an average C2c level of less than approximately 20,000 pg / mL. max This invention provides a method for obtaining in vivo plasma profiles of total α- and β-dihydrodutetrabenazine at steady state, including those obtained by the present invention.

[0114] In one embodiment, the present invention provides a method for treating hyperactive movement disorder in a subject requiring it, comprising the step of orally administering a multiparticle dosage form according to any one embodiment of the present invention to the subject once daily, wherein the multiparticle dosage form contains a total amount of 24 mg of deutetrabenazine microparticles, resulting in an average AUC of approximately 410,000 to 800,000 hours*pg / mL. 0-24 This invention provides an in vivo plasma profile of total α- and β-dihydrodutetrabenazine in steady state, including the present invention.

[0115] In one embodiment, the present invention provides a method for treating hyperactive movement disorder in a subject requiring it, comprising the step of orally administering a multiparticle dosage form according to any one embodiment of the present invention to the subject once daily, wherein the multiparticle dosage form contains 24 mg of deutetrabenazine microparticles, resulting in an average C2 level of less than approximately 40,000 pg / mL. max This invention provides a method for obtaining in vivo plasma profiles of total α- and β-dihydrodutetrabenazine at steady state, including those obtained by the present invention.

[0116] In one embodiment, the present invention provides a method for treating hyperactive movement disorder in a subject requiring it, comprising the step of orally administering a multiparticle dosage form according to any one embodiment of the present invention to the subject once daily, wherein the multiparticle dosage form contains a total amount of 36 mg of deutetrabenazine microparticles, resulting in an average AUC of approximately 615,000 to 1,200,000 hours*pg / mL. 0-24 This invention provides a method for obtaining in vivo plasma profiles of total α- and β-dihydrodutetrabenazine at steady state, including those obtained by the present invention.

[0117] In one embodiment, the present invention provides a method for treating hyperactive movement disorder in a subject requiring it, comprising the step of orally administering a multiparticle dosage form according to any one embodiment of the present invention to the subject once daily, wherein the multiparticle dosage form contains 36 mg of deutetrabenazine microparticles, resulting in an average C2 level of less than approximately 60,000 pg / mL. maxThis invention provides a method for obtaining in vivo plasma profiles of total α- and β-dihydrodutetrabenazine at steady state, including those obtained by the present invention.

[0118] In one embodiment, the present invention provides a method for treating hyperactive movement disorder in a subject requiring it, comprising the step of orally administering a multiparticle dosage form according to any one embodiment of the present invention to the subject once daily, wherein the multiparticle dosage form contains 48 mg of deutetrabenazine microparticles, resulting in an average AUC of approximately 820,000 to 1,600,000 hours*pg / mL. 0-24 This invention provides a method for obtaining in vivo plasma profiles of total α- and β-dihydrodutetrabenazine at steady state, including those obtained by the present invention.

[0119] In one embodiment, the present invention provides a method for treating hyperactive movement disorder in a subject requiring it, comprising the step of orally administering a multiparticle dosage form according to any one embodiment of the present invention to the subject once daily, wherein the multiparticle dosage form contains 48 mg of deutetrabenazine microparticles, resulting in an average C2 level of less than approximately 80,000 pg / mL. max This invention provides a method for obtaining in vivo plasma profiles of total α- and β-dihydrodutetrabenazine at steady state, including those obtained by the present invention.

[0120] In one embodiment, the present invention provides a method for treating hyperactivity disorder, comprising the step of administering a multi-particle drug formulation according to any one embodiment of the present invention, wherein, when tested with 500 mL of pH 3.0 phosphate buffer using a USPII dissolving device, 15% or less of the drug formulation is released after 2 hours.

[0121] In one embodiment, the present invention provides a method for treating hyperactive movement disorder in a subject requiring it, comprising the step of administering a multi-particle dosing form according to any one embodiment of the present invention to the subject once daily, wherein, when tested with 500 mL of pH 3.0 phosphate buffer using a USPII dissolving device, 60 wt% or less of the drug formulation is released within 8 hours.

[0122] In some embodiments, the present invention provides a method for treating hyperactivity disorder, comprising the step of administering a multi-particle drug formulation according to any one embodiment of the present invention, wherein, when tested with 500 mL of pH 3.0 phosphate buffer using a USPII dissolving apparatus, 15 wt% or less of the drug formulation is released after 2 hours, and 40-60 wt% of the drug formulation is released within 7 or 8 hours.

[0123] A method for manufacturing the core of an immediate-release bead or a sustained-release bead, a) A step of providing a dispersion of nano-sized deutetrabenazine and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient includes antioxidants, binders, defoamers, fillers, and surfactants. b) A step of forming immediate-release granules, immediate-release pellets, or immediate-release tablets from the dispersion of a), or a step of coating inert particles with the dispersion of a). Includes, The present specification further provides a method for generating the cores of either immediate-release beads or sustained-release beads, respectively.

[0124] A method for manufacturing sustained-release beads, a) A step of providing a core, wherein the core comprises immediate-release granules, immediate-release pellets, or immediate-release tablets comprising a dispersion of deutetrabenazine and a pharmaceutically acceptable excipient, or inert particles coated with a dispersion of deutetrabenazine and a pharmaceutically acceptable excipient. c)a) A step of coating the core with a pH-independent polymer coating, a pH-dependent polymer coating, or a pH-independent polymer coating and a pH-dependent polymer coating. Includes, This further provides a method for generating sustained-release beads.

[0125] In some embodiments of the core or immediate-release particles, pharmaceutically acceptable excipients include antioxidants comprising butylated hydroxyanisole and butylated hydroxytoluene NF, water-soluble binders comprising hydroxypropyl cellulose, antifoaming agents comprising simethicone, fillers comprising lactose monohydrate and sodium bicarbonate, and surfactants comprising sodium lauryl sulfate.

[0126] The drug formulation may be manufactured by loading a group of sustained-release beads, including a core and a pH-independent coating, into a capsule shell or sachet.

[0127] The drug may be manufactured by loading a group of immediate-release beads, as well as a group of sustained-release beads including a core and a pH-dependent coating, and a pH-dependent coating that targets the small intestine, into a capsule shell or sachet.

[0128] The drug formulation may be manufactured by loading a group of immediate-release beads, as well as a group of sustained-release beads including a core and pH-dependent coating, and a pH-dependent coating targeting the colon / colon, into a capsule shell or sachet.

[0129] The drug may be manufactured by loading a group of immediate-release beads, a group of sustained-release beads including a core and a pH-dependent coating targeting the small intestine, and a group of sustained-release beads including a core and a pH-dependent coating targeting the large intestine / colon into a capsule shell or sachet.

[0130] Nano-sized duetetrabenazine with a median particle size of approximately 0.02 to 2.0 microns is further provided. In some embodiments, the nano-sized duetetrabenazine has a particle size distribution characterized by D90 of approximately 0.8 to 1.6 microns, D50 of approximately 0.2 to 0.6 microns, and D10 of approximately 0.1 to 0.2 microns. [Examples]

[0131] The following examples are provided to complement the preceding disclosure and to give a better understanding of the subject matter of the invention described herein. These examples should not be considered limiting to the subject matter of the invention described herein. The examples and embodiments described herein are for illustrative purposes only, and it is understood that various modifications or changes in light of them should be obvious to those skilled in the art, be within the scope, and can be made without departing from the true scope of this disclosure.

[0132] (Example 1) Development of manufacturing methods The manufacturing method for multi-particle dosing forms includes the following: a. Process for producing a deutetrabenazine dispersion b. A process of coating particles with a deutetrabenazine dispersion to produce deutetrabenazine-coated particles, or producing core granules / pellets / tablets from a deutetrabenazine dispersion. c. A process of coating dutetrabenazine particles with a sustained release coating. d. Optional packaging / encapsulation process.

[0133] 1. Physical characterization of drug raw materials Table 1 shows the particle size distribution of deutetrabenazine after manufacturing (untreated), after micronization (air jet mill), and after nanomilling (Dyno bead mill).

[0134] [Table 1]

[0135] Dry measurements of micromilled and unmilled deutetrabenazine were performed using a Mastersizer 3000 (Malvern Instruments) with the following settings.

[0136] [Table 2]

[0137] Wet measurements of nanomilled deutetrabenazine were performed using a Mastersizer 3000 (Malvern Instruments) with the following settings.

[0138] [Table 3]

[0139] Dutetrabenazine is a weakly basic compound with relatively high solubility in acidic environments (pH < 4) and low solubility at pH > 4 (< 2.3 mg / mL). In rat perfusion models, dutetrabenazine permeates through the small intestine (SI) segment. In humans, human studies using dutetrabenazine administered as a powder in capsules (PIC) have shown [ 14 In the [C]-AME study, approximately 80% of the radiation dose was recovered in the urine, suggesting that the compound is well absorbed in the small intestine and large intestine / colon. The level of absorption of dutetrabenazine in the lower GI of rats was shown to be jejunum < mid-small intestine < colon < ileum, with ileal absorption at approximately 0.0006 cm / second.

[0140] The dosage forms disclosed herein were developed to achieve pharmacokinetics (PK) similar to those of a twice-dose AUSTEDO® 12 mg tablet at a once-daily dose (QD). Drug solubility at pH >3 was tested in unmilled drug raw material (DS) batches and compared with micromilled and nanomilled DS batches.

[0141] For all three batches, deutetrabenazine was dispersed in an excipient solution of butylated hydroxytoluene (antioxidant), butylated hydroxyanisole (antioxidant), hypromellose 2910 (hydroxypropyl methylcellulose, binder), lactose monohydrate (filler), sodium lauryl sulfate (surfactant), sodium bicarbonate (filler), and water. Simethicone 30% emulsion was added to prevent foaming during the process. For samples 1, 2, and 3, unmilled deutetrabenazine, deutetrabenazine with a particle size D90 < 10 microns, and deutetrabenazine with a particle size D90 < 1 micron were used, respectively. All three dispersions were sprayed onto 25 / 30 spheroidal sugars using a GPCG-2 Wurster processing unit. Table 2 (Table 4) shows the composition of the deutetrabenazine-coated spheres for samples 1, 2, and 3.

[0142] Particles coated with deutetrabenazine were encapsulated in size 0 capsule shells and dissolved in 500 mL of phosphate buffer at pH 6.8 using a USP-II instrument at 75 rpm. Samples were collected at 10, 20, 30, 40, 60, 80, 100, and 120 minutes.

[0143] [Table 4]

[0144] Figure 3 shows the dissolution profiles of samples 1, 2, and 3 in 500 mL phosphate buffer, pH 6.8, USPII instrument, 75 rpm. Micromilled and nanomilled particles show superior dissolution profiles at pH 6.8 compared to unmilled samples. Diamonds represent the release profile of unmilled samples, showing insufficient release (approximately 30–35 wt%) even after 2 hours, squares represent the release profile of micromilled deutetrabenazine, and triangles represent the release profile of nanomilled deutetrabenazine.

[0145] (Example 2) Milling of dutetrabenazine The particle size of deutetrabenazine was reduced to nanometer size (<1.0 micron) by several passes using a wet Dyno milling process. The milled deutetrabenazine was dispersed in the excipient as described above. The dispersion was passed through a 0.3 liter agitator bead mill containing 950 g of ultra-high density zirconium oxide beads. The dispersion was passed through the agitator mill for up to 2 hours to reduce the particle size to less than 1.0 micron. Table 3 (Table 5) shows the PSD of the dispersion after different milling times.

[0146] [Table 5]

[0147] After milling, solutions of lactose and sodium lauryl sulfate were prepared and added to the nanomilled dispersion, and mixed for 30 minutes using an air mixer. The resulting deutetrabenazine suspension was sprayed onto spheroidal sugars using a Glatt fluid bed coater to produce deutetrabenazine-coated particles. The first portion of the deutetrabenazine-coated particles was left as is (i.e., immediate-release population), the second portion was further coated with a sustained-release coating (a copolymer dispersion of methacrylic acid and ethyl acrylate, pH 5.5-7), and the third portion was coated with a second sustained-release coating (a copolymer dispersion of methacrylic acid and methyl methacrylate, pH > 7). The complete compositions of the three particle populations in the dosage form are provided in Table 4 (Table 6) below.

[0148] [Table 6]

[0149] Two sets of particles, immediate-release and sustained-release, were packed into capsule shells. The packed capsules were dissolved in a USPIII instrument at 10 dpm. The pH value in the instrument was selected based on the pH of GI. The pH gradient was 0–1 hour in 0.1N HCl, 1–3 hours in phosphate buffer, pH 6.8, and 3–6 hours in phosphate buffer, pH 7.2. Samples were collected at 1, 2, 3, 4, 5, and 6 hours. Figure 4 shows the dissolution profile obtained over the entire pH gradient.

[0150] (Example 3) Immediate-release and sustained-release drug delivery methods The compositions of drug formulations containing sustained-release beads with a pH-independent polymer coating and deuterabenazine-coated inert particles are provided as Samples 5-10 in Table 5 (Table 7).

[0151] [Table 7]

[0152] Nanomilled active coated pellets were coated with cellulose acetate and polyethylene glycol. Long-release particles were filled into capsules, and the drug release profile was evaluated for up to 24 hours at 75 RPM using USPII at pH 3.0, as shown in the graph in Figure 6.

[0153] Samples 11-12 are provided in Table 6 (Table 8).

[0154] [Table 8]

[0155] API-coated particles were further coated with ethyl cellulose and polyethylene glycol. The sustained-release beads were filled into capsule shells, and the drug release profile was evaluated for up to 24 hours at 75 RPM using USPII at pH 3.0; the graph is shown in Figure 5.

[0156] Samples 13-16 are provided in Table 7 (Table 9).

[0157] [Table 9]

[0158] Dutetrabenazine-coated particles were further coated with ethylcellulose and polyethylene glycol. The sustained-release beads were filled into capsules, and the drug release profile was evaluated for up to 24 hours at pH 3.0 using USPII at 75 RPM; the graph is shown in Figure 7. These data show a release profile of approximately 40–60 wt% over 7 hours.

[0159] (Example 4) Bioavailability evaluation of single doses The dosage form of fine particles containing deutetrabenazine will be prepared as disclosed in Example 1 and studied in a single-dose pharmacokinetic study.

[0160] The primary objective is to evaluate the comparative bioavailability (BA) of deutetrabenazine and deuterated α- and β-dihydrotetrabenazine (deuHTBZ) metabolites after a single dose of a microparticle dosage form (test) compared with a single dose of 12 mg Austedo® tablets administered twice at 12-hour intervals (bid) under fasting conditions.

[0161] Study population and number of participants: The study includes healthy non-smoking men and women.

[0162] Participation period: The study includes a 2-4 week screening period (Period 1), an open-label treatment period using the test drug formulation (Study) and reference formulation (Ref) (Period 2), and an outpatient visit at least 1 day later (Period 3). treatment: Treatment sequence A: Day 1 - The exam is administered. Days 2-3 - After administering Ref, wash out the test for at least 6 hours. Treatment sequence B: Day 1 - Administration of Ref Days 2-3 - After conducting the test, wash out the Ref for at least 6 hours. The main objective was addressed using the following parameters: - Observed maximum concentration (Cmax) - Area under plasma concentration-time (AUC) (AUC0-t) from time 0 to the last measurable plasma concentration time. - Infinitely inserted AUC (AUC0-∞) - AUC (AUC 0-24h) from 0 to 24 hours after drug administration

[0163] analysis AUC0-t, AUC0-∞, and AUC0-24h are calculated using the trapezoidal rule. The Cmax, AUC0-t, AUC0-∞, and AUC0-24h data are naturally log-transformed before statistical analysis. Comparisons of Cmax, AUC0-t, AUC0-∞, and AUC0-24h between treatments (T2A vs. R) will be performed using separate parametric analysis of variance (ANOVA) models with fixed-effect terms for sequence, duration, treatment group, and random effects of subjects within the sequence. The difference between the reference formulation (Ref) and the test formulation (test) will be assessed by constructing a 90% confidence interval for the test / Ref ratio based on the least-squares mean from the ANOVA for log-transformed Cmax, AUC0-t, AUC0-∞, and AUC0-24h. By inversely transforming the treatment difference and associated 90% confidence intervals inferred from ANOVA on a logarithmic scale, the estimated geometric mean ratio between the treatment group and the 90% confidence interval for this ratio can be obtained.

[0164] result The once-daily dose of the test dosing regimen yields similar deuHTBZ plasma concentrations to those observed with respect to Ref. The multiparticle dosing regimen disclosed herein is administered once daily, provides a similar therapeutic effect to that of AUSTEDO, and raises no safety concerns.

[0165] (Example 5) Bioavailability evaluation of multiple doses As disclosed in Example 1, a multi-particle dosing form containing 24 mg of deutetrabenazine was prepared and studied in an open-label, randomized, multi-dose, bidirectional crossover study with healthy volunteers.

[0166] The primary objective is to evaluate the bioequivalence (BE) of conducting a once-daily (qd) trial compared to a bid administration of Ref under fasting or feeding conditions.

[0167] The treatment involves repeated administration of the trial drug once daily for 7 days versus repeated administration of the Ref drug for 7 days.

[0168] AUCt and C for deutetrabenazine and deuHTBZ max t max , C min , C av We will analyze it in a steady state.

[0169] result Multiple doses in the trial resulted in pK parameters comparable to those of Ref at steady state. Therefore, a similar efficacy response can be expected with once-daily administration, and no safety concerns are observed.

[0170] (Example 6) Research on the effects of diet A multi-particle dosage form containing 24 mg of deutetrabenazine was prepared as disclosed in Example 1 and studied in an open-label, randomized, bidirectional crossover study to evaluate the comparative bioavailability of deutetrabenazine and deuHTBZ in a fed state compared to a fasted state after a single administration of 24 mg of the multi-particle formulation once daily (qd).

[0171] The treatment involves: A - A multiparticle formulation administered once daily (qd) as a single oral dose of 24 mg with water, after fasting for at least 10 hours overnight. B - A multiparticle formulation of 24 mg once daily (qd) administered as a single oral dose with water 30 minutes after initiation of a standardized high-calorie, high-fat breakfast, following at least 10 hours of overnight fasting. It includes.

[0172] Those affected will receive treatment A / B along with a washout period of at least 6 days.

[0173] AUCt, Cmax, tmax, Cmin, and Cav for deutetrabenazine and deuHTBZ will be analyzed.

[0174] result Following a single dose with or without food, similar plasma concentrations of deutetrabenazine and deuHTBZ demonstrate that the multi-particle dosing form can be administered regardless of food.

[0175] All patents, patent applications, and publications referenced in this specification indicate the level of expertise of those skilled in the art. All patents, patent applications, and publications are incorporated herein by reference to the same extent that individual documents are specifically indicated as being incorporated by reference. The inventions described exemplary herein can preferably be carried out in the absence of any elements not specifically disclosed herein. Thus, for example, in each case herein, any of the terms “including,” “essentially consisting of,” and “consisting of” can be replaced with any of the other two terms. The terms and expressions used are for illustrative purposes only and not for limiting purposes, and are not intended to exclude any equivalents of any feature or part thereof shown and described in the use of such terms and expressions, however it should be recognized that various modifications are possible within the scope of the claimed invention. Thus, although the invention is specifically disclosed by preferred embodiments and optional features, it should be understood that modifications and changes to the concepts disclosed herein may be made by those skilled in the art, and such modifications and changes are considered to be within the scope of the invention as defined by the appended claims.

[0176] With regard to the embodiments described herein, each embodiment disclosed herein is considered applicable to the respective other disclosed embodiments. For example, elements cited in the embodiment of the method can be used in the embodiments of the pharmaceutical composition, packaging, and use described herein, and vice versa.

Claims

1. A controlled-release oral dosing form for once-daily administration of deutetrabenazine, comprising a group of sustained-release beads, wherein the sustained-release beads comprise a core containing a certain amount of deutetrabenazine and a pharmaceutically acceptable excipient, and further comprise a pH-independent polymer coating, a pH-dependent polymer coating, or a pH-independent polymer coating further coated with a pH-dependent polymer coating, wherein the deutetrabenazine has a median particle size of 0.1 to 2.0 microns, the particle size being measured by laser diffraction.

2. The dosage form according to claim 1, wherein the core comprises a) immediate-release granules, immediate-release pellets, or immediate-release tablets comprising the deutetrabenazine and the pharmaceutically acceptable excipient, or b) inert particles coated with a dispersion of the deutetrabenazine and the pharmaceutically acceptable excipient.

3. The dosage form according to claim 1 or 2, further comprising a group of immediate-release beads, the group of immediate-release beads comprising a) immediate-release granules, immediate-release pellets, or immediate-release tablets comprising a certain amount of deutetrabenazine and a pharmaceutically acceptable excipient, or b) inert particles coated with a certain amount of deutetrabenazine and a pharmaceutically acceptable excipient.

4. The dosage form according to claim 3, wherein the amount of deutetrabenazine and / or the pharmaceutically acceptable excipient is the same in the core of the sustained-release beads and in the immediate-release beads, or the amount of deutetrabenazine and / or the pharmaceutically acceptable excipient is different in the core of the sustained-release beads and in the immediate-release beads.

5. The drug delivery form according to claim 1, wherein the deutetrabenazine has a volume particle size distribution characterized by a D90 of 0.8 to 1.6 microns.

6. The drug delivery method according to any one of claims 1 to 5, wherein the pharmaceutically acceptable excipient comprises one of an antioxidant, a binder, a filler, a surfactant, an antifoaming agent, or a combination thereof.

7. The drug delivery method according to any one of claims 1 to 6, wherein the sustained-release beads include a pH-independent polymer coating that coats the core, or the sustained-release beads include a pH-dependent polymer coating that coats the core.

8. The drug dosage form according to any one of claims 1 to 7, wherein the drug dosage form comprises a total of 6 mg to 72 mg of deutetrabenazine.

9. A dosage form according to any one of claims 1 to 8, comprising a group of sustained-release beads, further comprising a group of immediate-release beads, wherein the immediate-release beads comprise a) immediate-release granules, immediate-release pellets, or immediate-release tablets comprising a certain amount of deutetrabenazine and a pharmaceutically acceptable excipient, or b) inert particles coated with a certain amount of deutetrabenazine and a pharmaceutically acceptable excipient.

10. A dosage form according to any one of claims 1 to 9, for use in the treatment of vesicular monoamine transporter type 2 (VMAT2)-mediated disorders, comprising orally administering the dosage form to a patient in need thereof.

11. A method for producing a core of sustained-release beads as defined in Claim 1 or an immediate-release bead as defined in Claim 3, a) A step of providing a dispersion of nano-sized deutetrabenazine and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient includes antioxidants, binders, defoamers, fillers, and surfactants. b) A step of forming immediate-release granules, immediate-release pellets, or immediate-release tablets from the dispersion in a), or a step of coating inert particles with the dispersion in a). Includes, A method by which the cores of the immediate-release beads or the sustained-release beads are each generated.

12. A method for producing sustained-release beads in the dosage form described in any one of claims 1 to 10, a) A step of providing a core, wherein the core comprises immediate-release granules, immediate-release pellets, or immediate-release tablets containing a dispersion of deutetrabenazine and a pharmaceutically acceptable excipient, or inert particles coated with a dispersion of deutetrabenazine and a pharmaceutically acceptable excipient. b) The process of coating the core of a) with a pH-independent polymer coating, a pH-dependent polymer coating, or a pH-independent polymer coating and a pH-dependent polymer coating. Includes, As a result, sustained-release beads are produced, and optionally, the method for preparing the core is a) A step of providing a dispersion of nano-sized deutetrabenazine and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient includes antioxidants, binders, defoamers, fillers, and surfactants. b) A step of forming immediate-release granules, immediate-release pellets, or immediate-release tablets from the dispersion in a), or a step of coating inert particles with the dispersion in a). Includes, A method by which the cores of the immediate-release beads or the sustained-release beads are each generated.

13. The method according to claim 12, wherein the nano-sized deutetrabenazine is prepared by milling.

14. Nano-sized duetetrabenazine having a median particle size of 0.02 to 2.0 microns, or 0.02 to 0.9 microns, or 0.05 to 0.5 microns, or 0.1 to 2.0 microns, or 0.1 to 1.6 microns, or 0.2 to 1.6 microns, or 0.15 to 1.2 microns, or 0.15 to 1.0 microns, wherein the particle size is measured by laser diffraction.

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