Osmotic dosage forms containing deutetrabenazine and methods of use thereof

Abstract

To meet the demand for alternative dosage forms, such as a dosage form that can deliver deutetrabenazine in a controlled manner over an extended period of time.SOLUTION: Provided herein are osmotic dosage forms containing deutetrabenazine for use in the treatment of, e.g., hyperkinetic movement disorders. When orally administered to a subject on a once-daily basis, the dosage forms provide a favorable pharmacokinetic profile for the active agent indicating treatment efficacy over an extended period of time.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 037,369, filed June 10, 2020, U.S. Provisional Patent Application No. 63 / 037,953, filed June 11, 2020, and U.S. Provisional Patent Application No. 63 / 044,451, filed June 26, 2020, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to osmotic dosage forms and methods of using these dosage forms for treating hyperkinetic movement disorders resulting from conditions such as Huntington's disease, tardive dyskinesia, Tourette's syndrome, levodopa-induced dyskinesia, and dyskinesia in cerebral palsy. [Background technology]

[0003] Deutetrabenazine ((RR,SS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one) is a type 2 vesicular monoamine transporter (VMAT2) inhibitor. The biologically active metabolites formed from deutetrabenazine (alpha-dihydrodeutetrabenazine [α-deuHTBZ] and beta-dihydrodeutetrabenazine [β-deuHTBZ]), both identified as "deuHTBZ," are potent inhibitors of VMAT2 binding. Deutetrabenazine exhibits an increased half-life of its active metabolites compared to tetrabenazine (e.g., U.S. Pat. No. 8,524,733).

[0004] Deutetrabenazine is approved by the U.S. Food and Drug Administration under the trade name AUSTEDO® for the treatment of chorea (involuntary muscle movements) associated with Huntington's disease (HD) and for the treatment of tardive dyskinesia (TD) in adults. AUSTEDO® dosage forms are administered orally twice daily (bid) at a total daily dose of at least 12 mg of deutetrabenazine.

[0005] One factor that influences the gastrointestinal absorption of an orally administered drug is the rate at which the drug is released from the dosage form. Drug release rates for oral dosage forms are typically measured as the rate of in vitro dissolution, i.e., the amount of drug released from the dosage form per unit time, in, for example, FDA-approved systems. Such systems include, for example, United States Pharmacopeia (USP) dissolution apparatus I and II.

[0006] The therapeutic window of a drug is the period during which the plasma drug concentration is within the therapeutically effective range. However, as the plasma drug concentration declines over time, multiple doses of the drug dosage form must be administered at appropriate intervals to ensure that the plasma drug concentration remains within the therapeutic range or rises back up to the therapeutic range. At the same time, however, it is necessary to avoid or minimize plasma drug concentrations that result in undesirable side effects.

[0007] Several dosage forms containing 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 would allow for more advantageous dosing regimens, such as once-daily (qd) dosing, while maintaining the therapeutic effects currently achieved by AUSTEDO®. Such alternative dosage forms are needed. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] U.S. Patent No. 8,524,733 [Patent Document 2] U.S. Patent No. 9,296,739 [Patent Document 3] U.S. Patent No. 4,327,725 [Patent Document 4] U.S. Patent No. 4,612,008 [Patent Document 5] U.S. Patent No. 4,783,337 [Patent Document 6] U.S. Patent No. 5,082,668 [Patent Document 7] U.S. Patent No. 3,845,770 [Patent Document 8] U.S. Patent No. 3,916,899 [Patent Document 9] U.S. Patent No. 3,173,876 [Patent Document 10] U.S. Patent No. 3,276,586 [Patent Document 11] U.S. Patent No. 3,541,005 [Patent Document 12] U.S. Patent No. 3,541,006 [Patent Document 13] U.S. Patent No. 3,546,142 [Patent Document 14] U.S. Patent No. 4,200,098 [Patent Document 15] U.S. Patent No. 4,088,864 Summary of the Invention [Means for solving the problem]

[0009] Disclosed herein is a method for producing a medicament for the treatment of a pulmonary arthritis. a. A tablet core comprising an active layer containing a predetermined amount of deutetrabenazine microparticles and a push layer; b. a semipermeable layer surrounding the tablet core; and c. Holes extending through the semipermeable layer into the tablet core and a dosage form for once-daily administration of deutetrabenazine to a subject in need thereof, the dosage form comprising:

[0010] Also disclosed herein is a method of treating a hyperkinetic movement disorder in a subject, the method comprising administering to the subject once daily an osmotic dosage form disclosed herein. [Brief explanation of the drawings]

[0011] [Figure 1] 1 shows a cross-sectional view of an osmotic dosage form. [Figure 2a] 1 shows a flow chart of the overall manufacturing process for an osmotic dosage form according to the present disclosure. [Figure 2b] 1 shows a flow chart of the overall manufacturing process for an osmotic dosage form according to the present disclosure. [Figure 3a] 3A and 3B are graphs showing the concentration (pg / mL) of deutetrabenazine versus time (hours, "h") in subjects administered a 12 mg AUSTEDO® tablet bid ("R") or an osmotic dosage form containing 24 mg deutetrabenazine qd ("T2A"). Figure 3a shows a direct scale for the mean concentration. [Figure 3b] Figure 3b shows the concentration (pg / mL) of deutetrabenazine versus time (hours, "h") in subjects administered a 12 mg AUSTEDO® tablet bid ("R") or an osmotic dosage form containing 24 mg deutetrabenazine qd ("T2A"). Figure 3b shows the logarithmic scale for the mean concentrations. [Figure 4a] 4A and 4B are graphs showing concentrations (pg / mL) of α- and β-deuHTBZ (total deuHTBZ) versus time (hours, "h") in subjects receiving a 12 mg AUSTEDO® tablet bid ("R") or an osmotic dosage form containing 24 mg deutetrabenazine qd ("T2A"). Figure 4a shows a direct scale for the mean concentrations. [Figure 4b] 4A and 4B are graphs showing the concentration (pg / mL) of α- and β-deuHTBZ (total deuHTBZ) versus time (hours, "h") in subjects receiving a 12 mg AUSTEDO® tablet bid ("R") or an osmotic dosage form containing 24 mg deutetrabenazine qd ("T2A"). Figure 4b shows the logarithmic scale for the mean concentrations. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present subject matter may be more readily understood by reference to the following detailed description, which forms a part of this disclosure: It is to be understood that the present invention is not limited to the specific methods, conditions, or parameters described and / or illustrated herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only, and is not intended to be limiting of the claimed invention.

[0013] Unless otherwise defined herein, scientific and technical terms used in connection with this application have the meanings commonly understood by those skilled in the art. Furthermore, unless otherwise required by context, singular terms include plural terms and plural terms include the singular.

[0014] As employed above, and throughout this disclosure, the following terms and abbreviations, unless otherwise indicated, shall be understood to have the following meanings:

[0015] In this disclosure, the singular forms "a," "an," and "the" include plural references, and reference to a particular numerical value includes at least that particular value unless the content clearly dictates otherwise. Thus, for example, a reference to "a compound" is a reference to one or more of such compounds and equivalents thereof known in the art, and so forth. The term "plurality," as used herein, means more than one. When ranges of values ​​are expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, using the antecedent "about," it is understood that the particular value forms another embodiment. All ranges are inclusive and combinable.

[0016] As used herein, the terms "compound," "drug," "pharmacologically active agent," "active agent," or "medication" are used interchangeably herein to refer to one or more compounds or compositions of substances that, when administered to a subject (human or animal), elicit a desired pharmacological and / or physiological effect through local and / or systemic action. The active agent is preferably deutetrabenazine, as disclosed herein.

[0017] As used herein, "dosage form" refers to a drug form that has osmotic properties and is capable of releasing an active agent over an extended period of time, for example, a dosage form that releases 60 wt% or less of the active agent in the dosage form 8 hours after administration. The active agent is preferably deutetrabenazine, as disclosed herein.

[0018] As used herein, the term "drug formulation" refers to a solution or suspension of a drug, optionally including excipients, formed in situ under the aqueous conditions of the dosage form. The active agent is preferably deutetrabenazine, as disclosed herein.

[0019] The terms "pore" or "exit pore" are used interchangeably and refer to any suitable means and method for the exit of a drug or drug formulation from the core of the dosage form, e.g., any hole, passageway, channel, or similar opening through which a drug or drug formulation in the core of the dosage form can exit. Other expressions of such terms include, for example, exit means, aperture, or hole.

[0020] As used herein, the terms "treatment" or "therapy" (as well as different forms thereof) include preventative (e.g., prophylactic), curative, or palliative treatment. As used herein, the term "treating" includes alleviating or alleviating at least one adverse or negative effect or symptom of a condition, disease, or disorder. The condition, disease, or disorder can refer to hyperkinetic movement disorders such as, but not limited to, Huntington's disease, tardive dyskinesia, Tourette's syndrome, dystonia, dyskinesia in cerebral palsy, and levodopa-induced dyskinesia in Parkinson's disease.

[0021] The term "administering" means providing to a patient a pharmaceutical composition or dosage form (used interchangeably herein) disclosed herein.

[0022] The terms "subject," "individual," and "patient" are used interchangeably and refer to a human being to whom treatment, including prophylactic treatment, with the dosage forms disclosed herein is provided.

[0023] "Pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or excipients that are, within the scope of sound medical judgment, suitable for contact with human tissue without excessive toxicity, irritation, allergic response, or other problematic complication commensurate with a reasonable benefit / risk ratio.

[0024] The dosage forms of the present disclosure may include "derivatives" of certain dosage form materials or components, such as derivatives of cellulose or starch. As used herein, a "derivative" of a material can refer to synthetic or semi-synthetic versions of that material. For example, in the case of cellulose, derivatives can refer to cellophane, rayon, and semi-synthetic cellulose products such as cellulose acetate, cellulose esters, and cellulose ethers.

[0025] "Microparticles" refers to particles, e.g., deutetrabenazine particles, having a particle size (i.e., diameter) of less than 1 mm. In one embodiment, the median diameter (D 50 ) is about 0.05 to about 100 μm. In another embodiment, the D 50 In another embodiment, the D of the microparticles is about 0.05 to about 50 μm. 50 is about 1 μm to about 30 μm, or about 1 μm to about 25 μm, or about 5 μm to about 30 μm, or about 1 μm to about 20 μm, or about 5 μm to about 25 μm, or about 10 μm to about 20 μm. In one embodiment, the deutetrabenazine microparticles have a particle size distribution with a diameter of about 1 μm to about 30 μm. In another embodiment, the deutetrabenazine microparticles have a D of 15 μm. 90 (i.e., 90% of the particles have a diameter of 15 μm or less). In another embodiment, the deutetrabenazine microparticles have a D of 10 μm 50 (i.e., 50% of the particles have a diameter greater than 10 um and 50% of the particles have a diameter less than or equal to 10 um). In yet another embodiment, the deutetrabenazine microparticles have a D of 3 μm. 10 (i.e. 10% of the particles have a diameter less than 3 um).

[0026] Term D90 , D 50 , or D 10 is well understood in the art. The particle size distribution (i.e., diameter) of microparticles can be determined by one skilled in the art using conventional methods, such as dynamic or static light scattering of an aqueous dispersion of the microparticle composition. 90 Value and D 10 The value is D 50 Similarly, the value can be calculated from the particle size distribution of the fine particles.

[0027] Osmotic dosage forms generally utilize osmotic pressure to generate a driving force that causes fluid from, for example, the gastrointestinal (GI) tract to be absorbed, at least in part, into a compartment formed by a semipermeable wall, layer, or membrane that allows free diffusion of fluid but not drug or osmotic agent, if present. A constant rate of drug release can be achieved by designing a system that provides a relatively constant osmotic pressure and having a suitable exit means for the drug formulation that releases at a rate corresponding to the rate of fluid absorbed as a result of the relatively constant osmotic pressure. Without being limited by theory, osmotic systems can operate independently of pH, so that operation continues at a rate determined by osmotic pressure over an extended period of time, even as the dosage form passes through the GI tract and encounters different microenvironments with significantly different pH values.

[0028] One example of an osmotic device comprises two component layers within a compartment (referred to interchangeably herein as the core) formed by a semipermeable wall. One component layer (referred to herein as the active layer) contains a drug (i.e., deutetrabenazine) in a mixture with additives, and the second component layer (referred to herein as the push layer) contains an osmotically active agent in a drug-free mixture, optionally with additives. This core is further coated with a semipermeable wall, allowing aqueous fluids, i.e., the GI system, to enter the core. Without wishing to be limited by theory, upon imbibition of fluid into the dosage form, the active layer forms a drug formulation, and the osmotic agent in the push layer expands and pushes out the drug formulation, thereby facilitating release of the drug formulation at a substantially constant rate. See, e.g., U.S. Pat. Nos. 4,327,725, 4,783,337, and 5,082,668.

[0029] Although constant release dosage forms have proven effective for many different drug therapies, there are no clinical situations in which they are completely satisfactory. In some patients, the therapeutic effectiveness of the drug has been observed to decline below the therapeutic efficacy threshold before the end of the desired treatment period, despite maintaining a substantially constant drug release that is expected to provide continued efficacy.

[0030] It has been surprisingly discovered that oral dosage forms comprising deutetrabenazine can be achieved that exhibit desirable release rates, and thus desirable pharmacokinetic profiles, for extended periods of time. In some embodiments, the osmotic dosage forms of the present disclosure, when orally administered to a subject once daily (qd), provide a pharmacokinetic profile that is comparable, e.g., bioequivalent, to the pharmacokinetic profile of the AUSTEDO® dosage form administered bid. In certain embodiments, the osmotic dosage form provides a mean AUC of about 410,000 to 800,000 h*pg / mL. 0-24 and a mean C of less than approximately 40,000 pg / mL max The in vivo plasma profile for total deuHTBZ at steady state is provided.

[0031] The osmotic dosage forms of the present disclosure comprise a tablet core containing at least a push layer and an active layer, where the active layer comprises deutetrabenazine and one or more excipients to form a drug formulation when hydrated, and the push layer comprises at least one osmotic agent and one or more excipients. Both the push layer and the active layer are contained within a tablet core that is at least partially surrounded by a semipermeable layer having holes that serve as exit means for release of the drug formulation from the tablet core. In some embodiments, the two layers are compressed into a bilayer tablet core surrounded by a semipermeable membrane and further having suitable openings for drug release.

[0032] An embodiment of an oral osmotic dosage form disclosed herein is illustrated in cross-section in FIG. 1. Components are not drawn to scale. The dosage form (2) comprises a bilayered tablet core. The core comprises an active layer (4) containing a drug, e.g., deutetrabenazine, and one or more active layer additives, and a push layer (6) containing at least one osmotic agent along with one or more push layer additives. At least a portion of the active layer forms a drug formulation upon exposure to an aqueous environment. Suitable active and push layer additives are known in the art and include excipients, carriers, binders, fillers, controlled-release agents, and processing agents. A semipermeable membrane (8) surrounds the bilayered tablet core, and a suitably sized hole (10) extending from the semipermeable membrane to the active layer (4) is present to allow the drug formulation to be released from within the tablet core. As shown, the dosage form is longitudinally compressed, and the hole (10) is present on the side of the dosage form containing the active layer. In other embodiments, the dosage form is compressed along the transverse axis of the dosage form, and the holes are present at one end of the dosage form. In all embodiments, more than one hole may be present. Through the cooperation of the components of the osmotic dosage form, in the presence of an aqueous environment, the drug formulation is released from the active layer through the holes at the desired release rate over an extended period of time. Although not shown in Figure 1, an optional immediate-release layer (immediate-release coating) outside the semipermeable layer containing an additional drug (i.e., deutetrabenazine microparticles) may also be provided, as described elsewhere herein, if desired.

[0033] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: a. A tablet core comprising an active layer containing a predetermined amount of deutetrabenazine microparticles and a push layer; b. a semipermeable layer surrounding the tablet core; and c. Holes in the semipermeable layer extending into the tablet core The present invention provides an osmotic dosage form for once-daily administration to a subject in need thereof, comprising:

[0034] The active layer contained in the tablet core comprises deutetrabenazine and pharmaceutically acceptable active layer excipients. In a preferred embodiment, the deutetrabenazine is provided as deutetrabenazine microparticles. The deutetrabenazine microparticles may be present in the active layer in an amount of about 2% to 20% by weight (% w / % w) of the active layer relative to the total weight of the active layer (i.e., about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%).

[0035] In a specific embodiment, the active layer additive comprises an active layer controlled-release agent. In one embodiment of the present invention, the active layer controlled-release agent has a viscosity of about 50 to 150 mPa s. In a specific embodiment, the active layer controlled-release agent has a viscosity of about 55 to 90 mPa s. In a preferred embodiment, the active layer controlled-release agent comprises a polyoxyethylene polymer, an ionic hydrogel, a hydrophilic polymer, a hydrophobic polymer, or any mixture thereof. In another embodiment, the active layer controlled-release agent comprises a polyoxyethylene polymer that is polyethylene oxide. In yet another embodiment, the polyethylene oxide in the active layer has an average molecular weight of 100,000 to 500,000 daltons. In some embodiments, the polyethylene oxide in the active layer has an average molecular weight of about 200,000 daltons.

[0036] In another embodiment, the active layer controlled-release agent is present in the active layer in an amount of about 60% to about 98% by weight, based on the total weight of the active layer. In a specific embodiment, the active layer controlled-release agent is present in the active layer in an amount of about 70% to about 85% by weight, based on the total weight of the active layer. In a specific embodiment, the active layer controlled-release agent is present in the active layer in an amount of about 80% to about 90% by weight, based on the total weight of the active layer. In a specific embodiment, the active layer controlled-release agent is present in the active layer in an amount of about 85% to about 95% by weight, based on the total weight of the active layer.

[0037] In one embodiment, the weight ratio of the amount of deutetrabenazine microparticles in the active layer to the amount of active layer controlled-release agent is 2:3 to 1:50. In a specific embodiment, the weight ratio of the amount of deutetrabenazine microparticles in the active layer to the amount of active layer controlled-release agent is 2:5 to 1:5. In a specific embodiment, the weight ratio of the amount of deutetrabenazine microparticles in the active layer to the amount of active layer controlled-release agent is 1:4 to 1:9. In a specific embodiment, the weight ratio of the amount of deutetrabenazine microparticles in the active layer to the amount of active layer controlled-release agent is 1:5 to 1:19. In a specific embodiment, the weight ratio of the amount of deutetrabenazine microparticles in the active layer to the amount of active layer controlled-release agent is 1:5 to 1:10. In a specific embodiment, the weight ratio of the amount of deutetrabenazine microparticles in the active layer to the amount of active layer controlled-release agent is 1:5 to 1:7. In one specific embodiment, the weight ratio of the amount of deutetrabenazine microparticles in the active layer to the amount of the active layer controlled-release agent is 1:12 to 1:15. In one specific embodiment, the weight ratio of the amount of deutetrabenazine microparticles in the active layer to the amount of the active layer controlled-release agent is 1:20 to 1:30.

[0038] Optional additives in the active layer include antioxidants, binders, lubricants, colorants, etc. Such additives are well known to those skilled in the art. In some embodiments, the active layer comprises deutetrabenazine microparticles, an active layer additive, and optionally one or more of an antioxidant, a binder, a lubricant, a colorant, or any combination thereof.

[0039] In one embodiment, the active layer further comprises at least one active layer antioxidant. Preferably, the active layer antioxidant comprises tert-butyl-4-methoxyphenol (a mixture of the 2- and 3-isomers), 2,6-di-tert-butyl-p-cresol, propyl gallate, 6-ethoxy-1,2-dihydro(digydro)-2,2,4-trimethylquinoline (ethoxyquin), nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole, butylated hydroxytoluene, or any mixture thereof. In a specific embodiment, the active layer comprises a mixture of butylated hydroxyanisole and butylated hydroxytoluene. In one embodiment, the active layer antioxidant may be present in the active layer in an amount of about 0.001% to about 1% by weight, based on the total weight of the active layer.

[0040] In one embodiment, the active layer further comprises an active layer binder. In one embodiment, the active layer binder comprises hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, natural and synthetic gums, and any mixtures thereof. In another embodiment, the active layer binder comprises hypromellose. In one embodiment, the active layer binder may be present in the active layer in an amount of about 2% to about 20% by weight, based on the total weight of the active layer.

[0041] In one embodiment, the active layer further comprises one or more pharmaceutically acceptable lubricants. Suitable lubricants include, but are not limited to, talc, starch, zinc stearate, aluminum stearate, magnesium stearate, calcium stearate, boric acid, sodium chloride, paraffin, stearic acid, low-melting point waxes, hydrogenated vegetable oils, and saturated fatty acid esters. In a specific embodiment, the one or more lubricants may be present in the active layer in an amount of about 0.001% to about 0.2% by weight, based on the total weight of the active layer.

[0042] In one embodiment, the active layer comprises deutetrabenazine microparticles and an active layer controlled-release agent having a viscosity of about 55-90 mPa s. In some embodiments, the active layer controlled-release agent comprises polyethylene oxide. In yet another embodiment, the active layer comprises deutetrabenazine microparticles, polyethylene oxide, and further comprises butylated hydroxyanisole, butylated hydroxytoluene, hypromellose, and magnesium stearate.

[0043] Without being bound by theory, the push layer contained within the tablet core contains an osmotic agent that swells when exposed to an aqueous environment and acts as a fluid-attracting agent, pushing out the active layer, which allows the flow of the drug formulation from within the dosage form to the external environment. Osmotic agents are generally defined as non-volatile species that are water-soluble and create an osmotic pressure gradient, thereby allowing the osmotic influx of water. Species that fall under the category of osmotic agents include inorganic salts or carbohydrates. Non-limiting examples of osmotic agents are well known in the art and include magnesium sulfate, magnesium chloride, potassium sulfate, sodium chloride, sodium sulfate, lithium sulfate, sodium phosphate, potassium phosphate, d-mannitol, sorbitol, inositol, urea, magnesium succinate, tartaric acid, raffinose, and various monosaccharides, oligosaccharides, and polysaccharides, such as sucrose, glucose, lactose, fructose, and dextran, as well as mixtures of any one of these various species.

[0044] In one embodiment, the osmotic agent is present in the push layer in an amount of about 5% to about 50% by weight, based on the total weight of the dosage form. In one embodiment, the osmotic agent is present in the push layer in an amount of about 5% to about 20% by weight, based on the total weight of the dosage form. In another embodiment, the osmotic agent is present in the push layer in an amount of about 8% to about 10% by weight, based on the total weight of the dosage form.

[0045] In one embodiment, the penetrant is present in the push layer in an amount of about 20% to about 40% by weight, based on the total weight of the push layer. In one embodiment, the penetrant is about 30% by weight, based on the total weight of the push layer.

[0046] The push layer further comprises one or more additives, such as a controlled-release agent. In one embodiment, the push layer comprises an osmotic agent and a push layer controlled-release agent. The push layer controlled-release agent comprises a polymer that provides an expandable matrix upon contact with water. In one embodiment, the push layer controlled-release agent has a viscosity of about 5500-7500 mPa s.

[0047] Examples of push layer controlled-release agents include polyoxyethylene polymers, ionic hydrogels, hydrophilic polymers, hydrophobic polymers, and any mixtures thereof. In one embodiment, the push layer controlled-release agent comprises a polyoxyethylene polymer that is polyethylene oxide. In another embodiment, the polyethylene oxide in the push layer has an average molecular weight of 1,000,000 daltons to 7,000,000 daltons. In yet another embodiment, the polyethylene oxide in the push layer has an average molecular weight of 5,000,000 daltons.

[0048] In one embodiment, the push layer controlled-release agent is present in the push layer in an amount of about 50% to about 80% by weight, based on the total weight of the push layer. In another embodiment, the push layer controlled-release agent is present in the push layer in an amount of about 60% to about 70% by weight, based on the total weight of the push layer.

[0049] In one embodiment, the weight ratio of the osmotic agent in the push layer to the push layer controlled-release agent is 1:2 to 1:3.5, or about 1:2 to 1:2.5.

[0050] The push layer optionally further contains other pharmaceutically acceptable additives, e.g., to stabilize the layer, provide color for tablet orientation, etc. Exemplary additives include binders, colorants, and lubricants, and suitable examples of these types of additives are well known to those skilled in the art.

[0051] In one embodiment, the push layer further comprises a push layer binder. The push layer binder can be selected from hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, natural and synthetic gums, and any mixtures thereof. Preferably, the push layer binder is hypromellose. In one embodiment, the push layer binder is present in the push layer in an amount of about 2% to about 10% by weight, based on the total weight of the push layer. In another embodiment, the push layer binder is present in the push layer in an amount of about 3% to about 6% by weight, based on the total weight of the push layer.

[0052] The lubricant in the push layer can include any of the exemplary materials described above for the active layer. The push layer can also include disintegrants such as cross-linked polyvinylpyrrolidone, corn starch, potato starch, smectite clay (e.g., magnesium aluminum silicate such as Veegum®), bentonite, and citrus pulp. It may also be desirable to include a stabilizer for the drug. These include, but are not limited to, sodium bisulfite and histidine HCl.

[0053] In one specific embodiment, the push layer comprises sodium chloride, polyethylene oxide, hydroxypropyl methylcellulose, a colorant, and magnesium stearate.

[0054] The present osmotic dosage form comprises a semipermeable layer surrounding the tablet core, thereby allowing fluid inflow from the external fluid environment (e.g., the subject's gastrointestinal tract) into the tablet core while preventing drug egress from the core. The semipermeable layer is preferably formed from a material that has no harmful effects on the patient and is permeable to external fluids, such as water and biological fluids. The selectively permeable material forming the semipermeable layer is insoluble in body fluids and is non-erodible or bioerodible after a predetermined period of time, with bioerosion corresponding to the end of the drug formulation release period. As used herein, the terms "semipermeable layer," "semipermeable wall," and "semipermeable membrane" are interchangeable.

[0055] Generally, semipermeable materials useful for forming the semipermeable layer have a liquid permeability, expressed as a hydrostatic or osmotic pressure difference per atmosphere, of 10 psi across the wall at the temperature of use. -5 ~10 -1 (cc mils / cm 2 Suitable materials are known in the art, see, for example, U.S. Pat. Nos. 3,845,770 and 3,916,899.

[0056] Typical materials useful for forming the semipermeable layer include cellulose acetate, cellulose triacetate, agar acetate, amylose triacetate, beta-glucan acetate, cellulose diacetate, acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate, polyamides, polyurethanes, sulfonated polystyrene, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, cellulose acetate ethyl carbamate, cellulose acetate chloroacetate, cellulose dipalmitate, cellulose dioctanoate, cellulose dicaprate, cellulose acetate methyl ester ... Examples of suitable polyanions include cellulose dipentanlate, cellulose acetate valerate, cellulose acetate succinate, cellulose succinate propionate, methylcellulose, cellulose acetate p-toluenesulfonate, cellulose acetate butyrate, and permselective polymers formed by co-precipitation of polycations and polyanions as disclosed in U.S. Pat. No. 3,173,876, U.S. Pat. No. 3,276,586, U.S. Pat. No. 3,541,005, U.S. Pat. No. 3,541,006, and U.S. Pat. No. 3,546,142.

[0057] In one embodiment, the semipermeable layer comprises a water-soluble polymer or a water-insoluble polymer selected from cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate butyrate, cellulose ethers including ethyl cellulose, agar acetate, amylose triacetate, beta-glucan acetate, poly(vinyl methyl) ether copolymers, poly(orthoesters), polyacetals, and permselective poly(glycolic acid), poly(lactic acid) derivatives, and any mixture thereof. Cellulose acetate includes cellulose acetate polymers (e.g., Eudragit®). In one embodiment, the semipermeable layer comprises a water-insoluble polymer present in an amount of about 80% to about 99.9% by weight based on the weight of the semipermeable layer. In another embodiment, the water-insoluble polymer is present in an amount of about 85% to about 95% by weight based on the weight of the semipermeable layer. Preferably, the semipermeable layer comprises a water-insoluble polymer that is cellulose acetate and has an acetyl content of about 32% to 40%.

[0058] The semipermeable layer can further comprise a pore-forming agent or "pore-forming agent." Pore-forming agents include biocompatible materials that dissolve, disperse, or decompose upon contact with bodily fluids, creating pores or channels in the semipermeable layer material. Typically, water-soluble organic and inorganic materials, such as sugars (e.g., sucrose, dextrose), water-soluble salts (e.g., sodium chloride, sodium phosphate, potassium chloride, and sodium carbonate), water-soluble solvents such as N-methyl-2-pyrrolidone and polyethylene glycol, and water-soluble polymers (e.g., carboxymethylcellulose, hydroxypropylcellulose, etc.), are conventionally used as pore-forming agents. In one embodiment, the semipermeable layer comprises a pore-forming agent in addition to a water-soluble or water-insoluble polymer, which is selected from a water-soluble sugar, a water-soluble salt, a water-soluble solvent, and a water-soluble polymer, or any mixture thereof. In a specific embodiment, the pore-forming agent is a water-soluble solvent that is polyethylene glycol. In one embodiment, the pore-forming agent comprises about 0.1% to about 20% by weight of the semipermeable layer. Preferably, the pore-forming agent comprises about 8% to about 15% by weight of the semipermeable layer. In one embodiment, the weight ratio of the semipermeable layer to the tablet core is 1:8 to 1:10.

[0059] In one specific embodiment, the semipermeable layer comprises cellulose acetate and polyethylene glycol.

[0060] The dosage form contains pores independent of or in addition to the pore-forming agent. The pores are present in the semipermeable layer and extend from the exterior of the semipermeable layer into the tablet core, providing an exit means for the drug formulation from the active layer within the tablet core to the environment external to the dosage form. Exit pores are formed by any means known in the art, including mechanical perforation, laser perforation, erosion, extraction, dissolution, rupture, or leaching of an erodible element. For example, pores can be formed by mechanical or thermal means after coating, or using a light beam (e.g., laser), a particle beam, or other high-energy source, or can be formed in situ by rupturing a small portion of the coating. Such rupture can be controlled by intentionally incorporating relatively small weaknesses into the coating. Exit pores can also be formed in situ by erosion of a plug of water-soluble material or by rupturing a thin portion of the coating across an indentation in the core. Exit pores can also be formed by coating the core so that one or more small areas remain uncoated. Additionally, the exit holes can be mass holes or pores that can be formed between coatings. The exit holes can be pores formed by leaching sorbitol, lactose, or the like from a wall or layer, as disclosed in U.S. Pat. No. 4,200,098. This patent discloses controlled-size porous pores formed by dissolving, extracting, or leaching material from the wall, such as sorbitol from cellulose acetate. A preferred form of laser drilling is the use of a pulsed laser to incrementally remove material from a semipermeable layer to a desired depth to form the exit holes. In certain embodiments, a hole or holes can be formed by leaching, for example, a member selected from the group consisting of sorbitol, lactose, fructose, glucose, mannose, galactose, talose, sodium chloride, potassium chloride, sodium citrate, and mannitol to provide exit holes of uniform release dimensions. The exit means can have any shape, such as round, triangular, square, oval, etc., for uniform, metered-dose release of a drug formulation from the dosage form. The osmotic dosage form may be constructed with one or more exit holes in spatially separated relationship or on one or more surfaces of the osmotic dosage form.Such outlets, and equipment for forming such outlets, are disclosed, for example, in US Pat. No. 3,916,899 and US Pat. No. 4,088,864.

[0061] In one embodiment, the holes have a diameter of about 0.1 mm to about 1 mm, hi another embodiment, the holes have a diameter of about 0.4 mm to about 0.8 mm.

[0062] In some embodiments, the dosage form further comprises one or more seal coatings, for example, to ensure the integrity of one or more subportions of the dosage form. In one embodiment, the tablet core comprises a seal coating immediately outside the tablet core. For example, the seal coating of the tablet core can be applied to the outside of the compressed layered tablet core before applying the semipermeable layer. In certain embodiments, the tablet core comprises a semipermeable layer immediately outside the tablet core and a seal coating immediately outside the semipermeable layer. For example, the semipermeable layer seal coating can be applied to the outside of the dosage form following application of a semipermeable membrane to the tablet core. The seal coating material can include a binder, many types of which are disclosed above. In embodiments comprising a seal coating between the core and just outside the semipermeable membrane, holes extend from the outside of the seal coating through all layers to the core.

[0063] In one embodiment, a tablet core seal coat is applied to the outer surface of the tablet core.

[0064] In one embodiment, the semipermeable layer seal coat is applied to the outer surface of the semipermeable layer.

[0065] In one embodiment, the tablet core seal coat and / or semipermeable layer seal coat comprises a binder which may be selected from hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, natural and synthetic gums, and any mixtures thereof, hi another embodiment, the tablet core seal coat binder and / or semipermeable layer seal coat binder is hypromellose.

[0066] In one embodiment, the total amount of binder in the dosage form is about 0% to about 20% by mass, based on the total weight of the dosage form. In another embodiment, the total amount of binder in the dosage form is about 5% to about 20% by mass, based on the total weight of the dosage form. In yet another embodiment, the total amount of binder in the dosage form is about 8% to about 10% by mass, based on the total weight of the dosage form, or about 10% to about 20% by mass, based on the total weight of the dosage form.

[0067] The absolute amount of deutetrabenazine in the active layer of the osmotic dosage form will depend on the dosage strength of the particular embodiment. As described more fully below, the dosage form may further comprise an immediate release amount of deutetrabenazine microparticles located outside the active layer, preferably outside the semipermeable membrane layer.

[0068] In one embodiment, the dosage form disclosed herein further comprises an immediate-release coating comprising a second quantity of deutetrabenazine microparticles on the outside of the semipermeable membrane or on the outside of the semipermeable seal coating applied thereto.

[0069] In one embodiment, the immediate-release coating comprises from about 0.1% to about 25% by weight of deutetrabenazine microparticles, based on the total weight of the dosage form. In another embodiment, the immediate-release coating comprises from about 0.2% to about 5% by weight of deutetrabenazine microparticles, based on the total weight of the dosage form. In another embodiment, the immediate-release coating comprises from about 0.3% to about 2% by weight of deutetrabenazine microparticles, based on the total weight of the dosage form. In another embodiment, the dosage form comprises a total of 24 mg of deutetrabenazine microparticles, and the immediate-release coating comprises from about 1% to about 2% by weight of deutetrabenazine microparticles, based on the total weight of the dosage form. In another embodiment, the dosage form comprises a total of 12 mg of deutetrabenazine microparticles, and the immediate-release coating comprises from about 0.5% to about 1% by weight of deutetrabenazine microparticles, based on the total weight of the dosage form. In yet another embodiment, the dosage form comprises a total of 6 mg of deutetrabenazine microparticles and the immediate release coating comprises from about 0.1% to about 0.5% deutetrabenazine microparticles by weight, based on the total weight of the dosage form.

[0070] In one embodiment, at least 70% of the total amount of deutetrabenazine microparticles in the dosage form is present in the active layer. In another embodiment, approximately 70% to 100% of the total amount of deutetrabenazine microparticles in the dosage form is present in the active layer. In yet another embodiment, about 70% to 80% of the total amount of deutetrabenazine microparticles in the dosage form is present in the active layer. In some embodiments of osmotic dosage forms, deutetrabenazine is present only in the active layer.

[0071] In embodiments where the osmotic dosage form comprises an immediate-release coating, the immediate-release coating comprises up to about 30% of the total amount of deutetrabenazine microparticles in the dosage form. In one embodiment, about 8% to 30% of the total amount of deutetrabenazine microparticles in the dosage form are present in the immediate-release coating. In one embodiment, about 70% to about 80% of the total amount of deutetrabenazine microparticles in the dosage form are present in the active layer, and about 20% to about 30% of the total amount of deutetrabenazine microparticles in the dosage form are present in the immediate-release coating.

[0072] The dosage form of any embodiment of the present invention comprises deutetrabenazine microparticles in a total amount of about 6 mg to about 48 mg. In one embodiment, the total amount of deutetrabenazine microparticles in the dosage form is about 6 mg. In one embodiment, the total amount of deutetrabenazine microparticles in the dosage form is about 12 mg. In another embodiment, the total amount of deutetrabenazine microparticles in the dosage form is about 24 mg. In yet another embodiment, the total amount of deutetrabenazine microparticles in the dosage form is about 36 mg. In yet another embodiment, the total amount of deutetrabenazine microparticles in the dosage form is about 48 mg.

[0073] In one embodiment, the total amount of deutetrabenazine microparticles present in the dosage form is about 0.5% to about 15% by weight, based on the total weight of the dosage form. In another embodiment, the total amount of deutetrabenazine microparticles present in the dosage form is about 1% to about 10% by weight, based on the total weight of the dosage form. In another embodiment, the dosage form contains a total of 6 mg of deutetrabenazine microparticles, and the total amount of deutetrabenazine microparticles present in the dosage form is about 0.5% to about 3% by weight, based on the total weight of the dosage form. In another embodiment, the dosage form contains a total of 12 mg of deutetrabenazine microparticles, and the total amount of deutetrabenazine microparticles present in the dosage form is about 1% to about 5% by weight, based on the total weight of the dosage form. In another embodiment, the dosage form contains a total of 24 mg of deutetrabenazine microparticles, and the total amount of deutetrabenazine microparticles present in the dosage form is about 5% to about 10% by weight, based on the total weight of the dosage form.

[0074] In addition to the predetermined amount of deutetrabenazine microparticles, the immediate-release coating may further comprise one or more pharmaceutically acceptable additives, such as antioxidants, binders, and surfactants, or any combination thereof. The antioxidants, binders, and surfactants can be selected from a wide range of options known to those skilled in the art. Exemplary antioxidants and binders are disclosed above with respect to the other components of the dosage form. Surfactants may include, but are not limited to, esters of polyhydric alcohols, such as glycerol monolaurate, ethoxylated castor oil, polysorbates, esters or ethers of saturated alcohols, such as myristyl lactate (e.g., Cerafil® 50), and polyoxyethylene / polyoxypropylene block copolymers, such as Pluronic®.

[0075] In one embodiment, the immediate-release coating further comprises an antioxidant which may be selected from tert-butyl-4-methoxyphenol (a mixture of the 2- and 3-isomers), 2,6-di-tert-butyl-p-cresol, propyl gallate, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquin), nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole, butylated hydroxytoluene, and any mixtures thereof. In another embodiment, the immediate-release coating comprises a mixture of butylated hydroxyanisole and butylated hydroxytoluene. In another embodiment, the immediate-release coating comprises deutetrabenazine microparticles, butylated hydroxyanisole, butylated hydroxytoluene, hypromellose, and polysorbate 80.

[0076] In one embodiment, there is provided: a. i. an active layer comprising a predetermined amount of deutetrabenazine microparticles, and an active layer controlled-release agent comprising a polymer having a viscosity of about 55 to 90 mPa s, an active layer antioxidant, and an active layer binder; ii. A push layer comprising an osmotic agent, a polymer having a viscosity of about 5500-7500 mPa s, a push layer controlled-release agent, and a push layer binder. a tablet core; b. a tablet core seal coat containing a binder on the outer surface of the tablet core; c. A semipermeable layer comprising a water-insoluble polymer and a pore-forming agent surrounding the tablet core seal coat; d. a semipermeable layer seal coat containing a binder on the outer surface of the semipermeable layer; e. an immediate-release coating comprising a second amount of deutetrabenazine microparticles on the outer surface of the semipermeable seal coat and an immediate-release coating antioxidant; and f. Holes in the semipermeable seal coat that reach the tablet core and a once-daily osmotic dosage form for administration to a subject in need thereof, comprising:

[0077] In some embodiments, provided is an osmotic dosage form according to any one of the embodiments of the present invention, wherein no more than 15% of the drug formulation is released within 2 hours and / or no more than 60% of the drug formulation is released within 8 hours when the dosage form is tested in 500 mL of acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus.

[0078] Further provided herein is a method of treating hyperkinetic movement disorder in a subject, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the invention. Also provided is an osmotic dosage form according to any one of the embodiments disclosed herein for once-daily oral use to treat hyperkinetic movement disorder in a subject.

[0079] In some embodiments, the movement disorder is selected from chorea, akathisia, dyskinesia, tremor, or tics, hi some embodiments, the movement disorder is selected from chorea associated with Huntington's disease, tardive dyskinesia, tics associated with Tourette's syndrome, Parkinson's disease levodopa-induced dyskinesia, or dyskinesia in cerebral palsy.

[0080] In certain embodiments, the osmotic dosage form according to any one of the embodiments disclosed herein is administered with food.

[0081] In certain embodiments, the osmotic dosage form according to any one of the embodiments disclosed herein is administered under fasting conditions.

[0082] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein a single dose administration of the osmotic dosage form comprising a total of 6 mg of deutetrabenazine microparticles results in a geometric mean AUC of about 91,250 to 142,750 h*pg / mL. 0-infand providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine comprising:

[0083] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein a single dose administration of the osmotic dosage form comprising a total amount of 6 mg of deutetrabenazine microparticles produces a geometric mean C of less than about 4,600 pg / mL. max and providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine comprising:

[0084] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein a single dose administration of the osmotic dosage form comprising a total amount of 12 mg of deutetrabenazine microparticles results in a geometric mean AUC of about 182,500 to 285,500 h*pg / mL. 0-inf and providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine comprising:

[0085] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein a single dose administration of the osmotic dosage form comprising a total amount of 12 mg of deutetrabenazine microparticles produces a geometric mean C of less than about 9,200 pg / mL. max and providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine comprising:

[0086] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein a single dose administration of the osmotic dosage form comprising a total amount of 24 mg of deutetrabenazine microparticles results in a geometric mean AUC of about 365,000 to 571,000 h*pg / mL. 0-inf and providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine comprising:

[0087] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein a single dose administration of the osmotic dosage form comprising a total amount of 24 mg of deutetrabenazine microparticles produces a geometric mean C of less than about 18,400 pg / mL. max and providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine comprising:

[0088] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein a single dose administration of the osmotic dosage form comprising a total amount of 36 mg of deutetrabenazine microparticles results in a geometric mean AUC of about 547,500 to 856,500 h*pg / mL. 0-inf and providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine comprising:

[0089] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein a single dose administration of the osmotic dosage form comprising a total amount of 36 mg of deutetrabenazine microparticles produces a geometric mean C of less than about 27,600 pg / mL. maxand providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine comprising:

[0090] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein a single dose administration of the osmotic dosage form comprising a total amount of 48 mg of deutetrabenazine microparticles results in a geometric mean AUC of about 730,000 to 1,142,000 h*pg / mL. 0-inf and providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine comprising:

[0091] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein a single dose administration of the osmotic dosage form comprising a total amount of 48 mg of deutetrabenazine microparticles produces a geometric mean C of less than about 36,800 pg / mL. max and providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine comprising:

[0092] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein an osmotic dosage form comprising a total amount of 6 mg of deutetrabenazine microparticles has a mean AUC of about 102,500 to 200,000 h*pg / mL. 0-24 and providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine at steady state comprising:

[0093] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein the osmotic dosage form comprising a total amount of 6 mg of deutetrabenazine microparticles has a mean C of less than about 10,000 pg / mL. max and providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine at steady state comprising:

[0094] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein the osmotic dosage form comprising a total amount of 12 mg of deutetrabenazine microparticles has a mean AUC of about 205,000 to 400,000 h*pg / mL. 0-24 and providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine at steady state comprising:

[0095] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein the osmotic dosage form comprising a total amount of 12 mg of deutetrabenazine microparticles has a mean C of less than about 20,000 pg / mL. max and providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine at steady state comprising:

[0096] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein the osmotic dosage form comprising a total amount of 24 mg of deutetrabenazine microparticles has a mean AUC of about 410,000 to 800,000 h*pg / mL. 0-24and providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine at steady state comprising:

[0097] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein the osmotic dosage form comprising a total amount of 24 mg of deutetrabenazine microparticles has a mean C of less than about 40,000 pg / mL. max and providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine at steady state comprising:

[0098] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein the osmotic dosage form comprising a total amount of 36 mg of deutetrabenazine microparticles has a mean AUC of about 615,000 to 1,200,000 h*pg / mL. 0-24 and providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine at steady state comprising:

[0099] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein the osmotic dosage form comprising a total amount of 36 mg of deutetrabenazine microparticles has a mean C of less than about 60,000 pg / mL. max and providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine at steady state comprising:

[0100] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein the osmotic dosage form comprising a total amount of 48 mg of deutetrabenazine microparticles has a mean AUC of about 820,000 to 1,600,000 h*pg / mL. 0-24 and providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine at steady state comprising:

[0101] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein the osmotic dosage form comprising a total amount of 48 mg of deutetrabenazine microparticles has a mean C of less than about 80,000 pg / mL. max and providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine at steady state comprising:

[0102] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder, comprising administering an osmotic dosage form according to any one of the embodiments of the present invention, wherein no more than 15% of the drug formulation is released after 2 hours when tested in 500 mL of acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus.

[0103] In one embodiment, the present invention provides a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the present invention, wherein no more than 60% of the drug formulation is released within 8 hours when tested in 500 mL of acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus.

[0104] In some embodiments, the present invention provides a method of treating hyperkinetic movement disorder, comprising administering an osmotic dosage form according to any one of the embodiments of the present invention, wherein no more than 15% of the drug formulation is released after 2 hours and no more than 60% of the drug formulation is released within 8 hours when tested in 500 mL of acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus.

[0105] The present disclosure provides oral dosage forms and methods according to any of the following aspects:

[0106] Aspects 1. a. A tablet core comprising an active layer containing a predetermined amount of deutetrabenazine microparticles and a push layer; b. a semipermeable layer surrounding the tablet core; and c. Holes extending from the periphery of the dosage form into the tablet core 1. An osmotic dosage form for once-daily administration to a subject in need thereof, comprising: 2. The dosage form of aspect 1, wherein the active layer further comprises an active layer controlled-release agent. 3. The dosage form of aspect 2, wherein the active layer controlled-release agent comprises a polymer having a viscosity of about 50-150 mPa s or about 55-90 mPa s. 4. The dosage form of aspect 2 or aspect 3, wherein the active layer controlled-release agent comprises at least one of a polyoxyethylene polymer, an ionic hydrogel, a hydrophilic polymer, a hydrophobic polymer, or any mixture thereof. 5. The dosage form of aspect 4, wherein the active layer controlled-release agent comprises a polyoxyethylene polymer that is polyethylene oxide. 6. The dosage form of aspect 5, wherein the polyethylene oxide in the active layer has an average molecular weight of 100,000 daltons to 500,000 daltons. 7. The dosage form of aspect 6, wherein the polyethylene oxide in the active layer has an average molecular weight of 200,000 daltons. 8. The dosage form of any one of aspects 2 to 7, wherein the active layer controlled-release agent is present in the active layer in an amount of about 60% to about 98% by weight, based on the total weight of the active layer. 9. The dosage form of embodiment 8, wherein the active layer controlled-release agent is present in the active layer in an amount of about 70% to about 95% by weight, based on the total weight of the active layer, or about 80% to about 90% by weight, or about 85% to about 95% by weight, based on the total weight of the active layer. 10. The dosage form of any one of aspects 2 to 9, wherein the mass ratio of the amount of deutetrabenazine microparticles in the active layer to the active layer controlled-release agent is from 2:3 to 1:50, or from 2:5 to 1:5, or from 1:4 to 1:9, or from 1:5 to 1:19, or from 1:5 to 1:7, or from 1:12 to 1:15, or from 1:20 to 1:30. 11. The dosage form of any one of the preceding aspects, wherein the active layer further comprises at least one active layer antioxidant. 12. The dosage form of aspect 11, wherein the active layer antioxidant comprises at least one of tert-butyl-4-methoxyphenol (a mixture of 2- and 3-isomers), 2,6-di-tert-butyl-p-cresol, propyl gallate, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquin), nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole, butylated hydroxytoluene, or any mixture thereof. 13. The dosage form of aspect 12, wherein the active layer antioxidant comprises a mixture of butylated hydroxyanisole and butylated hydroxytoluene. 14. The dosage form of any one of aspects 11 to 13, wherein the active layer antioxidant is present in the active layer in an amount of about 0.001% to about 1% by weight, based on the total weight of the active layer. 15. The dosage form of any one of the preceding aspects, wherein the active layer further comprises at least one active layer binder. 16. The dosage form of aspect 15, wherein the active layer binder comprises at least one of hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, a natural or synthetic gum, or any mixture thereof. 17. The dosage form of aspect 16, wherein the active layer binder comprises hypromellose. 18. The dosage form of any one of aspects 15 to 17, wherein the active layer binder is present in the active layer in an amount of about 2% to about 20% by weight, based on the total weight of the active layer. 19. The dosage form of any one of the preceding aspects, wherein the active layer further comprises one or more pharmaceutically acceptable excipients. 20. The dosage form of any one of the preceding aspects, wherein the active layer comprises deutetrabenazine microparticles, and an active layer controlled-release agent that is a polymer having a viscosity of about 55-90 mPa s, and an antioxidant. 21. The dosage form of aspect 20, wherein the active layer comprises deutetrabenazine microparticles, butylated hydroxyanisole, butylated hydroxytoluene, polyethylene oxide, hypromellose, and magnesium stearate. 22. The dosage form of any one of the preceding aspects, wherein the push layer comprises an osmotic agent and a push layer controlled-release agent. 23. The dosage form of aspect 22, wherein the osmotic agent comprises an inorganic salt, a carbohydrate, or any mixture thereof. 24. The dosage form of aspect 23, wherein the osmotic agent comprises a carbohydrate that is d-mannitol, sorbitol, inositol, a monosaccharide, an oligosaccharide, a polysaccharide, or any mixture thereof. 25. The dosage form of aspect 23, wherein the osmotic agent comprises an inorganic salt that is magnesium sulfate, magnesium chloride, potassium sulfate, sodium chloride, sodium sulfate, lithium sulfate, sodium phosphate, potassium phosphate, or any mixture thereof. 26. The dosage form of aspect 25, wherein the osmotic agent is / comprises sodium chloride. 27. The dosage form of any one of aspects 22 to 26, wherein the osmotic agent is present in the dosage form in an amount of about 5% to about 50% by weight, based on the total weight of the dosage form. 28. The dosage form of aspect 27, wherein the osmotic agent is present in the dosage form in an amount of about 5% to about 20% by weight, based on the total weight of the dosage form. 29. The dosage form of aspect 27 or aspect 28, wherein the osmotic agent is present in the dosage form in an amount of about 8% to about 10% by weight, based on the total weight of the dosage form. 30. The dosage form of any one of aspects 27 to 29, wherein the osmotic agent is present in the push layer in an amount of about 20% to about 40% by weight, based on the total weight of the push layer. 31. The dosage form of aspect 30, wherein the osmotic agent is present in the push layer in an amount of about 30% by weight, based on the total weight of the push layer. 32. The dosage form of any one of aspects 22 to 31, wherein the push layer controlled-release agent comprises a polymer having a viscosity of about 5500 to 7500 mPa s. 33. The dosage form of aspect 32, wherein the polymer having a viscosity of about 5500 to 7500 mPa s is selected from a polyoxyethylene polymer, an ionic hydrogel, a hydrophilic polymer, a hydrophobic polymer, or any mixture thereof. 34. The dosage form of aspect 33, wherein the push layer controlled-release agent is polyethylene oxide. 35. The dosage form of aspect 34, wherein the polyethylene oxide in the push layer has an average molecular weight of 1,000,000 daltons to 7,000,000 daltons. 36. The dosage form of aspect 35, wherein the polyethylene oxide in the push layer has an average molecular weight of 5,000,000 daltons. 37. The dosage form of any one of aspects 32 to 36, wherein the push layer controlled-release agent is present in the push layer in an amount of about 50% to about 80% by weight, based on the total weight of the push layer. 38. The dosage form of embodiment 37, wherein the push layer controlled-release agent is present in the push layer in an amount of about 60% to about 70% by weight, based on the total weight of the push layer. 39. The dosage form of any one of aspects 22 to 38, wherein the weight ratio of osmotic agent in the push layer to push layer controlled-release agent is 1:2 to 1:3.5 or 1:2 to 1:2.5. 40. The dosage form of any one of aspects 22 to 39, wherein the push layer further comprises a push layer binder. 41. The dosage form of aspect 40, wherein the push layer binder comprises hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, a natural or synthetic gum, or any mixture thereof. 42. The dosage form of aspect 41, wherein the push layer binder comprises hypromellose. 43. The dosage form of any one of aspects 40 to 42, wherein the push layer binder is present in the push layer in an amount of about 2% to about 10% by weight, based on the total weight of the push layer. 44. The dosage form of embodiment 43, wherein the push layer binder is present in the push layer in an amount of about 4% to about 6% by weight, based on the total weight of the push layer, or about 3% to about 6% by weight, based on the total weight of the push layer. 45. The dosage form of any one of aspects 22 to 44, wherein the push layer further comprises a pharmaceutically acceptable excipient. 46. ​​The dosage form of any one of aspects 22 to 45, wherein the push layer comprises sodium chloride and a polymer having a viscosity of about 5500 to 7500 mPa s. 47. The dosage form of aspect 46, wherein the push layer comprises sodium chloride, polyethylene oxide, hydroxypropyl methylcellulose, a colorant, and magnesium stearate. 48. The dosage form of any one of the preceding aspects, wherein the semipermeable layer comprises a water-soluble polymer, a water-insoluble polymer, or any mixture thereof. 49. The dosage form of aspect 48, wherein the semipermeable layer comprises a water-insoluble polymer selected from cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate butyrate, cellulose ethers such as ethyl cellulose, agar acetate, amylose triacetate, beta-glucan acetate, poly(vinyl methyl) ether copolymers, poly(orthoesters), polyacetals and permselective poly(glycolic acid), poly(lactic acid) derivatives, Eudragit cellulose acetate, or any mixture thereof. 50. The dosage form of aspect 49, wherein the water-insoluble polymer is cellulose acetate and comprises an acetyl content of 32% to 39.8%. 51. The dosage form of any one of aspects 1 to 50, wherein the semipermeable layer comprises cellulose acetate and polyethylene glycol. 52. The dosage form of any one of aspects 48 to 51, wherein the water-insoluble polymer is present in the semipermeable layer in an amount of about 80% to about 99.9% by weight, based on the weight of the semipermeable layer, or about 85% to about 95% by weight, based on the weight of the semipermeable layer. 53. The dosage form of any one of aspects 1 to 52, wherein the semipermeable layer comprises a pore-forming agent. 54. The dosage form of aspect 53, wherein the pore-forming agent comprises a water-soluble sugar, a water-soluble salt, a water-soluble solvent, a water-soluble polymer, or any mixture thereof. 55. The dosage form of aspect 54, wherein the pore-forming agent is a water-soluble solvent that is polyethylene glycol. 56. The dosage form of any one of aspects 53 to 55, wherein the pore-forming agent is present in the semipermeable layer in an amount of about 0.1% to about 20% by weight of the semipermeable layer. 57. The dosage form of embodiment 56, wherein the pore-forming agent is present in the semipermeable layer in an amount of about 8% to about 15% by weight of the semipermeable layer. 58. The dosage form of any one of aspects 1 to 57, wherein the mass ratio of the semipermeable layer to the tablet core is 1:8 to 1:10. 59. The dosage form of any one of the preceding aspects, wherein the holes have a diameter of about 0.1 mm to about 1 mm. 60. The dosage form of aspect 59, wherein the holes have a diameter of about 0.4 mm to about 0.8 mm. 61. The dosage form of any one of the preceding aspects, further comprising a tablet core seal coat on the outer surface of the tablet core. 62. The dosage form of any one of the preceding aspects, further comprising a semipermeable layer seal coat on an outer surface of the semipermeable layer. 63. The dosage form of aspect 61 or 62, wherein the tablet core seal coat and / or the semipermeable layer seal coat comprises a binder. 64. The dosage form of aspect 63, wherein the tablet core seal coat binder and / or the semipermeable layer seal coat binder comprises hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, natural gum, synthetic gum, and any mixture thereof. 65. The dosage form of aspect 64, wherein the tablet core seal coat binder and / or the semipermeable layer seal coat binder is hypromellose. 66. The dosage form of any one of aspects 63 to 65, wherein the total amount of binder in the dosage form is from about 0 to about 20% by weight of the total dosage form, from 5% to about 15% by weight of the total dosage form, or from 5% to about 20% by weight of the total dosage form. 67. The dosage form of aspect 66, wherein the total amount of binder in the dosage form is from about 8% to about 10% by weight, based on the total weight of the dosage form, or from 10% to about 20% by weight, based on the total weight of the dosage form, or from about 10% to about 20% by weight, based on the total weight of the dosage form. 68. The dosage form of any one of the preceding aspects, further comprising an immediate-release coating exterior to the semipermeable membrane, the immediate-release coating comprising a second quantity of deutetrabenazine microparticles. 69. The dosage form of embodiment 68, wherein the immediate-release coating comprises from about 0.1% to about 25% by weight of deutetrabenazine microparticles relative to the total weight of the dosage form, or from about 0.2% to about 5% by weight of deutetrabenazine microparticles relative to the total weight of the dosage form, or from about 0.3% to about 2% by weight of deutetrabenazine microparticles relative to the total weight of the dosage form. 70. The dosage form of embodiment 69, comprising a total of 24 mg of deutetrabenazine microparticles, wherein the immediate-release coating comprises from about 1% to about 2% by weight of deutetrabenazine microparticles relative to the total weight of the dosage form, or a total of 12 mg of deutetrabenazine microparticles, wherein the immediate-release coating comprises from about 0.5% to about 1% by weight of deutetrabenazine microparticles relative to the total weight of the dosage form, or a total of 6 mg of deutetrabenazine microparticles, wherein the immediate-release coating comprises from about 0.1% to about 0.5% by weight of deutetrabenazine microparticles relative to the total weight of the dosage form. 71. The dosage form of any one of aspects 1 to 70, wherein about 70% to 99% of the total amount of deutetrabenazine microparticles in the dosage form are in the active layer. 72. The dosage form of any one of aspects 1 to 71, wherein about 5% to 30% of the total amount of deutetrabenazine microparticles in the dosage form are within the immediate-release coating. 73. The dosage form of any one of aspects 1 to 72, wherein about 70%-80% of the total amount of deutetrabenazine microparticles in the dosage form are in the active layer, and about 20%-30% of the total amount of deutetrabenazine microparticles in the dosage form are in the immediate-release coating. 74. The dosage form of any one of aspects 68 to 73, wherein the immediate release coating further comprises an immediate release coating antioxidant. 75. The dosage form of aspect 74, wherein the immediate-release coating antioxidant comprises tert-butyl-4-methoxyphenol (a mixture of 2- and 3-isomers), 2,6-di-tert-butyl-p-cresol, propyl gallate, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquin), nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole, butylated hydroxytoluene, and any mixture thereof. 76. The dosage form of aspect 75, wherein the immediate-release coating comprises a mixture of butylated hydroxyanisole and butylated hydroxytoluene. 77. The dosage form of any one of aspects 68 to 76, wherein the immediate release coating further comprises an additional pharmaceutically acceptable excipient. 78. The dosage form of any one of aspects 68 to 77, wherein the immediate-release coating comprises deutetrabenazine microparticles, butylated hydroxyanisole, butylated hydroxytoluene, hypromellose, and polysorbate 80. 79. The dosage form of any one of aspects 1 to 78, wherein the total amount of deutetrabenazine microparticles in the dosage form is from about 6 mg to about 48 mg. 80. The dosage form of any one of the preceding aspects, wherein the total amount of deutetrabenazine microparticles in the dosage form is about 6 mg. 81. The dosage form of any one of the preceding aspects, wherein the total amount of deutetrabenazine microparticles in the dosage form is about 12 mg. 82. The dosage form of any one of the preceding aspects, wherein the total amount of deutetrabenazine microparticles in the dosage form is about 24 mg. 83. The dosage form of any one of the preceding aspects, wherein the total amount of deutetrabenazine microparticles in the dosage form is about 48 mg. 84. The dosage form of any one of aspects 1 to 83, wherein the total amount of deutetrabenazine microparticles is about 0.5% to about 15% by weight, based on the total weight of the dosage form. 85. The dosage form of aspect 84, wherein the total amount of deutetrabenazine microparticles is about 1% to about 10% by weight, based on the total weight of the dosage form. 86. A dosage form according to aspect 85, comprising a total of 6 mg of deutetrabenazine microparticles, wherein the total amount of deutetrabenazine microparticles is from about 0.5% to about 3% by weight, relative to the total weight of the dosage form, or a total of 12 mg of deutetrabenazine microparticles, wherein the total amount of deutetrabenazine microparticles is from about 1% to about 5% by weight, relative to the total weight of the dosage form, or a total of 24 mg of deutetrabenazine microparticles, wherein the total amount of deutetrabenazine microparticles is from about 5% to about 10% by weight, relative to the total weight of the dosage form. 87. The dosage form of any one of aspects 1 to 86, wherein the deutetrabenazine microparticles have a diameter of from about 1 μm to about 30 μm in diameter. 88. Deutetrabenazine microparticles are 15 μm D 90 88. The dosage form of embodiment 87, having a particle size that results in: 89. Deutetrabenazine microparticles are 10 μm D 50 89. The dosage form of embodiment 87 or embodiment 88, having a particle size that results in 90. Deutetrabenazine microparticles are 3 μm D 10 90. The dosage form of any one of aspects 87 to 89, having a particle size that results in: 91. A method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form of any one of aspects 1 to 90. 92. The method of embodiment 91, wherein the movement disorder is selected from chorea, akathisia, dyskinesia, tremor, and tics. 93. The method of aspect 92, wherein the movement disorder is selected from chorea associated with Huntington's disease, tardive dyskinesia, tics associated with Tourette's syndrome, Parkinson's disease levodopa-induced dyskinesia, and dyskinesia in cerebral palsy. 94. A method comprising orally administering to a subject once daily an osmotic dosage form of any one of aspects 1 to 90, wherein a single dose of the osmotic dosage form comprising a total of 6 mg of deutetrabenazine microparticles achieves a geometric mean AUC of about 91,250 to 142,750 h*pg / mL. 0-inf94. The method of any one of aspects 91 to 93, wherein the method provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine comprising: 95. A method comprising orally administering to a subject once daily an osmotic dosage form of any one of aspects 1 to 90, wherein a single dose of the osmotic dosage form comprising a total of 6 mg of deutetrabenazine microparticles has a geometric mean C of less than about 4,600 pg / mL. max 95. The method of any one of aspects 91 to 94, wherein the method provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine comprising: 96. A method of orally administering to a subject once daily an osmotic dosage form of any one of aspects 1 to 90, wherein a single dose of the osmotic dosage form comprising a total of 12 mg of deutetrabenazine microparticles produces a geometric mean AUC of about 182,500 to 285,500 h*pg / mL. 0-inf 94. The method of any one of aspects 91 to 93, wherein the method provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine comprising: 97. A method comprising orally administering to a subject once daily an osmotic dosage form of any one of aspects 1 to 90, wherein a single dose of the osmotic dosage form comprising a total of 12 mg of deutetrabenazine microparticles has a geometric mean C of less than about 9,200 pg / mL. max 97. The method of any one of aspects 91 to 93 or 96, wherein the method provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine comprising: 98. A method of orally administering to a subject once daily an osmotic dosage form of any one of aspects 1 to 90, wherein a single dose of the osmotic dosage form containing a total of 24 mg of deutetrabenazine microparticles achieves a geometric mean AUC of about 365,000 to 571,000 h*pg / mL. 0-inf 94. The method of any one of aspects 91 to 93, wherein the method provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine comprising: 99. A method comprising orally administering to a subject once daily an osmotic dosage form of any one of aspects 1 to 90, wherein a single dose of the osmotic dosage form comprising a total of 24 mg of deutetrabenazine microparticles has a geometric mean C of less than about 18,400 pg / mL. max 99. A method according to any one of aspects 91 to 93 or aspect 98, wherein the method provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine comprising: 100. A method of orally administering to a subject once daily an osmotic dosage form of any one of aspects 1 to 90, wherein a single dose of the osmotic dosage form containing a total of 36 mg of deutetrabenazine microparticles achieves a geometric mean AUC of about 547,500 to 856,500 h*pg / mL. 0-inf 94. The method of any one of aspects 91 to 93, wherein the method provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine comprising: 101. A method comprising orally administering to a subject once daily an osmotic dosage form of any one of aspects 1 to 90, wherein a single dose of the osmotic dosage form comprising a total of 36 mg of deutetrabenazine microparticles has a geometric mean C of less than about 27,600 pg / mL. max 101. A method according to any one of aspects 91 to 93 or aspect 100, wherein the method provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine comprising: 102. A method of orally administering to a subject once daily an osmotic dosage form of any one of aspects 1 to 90, wherein a single dose of the osmotic dosage form containing a total of 48 mg of deutetrabenazine microparticles produces a geometric mean AUC of about 730,000 to 1,142,000 h*pg / mL. 0-inf 94. The method of any one of aspects 91 to 93, wherein the method provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine comprising: 103. A method comprising orally administering to a subject once daily an osmotic dosage form of any one of aspects 1 to 90, wherein a single dose of the osmotic dosage form comprising a total of 48 mg of deutetrabenazine microparticles has a geometric mean C of less than about 36,800 pg / mL. max103. A method according to any one of aspects 91 to 93 or aspect 102, wherein the method provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine comprising: 104. A method of administering to a subject once daily an osmotic dosage form of any one of aspects 1 to 90, wherein the osmotic dosage form containing a total of 6 mg of deutetrabenazine microparticles has a mean AUC of about 102,500 to 200,000 h*pg / mL. 0-24 94. The method of any one of aspects 91 to 93, wherein the method provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising: 105. A method comprising orally administering to a subject once daily an osmotic dosage form of any one of aspects 1 to 90, wherein the osmotic dosage form comprising a total of 6 mg of deutetrabenazine microparticles has a mean C of less than about 10,000 pg / mL. max 105. A method according to any one of aspects 91 to 93 or aspect 104, wherein the method provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising: 106. A method of administering to a subject once daily an osmotic dosage form of any one of aspects 1 to 90, wherein the osmotic dosage form containing a total of 12 mg of deutetrabenazine microparticles has a mean AUC of about 205,000 to 400,000 h*pg / mL. 0-24 94. The method of any one of aspects 91 to 93, wherein the method provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising: 107. A method of administering to a subject once daily an osmotic dosage form of any one of aspects 1 to 90, wherein the osmotic dosage form comprising a total of 12 mg of deutetrabenazine microparticles has a mean C of less than about 20,000 pg / mL. max 107. A method according to any one of aspects 91 to 93 or aspect 106, wherein the method provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising: 108. A method of administering to a subject once daily an osmotic dosage form of any one of aspects 1 to 90, wherein the osmotic dosage form containing a total of 24 mg of deutetrabenazine microparticles has a mean AUC of about 410,000 to 800,000 h*pg / mL. 0-24 94. The method of any one of aspects 91 to 93, wherein the method provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising: 109. A method comprising orally administering to a subject once daily an osmotic dosage form of any one of aspects 1 to 90, wherein the osmotic dosage form comprising a total of 24 mg of deutetrabenazine microparticles has a mean C of less than about 40,000 pg / mL. max 109. A method according to any one of aspects 91 to 93 or aspect 108, wherein the method provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising: 110. A method of administering to a subject once daily an osmotic dosage form of any one of aspects 1 to 90, wherein the osmotic dosage form containing a total of 36 mg of deutetrabenazine microparticles has a mean AUC of about 615,000 to 1,200,000 h*pg / mL. 0-24 94. The method of any one of aspects 91 to 93, wherein the method provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising: 111. A method comprising orally administering to a subject once daily an osmotic dosage form of any one of aspects 1 to 90, wherein the osmotic dosage form comprising a total of 36 mg of deutetrabenazine microparticles has a mean C of less than about 60,000 pg / mL. max 111. A method according to any one of aspects 91 to 93 or aspect 110, wherein the method provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising: 112. A method of administering to a subject once daily an osmotic dosage form of any one of aspects 1 to 90, wherein the osmotic dosage form containing a total of 48 mg of deutetrabenazine microparticles has a mean AUC of about 820,000 to 1,600,000 h*pg / mL. 0-2494. The method of any one of aspects 91 to 93, wherein the method provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising: 113. A method of administering to a subject once daily an osmotic dosage form of any one of aspects 1 to 90, wherein the osmotic dosage form comprising a total of 48 mg of deutetrabenazine microparticles has a mean C of less than about 80,000 pg / mL. max 113. A method according to any one of aspects 91 to 93 or aspect 112, wherein the method provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising: 114. A method according to any one of aspects 91 to 113, comprising administering the osmotic dosage form of any one of aspects 1 to 90, wherein no more than 15% of the drug formulation is released after 2 hours when tested in 500 mL of acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus. 115. A method according to any one of aspects 91 to 113, comprising administering the osmotic dosage form of any one of aspects 1 to 90, wherein no more than 60% of the drug formulation is released after 8 hours when tested in 500 mL of acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus. 116. The dosage form or method of any one of the preceding aspects, wherein the dosage form is administered with food. 117. The dosage form or method of any one of the preceding aspects, wherein the dosage form is administered under fasting conditions.

[0107] All patents, patent applications, and publications are incorporated herein by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. The invention illustratively described herein can be practiced in the absence of any element not specifically disclosed herein. The terms and expressions employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions to exclude any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, while the present invention has been specifically disclosed by preferred embodiments and optional features, it should be understood that any modifications and variations of the concepts disclosed herein may be employed by those skilled in the art, and that such modifications and variations are deemed to be within the scope of the invention as defined by the appended claims.

[0108] With respect to the above-described embodiments, it is contemplated that each embodiment disclosed herein is applicable to each of the other disclosed embodiments, e.g., elements described in a method embodiment can be used in the pharmaceutical composition, packaging, and use / method embodiments described herein, and vice versa. [Example]

[0109] The following examples are provided to supplement the previous disclosure and to provide a better understanding of the subject matter described herein. These examples should not be considered to limit the subject matter described herein. It is understood that the examples and embodiments described herein are for illustrative purposes only, and various modifications or changes in this respect are apparent to those skilled in the art and should be included within the true scope of the present disclosure and can be made without departing from the true scope of the present disclosure.

[0110] Example 1 Manufacturing process for deutetrabenazine 24 mg osmotic tablets 2a and 2b provide a flow chart of the overall manufacturing process for osmotic dosage forms according to the present disclosure. Tables 1-13 below provide non-limiting examples of materials and their relative amounts used to produce the dosage forms described herein. The preparation method was as follows:

[0111] A: Processing of Active Layer Material: Deutetrabenazine (fine powder) and active layer controlled-release agent were passed through a No. 30 mesh screen and combined with a binder (previously passed through a No. 20 mesh screen). The mixture was introduced into a high shear granulator and dry mixed for approximately 5 minutes. While mixing, an antioxidant (pre-dissolved in alcohol) was added to the blended powders to granulate the material. Further mixing was continued until the desired granulation endpoint was achieved. The resulting granules were wet screened to break down any oversized agglomerates. The material was fed into a diffusion mixer (V-blender) and blended for approximately 15 minutes. A lubricant passed through a No. 30 mesh screen was added to the blended material in the V-blender. The contents were lubricated for approximately 5 minutes.

[0112] B: Compression of tablet cores: The active layer materials were discharged into a double-layer rotary tablet press. The push layer materials (osmotic agent, push layer controlled-release agent, and optionally binder, colorant, and lubricant) were combined and further fed into a double-layer rotary tablet press. The tablet cores were compressed.

[0113] C: Optional tablet core seal coat: A tablet core seal coat containing a binder solution was applied to the tablet core.

[0114] D: Semipermeable layer: A semipermeable layer containing a solution of cellulose acetate and any pore-forming agent was applied to the tablet core or the tablet core was sealed using a pan coater.

[0115] E: Optional semipermeable seal coat: A semipermeable seal coat containing a binder solution was applied to the tablets compromising the semipermeable wall.

[0116] F: Creation of Exit Means: Pores were laser drilled through the layers into the active layer.

[0117] A final immediate release coating containing deutetrabenazine is optionally applied using similar materials to the active layer following processing steps as detailed above.

[0118] [Table 1]

[0119] [Table 2]

[0120] [Table 3]

[0121] [Table 4]

[0122] [Table 5]

[0123] [Table 6]

[0124] [Table 7]

[0125] [Table 8]

[0126] [Table 9]

[0127] [Table 10]

[0128] [Table 11]

[0129] [Table 12]

[0130] [Table 13]

[0131] Example 2 Single-dose bioavailability assessment Osmotic dosage forms containing 24 mg of deutetrabenazine were prepared as disclosed in Example 1 and tested in a single-dose pharmacokinetic study.

[0132] The primary objective was to assess the comparative bioavailability (BA) of deutetrabenazine and deuterated α- and β-dihydrotetrabenazine (deuHTBZ) metabolites following a single dose of a 24 mg once-daily (qd) osmotic formulation (Test) compared with a single 12 mg AUSTEDO® tablet administered twice 12 hours apart (bid) under fasting conditions.

[0133] Study population and number of subjects: The study included healthy, non-smoking male and female subjects aged 18 to 45. A total of eight healthy subjects (four per sequence) were enrolled in the study.

[0134] Subject Participation Period: The study included a 4-week screening period (Period 1), an open-label treatment period with the test product (Test2A) and the reference product (R) (Period 2), and a follow-up visit at least 1 day later (Period 3).

[0135] Treatment: Treatment Sequence A: Day 1 - Administration of Test2A. Days 2 and 3 - Test2A washout of at least 6 hours, followed by R administration. Treatment Sequence B: Day 1 - Administration of R. Days 2 and 3 - Washout of R for at least 6 hours, followed by administration of Test2A.

[0136] The primary objectives were assessed using the following parameters: - Maximum observed concentration (Cmax) - Area under plasma concentration-time (AUC) from time 0 to the time of the last measurable plasma concentration (AUC0-t) - AUC extrapolated to infinity (AUC0-∞) - AUC from time 0 to 24 hours after dosing (AUC0-24h)

[0137] analysis AUC0-t, AUC0-∞, and AUC0-24h were calculated using the trapezoidal rule. Cmax, AUC0-t, AUC0-∞, and AUC 0-24 Data were transformed to natural logarithms before statistical analysis. Between-treatment (Test2A vs. R) comparisons of Cmax, AUC0-t, AUC0-∞, and AUC0-24h were performed using separate parametric analysis of variance (ANOVA) models with fixed effect terms for sequence, period, treatment group, and subject-within-sequence random effects. Differences between the reference formulation (R) and the test formulation (Test2A) were assessed by constructing 90% confidence intervals for the test / reference ratio based on least-squares means from the ANOVA on log-transformed Cmax, AUC0-t, AUC0-∞, and AUC0-24h. The treatment differences and associated 90% confidence intervals estimated from the ANOVA on the log scale were inversely transformed to obtain an estimated ratio of geometric means between treatment groups and a 90% confidence interval for this ratio.

[0138] Figures 3a and 3b show the results (mean concentration of deutetrabenazine versus time) for the R treatment compared to the Test2A treatment on direct and logarithmic scales, respectively. Table 14 below provides the designated pK parameters observed for deutetrabenazine for Test2A compared to R.

[0139] [Table 14]

[0140] Figures 4a and 4b show metabolite data for treatments using R compared to Test2A on direct and logarithmic scales, respectively (mean concentration of total deuHTBZ versus time).

[0141] Table 15 below provides the assigned pK parameters observed for total deuHTBZ for Test2A compared to R.

[0142] [Table 15]

[0143] As shown in Tables 14 and 15, the once-daily dose of Test 2A provided acceptable deuHTBZ plasma concentrations observed in the reference. The osmotic dosage forms disclosed herein are administered once daily and provide acceptable therapeutic efficacy relative to that of AUSTEDO® without safety concerns.

[0144] Example 3 Multiple-dose bioavailability assessment An osmotic dosage form containing 24 mg of deutetrabenazine was produced as disclosed in Example 1 and tested in an open-label, randomized, multiple-dose, two-way crossover study in healthy volunteers.

[0145] The primary objective was to assess the bioequivalence (BE) of once-daily (qd) administration of Test2A compared with bid administration of R under fasted or fed conditions.

[0146] Treatment included 7 days of repeated dosing of Test2A once daily versus 7 days of repeated dosing of R bid.

[0147] Eligible models were used to calculate steady-state, AUCt, and C for deutetrabenazine and deuHTBZ concentrations. max , t max , C min , C av was used to predict.

[0148] Table 16 below provides simulation results for the steady-state pK parameters of deutetrabenazine for Test2A compared to R, as well as the pK parameters for total deuHTBZ for Test2A compared to R.

[0149] [Table 16]

[0150] Multiple dosing of Test2A has pK parameters at steady state that are comparable to those of R. Therefore, a similar efficacy response is expected with once-daily dosing, without safety concerns.

[0151] Example 4 Food Effect Testing An osmotic dosage form containing 24 mg of deutetrabenazine is produced as disclosed in Example 1 and tested in an open-label, randomized, two-way crossover study to evaluate the comparative bioavailability of deutetrabenazine and deuHTBZ in the fed state compared to the fasted state following a single administration of 24 mg, once daily (qd) of the osmotic formulation.

[0152] Treatment includes the following: A - 24 mg once daily (qd) osmotic formulation given as a single oral dose with water after an overnight fast of at least 10 hours. B - 24 mg once daily (qd) osmotic formulation given as a single oral dose with water 30 minutes after the start of a standardized high-calorie, high-fat breakfast administered after an overnight fast of at least 10 hours.

[0153] Subjects will receive Treatment A / B with a washout period of at least 6 days.

[0154] The AUCt, Cmax, tmax, Cmin, and Cav for deutetrabenazine and deuHTBZ will be analyzed.

[0155] result The similar plasma concentrations of deutetrabenazine and deuHTBZ after single dose administration with or without food indicate that the osmotic dosage form can be administered without regard to food. [Explanation of symbols]

[0156] 2. Dosage Form 4 Active layer 6. Push Layer 8 Semi-permeable membrane 10 holes

Claims

1. 1. A medicament for use in a method of administering a once daily dose of 6 to 48 mg of deutetrabenazine to treat hyperkinetic movement disorder in a subject in need thereof, comprising: the medicament is in an osmotic dosage form and contains deutetrabenazine in an amount of 6 to 48 mg; Medicines are a. a tablet core comprising an active layer and a push layer, wherein the active layer comprises a predetermined amount of deutetrabenazine microparticles and an active layer controlled-release agent, and the push layer comprises an osmotic agent and a push layer controlled-release agent; b. a semipermeable layer surrounding the tablet core; and c. Holes extending through the semipermeable layer into the tablet core Including, The method includes orally administering a medication to a subject once daily; Subjects must fast overnight for at least 10 hours prior to dosing. Medicine.

2. 2. The pharmaceutical composition according to claim 1, wherein the movement disorder is chorea, akathisia, dyskinesia, tremor, tics, chorea associated with Huntington's disease, tardive dyskinesia, tics associated with Tourette's syndrome, levodopa-induced dyskinesia in Parkinson's disease, or dyskinesia in cerebral palsy.

3. The medicament contains a total of 6 mg of deutetrabenazine microparticles, and a single dose thereof is Geometric mean AUC of approximately 91,250 to 142,750 h*pg / mL 0-inf an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine, including Geometric mean C less than approximately 4,600 pg / mL max an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine, including Geometric mean AUC of approximately 730,000 to 1,142,000 h*pg / mL 0-inf an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine, including Geometric mean C less than approximately 36,800 pg / mL max an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine, including Mean AUC of approximately 102,500 to 200,000 h*pg / mL 0-24 an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state, including Mean C less than approximately 10,000 pg / mL max providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine at steady state, including The pharmaceutical composition according to claim 1.

4. The medicament contains a total of 12 mg of deutetrabenazine microparticles, and a single dose thereof is Geometric mean AUC of approximately 182,500 to 285,500 h*pg / mL 0-inf an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine, including Geometric mean C less than approximately 9,200 pg / mL max an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine, including Mean AUC of approximately 205,000 to 400,000 h*pg / mL 0-24 an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state, including Mean C less than approximately 20,000 pg / mL max providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine at steady state, including The pharmaceutical composition according to claim 1.

5. The medicament contains a total of 24 mg of deutetrabenazine microparticles, and a single dose thereof is Geometric mean AUC of approximately 365,000 to 571,000 h*pg / mL 0-inf an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine, including Geometric mean C less than approximately 18,400 pg / mL max an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine, including Mean AUC of approximately 410,000 to 800,000 h*pg / mL 0-24 an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state, including Mean C less than approximately 40,000 pg / mL max providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine at steady state, including The pharmaceutical composition according to claim 1.

6. The medicament contains a total of 36 mg of deutetrabenazine microparticles, and a single dose thereof is Geometric mean AUC of approximately 547,500 to 856,500 h*pg / mL 0-inf an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine, including Geometric mean C less than approximately 27,600 pg / mL max an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine, including Mean AUC of approximately 615,000 to 1,200,000 h*pg / mL 0-24 an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state, including Mean C less than approximately 60,000 pg / mL max providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine at steady state, including The pharmaceutical composition according to claim 1.

7. The medicament contains a total of 48 mg of deutetrabenazine microparticles, and a single dose thereof is Geometric mean AUC of approximately 730,000 to 1,142,000 h*pg / mL 0-inf an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine, including Geometric mean C less than approximately 36,800 pg / mL max an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine, including Mean AUC of approximately 820,000 to 1,600,000 h*pg / mL 0-24 an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state, including Mean C less than approximately 80,000 pg / mL max providing an in vivo plasma profile for total α and β-dihydrodeutetrabenazine at steady state, including The pharmaceutical composition according to claim 1.

8. or 15% or less of a drug product containing said amount of deutetrabenazine is released after 2 hours when tested in 500 mL of acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus; or 60% or less of the drug is released after 8 hours when tested in 500 mL of acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus; The pharmaceutical composition according to claim 1.

9. Medicines, a. a tablet core comprising an active layer and a push layer, wherein the active layer comprises a predetermined amount of deutetrabenazine microparticles and an active layer controlled-release agent, the push layer comprises an osmotic agent and a push layer controlled-release agent, and the tablet core comprises an optional tablet seal coat on an outer surface of the tablet core; b. A semipermeable layer surrounding the tablet core; c. a hole extending through the semipermeable layer to the tablet core; and d. An optional immediate-release coating outside the semipermeable layer containing the second amount of deutetrabenazine microparticles. The pharmaceutical composition of claim 1, comprising:

10. The pharmaceutical composition of claim 9, wherein the active layer controlled release agent comprises a polymer having a viscosity of about 50 to 150 mPa s or about 55 to 90 mPa s.

11. The pharmaceutical composition of claim 10, wherein the active layer controlled release agent polymer comprises polyethylene oxide having an average molecular weight of 100,000 to 500,000 daltons in an amount of about 60% to about 98% by weight, based on the total weight of the active layer.

12. The active layer is a. an active layer antioxidant present in an amount of about 0.001% to about 1% by weight, based on the total weight of the active layer; and b. an active layer binder present in an amount of about 2% to about 20% by weight, based on the total weight of the active layer; The pharmaceutical composition of claim 9, further comprising at least one of the following:

13. 10. The medicament of claim 9, wherein the osmotic agent comprises an inorganic salt, a carbohydrate, or any mixture thereof.

14. 14. The medicament of claim 13, wherein the osmotic agent comprises an inorganic salt selected from magnesium sulfate, magnesium chloride, potassium sulfate, sodium chloride, sodium sulfate, lithium sulfate, sodium phosphate, potassium phosphate, or any mixture thereof, and is present in about 5% to about 50% by weight, based on the total weight of the medicament.

15. 10. The method of claim 9, wherein the push layer controlled-release agent comprises a polymer having a viscosity of about 5500 to 7500 mPa s and is present in an amount of about 50% to about 80% by weight, based on the total weight of the push layer.

16. 10. The pharmaceutical composition of claim 9, wherein the mass ratio of the osmotic agent in the push layer to the controlled-release agent in the push layer is 1:2 to 1:3.5 or 1:2 to 1:2.

5.

17. The push layer, a. push layer binder; and b. Pharmaceutically acceptable excipients The pharmaceutical composition of claim 9, further comprising at least one of the following:

18. 10. The pharmaceutical of claim 9, wherein the semipermeable layer comprises a water-soluble polymer, a water-insoluble polymer, or any mixture thereof.

19. 19. The pharmaceutical composition of claim 18, wherein the semipermeable layer comprises a water-insoluble polymer selected from cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate butyrate, cellulose ethers such as ethyl cellulose, agar acetate, amylose triacetate, beta-glucan acetate, poly(vinyl methyl) ether copolymers, poly(orthoesters), polyacetals, and permselective poly(glycolic acid), poly(lactic acid) derivatives, cellulose acetate polymers, or any mixture thereof, in an amount of about 80% to about 99.9% by weight, based on the weight of the semipermeable layer.

20. The pharmaceutical composition of claim 9, wherein the semipermeable layer comprises a pore-forming agent.

21. 21. The medicament of claim 20, wherein the pore-forming agent comprises a water-soluble sugar, a water-soluble salt, a water-soluble solvent, a water-soluble polymer, or any mixture thereof, and is present in the semipermeable layer in an amount of about 0.1% to about 20% by weight of the semipermeable layer.

22. 10. The pharmaceutical composition according to claim 9, wherein the mass ratio of the semipermeable layer to the tablet core is 1:8 to 1:

10.

23. 10. The method of claim 9, wherein the holes have a diameter of about 0.1 mm to about 1 mm.

24. 10. The pharmaceutical composition of claim 9, further comprising a semipermeable seal coat on the outer surface of the semipermeable layer.

25. 25. The medicament of claim 24, wherein the tablet core seal coat and the semipermeable layer seal coat each independently comprise a binder in an amount of up to about 20% by weight, based on the total weight of the medicament.

26. 10. The medicament of claim 9, comprising an immediate-release coating on the exterior of the semipermeable membrane, wherein the immediate-release coating comprises from about 0.1% to about 30% by weight of deutetrabenazine microparticles relative to the total weight of the medicament, or from about 0.2% to about 5% by weight of deutetrabenazine microparticles relative to the total weight of the medicament, or from about 0.3% to about 2% by weight of deutetrabenazine microparticles relative to the total weight of the medicament.

27. a. 6 mg total amount of deutetrabenazine microparticles, wherein the immediate-release coating comprises about 0.1% to about 0.5% by weight of deutetrabenazine microparticles based on the total weight of the medicament; or b. a total of 12 mg of deutetrabenazine microparticles, wherein the immediate-release coating comprises about 0.5% to about 1% by weight of deutetrabenazine microparticles based on the total weight of the medicament; or c. 24 mg total deutetrabenazine microparticles, wherein the immediate-release coating comprises about 1% to about 2% deutetrabenazine microparticles by weight based on the total weight of the medicament.

27. The pharmaceutical composition of claim 26, comprising:

28. 10. The medicament of claim 9, comprising from about 6 mg to about 48 mg of deutetrabenazine in the form of deutetrabenazine microparticles, wherein about 70% to 80% of the total amount of deutetrabenazine microparticles present in the medicament are present in the active layer and about 20% to 30% of the total amount of deutetrabenazine microparticles present in the medicament are present in the immediate-release coating.

29. a) a total amount of 6 mg of deutetrabenazine microparticles, the total amount of deutetrabenazine microparticles being about 0.5% to about 3% by weight based on the total weight of the medicament; or b) a total amount of 12 mg of deutetrabenazine microparticles, the total amount of deutetrabenazine microparticles being about 1% to about 5% by weight based on the total weight of the medicament; or c) 24 mg of deutetrabenazine microparticles, the total amount of which is about 5% to about 10% by weight based on the total weight of the medicament.

29. The pharmaceutical composition of claim 28, comprising:

30. 10. The pharmaceutical composition of claim 9, wherein the deutetrabenazine microparticles have a particle size of about 1 μm to about 30 μm in diameter.

31. The medicament of claim 30, wherein the deutetrabenazine microparticles have a particle size with a D 90 of 15 μm, a D 50 of 10 μm, and / or a D 10 of 3 μm.

32. 2. The pharmaceutical composition of claim 1, which provides bioavailability of deutetrabenazine and bioavailability of deuHTBZ in a subject independent of food effects.

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