Osmotic dosage form containing dutetracenazine and method of using the same

Abstract

Provided herein is an osmotic dosage form containing deutetrabenazine, for use, for example, in the treatment of hyperkinetic movement disorders. When administered orally on a once-daily basis to a subject, this dosage form provides a favorable pharmacokinetic profile of the active agent and exhibits a treatment effect over a long period of time.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Patent Application No. 17 / 835,435, filed Jun. 8, 2022, which is a continuation - in - part of U.S. Patent Application No. 17 / 344,271, filed Jun. 10, 2021, which claims the benefit of U.S. Provisional Patent Application No. 63 / 037,369, filed Jun. 10, 2020, U.S. Provisional Patent Application No. 63 / 037,953, filed Jun. 11, 2020, and U.S. Provisional Patent Application No. 63 / 044,451, filed Jun. 26, 2020, the entire contents of which are incorporated herein by reference.

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

Background Art

[0003] Dutetrabenazine ((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 vesicular monoamine transporter type 2 (VMAT2). Bioactive metabolites formed from dutetrabenazine (alpha - dihydrodutetrabenazine [α - deuHTBZ] and beta - dihydrodutetrabenazine [β - deuHTBZ]) are collectively identified as "deuHTBZ" and are potent inhibitors of VMAT2 binding. Dutetrabenazine has been shown to have a longer half - life of its active metabolites compared to tetrabenazine (e.g., U.S. Patent 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 movements) associated with Huntington's disease (HD) and for the treatment of tardive dyskinesia (TD) in adults. The AUSTEDO® dosage form is administered orally twice daily (bid) and results in a total daily dose of deutetrabenazine of 12 mg or more.

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

[0006] The therapeutic window of a drug is the period during which the plasma drug concentration is within the range of therapeutically effective plasma drug concentrations. However, since the plasma drug concentration decreases over time, it is necessary to administer multiple doses of the drug dosage form at appropriate intervals to ensure that the plasma drug concentration remains within the therapeutic window or rises back to the therapeutic window. At the same time, it is necessary to avoid or minimize plasma drug concentrations that cause undesirable side effects.

[0007] Some dosage forms containing deutetrabenazine are disclosed in U.S. Patent No. 9,296,739. Dosage forms that can deliver deutetrabenazine in a controlled manner over a long period of time would enable more advantageous dosing regimens, for example, a dosing regimen that allows once-daily (qd) administration while maintaining the treatment effect recently achieved by AUSTEDO®. Such alternative dosage forms are needed.

Prior Art Documents

Patent Documents

[0008]

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Summary of the Invention

Means for Solving the Problems

[0009] Disclosed herein is an osmotic dosage form for once-daily administration of dutetravanazine to a subject in need thereof, comprising a. a tablet core comprising an active layer and a push layer containing a predetermined amount of dutetravanazine fine particles; b. a semipermeable layer surrounding the tablet core; and c. A port that penetrates the semipermeable layer and extends to the tablet core, which is an osmotic dosage form.

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

Brief Description of the Drawings

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DETAILED DESCRIPTION OF THE INVENTION

[0012] The subject matter can be more readily understood by reference to the following detailed description, which forms a part of the present disclosure. It is to be understood that the invention is not limited to the specific methods, conditions, or parameters described and / or shown 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 limit the claimed invention.

[0013] Unless otherwise defined herein, scientific and technical terms used in connection with this application shall have the meanings commonly understood by one of ordinary skill in the art. Further, unless the context otherwise requires, singular terms shall include pluralities and plural terms shall include the singular.

[0014] When used above and throughout the present disclosure, the following terms and abbreviations shall be understood to have the following meanings unless otherwise indicated.

[0015] In the present disclosure, the singular forms "a", "an", and "the" include plural referents, and a reference to a particular numerical value includes at least that particular value unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound" is a reference to one or more such compounds and their equivalents known to those skilled in the art. As used herein, the term "plural" means two or more. When a range of values is recited, another embodiment includes from one particular value and / or to the other particular value. Similarly, when a value is expressed as an approximation by use of the preceding "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 "agent" are used interchangeably herein and refer to a composition of one or more compounds or substances that, when administered to a subject (human or animal), induces a desired pharmacological and / or physiological effect by local and / or systemic action. The active agent is preferably deutetrabenazine as disclosed herein.

[0017] As used herein, the term "dosage form" refers to a pharmaceutical form having osmotic properties and capable of releasing an active agent over an extended period of time. For example, the dosage form releases no more than 60 wt% 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 "pharmaceutical preparation" refers to a solution or suspension of a drug, optionally containing excipients, formed in situ under aqueous conditions of the dosage form. The active agent is preferably deutetrabenazine as disclosed herein.

[0019] The terms "port" or "exit port" are used interchangeably and refer to the means and methods suitable for the drug or pharmaceutical formulation to exit from the core of the dosage form, for example, any hole, passage, channel, or similar opening through which the drug or pharmaceutical formulation in the core of the dosage form can exit. Other expressions of such terms include, for example, exit means, opening, or hole.

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

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

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

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

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

[0025] "Fine particles" refer to particles with a particle size (i.e., diameter) of less than 1 mm, such as dutetravanazine particles. In one embodiment, the median diameter (D 50 ) of the fine particles is from about 0.05 to about 100 μm. In another embodiment, the D 50 of the fine particles is from about 0.05 to about 50 μm. In another embodiment, the D 50 of the fine particles is from about 1 μm to about 30 μm, or from about 1 μm to about 25 μm, or from about 5 μm to about 30 μm, or from about 1 μm to about 20 μm, or from about 5 μm to about 25 μm, or from about 10 μm to about 20 μm. In one embodiment, the dutetravanazine fine particles have a particle size distribution with a diameter of about 1 μm to about 30 μm. In another embodiment, the dutetravanazine fine particles have a D 90 of 15 μm (i.e., 90% of the particles have a diameter of 15 μm or less). In another embodiment, the dutetravanazine fine particles have a D 50 of 10 μm (i.e., 50% of the particles have a diameter greater than 10 μm and 50% of the particles have a diameter of 10 μm or less). In yet another embodiment, the dutetravanazine fine particles have a D 10 of 3 μm (i.e., 10% of the particles have a diameter less than 3 μm).

[0026] The terms D 90 , D 50 , or D 10 are well understood in the art. The particle size distribution (i.e., diameter) of the fine particles can be determined by those skilled in the art using conventional methods, such as dynamic or static light scattering of an aqueous dispersion of the fine particle composition. The D 90 and D 10 values are D 50Similar to the value, it can be calculated from the particle size distribution of the fine particles.

[0027] Osmotic pressure dosage forms generally utilize osmotic pressure to generate a driving force for absorbing fluid into a compartment formed, at least in part, by a semipermeable wall, layer, or membrane that allows free diffusion of fluid from, for example, the gastrointestinal (GI) tract but does not allow free diffusion of the 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 suitable outlet means for the drug formulation that is released 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 pressure systems can operate independently of pH, so that the operation continues at a rate determined by osmotic pressure over a long period even as the dosage form passes through the GI tract and encounters different microenvironments having significantly different pH values.

[0028] An example of one type of osmotic pressure device includes two component layers within a compartment (referred to herein as the core and used interchangeably) formed by a semipermeable wall. One component layer (referred to herein as the active layer) contains a drug (i.e., deutetrabenazine) mixed with an excipient, and the second component layer (referred to herein as the push layer) contains an osmotic active agent, optionally mixed with an excipient, but does not contain the drug. This core is further coated with a semipermeable wall, which allows entry of an aqueous fluid, i.e., an aqueous fluid from the GI system, into the core. Without wishing to be limited by theory, when fluid is absorbed into the dosage form, the active layer forms the drug formulation and the osmotic agent within the push layer expands to push the drug formulation, thereby releasing the drug formulation at a substantially constant rate. See, for example, U.S. Patent Nos. 4,327,725; 4,612,008; 4,783,337; and 5,082,668.

[0029] Certain dosage forms have proven effective for many different drug therapies, but there is no clinically satisfactory situation. For some patients, despite maintaining substantially constant drug release that is expected to provide continuous efficacy, it has been observed that the therapeutic efficacy of the drug decreases below the therapeutically effective threshold before the end of the desired treatment period.

[0030] Surprisingly, it has been discovered that an oral dosage form containing deutetrabenazine with a desired release rate and thus a desired pharmacokinetic profile over a long period can be achieved. In some embodiments, when the osmotic dosage forms disclosed herein are orally administered to a subject on a once-daily (q.d.) basis, a pharmacokinetic profile that is comparable, e.g., biologically equivalent, to that of the AUSTEDO® dosage form administered b.i.d. is provided. In certain embodiments, the osmotic dosage form provides a steady-state in vivo plasma profile of total deuHTBZ that includes an average AUC of about 410,000 - 800,000 h*pg / mL 0-24 and an average C of less than about 40,000 pg / mL. max

[0031] The osmotic dosage forms of the present disclosure include a tablet core containing at least a push layer and an active layer, the active layer containing deutetrabenazine and one or more excipients for forming a drug formulation when hydrated, and the push layer containing 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 ports that function as exit means for releasing the drug formulation from the tablet core. In some embodiments, the two layers are compressed into a two-layer tablet core surrounded by a semipermeable membrane and further having suitable openings for drug release therethrough.

[0032] The embodiments of the oral osmotic dosage form disclosed herein are shown in the cross-sectional view of FIG. 1. The components are not drawn to scale. The dosage form (2) includes a two-layer tablet core. The core includes an active layer (4) containing a drug, such as deutetrabenazine, and one or more active layer excipients, and a push layer (6) containing at least one osmotic agent together with one or more push layer excipients. At least a portion of the active layer forms a drug formulation when exposed to an aqueous environment. Suitable active layer and push layer excipients are known in the art and include diluents, carriers, binders, fillers, controlled release agents, and processing aids. The semipermeable membrane (8) surrounds the two-layer tablet core and has a port (10) of a suitable size extending from the semipermeable membrane to the active layer (4), whereby the drug formulation can be released from within the tablet core. As shown, the dosage form can be compressed longitudinally and the port (10) is on the side of the dosage form containing the active layer. In other embodiments, the dosage form is compressed along the lateral axis of the dosage form and the port is at one end of the dosage form. In all embodiments, multiple ports may be present. Through the cooperation of the osmotic agent components, in the presence of an aqueous environment, the drug formulation is released from the active layer through the port over a long period of time at a desired release rate. Although not shown in FIG. 1, as described elsewhere herein, an optional immediate release layer (immediate release coating) outside the semipermeable layer containing additional drug (i.e., deutetrabenazine microparticles) can be further provided if desired.

[0033] In one embodiment, the present invention is an osmotic dosage form for once-daily administration to a subject in need thereof, comprising: a. a tablet core comprising an active layer and a push layer containing a predetermined amount of deutetrabenazine microparticles; b. a semipermeable layer surrounding the tablet core; and c. a port in the semipermeable layer extending to the tablet core, thereby providing an osmotic dosage form.

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

[0035] In a specific embodiment, the active layer excipient 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 within the active layer has an average molecular weight of 100,000 to 500,000 Daltons. In some embodiments, the polyethylene oxide within 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 mass relative to the total mass 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 mass relative to the total mass 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 mass relative to the total mass 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 mass relative to the total mass of the active layer.

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

[0038] Optional excipients in the active layer include antioxidants, binders, lubricants, colorants, and the like. Such excipients are well known among those skilled in the art. In some embodiments, the active layer comprises duotetrahydrobenazine fine particles, active layer excipients, 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 tertiary-butyl-4-methoxyphenol (a mixture of 2-isomer and 3-isomer), 2,6-di-tertiary-butyl-p-cresol, propyl gallate, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (6-ethoxy-1,2-dihydro-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 mass based on the total mass 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 rubber and synthetic rubber, and any mixture 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 mass based on the total mass 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 wax, hydrogenated vegetable oil, and saturated fatty acid esters. In a specific embodiment, one or more lubricants may be present in the active layer in an amount of about 0.001% to about 0.2% by mass based on the total mass of the active layer.

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

[0043] The push layer contained within the tablet core includes an osmotic agent that, without being bound by theory, acts as a fluid-attracting agent that swells when exposed to an aqueous environment and pushes the active layer, enabling the flow of the pharmaceutical formulation from within the dosage form to the external environment. Osmotic agents are generally defined as non-volatile species that are, for example, generally water-soluble and create an osmotic gradient, thereby enabling the osmotic influx of water. Species that fall into the classification 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, and 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 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. In one embodiment, the osmotic agent is 30% by weight based on the total weight of the push layer.

[0046] The push layer further comprises one or more excipients 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 a swellable matrix when contacted with water. In one embodiment, the push layer controlled release agent has a viscosity of about 5500 to 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 mass ratio of the osmotic agent to the push layer controlled release agent in the push layer 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 excipients, for example, to stabilize the layer, color it for tablet orientation, etc. Exemplary excipients include binders, colorants, and lubricants, and suitable examples of these types of excipients are well known among 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 (hydroxypropylmethylcellulose), starch, gelatin, agar, natural and synthetic rubbers, and any mixture 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 within the push layer can include any of the exemplary materials described above with respect to the active layer. The push layer may also include a disintegrant, such as crosslinked polyvinylpyrrolidone, corn starch, potato starch, smectite clay (aluminum magnesium 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 a specific embodiment, the push layer includes sodium chloride, polyethylene oxide, hydroxypropylmethylcellulose, a colorant, and magnesium stearate.

[0054] The osmotic dosage form of the present invention includes a semipermeable layer surrounding the tablet core, thereby preventing the outflow of the drug from the core while allowing the inflow of fluid from the external fluid environment (e.g., the gastrointestinal tract of the subject) into the tablet core. The semipermeable layer is preferably formed from a material that does not have a harmful effect 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 either non-erosive or becomes erosive after a predetermined period with a bioerosion corresponding to the end of the drug release period of the pharmaceutical formulation. As used herein, "semipermeable layer", "semipermeable wall", and "semipermeable membrane" are interchangeable.

[0055] Generally, semipermeable materials useful for forming a semipermeable layer have a fluid permeability of 10 -5 ~10 -1 (cc mil / cm 2 ·hour·atm) across the wall at the use temperature. Suitable materials are known in the art; see, for example, U.S. Patent No. 3,845,770 and U.S. Patent No. 3,916,899.

[0056] Typical materials useful for forming a semipermeable layer include cellulose acetate, cellulose triacetate, agar acetate, amylose triacetate, beta-glucan acetate, cellulose diacetate, acetaldehyde dimethylacetate, cellulose acetate ethylcarbamate, polyamide, polyurethane, sulfonated polystyrene, cellulose acetate phthalate, cellulose acetate methylcarbamate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, cellulose acetate ethylcarbamate, cellulose acetate chloroacetate, cellulose dipalmitate, cellulose dioctanoate, cellulose dicaprate, cellulose dipentanlate, cellulose valerate acetate, cellulose acetate succinate, cellulose acetate propionate succinate, methylcellulose, cellulose acetate p-toluenesulfonate, cellulose acetate butyrate, and the selective permeable polymers formed by coprecipitation of the polycations and polyanions disclosed in U.S. Patent No. 3,173,876; 3,276,586; 3,541,005; 3,541,006; and 3,546,142, including materials known in the art.

[0057] In one embodiment, the semipermeable layer comprises a water-soluble polymer or a water-insoluble polymer, such as 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 copolymer, poly(orthoester), polyacetal, and a selectively permeable poly(glycolic acid), poly(lactic acid) derivative, and any mixtures thereof. Cellulose acetate includes cellulose acetate polymers (such as 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 about 85% to about 95% by weight based on the weight of the semipermeable layer. Preferably, the semipermeable layer is cellulose acetate and comprises a water-insoluble polymer having an acetyl content of about 32% to 40%.

[0058] The semi-permeable layer can further contain an agent that forms pores, or a "pore-forming agent". The agent that forms pores includes biocompatible materials that, when in contact with body fluids, dissolve, disperse, or decompose to create pores or channels in the semi-permeable 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., carboxymethyl cellulose, hydroxypropyl cellulose, etc.) have been conventionally used as pore-forming agents. In one embodiment, the semi-permeable layer contains, in addition to a water-soluble polymer or a water-insoluble polymer, an agent that forms pores, which is selected from water-soluble sugars, water-soluble salts, water-soluble solvents, and water-soluble polymers, or any mixture thereof. In a specific embodiment, the agent that forms pores is a water-soluble solvent, polyethylene glycol. In one embodiment, the agent that forms pores constitutes about 0.1% to about 20% by mass of the semi-permeable layer. Preferably, the agent that forms pores constitutes about 8% to about 15% by mass of the semi-permeable layer. In one embodiment, the mass ratio of the semi-permeable layer to the tablet core is 1:8 to 1:10.

[0059] In a specific embodiment, the semi-permeable layer contains cellulose acetate and polyethylene glycol.

[0060] This dosage form includes a port, either independently of the agent that forms the pores or in addition to the agent that forms the pores. The port is present within a semipermeable layer, extends from the outside of the semipermeable layer into the tablet core, and provides an exit means for the pharmaceutical formulation from the active layer within the tablet core to the environment outside the dosage form. The exit port is formed by any means known in the art, including mechanical drilling, laser drilling, erosion by erosive elements, extraction, dissolution, rupture, or leaching. For example, the port may be formed by mechanical or thermal means after coating, or by a light beam (e.g., a laser), a beam of particles, or other high-energy source, or may be formed in situ by the splitting of a small portion of the coating. Such splitting may be controlled by intentionally incorporating relatively small weak portions into the coating. The exit port may also be formed in situ by the erosion of a plug of water-soluble material or by the splitting of a thinner portion of the coating across a recess in the core. The exit port may be formed by coating the core such that one or more small regions remain uncoated. In addition, the exit port may be a number of holes or pores that can be formed during coating. The exit port may be pores formed by leaching sorbitol, lactose, etc. from a wall or layer, as disclosed in U.S. Patent No. 4,200,098. This patent discloses controlled-size porous pores formed by dissolving, extracting, or leaching a material from a wall, such as sorbitol from cellulose acetate. A preferred form of laser drilling is the use of a pulsed laser that gradually removes material from the semipermeable layer to a desired depth to form the exit port. In certain embodiments, one or more ports can be formed by leaching 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 an exit port with a uniform release dimension. The exit means can have any shape, such as circular, triangular, square, elliptical, etc., for the uniform quantitative dosing release of the pharmaceutical formulation from the dosage form.An osmotic dosage form can be constructed with one or more outlet ports in spaced relation, or one or more surfaces of the osmotic dosage form. Such outlets and the apparatus for forming such outlets are disclosed, for example, in U.S. Patent Nos. 3,916,899 and 4,088,864.

[0061] In one embodiment, the port has a diameter of from about 0.1 mm to about 1 mm. In another embodiment, the port has a diameter of from 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 sub-portions 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 may be applied outside 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 may be applied outside the dosage form following the application of the semipermeable membrane to the tablet core. The seal coating material can include a binder, many types of which are disclosed above. In embodiments that include a seal coating between the core and immediately outside the semipermeable membrane, the port extends through all layers from outside the seal coating to the core.

[0063] In one embodiment, the 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 the semipermeable layer seal coat may include a binder selected from hypromellose (hydroxypropylmethylcellulose), starch, gelatin, agar, natural rubber, synthetic rubber, and any mixtures thereof. In another embodiment, the tablet core seal coat binder and / or the semipermeable layer seal coat binder is hypromellose.

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

[0067] The absolute amount of deutetrabenazine in the active layer of the present osmotic dosage form depends on the dosage strength of a particular embodiment. As described more fully below, the dosage form may further include an immediate release amount of deutetrabenazine microparticles that are outside the active layer, preferably outside the semipermeable membrane layer.

[0068] In one embodiment, the dosage form disclosed herein further includes an immediate release coating containing a second amount of deutetrabenazine microparticles outside the semipermeable membrane or outside the semipermeable layer seal coating applied thereto.

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

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

[0071] In embodiments where the osmotic dosage form includes an immediate release coating, the immediate release coating constitutes up to about 30% of the total amount of deutetrabenazine fine particles in the dosage form. In one embodiment, about 8% to 30% of the total amount of deutetrabenazine fine particles in the dosage form is present within the immediate release coating. In one embodiment of the present invention, about 70% to about 80% of the total amount of deutetrabenazine fine particles in the dosage form is present within the active layer, and about 20% to about 30% of the total amount of deutetrabenazine fine particles in the dosage form is present within the immediate release coating.

[0072] The dosage form of any embodiment of the present invention contains a total amount of deutetrabenazine microparticles from 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] According to the present disclosure, the total amount of deutetrabenazine or the total daily dose of deutetrabenazine, which are used interchangeably herein, is administered to a subject as a once-daily dose (QD). Depending on the total daily dose, one or more (multiple) dosage forms may be administered to the subject in a single dose. Preferably, a single dosage form is administered in a single dose. In one embodiment, the total daily dose of deutetrabenazine is from 12 mg to 48 mg. In one embodiment, the total daily dose of deutetrabenazine is 12 mg. In one embodiment, the total daily dose of deutetrabenazine is 18 mg. In one embodiment, the total daily dose of deutetrabenazine is 24 mg. In one embodiment, the total daily dose of deutetrabenazine is 30 mg. In one embodiment, the total daily dose of deutetrabenazine is 36 mg. In one embodiment, the total daily dose of deutetrabenazine is 42 mg. In one embodiment, the total daily dose of deutetrabenazine is 48 mg.

[0074] Patients being treated with twice-daily (bid) deutetrabenazine can be switched to once-daily (qd) deutetrabenazine at the same total daily dose on the day following the last dose of bid deutetrabenazine.

[0075] Patients being treated with once-daily (qd) deutetrabenazine can be switched to twice-daily (bid) deutetrabenazine at the same total daily dose on the day following the last dose of qd deutetrabenazine.

[0076] Patients being treated with tetrabenazine can be switched to once-daily (qd) osmotic dosage form of deutetrabenazine disclosed herein on the day following the last dose of tetrabenazine.

[0077] In one embodiment, the total amount of deutetrabenazine microparticles present within the dosage form is from about 0.5% to about 15% by weight, based on the total weight of the osmotic dosage form. In another embodiment, the total amount of deutetrabenazine microparticles present within the dosage form is from about 1% to about 10% by weight, based on the total weight of the dosage form. In another embodiment, when the dosage form contains a total of 6 mg of deutetrabenazine microparticles, the total amount of deutetrabenazine microparticles present within the dosage form is from about 0.5% to about 3% by weight, based on the total weight of the dosage form. In another embodiment, when the dosage form contains a total of 12 mg of deutetrabenazine microparticles, the total amount of deutetrabenazine microparticles present within the dosage form is from about 1% to about 5% by weight, based on the total weight of the dosage form. In another embodiment, when the dosage form contains a total of 24 mg of deutetrabenazine microparticles, the total amount of deutetrabenazine microparticles present within the dosage form is from about 5% to about 10% by weight, based on the total weight of the dosage form.

[0078] In addition to the quantified dutetracenazine microparticles, the immediate release coating may further comprise one or more pharmaceutically acceptable excipients such as antioxidants, binders, and surfactants, or any combination thereof. The antioxidants, binders, and surfactants may 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 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., Ceraphyl® 50), and polyoxyethylene / polyoxypropylene block copolymers such as Pluronic®.

[0079] In one embodiment, the immediate release coating further comprises an antioxidant that can be selected from tertiary-butyl-4-methoxyphenol (a mixture of 2-isomer and 3-isomer), 2,6-di-tertiary-butyl-p-cresol, propyl gallate, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline) (ethoxyquin), nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole, butylated hydroxytoluene, and any mixture 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 dutetracenazine microparticles, butylated hydroxyanisole, butylated hydroxytoluene, hypromellose, and polysorbate 80.

[0080] In one embodiment, an osmotic dosage form for administering dutetracenazine once daily to a subject in need thereof,

[0081] a. i. An active layer comprising a controlled release agent for the active layer, an antioxidant for the active layer, and a binder for the active layer, the controlled release agent comprising a predetermined amount of deutetrabenazine fine particles and a polymer having a viscosity of about 55 to 90 mPa s; ii. A push layer comprising a controlled release agent for the push layer, and a binder for the push layer, the controlled release agent comprising an osmotic agent and a polymer having a viscosity of about 5500 to 7500 mPa s; comprising a tablet core; b. A tablet core seal coat containing a binder on the outer surface of the tablet core; c. A semipermeable layer surrounding the tablet core seal coat and containing a water-insoluble polymer and an agent for forming pores; d. A semipermeable layer seal coat containing a binder on the outer surface of the semipermeable layer; e. An immediate release coating containing a second amount of deutetrabenazine fine particles and an antioxidant for the immediate release coating on the outer surface of the semipermeable layer seal coat; and f. A port in the semipermeable layer seal coat reaching the tablet core, comprising an osmotic agent form is provided.

[0082] In some embodiments, there is provided an osmotic agent form according to any one of the embodiments of the present invention, wherein when the dosage form is tested in 500 mL of acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus, 15% or less of the drug formulation is released within 2 hours and / or 60% or less of the drug formulation is released within 8 hours.

[0083] Further provided herein is a method of treating hyperkinetic movement disorder in a subject, the method comprising orally administering to the subject an osmotic agent form according to any one of the embodiments of the present invention on a once-daily basis. Further provided is an osmotic agent form according to any one of the embodiments disclosed herein for once-daily oral use in treating hyperkinetic movement disorder in a subject.

[0084] In some embodiments, the movement disorder is selected from chorea, akathisia, dyskinesia, tremor, or tic. In some embodiments, the movement disorder is selected from chorea associated with Huntington's disease, tardive dyskinesia, tics associated with Tourette syndrome, Parkinson's disease levodopa-induced dyskinesia, or dyskinesia in cerebral palsy.

[0085] In certain embodiments, the osmotic dosage form described in any one of the embodiments disclosed herein is administered with food.

[0086] In certain embodiments, the osmotic dosage form described in any one of the embodiments disclosed herein is administered under fasting conditions.

[0087] In one embodiment, the present invention is a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, wherein a single administration of the osmotic dosage form containing a total of 6 mg of deutetrabenazine microparticles provides a geometric mean AUC of about 91,250 - 142,750 h*pg / mL 0-inf of the total α- and β-dihydrodeutetrabenazine in vivo plasma profile.

[0088] In one embodiment, the present invention is a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, wherein a single administration of the osmotic dosage form containing a total of 6 mg of deutetrabenazine microparticles provides a geometric mean C of less than about 4,600 pg / mL max of the total α- and β-dihydrodeutetrabenazine in vivo plasma profile.

[0089] In one embodiment, the present invention is a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, and by a single administration of the osmotic dosage form containing a total of 12 mg of deutetrabenazine fine particles, a geometric mean AUC of about 182,500-285,500 h*pg / mL 0-inf is provided, and an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine is provided.

[0090] In one embodiment, the present invention is a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, and by a single administration of the osmotic dosage form containing a total of 12 mg of deutetrabenazine fine particles, a geometric mean C of less than about 9,200 pg / mL max is provided, and an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine is provided.

[0091] In one embodiment, the present invention is a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, and by a single administration of the osmotic dosage form containing a total of 24 mg of deutetrabenazine fine particles, a geometric mean AUC of about 365,000-571,000 h*pg / mL 0-inf is provided, and an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine is provided.

[0092] In one embodiment, the present invention is a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, and by a single administration of the osmotic dosage form containing a total of 24 mg of deutetrabenazine fine particles, a geometric mean C of less than about 18,400 pg / mL max is provided, and an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine is provided.

[0093] In one embodiment, the present invention is a method for treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, wherein a single administration of the osmotic dosage form containing a total amount of 36 mg of deutetrabenazine fine particles provides a geometric mean AUC of about 547,500-856,500 h*pg / mL 0-inf of the total α- and β-dihydrodeutetrabenazine in vivo plasma profile is provided.

[0094] In one embodiment, the present invention is a method for treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, wherein a single administration of the osmotic dosage form containing a total amount of 36 mg of deutetrabenazine fine particles provides a geometric mean C of less than about 27,600 pg / mL max of the total α- and β-dihydrodeutetrabenazine in vivo plasma profile is provided.

[0095] In one embodiment, the present invention is a method for treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, wherein a single administration of the osmotic dosage form containing a total amount of 48 mg of deutetrabenazine fine particles provides a geometric mean AUC of about 730,000-1,142,000 h*pg / mL 0-inf of the total α- and β-dihydrodeutetrabenazine in vivo plasma profile is provided.

[0096] In one embodiment, the present invention is a method for treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, wherein a single administration of the osmotic dosage form containing a total amount of 48 mg of deutetrabenazine fine particles provides a geometric mean C of less than about 36,800 pg / mL maxA method is provided that provides an in vivo plasma profile of total α- and β-dihydrotetrabenazine, including

[0097] In one embodiment, the present invention is a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, wherein the osmotic dosage form containing a total of 6 mg of tetrabenazine microparticles provides an average AUC of about 102,500 - 200,000 h*pg / mL 0-24 A method is provided that provides an in vivo plasma profile of total α- and β-dihydrotetrabenazine, including

[0098] In one embodiment, the present invention is a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, wherein the osmotic dosage form containing a total of 6 mg of tetrabenazine microparticles provides an average C of less than about 10,000 pg / mL max A method is provided that provides an in vivo plasma profile of total α- and β-dihydrotetrabenazine, including

[0099] In one embodiment, the present invention is a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, wherein the osmotic dosage form containing a total of 12 mg of tetrabenazine microparticles provides an average AUC of about 205,000 - 400,000 h*pg / mL 0-24 A method is provided that provides an in vivo plasma profile of total α- and β-dihydrotetrabenazine, including

[0100] In one embodiment, the present invention is a method for treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, and the osmotic dosage form containing a total amount of 12 mg of deutetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine in steady state that includes an average C of less than about 20,000 pg / mL. max A method is provided that provides an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine in steady state that includes max .

[0101] In one embodiment, the present invention is a method for treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, and the osmotic dosage form containing a total amount of 24 mg of deutetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine in steady state that includes an average AUC of about 410,000 - 800,000 h*pg / mL. 0-24 A method is provided that provides an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine in steady state that includes 0-24 .

[0102] In one embodiment, the present invention is a method for treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, and the osmotic dosage form containing a total amount of 24 mg of deutetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine in steady state that includes an average C of less than about 40,000 pg / mL. max A method is provided that provides an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine in steady state that includes max .

[0103] In one embodiment, the present invention is a method for treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, and the osmotic dosage form containing a total amount of 36 mg of deutetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine in steady state that includes an average AUC of about 615,000 - 1,200,000 h*pg / mL. 0-24 A method is provided that provides an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine in steady state that includes 0-24 .

[0104] In one embodiment, the present invention is a method for treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, and using an osmotic dosage form containing a total amount of 36 mg of deutetrabenazine microparticles, the mean C max A method is provided that provides an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine in steady state, including.

[0105] In one embodiment, the present invention is a method for treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, and using an osmotic dosage form containing a total amount of 48 mg of deutetrabenazine microparticles, the mean AUC of about 820,000 - 1,600,000 h*pg / mL 0-24 A method is provided that provides an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine in steady state, including.

[0106] In one embodiment, the present invention is a method for treating hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, and using an osmotic dosage form containing a total amount of 48 mg of deutetrabenazine microparticles, the mean C of less than about 80,000 pg / mL max A method is provided that provides an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine in steady state, including.

[0107] In one embodiment, the present invention is a method for treating hyperkinetic movement disorder, comprising administering an osmotic dosage form according to any one of the embodiments of the present invention, and when tested in 500 mL of acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus, not more than 15% of the drug formulation is released after 2 hours.

[0108] In one embodiment, the present invention is a method of treating hyperkinetic movement disorder in a subject in need thereof, comprising administering to the subject an osmotic dosage form once daily according to any one of the embodiments of the present invention, wherein when tested in 500 mL of acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus, 60% or less of the drug formulation is released within 8 hours.

[0109] In some embodiments, the present invention is 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 when tested in 500 mL of acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus, 15% or less of the drug formulation is released after 2 hours and 60% or less of the drug formulation is released within 8 hours.

[0110] Further provided is a method of transitioning a human subject being treated with a total daily dose of deutetrabenazine twice daily (bid) to a total daily dose of deutetrabenazine once daily (qd) to control abnormal involuntary movements, a) administering to the human subject a final dose of deutetrabenazine twice daily (bid); and b) administering to the human subject a total daily dose of deutetrabenazine once daily (qd) the next day, comprising the method.

[0111] The once-daily deutetrabenazine is, for example, the deutetrabenazine sustained-release osmotic dosage form disclosed herein.

[0112] The twice-daily deutetrabenazine may refer to, for example, AUSTEDO® bid tablets or the like. As used herein, the term "final dose" refers to the discontinuation of the current treatment, for example, the discontinuation of treatment with twice-daily deutetrabenazine. In a specific embodiment, the final dose of twice-daily deutetrabenazine may refer to, for example, the second daily dose of twice-daily deutetrabenazine administered to the human subject in the afternoon or evening.

[0113] In one embodiment, a human subject is treated with twice-daily deutetrabenazine tablets at a total daily dose of 12 mg and is switched to once-daily deutetrabenazine at a total daily dose of 12 mg.

[0114] In another embodiment, a human subject is treated with twice-daily deutetrabenazine tablets at a total daily dose of 18 mg and is switched to once-daily deutetrabenazine at a total daily dose of 18 mg.

[0115] In another embodiment, a human subject is treated with twice-daily deutetrabenazine tablets at a total daily dose of 24 mg and is switched to once-daily deutetrabenazine at a total daily dose of 24 mg.

[0116] In another embodiment, a human subject is treated with twice-daily deutetrabenazine tablets at a total daily dose of 30 mg and is switched to once-daily deutetrabenazine at a total daily dose of 30 mg.

[0117] In another embodiment, a human subject is treated with twice-daily deutetrabenazine tablets at a total daily dose of 36 mg and is switched to once-daily deutetrabenazine at a total daily dose of 36 mg.

[0118] In another embodiment, a human subject is treated with twice-daily deutetrabenazine tablets at a total daily dose of 42 mg and is switched to once-daily deutetrabenazine at a total daily dose of 42 mg.

[0119] In another embodiment, a human subject is treated with twice-daily deutetrabenazine tablets at a total daily dose of 48 mg and is switched to once-daily deutetrabenazine at a total daily dose of 48 mg.

[0120] In a specific embodiment, once-daily deutetrabenazine is a sustained-release osmotic formulation, preferably a deutetrabenazine osmotic formulation according to any one of the embodiments of the present invention.

[0121] In yet another specific embodiment, the once-daily dutetravanazine osmotic form comprises the following: a. A tablet core comprising an active layer and a push layer, the active layer containing a predetermined amount of dutetravanazine fine particles and an active layer controlled-release agent, the push layer containing an osmotic agent and a push layer controlled-release agent, the active layer and the push layer, and an optional tablet seal coat on the outer surface of the tablet core, wherein about 70% to 80% of the total amount of dutetravanazine fine particles present in the dosage form is present in the active layer, about 20% to 30% of the total amount of dutetravanazine fine particles present in the dosage form is present in the immediate-release coating, and the dutetravanazine fine particles have a particle size such that D 90 is 15 μm, D 50 is 10 μm, and / or D 10 is 3 μm, the tablet core; b. A semipermeable layer surrounding the tablet core; c. A port extending through the semipermeable layer to the tablet core; and d. An optional immediate-release coating containing a second amount of dutetravanazine fine particles and located outside the semipermeable layer.

[0122] In one embodiment, the once-daily sustained-release dosage form of dutetravanazine is administered with food or without food.

[0123] In one embodiment, the abnormal involuntary movements controlled during the transition from twice-daily to once-daily dutetravanazine administration are chorea, akathisia, dyskinesia, tremor, tic, Huntington's disease-related chorea, tardive dyskinesia, Tourette syndrome-related tic, Parkinson's disease levodopa-induced dyskinesia, or cerebral palsy dyskinesia. In one embodiment, the abnormal involuntary movement being controlled is Huntington's disease-related chorea. In one embodiment, the abnormal involuntary movement being controlled is tardive dyskinesia.

[0124] Further provided is a method of transitioning a human subject being treated with once-daily total daily dose of deutetrabenazine for controlling abnormal involuntary movements to twice-daily (bid) deutetrabenazine tablets of the same total daily dose, comprising: a) administering the final once-daily dose of deutetrabenazine; and b) administering to the human subject the total daily dose of deutetrabenazine twice-daily on the following day.

[0125] As detailed above, the human subject transitions to the same total daily dose, such as 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, or 48 mg.

[0126] In one embodiment, the human subject is being treated with a once-daily dose of deutetrabenazine at a total daily dose of 12 mg and transitions to twice-daily deutetrabenazine tablets at a total daily dose of 12 mg.

[0127] In one embodiment, the human subject is being treated with a once-daily dose of deutetrabenazine at a total daily dose of 18 mg and transitions to twice-daily deutetrabenazine tablets at a total daily dose of 18 mg.

[0128] In one embodiment, the human subject is being treated with a once-daily dose of deutetrabenazine at a total daily dose of 24 mg and transitions to twice-daily deutetrabenazine tablets at a total daily dose of 24 mg.

[0129] In one embodiment, the human subject is being treated with a once-daily dose of deutetrabenazine at a total daily dose of 30 mg and transitions to twice-daily deutetrabenazine tablets at a total daily dose of 30 mg.

[0130] In one embodiment, the human subject is being treated with a once-daily dose of deutetrabenazine at a total daily dose of 36 mg and transitions to twice-daily deutetrabenazine tablets at a total daily dose of 36 mg.

[0131] In one embodiment, the human subject is being treated with a once-daily dose of deutetrabenazine at a total daily dose of 42 mg and is switched to deutetrabenazine tablets at a total daily dose of 42 mg twice daily.

[0132] In one embodiment, the human subject is being treated with a once-daily dose of deutetrabenazine at a total daily dose of 48 mg and is switched to deutetrabenazine tablets at a total daily dose of 48 mg twice daily.

[0133] In a specific embodiment, the once-daily deutetrabenazine is in a sustained-release dosage form, preferably an osmotic dosage form according to any one of the embodiments of the present invention. In one embodiment, the once-daily sustained-release dosage form of deutetrabenazine is administered with food or without food.

[0134] In one embodiment, the human subject is being treated with a once-daily osmotic dosage form of deutetrabenazine and is switched to a twice-daily dosage form of deutetrabenazine.

[0135] In one embodiment, the abnormal involuntary movements that are controlled during the switch from a once-daily deutetrabenazine dosage form to twice-daily deutetrabenazine tablets are chorea, akathisia, dyskinesia, tremor, tic, chorea associated with Huntington's disease, tardive dyskinesia, tic associated with Tourette syndrome, Parkinson's disease levodopa-induced dyskinesia, or dyskinesia in cerebral palsy. In one embodiment, the controlled abnormal involuntary movement is chorea associated with Huntington's disease. In one embodiment, the controlled abnormal involuntary movement is tardive dyskinesia.

[0136] Further provided is a method of switching a human subject being treated with a daily dose of tetrabenazine to a once-daily dose of deutetrabenazine to control abnormal involuntary movements, comprising: a) administering the final dose of tetrabenazine; and b) administering to the human subject, the next day, a once-daily osmotic dosage form of deutetrabenazine, The daily dose of tetrabenazine is 12.5 mg, and the once-daily dose of deutetrabenazine is 6 mg; or The daily dose of tetrabenazine is 25 mg, and the once-daily dose of deutetrabenazine is 12 mg; or The daily dose of tetrabenazine is 37.5 mg, and the once-daily dose of deutetrabenazine is 18 mg; or The daily dose of tetrabenazine is 50 mg, and the once-daily dose of deutetrabenazine is 24 mg; or The daily dose of tetrabenazine is 62.5 mg, and the once-daily dose of deutetrabenazine is 30 mg; or The daily dose of tetrabenazine is 75 mg, and the once-daily dose of deutetrabenazine is 36 mg; or The daily dose of tetrabenazine is 87.5 mg, and the once-daily dose of deutetrabenazine is 42 mg; or The daily dose of tetrabenazine is 100 mg, and the once-daily dose of deutetrabenazine is 48 mg, and administering a once-daily deutetrabenazine osmotic dosage form, a method comprising.

[0137] In some embodiments, the daily dose of tetrabenazine is administered in divided doses, such as two, three, or more divided doses.

[0138] In one embodiment, the abnormal involuntary movements controlled during the transition from tetrabenazine to once-daily dosing of deutetrabenazine are chorea, akathisia, dyskinesia, tremors, tics, chorea associated with Huntington's disease, tardive dyskinesia, tics associated with Tourette syndrome, Parkinson's disease levodopa-induced dyskinesia, or dyskinesia in cerebral palsy. In one embodiment, the abnormal involuntary movement being controlled is chorea associated with Huntington's disease. In one embodiment, the abnormal involuntary movement being controlled is tardive dyskinesia.

[0139] In one embodiment, the once-daily sustained-release dosage form of deutetrabenazine is administered with food or without food.

[0140] The present disclosure provides an oral dosage form and method according to any of the following aspects: Aspect 1. An osmotic dosage form for once-daily administration to a subject in need thereof, 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. A port extending from the periphery of the dosage form into the tablet core, the osmotic dosage form.

[0141] 2. The dosage form according to aspect 1, wherein the active layer further comprises an active layer controlled-release agent.

[0142] 3. The dosage form according to aspect 2, 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.

[0143] 4. The dosage form according to aspect 2 or 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.

[0144] 5. The dosage form according to aspect 4, wherein the active layer controlled-release agent comprises a polyoxyethylene polymer that is polyethylene oxide.

[0145] 6. The dosage form according to aspect 5, wherein the polyethylene oxide in the active layer has an average molecular weight of 100,000 to 500,000 Daltons.

[0146] 7. The dosage form according to aspect 6, wherein the polyethylene oxide in the active layer has an average molecular weight of 200,000 Daltons.

[0147] 8. The dosage form according to 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 mass based on the total mass of the active layer.

[0148] 9. The controlled-release agent for the active layer is present in the active layer in an amount of about 70% to about 95% by mass based on the total mass of the active layer, or in an amount of about 80% to about 90% or about 85% to about 95% by mass based on the total mass of the active layer, and the dosage form according to aspect 8.

[0149] 10. The mass ratio of the amount of deutetrabenazine fine particles in the active layer to the controlled-release agent for the active layer is 2:3 to 1:50, or 2:5 to 1:5, or 1:4 to 1:9, or 1:5 to 1:19, or 1:5 to 1:7, or 1:12 to 1:15, or 1:20 to 1:30, and the dosage form according to any one of aspects 2 to 9.

[0150] 11. The active layer further contains at least one antioxidant for the active layer, and the dosage form according to any one of the foregoing aspects.

[0151] 12. The antioxidant for the active layer contains at least one of tertiary-butyl-4-methoxyphenol (a mixture of 2-isomer and 3-isomer), 2,6-di-tertiary-butyl-p-cresol, propyl gallate, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline) (ethoxyquin), nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole, butylated hydroxytoluene, or any mixture thereof, and the dosage form according to aspect 11.

[0152] 13. The antioxidant for the active layer contains a mixture of butylated hydroxyanisole and butylated hydroxytoluene, and the dosage form according to aspect 12.

[0153] 14. The antioxidant for the active layer is present in the active layer in an amount of about 0.001% to about 1% by mass based on the total mass of the active layer, and the dosage form according to any one of aspects 11 to 13.

[0154] 15. The active layer further contains at least one of the active layer binders, and the dosage form according to any one of the foregoing aspects.

[0155] 16. The dosage form according to embodiment 15, wherein the active layer binder comprises at least one of hypromellose (hydroxypropylmethylcellulose), starch, gelatin, agar, natural rubber or synthetic rubber, or any mixture thereof.

[0156] 17. The dosage form according to embodiment 16, wherein the active layer binder comprises hypromellose.

[0157] 18. The dosage form according to any one of embodiments 15 to 17, wherein the active layer binder is present in the active layer in an amount of about 2% to about 20% by mass based on the total mass of the active layer.

[0158] 19. The dosage form according to any of the foregoing embodiments, wherein the active layer further comprises one or more pharmaceutically acceptable excipients.

[0159] 20. The dosage form according to any of the foregoing embodiments, wherein the active layer comprises deutetrabenazine microparticles, an active layer controlled release agent which is a polymer having a viscosity of about 55 to 90 mPa s, and an antioxidant.

[0160] 21. The dosage form according to embodiment 20, wherein the active layer comprises deutetrabenazine microparticles, butylated hydroxyanisole, butylated hydroxytoluene, polyethylene oxide, hypromellose and magnesium stearate.

[0161] 22. The dosage form according to any of the foregoing embodiments, wherein the push layer comprises an osmotic agent and a push layer controlled release agent.

[0162] 23. The dosage form according to embodiment 22, wherein the osmotic agent comprises an inorganic salt, a carbohydrate, or any mixture thereof.

[0163] 24. The dosage form according to embodiment 23, wherein the osmotic agent comprises a carbohydrate which is d-mannitol, sorbitol, inositol, monosaccharide, oligosaccharide, polysaccharide, or any mixture thereof.

[0164] 25. The dosage form according to embodiment 23, wherein the osmotic agent comprises an inorganic salt which is magnesium sulfate, magnesium chloride, potassium sulfate, sodium chloride, sodium sulfate, lithium sulfate, sodium phosphate, potassium phosphate, or any mixture thereof.

[0165] 26. The dosage form according to embodiment 25, wherein the osmotic agent is sodium chloride / comprises sodium chloride.

[0166] 27. The dosage form according to any one of embodiments 22 - 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.

[0167] 28. The dosage form according to embodiment 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.

[0168] 29. The dosage form according to embodiment 27 or 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.

[0169] 30. The dosage form according to any one of embodiments 27 - 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.

[0170] 31. The dosage form according to embodiment 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.

[0171] 32. The dosage form according to any one of embodiments 22 - 31, wherein the push layer controlled - release agent comprises a polymer having a viscosity of about 5500 - 7500 mPa s.

[0172] 33. The dosage form according to embodiment 32, wherein the polymer having a viscosity of about 5500 - 7500 mPa s is selected from polyoxyethylene polymers, ionic hydrogels, hydrophilic polymers, hydrophobic polymers, or any mixture thereof.

[0173] 34. The dosage form according to aspect 33, wherein the push layer controlled release agent is polyethylene oxide.

[0174] 35. The dosage form according to 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.

[0175] 36. The dosage form according to aspect 35, wherein the polyethylene oxide in the push layer has an average molecular weight of 5,000,000 Daltons.

[0176] 37. The dosage form according to 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% by mass to about 80% by mass based on the total mass of the push layer.

[0177] 38. The dosage form according to aspect 37, wherein the push layer controlled release agent is present in the push layer in an amount of about 60% by mass to about 70% by mass based on the total mass of the push layer.

[0178] 39. The dosage form according to any one of aspects 22 to 38, wherein the mass ratio of the osmotic pressure agent to the push layer controlled release agent in the push layer is 1:2 to 1:3.5 or 1:2 to 1:2.5.

[0179] 40. The dosage form according to any one of aspects 22 to 39, wherein the push layer further comprises a push layer binder.

[0180] 41. The dosage form according to aspect 40, wherein the push layer binder comprises hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, natural rubber or synthetic rubber, or any mixture thereof.

[0181] 42. The dosage form according to aspect 41, wherein the push layer binder comprises hypromellose.

[0182] 43. The dosage form according to any one of aspects 40 to 42, wherein the push layer binder is present in the push layer in an amount of about 2% by mass to about 10% by mass based on the total mass of the push layer.

[0183] 44. The dosage form according to embodiment 43, wherein the push layer binder is present in the push layer in an amount of about 4% to about 6% by mass, or about 3% to about 6% by mass based on the total mass of the push layer.

[0184] 45. The dosage form according to any one of embodiments 22 to 44, wherein the push layer further comprises a pharmaceutically acceptable excipient.

[0185] 46. The dosage form according to any one of embodiments 22 to 45, wherein the push layer comprises sodium chloride and a polymer having a viscosity of about 5500 to 7500 mPa s.

[0186] 47. The dosage form according to embodiment 46, wherein the push layer comprises sodium chloride, polyethylene oxide, hydroxypropyl methylcellulose, a colorant, and magnesium stearate.

[0187] 48. The dosage form according to any of the foregoing embodiments, wherein the semipermeable layer comprises a water-soluble polymer, a water-insoluble polymer, or any mixture thereof.

[0188] 49. The dosage form according to embodiment 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 copolymer, poly(orthoester), polyacetal, and a selectively permeable poly(glycolic acid), poly(lactic acid) derivative, Eudragit cellulose acetate, or any mixture thereof.

[0189] 50. The dosage form according to embodiment 49, wherein the water-insoluble polymer is cellulose acetate and has an acetyl content of 32% to 39.8%.

[0190] 51. The dosage form according to any of the foregoing embodiments, wherein the semipermeable layer comprises cellulose acetate and polyethylene glycol.

[0191] 52. The pharmaceutical dosage form according to 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 mass, or about 85% to about 95% by mass, based on the mass of the semipermeable layer.

[0192] 53. The pharmaceutical dosage form according to any of the preceding aspects, wherein the semipermeable layer contains an agent that forms pores.

[0193] 54. The pharmaceutical dosage form according to aspect 53, wherein the agent that forms pores comprises a water-soluble sugar, a water-soluble salt, a water-soluble solvent, a water-soluble polymer, or any mixture thereof.

[0194] 55. The pharmaceutical dosage form according to aspect 54, wherein the agent that forms pores is a water-soluble solvent that is polyethylene glycol.

[0195] 56. The pharmaceutical dosage form according to any one of aspects 53 to 55, wherein the agent that forms pores is present in the semipermeable layer in an amount of about 0.1% to about 20% by mass of the semipermeable layer.

[0196] 57. The pharmaceutical dosage form according to aspect 56, wherein the agent that forms pores is present in the semipermeable layer in an amount of about 8% to about 15% by mass of the semipermeable layer.

[0197] 58. The pharmaceutical dosage form according to any of the preceding aspects, wherein the mass ratio of the semipermeable layer to the tablet core is 1:8 to 1:10.

[0198] 59. The pharmaceutical dosage form according to any of the preceding aspects, wherein the port has a diameter of about 0.1 mm to about 1 mm.

[0199] 60. The pharmaceutical dosage form according to aspect 59, wherein the port has a diameter of about 0.4 mm to about 0.8 mm.

[0200] 61. The pharmaceutical dosage form according to any of the preceding aspects, further comprising a tablet core seal coat on the outer surface of the tablet core.

[0201] 62. The pharmaceutical dosage form according to any of the preceding aspects, further comprising a semipermeable layer seal coat on the outer surface of the semipermeable layer.

[0202] 63. The dosage form according to any one of aspects 61 to 62, wherein the tablet core seal coat and / or the semi-permeable layer seal coat contains a binder.

[0203] 64. The dosage form according to aspect 63, wherein the tablet core seal coat binder and / or the semi-permeable layer seal coat binder contains hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, natural rubber, synthetic rubber, and any mixture thereof.

[0204] 65. The dosage form according to aspect 64, wherein the tablet core seal coat binder and / or the semi-permeable layer seal coat binder is hypromellose.

[0205] 66. The dosage form according to any one of aspects 63 to 65, wherein the total amount of the binder in the dosage form is about 0 to about 20% by mass; 5% to about 15% by mass based on the total mass of the dosage form; or 5% to about 20% by mass based on the total mass of the dosage form.

[0206] 67. The dosage form according to aspect 66, wherein the total amount of the binder in the dosage form is about 8% to about 10% by mass; about 10% to about 20% by mass; or about 10% to about 20% by mass based on the total mass of the dosage form.

[0207] 68. The dosage form according to any one of the foregoing aspects, further comprising an immediate release coating on the outside of the semi-permeable membrane, and the immediate release coating contains a second amount of dutetracenazine microparticles.

[0208] 69. The dosage form according to aspect 68, wherein the immediate release coating contains about 0.1% to about 25% by mass of dutetracenazine microparticles; about 0.2% to about 5% by mass of dutetracenazine microparticles; or about 0.3% to about 2% by mass of dutetracenazine microparticles based on the total mass of the dosage form.

[0209] 70. The dosage form contains a total of 24 mg of deutetrabenazine microparticles, and the immediate-release coating contains from about 1% to about 2% by weight of deutetrabenazine microparticles based on the total weight of the dosage form, or the dosage form contains a total of 12 mg of deutetrabenazine microparticles, and the immediate-release coating contains from about 0.5% to about 1% by weight of deutetrabenazine microparticles based on the total weight of the dosage form, or the dosage form contains a total of 6 mg of deutetrabenazine microparticles, and the immediate-release coating contains from about 0.1% to about 0.5% by weight of deutetrabenazine microparticles based on the total weight of the dosage form, the dosage form according to embodiment 69.

[0210] 71. About 70% to 99% of the total amount of deutetrabenazine microparticles in the dosage form is within the active layer, the dosage form according to any one of the foregoing embodiments.

[0211] 72. About 5% to 30% of the total amount of deutetrabenazine microparticles in the dosage form is within the immediate-release coating, the dosage form according to any one of the foregoing embodiments.

[0212] 73. About 70% to 80% of the total amount of deutetrabenazine microparticles in the dosage form is within the active layer, and about 20% to 30% of the total amount of deutetrabenazine microparticles in the dosage form is within the immediate-release coating, the dosage form according to any one of the foregoing embodiments.

[0213] 74. The immediate-release coating further contains an immediate-release coating antioxidant, the dosage form according to any one of embodiments 68 to 73.

[0214] 75. The dosage form according to embodiment 74, wherein the immediate-release coating antioxidant comprises tertiary-butyl-4-methoxyphenol (a mixture of 2-isomer and 3-isomer), 2,6-di-tertiary-butyl-p-cresol, propyl gallate, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline) (ethoxyquin), nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole, butylated hydroxytoluene, and any mixture thereof.

[0215] 76. The dosage form according to embodiment 75, wherein the immediate-release coating comprises a mixture of butylated hydroxyanisole and butylated hydroxytoluene.

[0216] 77. The dosage form according to any one of embodiments 68-76, wherein the immediate-release coating further comprises an additional pharmaceutically acceptable excipient.

[0217] 78. The dosage form according to any one of embodiments 68-77, wherein the immediate-release coating comprises deutetrabenazine microparticles, butylated hydroxyanisole, butylated hydroxytoluene, hypromellose, and polysorbate 80.

[0218] 79. The dosage form according to any of the foregoing embodiments, wherein the total amount of deutetrabenazine microparticles in the dosage form is from about 6 mg to about 48 mg.

[0219] 80. The dosage form according to any of the foregoing embodiments, wherein the total amount of deutetrabenazine microparticles in the dosage form is about 6 mg.

[0220] 81. The dosage form according to any of the foregoing embodiments, wherein the total amount of deutetrabenazine microparticles in the dosage form is about 12 mg.

[0221] 82. The dosage form according to any of the foregoing embodiments, wherein the total amount of deutetrabenazine microparticles in the dosage form is about 24 mg.

[0222] 83. The dosage form according to any of the foregoing aspects, wherein the total amount of deutetrabenazine fine particles in the dosage form is about 48 mg.

[0223] 84. The dosage form according to any of the foregoing aspects, wherein the total amount of deutetrabenazine fine particles is about 0.5% to about 15% by mass based on the total mass of the dosage form.

[0224] 85. The dosage form according to aspect 84, wherein the total amount of deutetrabenazine fine particles is about 1% to about 10% by mass based on the total mass of the dosage form.

[0225] 86. The dosage form according to aspect 85, which contains a total of 6 mg of deutetrabenazine fine particles and the total amount of deutetrabenazine fine particles is about 0.5% to about 3% by mass based on the total mass of the dosage form, or the dosage form contains a total of 12 mg of deutetrabenazine fine particles and the total amount of deutetrabenazine fine particles is about 1% to about 5% by mass based on the total mass of the dosage form, or the dosage form contains a total of 24 mg of deutetrabenazine fine particles and the total amount of deutetrabenazine fine particles is about 5% to about 10% by mass based on the total mass of the dosage form.

[0226] 87. The dosage form according to any of the foregoing aspects, wherein the deutetrabenazine fine particles have a particle size of about 1 μm to about 30 μm.

[0227] 88. The dosage form according to aspect 87, wherein the deutetrabenazine fine particles have a particle size that results in a D 90 of 15 μm.

[0228] 89. The dosage form according to aspect 87 or 88, wherein the deutetrabenazine fine particles have a particle size that results in a D 50 of 10 μm.

[0229] 90. The dosage form according to any one of aspects 87 to 89, wherein the deutetrabenazine fine particles have a particle size that results in a D 10 of 3 μm.

[0230] 91. A method for treating hyperkinetic movement disorder in a subject in need thereof, the method comprising orally administering to the subject, on a once-daily basis, an osmotic dosage form according to any one of the foregoing aspects.

[0231] 92. The method according to aspect 91, wherein the movement disorder is selected from chorea, akathisia, dystonia, tremor, and tic.

[0232] 93. The method according to aspect 92, wherein the movement disorder is selected from chorea associated with Huntington's disease, tardive dystonia, tic associated with Tourette syndrome, levodopa-induced dystonia in Parkinson's disease, and dystonia in cerebral palsy.

[0233] 94. The method according to any one of aspects 91 to 93, comprising orally administering to the subject, on a once-daily basis, an osmotic dosage form according to any one of aspects 1 to 90, wherein a single administration of an osmotic dosage form containing a total of 6 mg of deutetrabenazine microparticles provides a geometric mean AUC of about 91,250 - 142,750 h*pg / mL 0-inf for the total α- and β-dihydrodeutetrabenazine in vivo plasma profile.

[0234] 95. The method according to any one of aspects 91 to 94, comprising orally administering to the subject, on a once-daily basis, an osmotic dosage form according to any one of aspects 1 to 90, wherein a single administration of an osmotic dosage form containing a total of 6 mg of deutetrabenazine microparticles provides a geometric mean C of less than about 4,600 pg / mL max for the total α- and β-dihydrodeutetrabenazine in vivo plasma profile.

[0235] 96. The method according to any one of aspects 91 to 95, comprising orally administering to the subject, on a once-daily basis, an osmotic dosage form according to any one of aspects 1 to 90, wherein a single administration of an osmotic dosage form containing a total of 12 mg of deutetrabenazine microparticles provides a geometric mean AUC of about 182,500 - 285,500 h*pg / mL 0-infThe method according to any one of aspects 91 to 93, which provides an in vivo plasma profile of total α- and β-dihydrotetrabenazine, including

[0236] 97. Administering orally to a subject once a day an osmotic dosage form according to any one of aspects 1 to 90, wherein a single administration of an osmotic dosage form containing a total of 12 mg of tetrabenazine microparticles results in a geometric mean C of less than about 9,200 pg / mL max The method according to any one of aspects 91 to 93 or 96, which provides an in vivo plasma profile of total α- and β-dihydrotetrabenazine, including

[0237] 98. Administering orally to a subject once a day an osmotic dosage form according to any one of aspects 1 to 90, wherein a single administration of an osmotic dosage form containing a total of 24 mg of tetrabenazine microparticles results in a geometric mean AUC of about 365,000 - 571,000 h*pg / mL 0-inf The method according to any one of aspects 91 to 93, which provides an in vivo plasma profile of total α- and β-dihydrotetrabenazine, including

[0238] 99. Administering orally to a subject once a day an osmotic dosage form according to any one of aspects 1 to 90, wherein a single administration of an osmotic dosage form containing a total of 24 mg of tetrabenazine microparticles results in a geometric mean C of less than about 18,400 pg / mL max The method according to any one of aspects 91 to 93 or aspect 98, which provides an in vivo plasma profile of total α- and β-dihydrotetrabenazine, including

[0239] 100. Administering orally to a subject once a day an osmotic dosage form according to any one of aspects 1 to 90, wherein a single administration of an osmotic dosage form containing a total of 36 mg of tetrabenazine microparticles results in a geometric mean AUC of about 547,500 - 856,500 h*pg / mL 0-inf The method according to any one of aspects 91 to 93, which provides an in vivo plasma profile of total α- and β-dihydrotetrabenazine, including

[0240] 101. Administering once daily to a subject an osmotic dosage form according to any one of Aspects 1-90, comprising a single administration of an osmotic dosage form containing a total of 36 mg of deutetrabenazine microparticles, resulting in a geometric mean C of less than about 27,600 pg / mL max A method according to any one of Aspects 91-93 or 100, which provides an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine, including C

[0241] 102. Administering once daily to a subject an osmotic dosage form according to any one of Aspects 1-90, comprising a single administration of an osmotic dosage form containing a total of 48 mg of deutetrabenazine microparticles, resulting in a geometric mean AUC of about 730,000-1,142,000 h*pg / mL 0-inf A method according to any one of Aspects 91-93, which provides an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine, including AUC

[0242] 103. Administering once daily to a subject an osmotic dosage form according to any one of Aspects 1-90, comprising a single administration of an osmotic dosage form containing a total of 48 mg of deutetrabenazine microparticles, resulting in a geometric mean C of less than about 36,800 pg / mL max A method according to any one of Aspects 91-93 or 102, which provides an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine, including C

[0243] 104. Administering once daily to a subject an osmotic dosage form according to any one of Aspects 1-90, with an osmotic dosage form containing a total of 6 mg of deutetrabenazine microparticles, resulting in an average AUC of about 102,500-200,000 h*pg / mL 0-24 A method according to any one of Aspects 91-93, which provides an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine at steady state, including AUC

[0244] 105. Administering once daily to a subject an osmotic dosage form according to any one of embodiments 1 to 90, and providing an in vivo plasma profile of total α- and β-dihydrotetrabenazine in steady state that includes an average C of less than about 10,000 pg / mL by the osmotic dosage form containing a total amount of 6 mg of tetrabenazine microparticles. max The method according to any one of embodiments 91 to 93 or embodiment 104, wherein an in vivo plasma profile of total α- and β-dihydrotetrabenazine in steady state is provided.

[0245] 106. Administering once daily to a subject an osmotic dosage form according to any one of embodiments 1 to 90, and providing an in vivo plasma profile of total α- and β-dihydrotetrabenazine in steady state that includes an average AUC of about 205,000 - 400,000 h*pg / mL by the osmotic dosage form containing a total amount of 12 mg of tetrabenazine microparticles. 0-24 The method according to any one of embodiments 91 to 93, wherein an in vivo plasma profile of total α- and β-dihydrotetrabenazine in steady state is provided.

[0246] 107. Administering once daily to a subject an osmotic dosage form according to any one of embodiments 1 to 90, and providing an in vivo plasma profile of total α- and β-dihydrotetrabenazine in steady state that includes an average C of less than about 20,000 pg / mL by the osmotic dosage form containing a total amount of 12 mg of tetrabenazine microparticles. max The method according to any one of embodiments 91 to 93 or embodiment 106, wherein an in vivo plasma profile of total α- and β-dihydrotetrabenazine in steady state is provided.

[0247] 108. Administering once daily to a subject an osmotic dosage form according to any one of embodiments 1 to 90, and providing an in vivo plasma profile of total α- and β-dihydrotetrabenazine in steady state that includes an average AUC of about 410,000 - 800,000 h*pg / mL by the osmotic dosage form containing a total amount of 24 mg of tetrabenazine microparticles. 0-24 The method according to any one of embodiments 91 to 93, wherein an in vivo plasma profile of total α- and β-dihydrotetrabenazine in steady state is provided.

[0248] 109. Administering once daily to a subject an osmotic dosage form according to any one of embodiments 1 to 90, wherein the osmotic dosage form contains a total amount of 24 mg of deutetrabenazine microparticles, and the average C is less than about 40,000 pg / mL max is provided, and an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine in the steady state is provided, according to any one of embodiments 91 to 93 or embodiment 108.

[0249] 110. Administering once daily to a subject an osmotic dosage form according to any one of embodiments 1 to 90, wherein the osmotic dosage form contains a total amount of 36 mg of deutetrabenazine microparticles, and the average AUC is about 615,000 - 1,200,000 h*pg / mL 0-24 is provided, and an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine in the steady state is provided, according to any one of embodiments 91 to 93.

[0250] 111. Administering once daily to a subject an osmotic dosage form according to any one of embodiments 1 to 90, wherein the osmotic dosage form contains a total amount of 36 mg of deutetrabenazine microparticles, and the average C is less than about 60,000 pg / mL max is provided, and an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine in the steady state is provided, according to any one of embodiments 91 to 93 or embodiment 110.

[0251] 112. Administering once daily to a subject an osmotic dosage form according to any one of embodiments 1 to 90, wherein the osmotic dosage form contains a total amount of 48 mg of deutetrabenazine microparticles, and the average AUC is about 820,000 - 1,600,000 h*pg / mL 0-24 is provided, and an in vivo plasma profile of total α- and β-dihydrodeutetrabenazine in the steady state is provided, according to any one of embodiments 91 to 93.

[0252] 113. Administering an osmotic dosage form according to any one of embodiments 1 to 90 once daily to a subject, and by an osmotic dosage form containing a total of 48 mg of deutetrabenazine microparticles, an average C of less than about 80,000 pg / mL max is provided, a method according to any one of embodiments 91 to 93 or embodiment 112, wherein the in vivo plasma profile of total α- and β-dihydrodeutetrabenazine in the steady state is provided.

[0253] 114. A method according to any one of embodiments 91 to 113, comprising administering an osmotic dosage form according to any one of embodiments 1 to 90, and when tested in 500 mL of acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus, 15% or less of the drug formulation is released after 2 hours.

[0254] 115. A method according to any one of embodiments 91 to 113, comprising administering an osmotic dosage form according to any one of embodiments 1 to 90, and when tested in 500 mL of acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus, 60% or less of the drug formulation is released after 8 hours.

[0255] 116. The dosage form or method according to any of the preceding embodiments, wherein the dosage form is administered with food.

[0256] 117. The dosage form or method according to any one of embodiments 1 to 115, wherein the dosage form is administered under fasting conditions.

[0257] All patents, patent applications, and publications are hereby incorporated by reference as if each individual publication was specifically and individually indicated to be incorporated by reference. The invention exemplified herein can be practiced even in the absence of any element not specifically disclosed herein. The terms and expressions used are used as terms of description and not of limitation, and in the use of such terms and expressions, it is not intended to exclude equivalents of the features shown and described or portions thereof, and it is recognized that various modifications are possible within the scope of the invention as set forth in the claims. Accordingly, although the invention is specifically disclosed by the preferred embodiments and any features, modifications and variations of the concepts disclosed herein are possible by those skilled in the art, and it should be understood that such modifications and variations are considered to be within the scope of the invention as defined by the appended claims.

[0258] Regarding the foregoing embodiments, each embodiment disclosed herein is intended to be applicable to each of the other disclosed embodiments. For example, the elements recited in a method embodiment can be used in the pharmaceutical compositions, packages, and use / method embodiments described herein, and vice versa.

Examples

[0259] The following examples are provided to supplement the previous disclosure and provide a better understanding of the subject matter described herein. These examples should not be considered as limiting the described subject matter. The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes therefrom will be apparent to those skilled in the art and should be included within the true scope of the disclosure and can be made without departing from the true scope of the disclosure.

[0260] (Example 1) Manufacturing process of osmotic tablets, 24 mg of deutetrabenazine Figures 2a and 2b show the flowchart of the overall manufacturing process of the osmotic dosage form according to the present disclosure. The following Table 1 to Table 13 provide non-limiting examples of the materials used to generate the dosage forms described herein and their relative amounts. The preparation method was as follows: A: Treatment of the active layer material: Dutetrabenazine (micronized) and the active layer controlled release agent were passed through a 30-mesh screen and combined with a binder (previously passed through a 20-mesh screen). The mixture was introduced into a high-shear granulator and dry mixed for about 5 minutes. While mixing, an antioxidant (pre-dissolved in alcohol) was added to the powder being mixed to granulate the material. Mixing was continued until the desired granulation endpoint was achieved. The resulting granules were wet screened to break any over-sized aggregates. The material was fed into a diffusion mixer (V blender) and blended for about 15 minutes. A lubricant passed through a 30-mesh screen was added to the material blended in the V blender. The contents were lubricated for about 5 minutes. B: Compression of the tablet core: The active layer material was discharged into a two-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 the two-layer rotary tablet press. The tablet core was compressed. C: Optional tablet core seal coat: A tablet core seal coat containing a binder solution was applied to the tablet core. D: Semipermeable layer: A semipermeable layer containing a solution of cellulose acetate and an optional pore-forming agent was applied to the tablet core, or the sealed tablet core, using a pan coater. E: Optional semipermeable layer seal coat: A semipermeable layer seal coat containing a binder solution was applied to the tablets that compromise the semipermeable wall. F: Creation of the exit means: Pores were laser drilled through the layers to the active layer.

[0261] The final immediate release coating containing dutetrabenazine is optionally applied to the active layer following the processing steps as detailed above using similar materials.

[0262]

Table 1

[0263]

Table 2

[0264]

Table 3

[0265]

Table 4

[0266]

Table 5

[0267]

Table 6

[0268]

Table 7

[0269]

Table 8

[0270]

Table 9

[0271]

Table 10

[0272]

Table 11

[0273]

Table 12

[0274]

Table 13

[0275]

Table 14

[0276]

Table 15

[0277] (Example 2) Bioavailability Evaluation of Single-Dose An osmotic dosage form containing 24 mg of deutetrabenazine was generated as disclosed in Example 1 and studied in a single-dose pharmacokinetic study.

[0278] The primary objective was to evaluate the comparative bioavailability (BA) of deutetrabenazine and deuterated α- and β-dihydrotetrabenazine (deuHTBZ) metabolites following a single dose of a 24 mg, once-daily (q.d.) osmotic formulation (Test), compared to a single 12 mg dose of AUSTEDO® tablets administered twice daily (b.i.d.) at 12-hour intervals under fasting conditions.

[0279] Study Population and Number of Subjects: The study included healthy, non-smoking male and female subjects aged 18 to 45 years. A total of 8 healthy subjects (4 per sequence) were enrolled in the study.

[0280] Participation period of the subjects: The study included a 4-week screening period (Period 1), an open-label treatment period (Period 2) using the test formulation (Test2A) and the reference formulation (R), and a follow-up visit at least 1 day later (Period 3).

[0281] Treatment: Treatment sequence A: Day 1 - Administration of Test2A. Days 2 - 3 - After washing out Test2A for at least 6 hours, administer R. Treatment sequence B: Day 1 - Administration of R. Days 2 - 3 - After washing out R for at least 6 hours, administer Test2A. For the primary objective, the following parameters were used to address it: - Observed maximum concentration (Cmax) - Area under the plasma concentration-time curve (AUC) from time 0 to the time of the final measurable plasma concentration (AUC0-t) - AUC extrapolated to infinity (AUC0-∞) - AUC from time 0 to 24 hours after administration (AUC0-24h)

[0282] Analysis AUC0-t, AUC0-∞, and AUC0-24h were calculated using the trapezoidal rule. The data of Cmax, AUC0-t, AUC0-∞, and AUC0-24h were natural logarithm-transformed before statistical analysis. The comparison of Cmax, AUC0-t, AUC0-∞, and AUC0-24h between treatments (T2A vs. R) was performed using a fixed effect term regarding the sequence, period, treatment group, and random effect of the subjects within the sequence, and an individual parametric analysis of variance (ANOVA) model was used. The difference between the reference formulation (R) and the test formulation (Test2A) was evaluated by constructing a 90% confidence interval for the test / reference ratio based on the least squares means from ANOVA for the logarithm-transformed Cmax, AUC0-t, AUC0-∞, and AUC0-24h. The treatment differences and the associated 90% confidence intervals estimated from ANOVA on the logarithmic scale were back-transformed to obtain the estimated ratio of geometric means between treatment groups and the 90% confidence interval for this ratio.

[0283] Figures 3a and 3b show the results (mean concentration of dutetravanazine vs. time) of the R treatment compared to the Test2A treatment on the direct scale and logarithmic scale, respectively. The following Table 14 (Table 16) provides the specified pK parameters observed for dutetravanazine regarding Test2A compared to R.

[0284]

Table 16

[0285] Figures 4a and 4b show the data of metabolites (mean concentration of total deuHTBZ vs. time) regarding the treatment using R compared to Test2A on the direct scale and logarithmic scale, respectively. The following Table 15 (Table 17) provides the specified pK parameters observed for total deuHTBZ regarding Test2A compared to R.

[0286]

Table 17

[0287] As shown in Table 14 (Table 16) and Table 15 (Table 17), the once-daily dose of Test2A provided the acceptable deuHTBZ plasma concentration observed in the reference. The osmotic dosage forms disclosed herein are administered once daily, provide an acceptable treatment effect against the effect of AUSTEDO® and have no safety concerns.

[0288] The results of this study with a crossover design further show that patients can safely and effectively transition from twice-daily (split-dose) administration of deutetrabenazine tablets to once-daily osmotic dosage forms. The results of this study with a crossover design also show that patients can safely and effectively transition from once-daily osmotic dosage forms to twice-daily (split-dose) administration of deutetrabenazine tablets.

[0289] (Example 3) Bioavailability Evaluation of Multiple Doses As disclosed in Example 1, an osmotic dosage form containing 24 mg of deutetrabenazine is produced and studied in an open-label, randomized, multiple-dose, two-way crossover study in healthy volunteers.

[0290] The primary objective was to evaluate the bioequivalence (BE) of once-daily (qd) administration of Test2A compared to bid administration of R under fasting or fed conditions.

[0291] Treatments included once-daily 7-day repeated dosing of Test2A versus bid 7-day repeated dosing of R.

[0292] A qualified model was used to predict the steady state, AUCt, C max , t max , C min , C av for deutetrabenazine and deuHTBZ concentrations.

[0293] The following Table 16 (Table 18) provides simulation results regarding the steady-state pK parameters of dutetravanazine for Test 2A compared to R, and the pK parameters regarding the total deuHTBZ of Test 2A compared to R.

[0294] [Table 18]

[0295] Research Results Reproducible concentration-time profiles were obtained for all analytes following treatment, dosing of Test 2A and R.

[0296] The primary objective of demonstrating the bioequivalence (BE) of dutetravanazine and deuHTBZ (individual and total) between the Test 2A formulation and the R formulation in terms of AUC 0-24h,ss was achieved. The geometric LS mean ratios of AUC 0-24h,ss were 115.15% for dutetravanazine and 95.05% for total deuHTBZ.

[0297] The results of this study with a crossover design further show that patients can safely and effectively switch from twice-daily dosing of dutetravanazine tablets to once-daily osmotic formulations. The results of this study with a crossover design further show that patients can safely and effectively switch from once-daily osmotic formulations to twice-daily dosing of dutetravanazine tablets.

[0298] (Example 4) Study of Food Effect As disclosed in Example 1, an osmotic formulation containing 24 mg of dutetravanazine was generated and studied in an open-label randomized 3-period, 3-treatment, 6-sequence, crossover study to evaluate the comparative bioavailability of dutetravanazine and deuHTBZ in the fed state compared to the fasting state following a single administration of a 24 mg osmotic formulation once daily (qd).

[0299] The treatment includes the following: Subjects were randomly assigned to receive one of three treatments, each of which was one of six treatment sequences: Test2A in the fed state (fed QD), Test2A in the fasted state (fasted QD), and R in the fed state at 12-hour intervals [fed twice daily (BID)], as shown in Figure 5. There was at least a 6-day washout period between the first dose of one period and the first dose of the next period. The treatment drug was orally administered to the subjects in a sitting position on the morning of the first day (Day 1) of each dosing period. The second dose of R in the fed BID group was administered exactly 12 hours after the morning dose.

[0300] During each period, all subjects fasted overnight at least 10 hours before the first dose. Subjects receiving R BID in the fed state or Test2A tablets in the fed state were provided with a standardized high-calorie, high-fat breakfast (containing 800 - 1000 kilocalories [kcal] with 50% fat) 30 minutes before the first dose. For R BID in the fed state, a standardized dinner was provided 30 minutes before the second dose, and for Test2A tablets in the fed state, a standardized dinner was provided at the corresponding time.

[0301] Blood samples for pharmacokinetic analysis were collected before dosing and up to 96 hours after dosing during all treatment periods.

[0302] AUClast, Cmax, tmax, Cmin, and Cav were analyzed for dutetravanazine and deuHTBZ.

[0303] Results For all analytes, the variability of the Test2A fed treatment was generally similar to the variability of the Test2A fasted treatment, indicating that the variability of the pharmacokinetics of the metabolites did not increase significantly when a single 24-mg tablet was administered in the fed state compared to when a single 24-mg tablet was administered in the fasted state.

[0304] After a single oral administration of one 24 mg QD osmotic tablet under fed and fasted conditions, all analytes met the BE criteria. A significant food effect on PK was not apparent, and the 24 mg QD tablet can be administered with or without food.

[0305] In healthy subjects, a single dose of 24 mg deutetrabenazine QD osmotic tablets, either under fed or fasted conditions, and twice-daily administration of 12 mg deutetrabenazine tablets (fed condition) appeared to be safe and well tolerated.

Explanation of symbols

[0306] 2 dosage forms 4 active layers 6 push layers 8 semipermeable membranes 10 ports

Claims

1. A method of transitioning a human subject being treated with deutetrabenazine at a total daily dose of twice a day (bid) to once a day of the total daily dose of deutetrabenazine for controlling abnormal involuntary movements, comprising: a) administering to the human subject the final dose of deutetrabenazine twice a day; and b) administering to the human subject once a day the total daily dose of deutetrabenazine the next day. A method as described above.

2. The method according to claim 1, wherein the total daily dose of deutetrabenazine is 12 mg to 48 mg; or 12 mg; or 18 mg; or 24 mg; or 30 mg; or 36 mg; or 42 mg; or 48 mg.

3. The method according to claim 1, wherein the once-daily deutetrabenazine is administered as a sustained-release osmotic dosage form.

4. The osmotic dosage form is: a. A tablet core comprising an active layer and a push layer, wherein the active layer contains a predetermined amount of deutetrabenazine fine particles and an active layer controlled-release agent, and the push layer contains an osmotic agent and a push layer controlled-release agent, the active layer and the push layer, and an optional tablet seal coat on the outer surface of the tablet core; b. A semi-permeable layer surrounding the tablet core; c. A port extending through the semi-permeable layer to the tablet core; and d. An optional immediate-release coating containing a second amount of deutetrabenazine fine particles on the outside of the semi-permeable layer.

5. The method according to claim 4, wherein about 70% to 80% of the total amount of deutetrabenazine fine particles present in the osmotic dosage form is present in the active layer, and about 20% to 30% of the total amount of deutetrabenazine fine particles present in the osmotic dosage form is present in the immediate-release coating.

6. The dutetravazine microparticles are D 90 is 15 μm, D 50 is 10 μm, and / or D 10 has a particle size of 3 μm, the method according to claim 1.

7. The method according to claim 1, wherein the abnormal involuntary movement is chorea, akathisia, dyskinesia, tremor, tic, chorea associated with Huntington's disease, tardive dyskinesia, tic associated with Tourette syndrome, Parkinson's disease levodopa-induced dyskinesia, or dyskinesia in cerebral palsy.

8. The method according to claim 1, wherein the total daily dose of once-daily deutetrabenazine is administered with food or without food.

9. A method of transitioning a human subject being treated with once-daily total daily dose of deutetrabenazine to twice-daily (bid) the same total daily dose of deutetrabenazine to control abnormal involuntary movements, comprising: a) administering the last once-daily dose of said deutetrabenazine; and b) administering to said subject the next day the twice-daily total daily dose of said deutetrabenazine. **Claim 10** The method according to claim 9, wherein the total daily dose of deutetrabenazine is 12 mg to 48 mg; or 12 mg; or 18 mg; or 24 mg; or 30 mg; or 36 mg; or 42 mg; or 48 mg. **Claim 11** The method according to claim 9, wherein the once-daily dose of deutetrabenazine is administered as a sustained-release osmotic dosage form. **Claim 12** The osmotic dosage form is: a. A tablet core comprising an active layer and a push layer, wherein the active layer contains a predetermined amount of deutetrabenazine fine particles and an active layer controlled release agent, and the push layer contains an osmotic agent and a push layer controlled release agent, the active layer and the push layer, and an optional tablet seal coat on the outer surface of the tablet core; b. A semipermeable layer surrounding the tablet core; c. A port extending through the semipermeable layer to the tablet core; and d. An optional immediate release coating containing a second amount of deutetrabenazine fine particles outside the semipermeable layer. **Claim 13** The method according to claim 12, wherein about 70% to 80% of the total amount of deutetrabenazine fine particles present in the osmotic dosage form is present in the active layer, and about 20% to 30% of the total amount of deutetrabenazine fine particles present in the osmotic dosage form is present in the immediate release coating. **Claim 14** The dutetravazine microparticles are D 90 is 15 μm, D 50 is 10 μm, and / or D 10 has a particle size of 3 μm, the method according to claim 12. **Claim 15** The method according to claim 9, wherein the abnormal involuntary movement is chorea, akathisia, dyskinesia, tremor, tic, chorea associated with Huntington's disease, tardive dyskinesia, tic associated with Tourette syndrome, Parkinson's disease levodopa-induced dyskinesia, or dyskinesia in cerebral palsy. **Claim 16** The method according to claim 9, wherein the total daily dose of once-daily deutetrabenazine is administered with food or without food. **Claim 17** A method of transitioning a human subject being treated with a daily dose of tetrabenazine to a once-daily dose of dutetrabenazine to control abnormal involuntary movements, comprising: a) administering a final dose of tetrabenazine; and b) administering to the subject, the next day, a once-daily osmotic dosage form of dutetrabenazine, wherein the daily dose of tetrabenazine is 12.5 mg and the once-daily dose of dutetrabenazine is 6 mg; or wherein the daily dose of tetrabenazine is 25 mg and the once-daily dose of dutetrabenazine is 12 mg; or wherein the daily dose of tetrabenazine is 37.5 mg and the once-daily dose of dutetrabenazine is 18 mg; or wherein the daily dose of tetrabenazine is 50 mg and the once-daily dose of dutetrabenazine is 24 mg; or wherein the daily dose of tetrabenazine is 62.5 mg and the once-daily dose of dutetrabenazine is 30 mg; or wherein the daily dose of tetrabenazine is 75 mg and the once-daily dose of dutetrabenazine is 36 mg; or wherein the daily dose of tetrabenazine is 87.5 mg and the once-daily dose of dutetrabenazine is 42 mg; or wherein the daily dose of tetrabenazine is 100 mg and the once-daily dose of dutetrabenazine is 48 mg, and administering a once-daily osmotic dosage form of dutetrabenazine; and wherein the osmotic dosage form comprises: a. a tablet core comprising an active layer and a push layer, the active layer comprising a predetermined amount of dutetrabenazine microparticles and an active layer controlled release agent, the push layer comprising an osmotic agent and a push layer controlled release agent, the active layer and the push layer, and an optional tablet seal coat on the outer surface of the tablet core; b. a semipermeable layer surrounding the tablet core; c. a port extending through the semipermeable layer and into the tablet core; and d. an optional immediate release coating on the outside of the semipermeable layer, the optional immediate release coating comprising a second amount of dutetrabenazine microparticles; A method comprising the above.

18. The method according to claim 17, wherein about 70% to 80% of the total amount of dutetrabenazine microparticles present in the osmotic dosage form is present within the active layer, and about 20% to 30% of the total amount of dutetrabenazine microparticles present in the osmotic dosage form is present within the immediate release coating.

19. The dutetravazine microparticles are D 90 is 15 μm, D 50 is 10 μm, and / or D 10 has a particle size of 3 μm, the method according to claim 17.

20. The method according to claim 17, wherein the abnormal involuntary movement is chorea, akathisia, dyskinesia, tremor, tic, chorea associated with Huntington's disease, tardive dyskinesia, tic associated with Tourette syndrome, Parkinson's disease levodopa-induced dyskinesia, or dyskinesia in cerebral palsy.

21. The method according to claim 17, wherein the once-daily dosage form of deutetrabenazine is administered with food or without food.

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