Permeable dosage forms comprising deuterated tetrabenazine and methods of use thereof

Abstract

Provided herein are osmotic dosage forms containing deuterated tetrabenazine for use in the treatment of, for example, hyperactivity dyskinesia. When orally administered to a subject once a day, the dosage form provides advantageous pharmacokinetic profile to the active agent, indicating therapeutic efficacy over an extended period of time.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Application No. 17 / 835,435, filed on June 8, 2022, which is a continuation-in-part of U.S. Application No. 17 / 344,271, filed on June 10, 2021, which claims the benefit of U.S. Provisional Application No. 63 / 037,369, filed on June 10, 2020, U.S. Provisional Application No. 63 / 037,953, filed on June 11, 2020, and U.S. Provisional Application No. 63 / 044,451, filed on June 26, 2020, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to osmotic dosage forms and methods of using those dosage forms to treat hyperkinetic movement disorders arising from conditions such as Huntington's disease, tardive dyskinesia, Tourette's syndrome, levodopa-induced dyskinesias, and movement disorders in cerebral palsy. Background Art

[0004] Deutetrabenazine ((RR,SS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one) is a vesicular monoamine transporter type 2 (VMAT2). The biologically active metabolites formed from deutetrabenazine (alpha-dihydrodeutetrabenazine [α-deuHTBZ](alpha-dihydrodeutetrabenazine) and beta-dihydrodeutetrabenazine [β-deuHTBZ](beta-dihydrodeutetrabenazine)) are collectively identified as "deuHTBZ", which are potent inhibitors of VMAT2 binding. Deuterated tetrabenazine exhibits an increased half-life of its active metabolite relative to tetrabenazine (eg, US Pat. No. 8,524,733).

[0005] Deutetrabenazine is sold under the trade name It is approved by the U.S. Food and Drug Administration for the treatment of chorea (involuntary muscle movements) associated with Huntington's disease (HD) and for the treatment of tardive dyskinesia (TD) in adults. The dosage form is administered orally twice daily (bid), with a total daily dose of deutetrabenazine of 12 mg or more.

[0006] One factor that affects gastrointestinal absorption of orally administered drugs is the rate at which the drug is released from the dosage form. The drug release rate of an oral dosage form is usually measured in the form of an in vitro dissolution rate, i.e., the amount of drug released from the dosage form per unit time in, for example, an FDA-approved system. Such systems include, for example, United States Pharmacopeia (USP) dissolution apparatus I and II.

[0007] The therapeutic window of a drug is the time period during which the plasma drug concentration is within the therapeutically effective plasma drug concentration range. However, since the plasma drug concentration decreases over time, multiple doses of the drug dosage form must be administered at appropriate intervals to ensure that the plasma drug concentration remains within the therapeutic window or rises to the therapeutic window again. However, at the same time, it is necessary to avoid or minimize plasma drug concentrations that cause undesirable side effects.

[0008] Several dosage forms containing deuterated tetrabenazine are disclosed in U.S. Pat. No. 9,296,739. A dosage form that can deliver deuterated tetrabenazine in a controlled manner over an extended period of time would allow for a more advantageous dosing regimen, for example allowing once daily (qd) administration while maintaining the current regimen of There is a need for alternative dosage forms that achieve the desired therapeutic effect. Summary of the invention

[0009] Disclosed herein is an osmotic dosage form for once-daily administration of deuterated tetrabenazine to a subject in need thereof, comprising:

[0010] a. a tablet core comprising an active layer and a push layer, wherein the active layer comprises a certain amount of deuterated tetrabenazine particles;

[0011] b. a semipermeable layer surrounding the core; and

[0012] c. A port extending through the semipermeable layer into the core.

[0013] Further disclosed herein are methods of treating a hyperkinetic movement disorder in a subject, comprising: administering to the subject once daily an osmotic dosage form disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 A cross-sectional illustration of an osmotic dosage form is provided.

[0015] Figure 2a and Figure 2b A flow chart of a general manufacturing process for an osmotic dosage form according to the present disclosure is provided.

[0016] Figure 3a and Figure 3b It is shown that 12 mg is administered Plot of concentration of deuterated tetrabenazine (pg / mL) versus time (hours, "h") in subjects taking tablets bid ("R") or an osmotic dosage form containing 24 mg deuterated tetrabenazine qd ("T2A"). Figure 3a A direct scale of mean concentrations is shown, Figure 3b The logarithmic scale of the mean concentrations is shown.

[0017] Figure 4a and Figure 4b It is shown that 12 mg is administered Plot of concentration (pg / mL) of α- and β-deuHTBZ (total deuHTBZ) versus time (hours, "h") in subjects taking tablets bid ("R") or an osmotic dosage form containing 24 mg deutetrabenazine qd ("T2A"). Figure 4a A direct scale of mean concentrations is shown, Figure 4b The logarithmic scale of the mean concentrations is shown.

[0018] Figure 5 is a graph summarizing the food effect study described in Example 4. DETAILED DESCRIPTION

[0019] The subject matter may be more readily understood by reference to the following detailed description which forms a part of this disclosure. It should be understood that the present invention is not limited to the specific methods, conditions or parameters described and / or shown herein, and that the terminology used herein is only for the purpose of describing specific embodiments by way of example and is not intended to limit the claimed invention.

[0020] Unless otherwise defined herein, scientific and technical terms used in conjunction with this application shall have the meanings commonly understood by those of ordinary skill in the art. In addition, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0021] As employed above and throughout this disclosure, unless otherwise indicated, the following terms and abbreviations shall be understood to have the following meanings.

[0022] In this disclosure, the singular forms "a", "an", and "the" include plural references, and references to a particular value include at least that particular value unless the context clearly indicates otherwise. Thus, for example, a reference to a "compound" is a reference to one or more of such compounds and equivalents thereof known to those skilled in the art, and so on. As used herein, the term "plurality" means more than one. When a range of values ​​is expressed, another embodiment includes from one particular value and / or to another particular value. Similarly, when the antecedent "about" is used to express a value as an approximation, it is understood that the particular value forms another embodiment. All ranges are inclusive and combinable.

[0023] As used herein, the terms "compound", "drug", "pharmacologically active agent", "active agent" or "medicament" are used interchangeably herein and refer to one or more compounds or compositions of matter that induce a desired pharmacological and / or physiological effect by local and / or systemic action when administered to a subject (human or animal). The active agent is preferably deuterated tetrabenazine as disclosed herein.

[0024] As used herein, "dosage form" refers to a pharmaceutical form that has osmotic properties and is 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 within 8 hours after administration. The active agent is preferably deuterated tetrabenazine as disclosed herein.

[0025] As used herein, the term "pharmaceutical formulation" refers to a solution or suspension of a drug formed in situ under aqueous conditions of a dosage form, optionally together with an excipient. The active agent is preferably deuterated tetrabenazine as disclosed herein.

[0026] The term "port" or "outlet" used interchangeably refers to a device and method suitable for the drug or drug formulation to be discharged from the dosage form core, for example, any hole, passage, channel or similar opening through which the drug or drug formulation in the dosage form core can be discharged. Other expressions of this term include, for example, outlet means, orifice or hole.

[0027] As used herein, the term "treat" or "therapy" (and its various forms) includes preventative (e.g., prophylactic), curative or palliative treatment. As used herein, the term "treat" includes alleviating or reducing at least one adverse or negative effect or symptom of a condition, disease or disorder. The condition, disease or disorder may refer to a hyperkinetic movement disorder, such as, but not limited to, Huntington's disease, tardive dyskinesia, Tourette's syndrome, dystonia, dyskinesia in cerebral palsy, and levodopa-induced dyskinesia in Parkinson's disease.

[0028] The term "administering" means providing a pharmaceutical composition or dosage form disclosed herein (used interchangeably herein) to a patient.

[0029] The terms "subject," "individual," and "patient" are used interchangeably herein and refer to a human to whom treatment (including prophylactic treatment) with the dosage forms disclosed herein is provided.

[0030] "Pharmaceutically acceptable" refers to those compounds, materials, compositions and / or excipients which are, within the scope of sound medical judgment, suitable for contact with human tissues without excessive toxicity, irritation, allergic response, or other problematic complications, commensurate with a reasonable benefit / risk ratio.

[0031] The dosage forms disclosed herein may include "derivatives" of certain dosage form materials or ingredients, such as derivatives of cellulose or starch. As used herein, a "derivative" of a material may refer to a synthetic or semi-synthetic product of that material. For example, in the case of cellulose, a derivative may refer to a semi-synthetic cellulose product, such as cellophane, rayon, and cellulose acetate, cellulose esters, and cellulose ethers.

[0032] "Microparticles" refer to particles having a particle size (i.e., diameter) of less than 1 mm, such as deuterated tetrabenazine particles. In one embodiment, the median diameter (D 50 ) is from about 0.05 to about 100 μm. In another embodiment, the D 50 In another embodiment, the D 50 The deuterated tetrabenazine microparticles have a particle size distribution of about 1 μm to about 30 μm, or about 1 μm to about 25 μm, or about 5 μm to about 30 μm, or about 1 μm to about 20 μm, or about 5 μm to about 25 μm, or about 10 μm to about 20 μm. In one embodiment, the deuterated tetrabenazine microparticles have a particle size distribution of about 1 μm to about 30 μm in diameter. In another embodiment, the deuterated tetrabenazine microparticles have a diameter of 15 μm. 90 (ie, 90% of the particles have a diameter less than or equal to 15 μm). In another embodiment, the deuterated tetrabenazine microparticles have a diameter of 10 μm. 50 (ie, 50% of the particles have a diameter greater than 10 μm and 50% of the particles have a diameter less than or equal to 10 μm). In another embodiment, the deuterated tetrabenazine microparticles have a D of 3 μm. 10 (ie 10% of the particles have a diameter less than 3 μm).

[0033] Terminology D 90 , D 50 or D 10 The particle size distribution (i.e., diameter) of the microparticles can be determined by a person skilled in the art using conventional methods, such as dynamic or static light scattering of an aqueous dispersion of the microparticle composition. 90 and D 10 Value, such as D 50 The value can generally be calculated from the particle size distribution of the particles.

[0034] Osmotic dosage forms typically utilize osmotic pressure to generate a driving force for absorbing fluid, for example, from the gastrointestinal (GI) tract into a compartment formed at least in part by a semipermeable wall, layer, or membrane that allows free diffusion of fluid, but does not allow free diffusion of drug or one or more osmotic agents (if present). By designing the system to provide a relatively constant osmotic pressure and equipping it with an appropriate outlet device, a constant drug release rate can be achieved by releasing the drug formulation at a rate corresponding to the liquid intake rate caused by the relatively constant osmotic pressure. Without being limited to theory, an osmotic system can operate independently of pH, so that even if the dosage form passes through the gastrointestinal tract and encounters different microenvironments with significantly different pH values, the operation continues at a rate determined by the osmotic pressure over an extended period of time.

[0035] The example of a type of osmotic device comprises two component layers in a compartment (referred to herein as a core, and interchangeably used with a core) formed by a semipermeable wall. One component layer (referred to herein as an active layer) comprises a drug (i.e., deuterated tetrabenazine) mixed with one or more excipients, and a second component layer (referred to herein as a push layer) comprises one or more osmotic active agents optionally mixed with an excipient, but does not contain a drug. The core is further coated with a semipermeable wall, which allows aqueous fluids (i.e., from the gastrointestinal system) to enter the core. It is not desirable to be limited to theory, when fluid is absorbed into the dosage form, the active layer forms a pharmaceutical preparation, and one or more osmotic agents in the push layer swell and push the pharmaceutical preparation, thereby promoting the release of the pharmaceutical preparation 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.

[0036] Although constant release dosage forms have been shown to be effective for many different drug therapies, these dosage forms are not completely satisfactory in certain clinical situations. It has been observed that for some patients, despite maintaining a substantially constant drug release that is expected to provide sustained effectiveness, the therapeutic effectiveness of the drug still decreases below the therapeutic effectiveness threshold before the end of the desired treatment period.

[0037] It has surprisingly been found that oral dosage forms comprising deuterated tetrabenazine can be obtained that exhibit a desired release rate and thus a desired pharmacokinetic profile over an extended period of time. In some embodiments, when orally administered to a subject on a once daily (qd) basis, the osmotic dosage forms disclosed herein provide comparable release rates to those administered twice daily (bid). In certain embodiments, the osmotic dosage form provides an in vivo plasma profile of total deuHTBZ at steady state that includes an average AUC of about 410,000 to 800,000 h*pg / mL. 0-24 and an average C of less than about 40,000 pg / mL max .

[0038] The osmotic dosage form of the present disclosure includes a tablet core containing at least a push layer and an active layer, wherein the active layer includes deuterated tetrabenazine and one or more excipients for forming a drug formulation when hydrated, and wherein the push layer includes at least one osmotic agent and one or more excipients. The push layer and the active layer are both contained in the tablet core, and the tablet core is at least partially surrounded by a semipermeable layer, and the semipermeable layer has a port used as an outlet device for the drug formulation to be released from the tablet core. In some embodiments, the two layers are compressed into a double-layer tablet core, and the tablet core is surrounded by a semipermeable membrane and also has a suitable orifice for drug release therethrough.

[0039] One embodiment of the oral osmotic dosage form disclosed herein is Figure 1 . The components are not drawn to scale. The dosage form (2) comprises a bilayer tablet core. The core comprises an active layer (4) and a push layer (6), wherein the active layer (4) contains a drug such as deuterated tetrabenazine and one or more active layer excipients, and the push layer (6) contains at least one permeabilizing agent and 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, adhesives, fillers, controlled release agents, and processing aids. A semipermeable membrane (8) surrounds the bilayer tablet core, and there is a port (10) of appropriate size extending from the semipermeable membrane into the active layer (4) to allow the drug formulation to be released from the tablet core. As shown, the dosage form can be compressed longitudinally, and the port (10) is present on one side of the dosage form containing the active layer. In other embodiments, the dosage form is compressed along the transverse axis of the dosage form, and the port is present on one end of the dosage form. In all embodiments, there can be more than one port. Through the cooperation of the osmotic dosage form components and in the presence of an aqueous environment, the drug formulation is released from the active layer through the port at a desired release rate for an extended period of time. Figure 1 Not shown, but as described elsewhere herein, an optional immediate release layer (immediate release coating) external to the semipermeable layer may be further provided if desired, comprising additional drug (ie, deuterated tetrabenazine microparticles).

[0040] In one embodiment, the present invention provides an osmotic dosage form for once-daily administration to a subject in need thereof, comprising:

[0041] a. a core comprising an active layer and a push layer, wherein the active layer comprises a certain amount of deuterated tetrabenazine particles;

[0042] b. a semipermeable layer surrounding the core; and

[0043] c. A port in the semipermeable layer extending to the core.

[0044] The active layer contained in the tablet core includes deuterated tetrabenazine and a pharmaceutically acceptable active layer excipient. In a preferred embodiment, deuterated tetrabenazine is provided as deuterated tetrabenazine microparticles. Deuterated tetrabenazine microparticles can be present in the active layer in an amount (% w / % w) 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 weight based on the total weight of the active layer.

[0045] In a specific embodiment, the active layer excipient comprises an active layer controlled release agent. In one embodiment of the invention, the active layer controlled release agent has a viscosity of about 50-150mPa s. In a specific embodiment, the active layer controlled release agent has a viscosity of about 55-90mPa 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, which is polyethylene oxide. In yet another embodiment, the polyethylene oxide in the active layer has a mean molecular weight of 100,000 daltons to 500,000 daltons. In some embodiments, the polyethylene oxide in the active layer has a mean molecular weight of about 200,000 daltons.

[0046] In another embodiment, the active layer controlled release agent is present in the active layer in an amount of about 60% to about 98% by weight based on the total weight of the active layer. In a specific embodiment, the active layer controlled release agent is present in the active layer in an amount of about 70% to about 85% by weight based on the total weight of the active layer. In a specific embodiment, the active layer controlled release agent is present in the active layer in an amount of about 80% to about 90% by weight based on the total weight of the active layer. In a specific embodiment, the active layer controlled release agent is present in the active layer in an amount of about 85% to about 95% by weight based on the total weight of the active layer.

[0047] In one embodiment, the weight ratio of the amount of deuterated tetrabenazine microparticles in the active layer to the amount of the active layer controlled release agent is 2:3-1:50. In a specific embodiment, the weight ratio of the amount of deuterated tetrabenazine microparticles in the active layer to the amount of the active layer controlled release agent is 2:5-1:5. In a specific embodiment, the weight ratio of the amount of deuterated tetrabenazine microparticles in the active layer to the amount of the active layer controlled release agent is 1:4-1:9. In a specific embodiment, the weight ratio of the amount of deuterated tetrabenazine microparticles in the active layer to the amount of the active layer controlled release agent is 1:5-1:19. In a specific embodiment, the weight ratio of the amount of deuterated tetrabenazine microparticles in the active layer to the amount of the active layer controlled release agent is 1:5 to 1:10. In a specific embodiment, the weight ratio of the amount of deuterated tetrabenazine microparticles in the active layer to the amount of the active layer controlled release agent is 1:5-1:7. In a specific embodiment, the weight ratio of the amount of deuterated tetrabenazine microparticles in the active layer to the amount of the active layer controlled release agent is 1:12 to 1:15. In a specific embodiment, the weight ratio of the amount of deuterated tetrabenazine microparticles in the active layer to the amount of the active layer controlled release agent is 1:20 to 1:30.

[0048] Optional excipients in the active layer include antioxidants, binders, lubricants, colorants, etc. Such excipients are well known to those of ordinary skill in the art. In some embodiments, the active layer comprises deuterated tetrabenazine microparticles, active layer excipients, and optionally one or more antioxidants, binders, lubricants, colorants, or any combination thereof.

[0049] In one embodiment, the active layer further comprises at least one active layer antioxidant. Preferably, the active layer antioxidant comprises: tert-butyl-4-methoxyphenol (mixture of 2- and 3-isomers), 2,6-di-tert-butyl-p-cresol, propyl gallate, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquin), nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole, butylated hydroxytoluene or any mixture thereof. 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 wt % to about 1 wt % based on the total weight of the active layer.

[0050] In one embodiment, the active layer further comprises an active layer binder. In one embodiment, the active layer binder comprises hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, natural and synthetic gums and any mixture thereof. In another embodiment, the active layer binder comprises hypromellose. In one embodiment, the active layer binder can be present in the active layer in an amount of about 2 wt % to about 20 wt % based on the gross weight of the active layer.

[0051] 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 wt % to about 0.2 wt % based on the total weight of the active layer.

[0052] In one embodiment, the active layer comprises deuterated tetrabenazine microparticles and an active layer controlled release agent having a viscosity of about 55-90 mPa s. In some embodiments, the active layer controlled release agent comprises polyethylene oxide. In yet another embodiment, the active layer comprises deuterated tetrabenazine microparticles, polyethylene oxide, and further comprises butylated hydroxyanisole, butylated hydroxytoluene, hypromellose, and magnesium stearate.

[0053] The push layer contained in the core comprises an osmotic agent, which is not bound by theory and acts as a fluid attractant. It swells and pushes the active layer when exposed to an aqueous environment so that the pharmaceutical preparation can flow out from the dosage form into the external environment. An osmotic agent is defined as, for example, a non-volatile substance that is generally soluble in water and produces an osmotic gradient, thereby enabling water to penetrate and flow in. The material belonging to the osmotic agent category includes an inorganic salt or a carbohydrate. The 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 any mixture of these various substances.

[0054] In one embodiment, the osmotic agent is present in the push layer in an amount of about 5 wt % to about 50 wt % based on the gross weight of the dosage form. In one embodiment, the osmotic agent is present in the push layer in an amount of about 5 wt % to about 20 wt % based on the gross weight of the dosage form. In another embodiment, the osmotic agent is present in the push layer in an amount of about 8 wt % to about 10 wt % based on the gross weight of the dosage form.

[0055] In one embodiment, the osmotic agent is present in the push layer in an amount of about 20 wt% to about 40 wt% based on the total weight of the push layer. In one embodiment, the osmotic agent is about 30 wt% based on the total weight of the push layer.

[0056] The push layer also includes one or more excipients, such as a controlled release agent. In one embodiment, the push layer includes an osmotic agent and a push layer controlled release agent. The push layer controlled release agent includes a polymer that provides a swellable matrix when in contact with water. In one embodiment, the push layer controlled release agent has a viscosity of about 5500-7500 mPa s.

[0057] 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, which 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.

[0058] In one embodiment, the push layer controlled release agent is present in the push layer in an amount of about 50% by weight 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% by weight to about 70% by weight based on the total weight of the push layer.

[0059] In one embodiment, the weight ratio of the osmotic agent in the push layer to the push layer controlled release agent is at or about 1:2 to 1:3.5.

[0060] The push layer optionally also contains other pharmaceutically acceptable excipients, for example to stabilize the layer, provide color for tablet orientation, etc. Exemplary excipients include binders, colorants, and lubricants, and suitable examples of these types of excipients are well known to those of ordinary skill in the art.

[0061] In one embodiment, the push layer further comprises a push layer binder. The push layer binder may be selected from hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, natural and synthetic gums 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% by weight 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% by weight to about 6% by weight based on the total weight of the push layer.

[0062] The lubricant in the push layer may include any of the exemplary materials described above in conjunction with the active layer. The push layer may also include a disintegrant, such as cross-linked polyvinyl pyrrolidone, corn starch, potato starch, montmorillonite clay (e.g., magnesium aluminum silicate, e.g., ), bentonite and citrus pulp. It may also be necessary to include stabilizers for pharmaceuticals. These stabilizers include, but are not limited to, sodium bisulfite and histidine hydrochloride.

[0063] In a specific embodiment, the push layer comprises sodium chloride, polyethylene oxide, hydroxypropyl methylcellulose, colorant, and magnesium stearate.

[0064] The osmotic dosage form of the present invention includes a semipermeable layer around the core, so that fluid can flow into the core from the external fluid environment (e.g., the gastrointestinal tract of the subject) while preventing the drug from flowing out of the core. The semipermeable layer is preferably formed by a material that does not adversely affect the patient and is permeable to external fluids, such as water and biological fluids. The selective permeability material forming the semipermeable layer is insoluble in body fluids and is non-erodible or bioerodible after a predetermined period of time, wherein bioerosion corresponds to the end of the release phase of the drug formulation. As used herein, "semipermeable layer", "semipermeable wall" and "semipermeable membrane" are interchangeable.

[0065] Generally, the semipermeable material that can be used to form the semipermeable layer can have a thickness of 10 -5 Up to 10 -1 (cc mil / cm 2 hr atm) fluid permeability, which is expressed as the hydrostatic or osmotic pressure difference per atmosphere of pressure across the wall at the temperature of use. Suitable materials are known in the art, see, for example, U.S. Pat. Nos. 3,845,770 and 3,916,899.

[0066] Typical materials that can be used to form the semipermeable layer include materials known in the art, including cellulose acetate, cellulose triacetate, acetate agar, triacetate amylose, acetate beta glucan, cellulose diacetate, acetaldehyde dimethyl acetate, 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 dioctanoate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, cellulose acetate ethylcarbamate, cellulose acetate chloroacetate, cellulose dipalmitate, cellulose dioctanoate, cellulose acetate succinate ... dicaprylate), cellulose divalerate, cellulose acetate valerate, cellulose acetate succinate, cellulose propionate succinate, methylcellulose, cellulose acetate p-toluenesulfonate, cellulose acetate butyrate, selectively permeable polymers formed by coprecipitation of polycations and polyanions disclosed in U.S. Pat. Nos. 3,173,876, 3,276,586, 3,541,005, 3,541,006, and 3,546,142.

[0067] In one embodiment, the semipermeable layer comprises a water-soluble polymer or a water-insoluble polymer, including cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate butyrate; cellulose ethers, including ethylcellulose; acetate agar, amylose triacetate, beta glucan acetate, poly (vinyl methyl) ether copolymers, poly (orthoesters), polyacetals, and selectively permeable poly (glycolic acid), poly (lactic acid) derivatives, and any mixtures thereof. Cellulose acetate includes cellulose acetate polymers (e.g. ). 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 comprises a water-insoluble polymer that is cellulose acetate and comprises about 32%-40% acetyl content.

[0068] The semipermeable layer may also include a pore former or "pore former". Pore formers include biocompatible materials that dissolve, disperse or degrade to produce holes or channels in the semipermeable layer material when in contact with body fluids. Typically, water-soluble organic and non-organic 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.) can be conveniently used as pore formers. In one embodiment, in addition to water-soluble polymers or water-insoluble polymers, the semipermeable layer also includes a pore former selected from water-soluble sugars, water-soluble salts, water-soluble solvents and water-soluble polymers or any mixture thereof. In a specific embodiment, the pore former is a water-soluble solvent, which is polyethylene glycol. In one embodiment, the pore former accounts for about 0.1% by weight to about 20% by weight of the semipermeable layer. Preferably, the pore former accounts for about 8% by weight to about 15% by weight of the semipermeable layer. In one embodiment, the weight ratio of the semipermeable layer to the core is from 1:8 to 1:10.

[0069] In a specific embodiment, the semipermeable layer comprises cellulose acetate and polyethylene glycol.

[0070] Independent of or in addition to the pore-forming agent, the dosage form of the present invention includes one or more ports. The port is present in the semipermeable layer and extends from the outside of the semipermeable layer into the tablet core, providing an outlet device for the drug preparation to enter the environment outside the dosage form from the active layer in the tablet core. One or more outlets are formed by any means known in the art, including mechanical drilling, laser drilling, erosion of erodible elements, extraction, dissolution, blasting or by leaching. For example, one or more ports can be formed by mechanical or thermal means after coating or by using a light beam (e.g., laser), a particle beam or other high energy source, or can be formed in situ by a small part of the coating rupture. This rupture can be controlled by intentionally incorporating a relatively small weak part into the coating. One or more outlets can also be formed in situ by erosion of a water-soluble material plug or by rupturing a thinner part of the coating above the indentation in the core. One or more outlets can be formed by coating the core so that one or more small areas remain uncoated. In addition, one or more outlets can be a large number of holes or holes formed during coating. One or more outlets can be holes formed by leaching sorbitol, lactose, etc. from a wall or layer, as disclosed in U.S. Patent No. 4,200,098. The patent discloses holes with controlled size porosity formed by dissolving, extracting or leaching materials (e.g., dissolving, extracting or leaching sorbitol from cellulose acetate) from a wall. The preferred form of laser drilling is to use a pulsed laser, which incrementally removes material from a semipermeable layer to a desired depth to form an outlet. In certain embodiments, a port or multiple ports can be formed, for example, 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 outlet of uniform release size. The outlet device can have any shape, such as a circle, triangle, square, ellipse, etc., for uniformly dosing the release of a pharmaceutical preparation from a dosage form. The osmotic dosage form can be constructed with one or more outlets or one or more surfaces of an osmotic dosage form that are spaced apart. Such outlets and apparatus for forming such outlets are disclosed, for example, in US Pat. Nos. 3,916,899 and 4,088,864.

[0071] In one embodiment, the port has a diameter of about 0.1 mm to about 1 mm. In another embodiment, the port has a diameter of about 0.4 mm to about 0.8 mm.

[0072] In some embodiments, the dosage form also includes 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 core comprises a seal coating immediately outside the core. For example, the core seal coating can be applied to the outer surface of the compressed layered core before applying the semipermeable layer. In certain embodiments, the core comprises a semipermeable layer immediately outside the core and a seal coating immediately outside the semipermeable layer. For example, after the semipermeable membrane is applied to the core, the semipermeable layer seal coating can be applied to the outer surface of the dosage form. The seal coating material can include an adhesive, and various types of adhesives are disclosed above. In an embodiment comprising a seal coating between the core and the semipermeable membrane, the port will pass through all layers from the outside of the seal coating and enter the core.

[0073] In one embodiment, a core seal coat is applied to the outer surface of the core.

[0074] In one embodiment, a semipermeable layer seal coat is applied to the outer surface of the semipermeable layer.

[0075] In one embodiment, the core seal coating and / or the semipermeable layer seal coating comprises a binder which may be selected from the group consisting of: hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, natural and synthetic gums and any mixtures thereof. In another embodiment, the core seal coating binder and / or the semipermeable layer seal coating binder is hypromellose.

[0076] In one embodiment, the total amount of adhesive in the dosage form is about 0 to about 20 weight % based on the total weight of the dosage form. In another embodiment, the total amount of adhesive in the dosage form is about 5 weight % to about 20 weight % based on the total weight of the dosage form. In another embodiment, the total amount of adhesive in the dosage form is about 8 weight % to about 10 weight % based on the total weight of the dosage form, or about 10 weight % to about 20 weight % based on the total weight of the dosage form.

[0077] The absolute amount of deuterated tetrabenazine in the active layer of the osmotic dosage form of the present invention will depend on the dosage strength of the particular embodiment. As described more fully below, the dosage form may also include an immediate release amount of deuterated tetrabenazine microparticles outside the active layer, preferably outside the semipermeable membrane layer.

[0078] In one embodiment, the dosage form disclosed herein further comprises an immediate release coating located outside the semipermeable layer seal coating on the outside of the semipermeable membrane or applied thereto, comprising a second amount of deuterated tetrabenazine microparticles.

[0079] In one embodiment, the immediate release coating comprises deuterated tetrabenazine microparticles of about 0.1 wt % to about 25 wt % based on the total weight of the dosage form. In another embodiment, the immediate release coating comprises deuterated tetrabenazine microparticles of about 0.2 wt % to about 5 wt % based on the total weight of the dosage form. In another embodiment, the immediate release coating comprises deuterated tetrabenazine microparticles of about 0.3 wt % to about 2 wt % based on the total weight of the dosage form. In another embodiment, wherein the dosage form comprises a total of 24 mg of deuterated tetrabenazine microparticles, the immediate release coating comprises deuterated tetrabenazine microparticles of about 1 wt % to about 2 wt % based on the total weight of the dosage form. In another embodiment, wherein the dosage form comprises a total of 12 mg of deuterated tetrabenazine microparticles, the immediate release coating comprises deuterated tetrabenazine microparticles of about 0.5 wt % to about 1 wt % based on the total weight of the dosage form. In yet another embodiment, wherein the dosage form comprises a total of 6 mg of deuterated tetrabenazine microparticles, the immediate release coat comprises from about 0.1 wt % to about 0.5 wt % of deuterated tetrabenazine microparticles based on the total weight of the dosage form.

[0080] In one embodiment, at least 70% of the total amount of deuterated tetrabenazine microparticles in the dosage form are present in the active layer. In another embodiment, 70% to 100% of the total amount of deuterated tetrabenazine microparticles in the dosage form are present in the active layer. In yet another embodiment, about 70% to 80% of the total amount of deuterated tetrabenazine microparticles in the dosage form are present in the active layer. In some embodiments of the osmotic dosage form, deuterated tetrabenazine is present only in the active layer.

[0081] In an embodiment where the osmotic dosage form comprises an immediate release coating, the immediate release coating comprises up to about 30% of the total amount of deuterated tetrabenazine microparticles in the dosage form. In one embodiment, about 8% to 30% of the total amount of deuterated tetrabenazine microparticles in the dosage form are present in the immediate release coating. In one embodiment of the invention, about 70% to about 80% of the total amount of deuterated tetrabenazine microparticles in the dosage form are present in the active layer, and about 20% to about 30% of the total amount of deuterated tetrabenazine microparticles in the dosage form are present in the immediate release coating.

[0082] The dosage form of any embodiment of the present invention comprises a total amount of about 6 mg to about 48 mg of deuterated tetrabenazine microparticles. In one embodiment, the total amount of deuterated tetrabenazine microparticles in the dosage form is about 6 mg. In one embodiment, the total amount of deuterated tetrabenazine microparticles in the dosage form is about 12 mg. In another embodiment, the total amount of deuterated tetrabenazine microparticles in the dosage form is about 24 mg. In yet another embodiment, the total amount of deuterated tetrabenazine microparticles in the dosage form is about 36 mg. In another embodiment, the total amount of deuterated tetrabenazine microparticles in the dosage form is about 48 mg.

[0083] According to the present disclosure, the total amount of deuterated tetrabenazine or the total daily dose of deuterated tetrabenazine used interchangeably herein is administered to the subject as a daily dose (QD). Depending on the total daily dose, one or more than one (multiple) dosage forms may be administered to the subject in one dose. Preferably, a single dosage form is administered in one dose. In one embodiment, the total daily dose of deuterated tetrabenazine is 12mg to 48mg. In one embodiment, the total daily dose of deuterated tetrabenazine is 12mg. In one embodiment, the total daily dose of deuterated tetrabenazine is 18mg. In one embodiment, the total daily dose of deuterated tetrabenazine is 24mg. In one embodiment, the total daily dose of deuterated tetrabenazine is 30mg. In one embodiment, the total daily dose of deuterated tetrabenazine is 36mg. In one embodiment, the total daily dose of deuterated tetrabenazine is 42mg. In one embodiment, the total daily dose of deuterated tetrabenazine is 48mg.

[0084] Patients treated with deutetrabenazine twice daily (bid) may be switched to deutetrabenazine once daily (qd) the day after the last dose of bid deutetrabenazine, for the same total daily dose.

[0085] Patients treated with once-daily (qd) deutetrabenazine may be switched to twice-daily (bid) deutetrabenazine the day after the last dose of qd deutetrabenazine, for the same total daily dose.

[0086] Patients treated with tetrabenazine can be switched to a once daily (qd) osmotic dosage form of deuterated tetrabenazine disclosed herein the day after the last dose of tetrabenazine.

[0087] In one embodiment, the total amount of deuterated tetrabenazine microparticles present in the dosage form is about 0.5% to about 15% by weight based on the total weight of the permeated dosage form. In another embodiment, the total amount of deuterated tetrabenazine microparticles present in the dosage form is about 1% to about 10% by weight based on the total weight of the dosage form. In another embodiment, where the dosage form contains a total of 6 mg of deuterated tetrabenazine microparticles, the total amount of deuterated tetrabenazine microparticles present in the dosage form is about 0.5% to about 3% by weight based on the total weight of the dosage form. In another embodiment, where the dosage form contains a total of 12 mg of deuterated tetrabenazine microparticles, the total amount of deuterated tetrabenazine microparticles present in the dosage form is about 1% to about 5% by weight based on the total weight of the dosage form. In another embodiment, where the dosage form contains a total of 24 mg of deuterated tetrabenazine microparticles, the total amount of deuterated tetrabenazine microparticles present in the dosage form is about 5% to about 10% by weight based on the total weight of the dosage form.

[0088] In addition to a certain amount of deuterated tetrabenazine microparticles, the immediate release coating may also include one or more pharmaceutically acceptable excipients, such as antioxidants, binders and surfactants or any combination thereof. Antioxidants, binders and surfactants can be selected from a variety of options known to those skilled in the art. Exemplary antioxidants and binders are disclosed above in conjunction with other components of the dosage form. Surfactants may include, but are not limited to, esters of polyols such as monolaurin, ethoxylated castor oil, polysorbates, esters or ethers of saturated alcohols such as myristyl lactate (e.g. 50) and polyoxyethylene / polyoxypropylene block copolymers such as

[0089] In one embodiment, the immediate release coating further comprises an antioxidant which may be selected from: tert-butyl-4-methoxyphenol (a mixture of 2- and 3-isomers), 2,6-di-tert-butyl-p-cresol, propyl gallate, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquinoline), 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 deuterated tetrabenazine microparticles, butylated hydroxyanisole, butylated hydroxytoluene, hydroxypropyl methylcellulose and polysorbate 80.

[0090] In one embodiment, an osmotic dosage form for once-daily administration of deuterated tetrabenazine to a subject in need thereof is provided, comprising:

[0091] a. A core comprising:

[0092] i. An active layer comprising a certain amount of deuterated tetrabenazine microparticles and an active layer controlled release agent, an active layer antioxidant, and an active layer binder, wherein the active layer controlled release agent comprises a polymer having a viscosity of about 55-90 mPa s;

[0093] ii. a push layer comprising an osmotic agent, a push layer controlled release agent and a push layer adhesive, wherein the push layer controlled release agent comprises a polymer having a viscosity of about 5500-7500 mPa s;

[0094] b. a core seal coating on the outer surface of the core, comprising a binder;

[0095] c. a semipermeable layer surrounding the core seal coat, comprising a water-insoluble polymer and a pore-forming agent;

[0096] d. a semipermeable layer seal coating on the outer surface of the semipermeable layer, comprising an adhesive;

[0097] e. an immediate release coating on the outer surface of the semipermeable seal coat, comprising a second amount of deuterated tetrabenazine microparticles and an immediate release coating antioxidant; and

[0098] f. A port in the semipermeable layer seal coating that reaches the core tablet.

[0099] In some embodiments, an osmotic dosage form according to any one of the embodiments of the present invention is provided, wherein when the dosage form is tested using a USPII dissolution apparatus in 500 mL of acidic phosphate buffer at pH 3.0, no more than 15% of the drug formulation is released within 2 hours and / or no more than 60% of the drug formulation is released within 8 hours.

[0100] Also provided herein is a method for treating a hyperkinetic movement disorder in a subject, comprising orally administering to the subject an osmotic dosage form according to any one of the embodiments of the present invention once daily. Also provided is an osmotic dosage form according to any one of the embodiments disclosed herein, which is used for oral administration once daily for treating a hyperkinetic movement disorder in a subject.

[0101] In some embodiments, the movement disorder is selected from chorea, akathisia, dyskinesia, tremor, or tics. In some embodiments, the movement disorder is selected from chorea associated with Huntington's disease, tardive dyskinesia, tics associated with Tourette syndrome, levodopa-induced dyskinesia in Parkinson's disease, or dyskinesia in cerebral palsy.

[0102] In certain embodiments, the osmotic dosage form according to any of the embodiments disclosed herein is administered with food.

[0103] In certain embodiments, the osmotic dosage form according to any of the embodiments disclosed herein is administered under fasting conditions.

[0104] In one embodiment, the present invention provides a method of treating a 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 dose of the osmotic dosage form comprising a total amount of 6 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine comprising a geometric mean AUC of about 91,250 to 142,750 h*pg / mL 0-inf .

[0105] In one embodiment, the present invention provides a method of treating a 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 dose of the osmotic dosage form comprising a total amount of 6 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine comprising a geometric mean C < 0.0545 pg / mL. max .

[0106] In one embodiment, the present invention provides a method of treating a 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 dose of the osmotic dosage form comprising a total amount of 12 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine comprising a geometric mean AUC of about 182,500 to 285,500 h*pg / mL 0-inf .

[0107] In one embodiment, the present invention provides a method of treating a 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 dose of the osmotic dosage form comprising a total amount of 12 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine comprising a geometric mean C < 0.0545 pg / mL. max .

[0108] In one embodiment, the present invention provides a method of treating a 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 dose of the osmotic dosage form comprising a total amount of 24 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine comprising a geometric mean AUC of about 365,000 to 571,000 h*pg / mL 0-inf .

[0109] In one embodiment, the present invention provides a method of treating a 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 dose of the osmotic dosage form comprising a total amount of 24 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine comprising a geometric mean C < 0.0545 pg / mL. max .

[0110] In one embodiment, the invention provides a method of treating a 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 invention, wherein a single dose of the osmotic dosage form comprising a total amount of 36 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine comprising a geometric mean AUC of about 547,500 to 856,500 h*pg / mL 0-inf .

[0111] In one embodiment, the present invention provides a method of treating a 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 dose of the osmotic dosage form comprising a total amount of 36 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine comprising a geometric mean C < 0.0545 pg / mL. max .

[0112] In one embodiment, the present invention provides a method of treating a 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 dose of the osmotic dosage form comprising a total amount of 48 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine comprising a geometric mean AUC of about 730,000 to 1,142,000 h*pg / mL 0-inf .

[0113] In one embodiment, the present invention provides a method of treating a 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 dose of the osmotic dosage form comprising a total amount of 48 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine comprising a geometric mean C < 0.0545 pg / mL. max .

[0114] In one embodiment, the present invention provides a method of treating a 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 comprising a total amount of 6 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine at steady state, comprising an average AUC of about 102,500 to 200,000 h*pg / mL 0-24 .

[0115] In one embodiment, the present invention provides a method of treating a 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 comprising a total amount of 6 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine at steady state, comprising a mean C max .

[0116] In one embodiment, the present invention provides a method of treating a 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 comprising a total amount of 12 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine at steady state, comprising an average AUC of about 205,000 to 400,000 h*pg / mL 0-24 .

[0117] In one embodiment, the present invention provides a method of treating a 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 comprising a total amount of 12 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine at steady state, comprising a mean C max .

[0118] In one embodiment, the present invention provides a method of treating a 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 comprising a total amount of 24 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine at steady state, comprising an average AUC of about 410,000 to 800,000 h*pg / mL 0-24 .

[0119] In one embodiment, the present invention provides a method of treating a 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 comprising a total amount of 24 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine at steady state, comprising a mean C of less than about 40,000 pg / mL. max .

[0120] In one embodiment, the present invention provides a method of treating a 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 comprising a total amount of 36 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine at steady state, comprising an average AUC of about 615,000 to 1,200,000 h*pg / mL 0-24 .

[0121] In one embodiment, the present invention provides a method of treating a 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 comprising a total amount of 36 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine at steady state, comprising a mean C of less than about 60,000 pg / mL. max .

[0122] In one embodiment, the present invention provides a method of treating a 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 comprising a total amount of 48 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine at steady state, comprising an average AUC of about 820,000 to 1,600,000 h*pg / mL 0-24 .

[0123] In one embodiment, the present invention provides a method of treating a 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 comprising a total amount of 48 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine at steady state, comprising a mean C of less than about 80,000 pg / mL. max .

[0124] In one embodiment, the present invention provides a method for treating hyperkinetic movement disorders, comprising: administering an osmotic dosage form according to any one of the embodiments of the present invention, wherein when tested using a USPII dissolution apparatus in 500 mL of acidic phosphate buffer at pH 3.0, no more than 15% of the drug formulation is released after 2 hours.

[0125] In one embodiment, the present invention provides a method for treating a hyperkinetic movement disorder in a subject in need thereof, comprising: administering to the subject a once-daily osmotic dosage form according to any one of the embodiments of the present invention, wherein when tested using a USPII dissolution apparatus in 500 mL of acidic phosphate buffer at pH 3.0, no more than 60% of the drug formulation is released within 8 hours.

[0126] In some embodiments, the present invention provides a method for treating hyperkinetic movement disorders, comprising: administering an osmotic dosage form according to any one of the embodiments of the present invention, wherein when tested using a USPII dissolution apparatus in 500 mL of acidic phosphate buffer at pH 3.0, no more than 15% of the drug formulation is released after 2 hours, and no more than 60% of the drug formulation is released within 8 hours.

[0127] Also provided is a method of converting a human subject treated with a total daily dose of twice daily (bid) deuterated tetrabenazine to said total daily dose of once daily deuterated tetrabenazine for controlling abnormal involuntary movements, comprising:

[0128] a) administering to said human subject the last dose of said twice daily (bid) deutetrabenazine; and

[0129] b) on the second day, administering to the human subject the total daily dose of deuterated tetrabenazine once daily (qd).

[0130] The once daily deuterated tetrabenazine is, for example, a deuterated tetrabenazine extended release osmotic dosage form disclosed herein.

[0131] Twice daily deutetrabenazine may refer to e.g. Twice daily tablets or any equivalent thereof. As used herein, the term "last dose" refers to discontinuation of current treatment, e.g., discontinuation of twice daily deutetrabenazine treatment. In specific embodiments, the last dose of twice daily deutetrabenazine may refer to the second daily dose of twice daily deutetrabenazine, e.g., administered to a human subject in the afternoon or evening.

[0132] In one embodiment, the human subject is being 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.

[0133] In another embodiment, the human subject is being 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.

[0134] In another embodiment, the human subject is being 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.

[0135] In one embodiment, the human subject is being treated with deuterated tetrabenazine twice daily tablets at a total daily dose of 30 mg and is switched to deuterated tetrabenazine once daily at a total daily dose of 30 mg.

[0136] In another embodiment, the human subject is being treated with deuterated tetrabenazine twice daily tablets at a total daily dose of 36 mg and is switched to deuterated tetrabenazine once daily at a total daily dose of 36 mg.

[0137] In another embodiment, the human subject is being treated with deuteratedetrabenazine twice daily tablets at a total daily dose of 42 mg and is switched to deuteratedetrabenazine once daily at a total daily dose of 42 mg.

[0138] In another embodiment, the human subject is being treated with deuterated tetrabenazine twice daily tablets at a total daily dose of 48 mg and is switched to deuterated tetrabenazine once daily at a total daily dose of 48 mg.

[0139] In a specific embodiment, the once-daily deuterated tetrabenazine is in an extended release osmotic dosage form, preferably a deuterated tetrabenazine osmotic dosage form according to any one of the embodiments of the present invention.

[0140] In yet another specific embodiment, the once-daily osmotic dosage form of deuterated tetrabenazine comprises:

[0141] a. a tablet core comprising an active layer and a push layer, wherein the active layer comprises a certain amount of deuterated tetrabenazine microparticles and an active layer controlled release agent, and wherein the push layer comprises an osmotic agent and a push layer controlled release agent, and an optional tablet seal coat on the outer surface of the tablet core, wherein about 70%-80% of the total amount of deuterated tetrabenazine microparticles present in the dosage form are present in the active layer, and wherein about 20%-30% of the total amount of deuterated tetrabenazine microparticles are present in the immediate release coat, and wherein the deuterated tetrabenazine microparticles have a D 90 15μm, D 50 10μm and / or D 10 The particle size is 3 μm;

[0142] b. a semipermeable layer surrounding the core;

[0143] c. a port extending through said semipermeable layer into said core; and

[0144] d. an optional immediate release coating on the outside of the semipermeable layer comprising a second amount of deuterated tetrabenazine microparticles.

[0145] In one embodiment, the deuterated tetrabenazine once daily extended release dosage form is administered with or without food.

[0146] In one embodiment, the abnormal involuntary movement controlled during the transition from twice daily deutetrabenazine to once daily deutetrabenazine dosage is chorea, akathisia, dyskinesia, tremor, tics, chorea associated with Huntington's disease, tardive dyskinesia, tics associated with Tourette syndrome, levodopa-induced dyskinesia in Parkinson's disease, or dyskinesia in cerebral palsy. In one embodiment, the abnormal involuntary movement controlled is chorea associated with Huntington's disease. In one embodiment, the abnormal involuntary movement controlled is tardive dyskinesia.

[0147] Also provided is a method of converting a human subject treated with a total daily dose of once-daily deutetrabenazine to the same total daily dose of deutetrabenazine taken twice-daily (bid) tablets for controlling abnormal involuntary movements, comprising:

[0148] a) administering the last dose of said once-daily deutetrabenazine; and

[0149] b) on the second day, administering to said human subject said total daily dose of deuterated tetrabenazine twice daily.

[0150] As detailed above, human subjects are converted to the same total daily dose, e.g., 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, or 48 mg.

[0151] 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 is transitioned to a twice daily tablet of deutetrabenazine for a total daily dose of 12 mg.

[0152] 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 is transitioned to a twice daily tablet of deutetrabenazine for a total daily dose of 18 mg.

[0153] 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 is transitioned to a twice daily deutetrabenazine tablet for a total daily dose of 24 mg.

[0154] 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 is converted to a twice daily tablet of deutetrabenazine for a total daily dose of 30 mg.

[0155] 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 is transitioned to a twice daily tablet of deutetrabenazine for a total daily dose of 36 mg.

[0156] 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 transitioned to a twice daily deutetrabenazine tablet for a total daily dose of 42 mg.

[0157] 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 converted to a deutetrabenazine twice daily tablet for a total daily dose of 48 mg.

[0158] In a specific embodiment, the once daily deutetrabenazine is an extended release dosage form, preferably an osmotic dosage form according to any of the embodiments of the invention. In one embodiment, the once daily deutetrabenazine extended release dosage form is administered with or without food.

[0159] In one embodiment, the human subject is treated with a once-daily osmotic dosage form of deuterated tetrabenazine and is switched to a twice-daily dosage form of deuterated tetrabenazine.

[0160] In one embodiment, the abnormal involuntary movement controlled during the transition from a once-daily deutetrabenazine dosage form to a twice-daily deutetrabenazine tablet is chorea, akathisia, dyskinesia, tremor, tics, chorea associated with Huntington's disease, tardive dyskinesia, tics associated with Tourette's syndrome, levodopa-induced dyskinesia in Parkinson's disease, or dyskinesia in cerebral palsy. In one embodiment, the abnormal involuntary movement controlled is chorea associated with Huntington's disease. In one embodiment, the abnormal involuntary movement controlled is tardive dyskinesia.

[0161] Also provided is a method of converting a human subject treated with a daily dose of tetrabenazine to a once-daily dose of deuterated tetrabenazine for controlling abnormal involuntary movements, comprising:

[0162] a) administering the last dose of tetrabenazine; and

[0163] b) the next day, administering to the human subject a once-daily osmotic dosage form of deuterated tetrabenazine, wherein:

[0164] The daily dose of tetrabenazine is 12.5 mg, and the once daily dose of deuterated tetrabenazine is 6 mg; or

[0165] wherein the daily dose of tetrabenazine is 25 mg, and the once daily dose of deuterated tetrabenazine is 12 mg; or

[0166] wherein the daily dose of tetrabenazine is 37.5 mg, and the once daily dose of deuterated tetrabenazine is 18 mg; or

[0167] wherein the daily dose of tetrabenazine is 50 mg, and the once-daily dose of deuterated tetrabenazine is 24 mg; or

[0168] wherein the daily dose of tetrabenazine is 62.5 mg, and the once daily dose of deuterated tetrabenazine is 30 mg; or

[0169] wherein the daily dose of tetrabenazine is 75 mg, and the once daily dose of deuterated tetrabenazine is 36 mg; or

[0170] wherein the daily dose of tetrabenazine is 87.5 mg, and the once daily dose of deuterated tetrabenazine is 42 mg; or

[0171] The daily dosage of tetrabenazine is 100 mg, and the daily dosage of deuterated tetrabenazine is 48 mg.

[0172] In some embodiments, the daily dose of tetrabenazine is administered in divided doses, for example, in two, three or more divided doses.

[0173] In one embodiment, the abnormal involuntary movement controlled during the transition from tetrabenazine to the once daily dose of deutetrabenazine is chorea, akathisia, dyskinesia, tremor, tics, chorea associated with Huntington's disease, tardive dyskinesia, tics associated with Tourette's syndrome, levodopa-induced dyskinesia in Parkinson's disease, or dyskinesia in cerebral palsy. In one embodiment, the abnormal involuntary movement controlled is chorea associated with Huntington's disease. In one embodiment, the abnormal involuntary movement controlled is tardive dyskinesia.

[0174] In one embodiment, the once daily extended release dosage form of deutetrabenazine is administered with or without food.

[0175] The present disclosure provides oral dosage forms and methods according to any of the following aspects:

[0176] aspect

[0177] 1. An osmotic dosage form for once-daily administration to a subject in need thereof, comprising:

[0178] a. a core comprising an active layer and a push layer, wherein the active layer comprises a certain amount of deuterated tetrabenazine particles;

[0179] b. a semipermeable layer surrounding the core; and

[0180] c. A port extending from the periphery of the dosage form into the core.

[0181] 2. The dosage form of aspect 1, wherein the active layer further comprises an active layer controlled release agent.

[0182] 3. The dosage form of aspect 2, wherein the active layer controlled release agent comprises a polymer having a viscosity of about 50-150 mPa s or about 55-90 mPa s.

[0183] 4. The dosage form of aspect 2 or aspect 3, wherein the active layer controlled release agent comprises at least one of a polyoxyethylene polymer, an ionic hydrogel, a hydrophilic polymer, a hydrophobic polymer, or any mixture thereof.

[0184] 5. The dosage form of aspect 4, wherein the active layer controlled release agent comprises a polyoxyethylene polymer which is polyethylene oxide.

[0185] 6. The dosage form of aspect 5, wherein the polyethylene oxide in the active layer has an average molecular weight of 100,000 Daltons to 500,000 Daltons.

[0186] 7. The dosage form of aspect 6, wherein the polyethylene oxide in the active layer has an average molecular weight of 200,000 Daltons.

[0187] 8. The dosage form of any one of aspects 2-7, wherein the active layer controlled release agent is present in the active layer in an amount of about 60 wt % to about 98 wt % based on the total weight of the active layer.

[0188] 9. The dosage form of aspect 8, wherein the active layer controlled release agent is present in the active layer in an amount of about 70 wt % to about 95 wt % based on the total weight of the active layer, or about 80 wt % to about 90 wt %, or about 85 wt % to about 95 wt % based on the total weight of the active layer.

[0189] 10. The dosage form of any one of aspects 2-9, wherein the weight ratio of the amount of deuterated tetrabenazine microparticles in the active layer to the amount of the active layer controlled release agent is 2:3-1:50 or 2:5-1:5 or 1:4-1:9 or 1:5-1:19 or 1:5-1:7 or 1:12-1:15 or 1:20-1:30.

[0190] 11. The dosage form of any preceding aspect, wherein the active layer further comprises at least one active layer antioxidant.

[0191] 12. The dosage form of aspect 11, wherein the active layer antioxidant comprises at least one of tert-butyl-4-methoxyphenol (a mixture of 2- and 3-isomers), 2,6-di-tert-butyl-p-cresol, propyl gallate, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquinoline), nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole, butylated hydroxytoluene, or any mixture thereof.

[0192] 13. The dosage form of aspect 12, wherein the active layer antioxidant comprises a mixture of butylated hydroxyanisole and butylated hydroxytoluene.

[0193] 14. The dosage form of any one of aspects 11-13, wherein the active layer antioxidant is present in the active layer in an amount of about 0.001 wt % to about 1 wt % based on the total weight of the active layer.

[0194] 15. The dosage form of any preceding aspect, wherein the active layer further comprises at least one of an active layer binder.

[0195] 16. The dosage form of aspect 15, wherein the active layer binder comprises at least one of hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, a natural or synthetic gum, or any mixture thereof.

[0196] 17. The dosage form of aspect 16, wherein the active layer binder comprises hypromellose.

[0197] 18. The dosage form of any one of aspects 15-17, wherein the active layer binder is present in the active layer in an amount of about 2 wt % to about 20 wt % based on the total weight of the active layer.

[0198] 19. The dosage form of any preceding aspect, wherein the active layer further comprises one or more pharmaceutically acceptable excipients.

[0199] 20. The dosage form of any preceding aspect, wherein the active layer comprises deuterated tetrabenazine microparticles, an active layer controlled release agent, and an antioxidant, the active layer controlled release agent being a polymer having a viscosity of about 55-90 mPa s.

[0200] 21. The dosage form of aspect 20, wherein the active layer comprises deuterated tetrabenazine microparticles, butylated hydroxyanisole, butylated hydroxytoluene, polyethylene oxide, hypromellose, and magnesium stearate.

[0201] 22. The dosage form of any preceding aspect, wherein the push layer comprises an osmotic agent and a push layer controlled release agent.

[0202] 23. The dosage form of aspect 22, wherein the osmotic agent comprises an inorganic salt, a carbohydrate, or any mixture thereof.

[0203] 24. The dosage form of aspect 23, wherein the osmotic agent comprises a carbohydrate, and the carbohydrate is d-mannitol, sorbitol, inositol, a monosaccharide, an oligosaccharide, a polysaccharide, or any mixture thereof.

[0204] 25. The dosage form of aspect 23, wherein the osmotic agent comprises an inorganic salt, and the inorganic salt is magnesium sulfate, magnesium chloride, potassium sulfate, sodium chloride, sodium sulfate, lithium sulfate, sodium phosphate, potassium phosphate, or any mixture thereof.

[0205] 26. The dosage form of aspect 25, wherein the osmotic agent comprises sodium chloride.

[0206] 27. The dosage form of any one of aspects 22-26, wherein the osmotic agent is present in the dosage form in an amount of about 5 wt % to about 50 wt % based on the total weight of the dosage form.

[0207] 28. The dosage form of aspect 27, wherein the osmotic agent is present in the dosage form in an amount of about 5 wt % to about 20 wt % based on the total weight of the dosage form.

[0208] 29. The dosage form of aspect 27 or aspect 28, wherein the osmotic agent is present in the dosage form in an amount of about 8 wt % to about 10 wt % based on the total weight of the dosage form.

[0209] 30. The dosage form of any one of aspects 27-29, wherein the osmotic agent is present in the push layer in an amount of about 20 wt % to about 40 wt % based on the total weight of the push layer.

[0210] 31. The dosage form of aspect 30, wherein the osmotic agent is present in the push layer in an amount of about 30 weight percent based on the total weight of the push layer.

[0211] 32. The dosage form of any one of aspects 22-31, wherein the push layer controlled release agent comprises a polymer having a viscosity of about 5500-7500 mPa s.

[0212] 33. The dosage form of aspect 32, wherein the polymer having a viscosity of about 5500-7500 mPa s is selected from a polyoxyethylene polymer, an ionic hydrogel, a hydrophilic polymer, a hydrophobic polymer, or any mixture thereof.

[0213] 34. The dosage form of aspect 33, wherein the push layer controlled release agent is polyethylene oxide.

[0214] 35. The dosage form of aspect 34, wherein the polyethylene oxide within the push layer has an average molecular weight of 1,000,000 Daltons to 7,000,000 Daltons.

[0215] 36. The dosage form of aspect 35, wherein the polyethylene oxide within the push layer has an average molecular weight of 5,000,000 Daltons.

[0216] 37. The dosage form of any one of aspects 32-36, wherein the push layer controlled release agent is present in the push layer in an amount of about 50 wt % to about 80 wt % based on the total weight of the push layer.

[0217] 38. The dosage form of aspect 37, wherein the push layer controlled release agent is present in the push layer in an amount of about 60 wt % to about 70 wt % based on the total weight of the push layer.

[0218] 39. The dosage form of any one of aspects 22-38, wherein the weight ratio of the osmotic agent in the push layer to the push layer controlled release agent is 1:2-1:3.5 or 1:2-1:2.5.

[0219] 40. The dosage form of any one of aspects 22-39, wherein the push layer further comprises a push layer binder.

[0220] 41. The dosage form of aspect 40, wherein the push layer binder comprises hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, a natural or synthetic gum, or any mixture thereof.

[0221] 42. The dosage form of aspect 41, wherein the push layer binder comprises hypromellose.

[0222] 43. The dosage form of any one of aspects 40-42, wherein the push layer binder is present in the push layer in an amount of about 2 wt % to about 10 wt % based on the total weight of the push layer.

[0223] 44. The dosage form of aspect 43, wherein the push layer binder is present in the push layer in an amount of about 4 wt % to about 6 wt % based on the total weight of the push layer or about 3 wt % to about 6 wt % based on the total weight of the push layer.

[0224] 45. The dosage form of any one of aspects 22-44, wherein the push layer further comprises a pharmaceutically acceptable excipient.

[0225] 46. ​​The dosage form of any one of aspects 22-45, wherein the push layer comprises sodium chloride and a polymer having a viscosity of about 5500-7500 mPa s.

[0226] 47. The dosage form of aspect 46, wherein the push layer comprises sodium chloride, polyethylene oxide, hydroxypropyl methylcellulose, a colorant, and magnesium stearate.

[0227] 48. The dosage form of any preceding aspect, wherein the semipermeable layer comprises a water-soluble polymer, a water-insoluble polymer, or any mixture thereof.

[0228] 49. The dosage form of aspect 48, wherein the semipermeable layer comprises a water-insoluble polymer selected from the group consisting of cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate butyrate, cellulose ethers such as ethylcellulose, acetate agar, amylose triacetate, beta glucan acetate, poly(vinyl methyl) ether copolymers, poly(orthoesters), polyacetals, and selectively permeable poly(glycolic acid), poly(lactic acid) derivatives, Eudragit cellulose acetate, or any mixture thereof.

[0229] 50. The dosage form of aspect 49, wherein the water-insoluble polymer is cellulose acetate comprising 32% to 39.8% acetyl content.

[0230] 51. The dosage form of any preceding aspect, wherein the semipermeable layer comprises cellulose acetate and polyethylene glycol.

[0231] 52. The dosage form of any one of aspects 48-51, wherein the water-insoluble polymer is present in the semipermeable layer in an amount of about 80 wt % to about 99.9 wt % based on the weight of the semipermeable layer or about 85 wt % to about 95 wt % based on the weight of the semipermeable layer.

[0232] 53. The dosage form of any preceding aspect, wherein the semipermeable layer comprises a pore former.

[0233] 54. The dosage form of aspect 53, wherein the pore former comprises a water-soluble sugar, a water-soluble salt, a water-soluble solvent, a water-soluble polymer, or any mixture thereof.

[0234] 55. The dosage form of aspect 54, wherein the pore former is a water-soluble solvent which is polyethylene glycol.

[0235] 56. The dosage form of any one of aspects 53-55, wherein the pore former is present in the semipermeable layer in an amount of about 0.1% to about 20% by weight of the semipermeable layer.

[0236] 57. The dosage form of aspect 56, wherein the pore former is present in the semipermeable layer in an amount of about 8% to about 15% by weight of the semipermeable layer.

[0237] 58. The dosage form of any preceding aspect, wherein the weight ratio of the semipermeable layer to the core is 1:8-1:10.

[0238] 59. The dosage form of any preceding aspect, wherein the port has a diameter of about 0.1 mm to about 1 mm.

[0239] 60. The dosage form of aspect 59, wherein the port has a diameter of about 0.4 mm to about 0.8 mm.

[0240] 61. The dosage form of any preceding aspect, further comprising a core seal coat on the outer surface of the core.

[0241] 62. The dosage form of any preceding aspect, further comprising a semipermeable layer seal coat on the outer surface of the semipermeable layer.

[0242] 63. The dosage form according to any one of aspects 61-62, wherein the core seal coat and / or the semipermeable layer seal coat comprises a binder.

[0243] 64. The dosage form of aspect 63, wherein the core seal coating binder and / or the semipermeable layer seal coating binder comprises: hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, natural gum, synthetic gum and any mixture thereof.

[0244] 65. The dosage form of aspect 64, wherein the core seal coat binder and / or the semipermeable layer seal coat binder is hypromellose.

[0245] 66. The dosage form of any one of aspects 63-65, wherein the total amount of the binder in the dosage form is from about 0 to about 20 weight % based on the total weight of the dosage form, from 5 weight % to about 15 weight % based on the total weight of the dosage form, or from 5 weight % to about 20 weight % based on the total weight of the dosage form.

[0246] 67. The dosage form of aspect 66, wherein the total amount of the binder in the dosage form is from about 8 wt % to about 10 wt % based on the total weight of the dosage form, or from about 10 wt % to about 20 wt % based on the total weight of the dosage form, or from about 10 wt % to about 20 wt % based on the total weight of the dosage form.

[0247] 68. The dosage form of any preceding aspect, further comprising an immediate release coating external to the semipermeable membrane, the immediate release coating comprising a second amount of deuterated tetrabenazine microparticles.

[0248] 69. The dosage form of aspect 68, wherein the immediate release coating comprises from about 0.1 wt % to about 25 wt % of deuterated tetrabenazine microparticles based on the total weight of the dosage form, or from about 0.2 wt % to about 5 wt % of deuterated tetrabenazine microparticles based on the total weight of the dosage form, or from about 0.3 wt % to about 2 wt % of deuterated tetrabenazine microparticles based on the total weight of the dosage form.

[0249] 70. The dosage form of aspect 69, wherein the dosage form comprises a total of 24 mg of deuterated tetrabenazine microparticles and the immediate-release coating comprises from about 1 wt % to about 2 wt % of deuterated tetrabenazine microparticles, based on the total weight of the dosage form, or wherein the dosage form comprises a total of 12 mg of deuterated tetrabenazine microparticles and the immediate-release coating comprises from about 0.5 wt % to about 1 wt % of deuterated tetrabenazine microparticles, based on the total weight of the dosage form, or wherein the dosage form comprises a total of 6 mg of deuterated tetrabenazine microparticles and the immediate-release coating comprises from about 0.1 wt % to about 0.5 wt % of deuterated tetrabenazine microparticles, based on the total weight of the dosage form.

[0250] 71. The dosage form of any preceding aspect, wherein about 70% to 99% of the total amount of deuterated tetrabenazine microparticles in the dosage form are within the active layer.

[0251] 72. The dosage form of any preceding aspect, wherein about 5% to 30% of the total amount of deuterated tetrabenazine microparticles in the dosage form are within the immediate release coat.

[0252] 73. The dosage form of any preceding aspect, wherein about 70%-80% of the total amount of deuterated tetrabenazine microparticles in the dosage form are within the active layer, and wherein about 20%-30% of the total amount of deuterated tetrabenazine microparticles in the dosage form are within the immediate release coat.

[0253] 74. The dosage form of any one of aspects 68-73, wherein the immediate release coating further comprises an immediate release coating antioxidant.

[0254] 75. The dosage form of aspect 74, wherein the immediate release coated antioxidant comprises: tert-butyl-4-methoxyphenol (mixture of 2- and 3-isomers), 2,6-di-tert-butyl-p-cresol, propyl gallate, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquinoline), nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole, butylated hydroxytoluene, and any mixture thereof.

[0255] 76. The dosage form of aspect 75, wherein the immediate release coating comprises a mixture of butylated hydroxyanisole and butylated hydroxytoluene.

[0256] 77. The dosage form according to any one of aspects 68 to 76, wherein the immediate release coating further comprises an additional pharmaceutically acceptable excipient.

[0257] 78. The dosage form of any one of aspects 68-77, wherein the immediate release coating comprises: deuterated tetrabenazine microparticles, butylated hydroxyanisole, butylated hydroxytoluene, hypromellose, and polysorbate 80.

[0258] 79. The dosage form of any preceding aspect, wherein the total amount of deuterated tetrabenazine microparticles in the dosage form is from about 6 mg to about 48 mg.

[0259] 80. The dosage form of any preceding aspect, wherein the total amount of deuterated tetrabenazine microparticles in the dosage form is about 6 mg.

[0260] 81. The dosage form of any preceding aspect, wherein the total amount of deuterated tetrabenazine microparticles in the dosage form is about 12 mg.

[0261] 82. The dosage form of any preceding aspect, wherein the total amount of deuterated tetrabenazine microparticles in the dosage form is about 24 mg.

[0262] 83. The dosage form of any preceding aspect, wherein the total amount of deuterated tetrabenazine microparticles in the dosage form is about 48 mg.

[0263] 84. The dosage form of any preceding aspect, wherein the total amount of deuterated tetrabenazine microparticles is from about 0.5 wt % to about 15 wt % based on the total weight of the dosage form.

[0264] 85. The dosage form of aspect 84, wherein the total amount of deuterated tetrabenazine microparticles is from about 1 weight % to about 10 weight % based on the total weight of the dosage form.

[0265] 86. The dosage form of aspect 85, comprising a total of 6 mg of deuterated tetrabenazine microparticles, wherein the total amount of deuterated tetrabenazine microparticles is from about 0.5 weight % to about 3 weight % based on the total weight of the dosage form, or a dosage form comprising a total of 12 mg of deuterated tetrabenazine microparticles, wherein the total amount of deuterated tetrabenazine microparticles is from about 1 weight % to about 5 weight % based on the total weight of the dosage form, or a dosage form comprising a total of 24 mg of deuterated tetrabenazine microparticles, wherein the total amount of deuterated tetrabenazine microparticles is from about 5 weight % to about 10 weight % based on the total weight of the dosage form.

[0266] 87. The dosage form of any preceding aspect, wherein the deuterated tetrabenazine microparticles have a particle size of about 1 μm to about 30 μm in diameter.

[0267] 88. The dosage form of aspect 87, wherein the deuterated tetrabenazine microparticles have a D 90 The granularity.

[0268] 89. The dosage form of aspect 87 or aspect 88, wherein the deuterated tetrabenazine microparticles have a D providing 10 μm. 50 The granularity.

[0269] 90. The dosage form of any one of aspects 87-89, wherein the deuterated tetrabenazine microparticles have a D 10 The granularity.

[0270] 91. A method of treating a hyperkinetic movement disorder in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the preceding aspects.

[0271] 92. The method of aspect 91, wherein the movement disorder is selected from chorea, akathisia, dyskinesia, tremor and tics.

[0272] 93. The method of aspect 92, wherein the movement disorder is selected from the group consisting of chorea associated with Huntington's disease, tardive dyskinesia, tics associated with Tourette's syndrome, levodopa-induced dyskinesias in Parkinson's disease, and movement disorders in cerebral palsy.

[0273] 94. The method of any one of aspects 91-93, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of aspects 1-90, wherein a single dose administration of the osmotic dosage form comprising a total amount of 6 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine comprising a geometric mean AUC of about 91,250 to 142,750 h*pg / mL 0-inf .

[0274] 95. The method of any one of aspects 91-94, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of aspects 1-90, wherein a single dose administration of the osmotic dosage form comprising a total amount of 6 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine comprising a geometric mean C 20 of less than about 4,600 pg / mL. max .

[0275] 96. The method of any one of aspects 91-93, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of aspects 1-90, wherein a single dose administration of the osmotic dosage form comprising a total amount of 12 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine comprising a geometric mean AUC of about 182,500 to 285,500 h*pg / mL 0-inf .

[0276] 97. The method of any one of aspects 91-93 or 96, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of aspects 1-90, wherein a single dose administration of the osmotic dosage form comprising a total amount of 12 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine comprising a geometric mean C < 0.054 g / mL of less than about 9,200 pg / mL. max .

[0277] 98. The method of any one of aspects 91-93, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of aspects 1-90, wherein a single dose administration of the osmotic dosage form comprising a total amount of 24 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine comprising a geometric mean AUC of about 365,000 to 571,000 h*pg / mL 0-inf .

[0278] 99. The method of any one of aspects 91-93 or aspect 98, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of aspects 1-90, wherein a single dose administration of the osmotic dosage form comprising a total amount of 24 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine comprising a geometric mean C < 0.05 of less than about 18,400 pg / mL. max .

[0279] 100. The method of any one of aspects 91-93, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of aspects 1-90, wherein a single dose administration of the osmotic dosage form comprising a total amount of 36 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine comprising a geometric mean AUC of about 547,500 to 856,500 h*pg / mL 0-inf .

[0280] 101. The method of any one of aspects 91-93 or aspect 100, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of aspects 1-90, wherein a single dose administration of the osmotic dosage form comprising a total amount of 36 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine comprising a geometric mean C < 0.05 of less than about 27,600 pg / mL. max .

[0281] 102. The method of any one of aspects 91-93, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of aspects 1-90, wherein a single dose administration of the osmotic dosage form comprising a total amount of 48 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine comprising a geometric mean AUC of about 730,000 to 1,142,000 h*pg / mL 0-inf .

[0282] 103. The method of any one of aspects 91-93 or aspect 102, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of aspects 1-90, wherein a single dose administration of the osmotic dosage form comprising a total amount of 48 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine comprising a geometric mean C < 0.05 of less than about 36,800 pg / mL. max .

[0283] 104. The method of any one of aspects 91-93, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of aspects 1-90, wherein the osmotic dosage form comprising a total amount of 6 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine at steady state comprising a mean AUC of about 102,500 to 200,000 h*pg / mL 0-24 .

[0284] 105. The method of any one of aspects 91-93 or aspect 104, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of aspects 1-90, wherein the osmotic dosage form comprising a total amount of 6 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine at steady state comprising a mean C<0.054> of less than about 10,000 pg / mL. max .

[0285] 106. The method of any one of aspects 91-93, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of aspects 1-90, wherein the osmotic dosage form comprising a total amount of 12 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine at steady state comprising a mean AUC of about 205,000 to 400,000 h*pg / mL 0-24 .

[0286] 107. The method of any one of aspects 91-93 or aspect 106, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of aspects 1-90, wherein the osmotic dosage form comprising a total amount of 12 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine at steady state comprising a mean C<0.054> of less than about 20,000 pg / mL. max .

[0287] 108. The method of any one of aspects 91-93, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of aspects 1-90, wherein the osmotic dosage form comprising a total amount of 24 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine at steady state comprising a mean AUC of about 410,000 to 800,000 h*pg / mL 0-24 .

[0288] 109. The method of any one of aspects 91-93 or aspect 108, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of aspects 1-90, wherein the osmotic dosage form comprising a total amount of 24 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine at steady state comprising a mean C<0.054> of less than about 40,000 pg / mL. max .

[0289] 110. The method of any one of aspects 91-93, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of aspects 1-90, wherein the osmotic dosage form comprising a total amount of 36 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine at steady state comprising a mean AUC of about 615,000 to 1,200,000 h*pg / mL 0-24 .

[0290] 111. The method of any one of aspects 91-93 or aspect 110, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of aspects 1-90, wherein the osmotic dosage form comprising a total amount of 36 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine at steady state comprising a mean C<0.054> of less than about 60,000 pg / mL. max .

[0291] 112. The method of any one of aspects 91-93, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of aspects 1-90, wherein the osmotic dosage form comprising a total amount of 48 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine at steady state comprising a mean AUC of about 820,000 to 1,600,000 h*pg / mL 0-24 .

[0292] 113. The method of any one of aspects 91-93 or aspect 112, comprising orally administering to the subject a once-daily osmotic dosage form according to any one of aspects 1-90, wherein the osmotic dosage form comprising a total amount of 48 mg of deuterated tetrabenazine microparticles provides an in vivo plasma profile of total α- and β-dihydrodeuterated tetrabenazine at steady state comprising a mean C<0.054> of less than about 80,000 pg / mL. max .

[0293] 114. The method of any one of aspects 91-113, comprising administering the osmotic dosage form of any one of aspects 1-90, wherein no more than 15% of the drug formulation is released after 2 hours when tested using a USPII dissolution apparatus in 500 mL of acidic phosphate buffer at pH 3.0.

[0294] 115. The method of any one of aspects 91-113, comprising administering the osmotic dosage form of any one of aspects 1-90, wherein no more than 60% of the drug formulation is released after 8 hours when tested using a USPII dissolution apparatus in 500 mL of acidic phosphate buffer at pH 3.0.

[0295] 116. The dosage form or method of any preceding aspect, wherein the dosage form is administered with food.

[0296] 117. The dosage form or method of any one of aspects 1-115, wherein the dosage form is administered under fasting conditions.

[0297] All patents, patent applications and publications are incorporated herein by reference to the extent that each individual publication is specifically and individually indicated to be incorporated by reference. The invention illustratively described herein can be implemented in the absence of any element not specifically disclosed herein. The terms and expressions that have been adopted are used as terms of description rather than limitation, and when using these terms and expressions, it is not intended to exclude any equivalents of the features shown and described or parts thereof, but it should be recognized that various modifications can be made within the scope of the claimed invention. Therefore, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, those skilled in the art may resort to modifications and variations of the concepts disclosed herein, and such modifications and variations are considered to be within the scope of the invention defined by the appended claims.

[0298] For the foregoing embodiments, each embodiment disclosed herein is intended to be applicable to each of the other disclosed embodiments. For example, elements listed in the method embodiments can be used in the pharmaceutical compositions, packaging and use / method embodiments described herein, and vice versa.

[0299] Example

[0300] 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 subject matter described. It should be understood that the embodiments and embodiments described herein are for illustrative purposes only, and various modifications or changes made therefrom will be apparent to those skilled in the art, and will be included in the true scope of the present disclosure and can be carried out without departing from the true scope of the present disclosure.

[0301] Example 1-24 mg deuterated tetrabenazine osmotic tablet manufacturing process

[0302] Figure 2a and Figure 2b A flow chart of a general manufacturing process of an osmotic dosage form according to the present disclosure is provided. Tables 1-13 below provide non-limiting examples of materials and their relative amounts used to prepare the dosage forms described herein. The preparation method is as follows:

[0303] A: Active layer material processing: Deuterated tetrabenazine (micronized) and active layer controlled release agent are passed through a #30 sieve and combined with a binder (previously passed through a #20 sieve). The mixture is introduced into a high shear granulator and dry mixed for about 5 minutes. While mixing, an antioxidant (previously dissolved in alcohol) is added to the mixed powder to granulate the material. Continue to mix additionally until the desired granulation endpoint is reached. The resulting granules are wet screened to break up any oversized agglomerates. The material is fed into a diffusion mixer (V-type mixer) where it is blended for about 15 minutes. The lubricant that has passed through a #30 sieve is added to the blended material in the V-type mixer. The contents are lubricated for about 5 minutes.

[0304] B: Tablet core compression: The active layer materials are discharged into a double-layer rotary tablet press. The push layer materials (osmotic agent, push layer controlled release agent and optional binder, colorant and lubricant) are combined and further fed into a double-layer rotary tablet press. The tablet core is compressed.

[0305] C: Optional Core Seal Coat: A core seal coat comprising a binder solution is applied to the core tablets.

[0306] D: Semipermeable layer: A semipermeable layer comprising a cellulose acetate solution and optionally a pore former is applied to the tablet core or sealed tablet core using a pan coater.

[0307] E: Optional Semipermeable Seal Coat: A semipermeable seal coat comprising a binder solution is applied to the tablet, thereby compromising the semipermeable wall.

[0308] F: Creation of exit means: Laser drilling through the layer to obtain holes into the active layer.

[0309] A final immediate release coat comprising deuterated tetrabenazine is optionally applied using similar materials and following the processing steps as detailed above for the active layer.

[0310] Table 1

[0311]

[0312] Table 2

[0313]

[0314] Table 3

[0315]

[0316] Table 4

[0317]

[0318] Table 5

[0319]

[0320]

[0321] Table 6

[0322]

[0323] Table 7

[0324]

[0325]

[0326] Table 8

[0327]

[0328] Table 9

[0329]

[0330] Table 10

[0331]

[0332] Table 11

[0333]

[0334] Table 12

[0335]

[0336] Table 13

[0337]

[0338] 1FD&C Red No. 40 is listed in the FDA Inactive Ingredient Database and is within recommended limits. 2Water, acetone, ethanol, and isopropyl alcohol are used in tablet preparation but are removed during processing.

[0339] Table 14

[0340]

[0341]

[0342] Table 15

[0343]

[0344] Example 2 - Single-dose bioavailability evaluation

[0345] As disclosed in Example 1, an osmotic dosage form containing 24 mg of deuterated tetrabenazine was prepared and studied in a single-dose pharmacokinetic study.

[0346] The primary objective was to evaluate the efficacy of a single 12 mg tablet given twice 12 hours apart (bid) under fasting conditions. Comparative bioavailability (BA) of deuterated tetrabenazine and deuterated α- and β-dihydrotetrabenazine (deuHTBZ) metabolites following a single administration of a 24 mg once daily (qd) osmotic formulation (Test) compared to a tablet.

[0347] Study Population and Number of Subjects: The study included healthy male and female non-smoking subjects aged between 18 and 45 years. A total of 8 healthy subjects (4 in each series) were enrolled in this study.

[0348] Duration of Subject Participation: The study consisted of a 4-week screening period (Period 1), an open-label treatment period with the test formulation (Test2A) and the reference formulation (R) (Period 2), and a follow-up visit after at least 1 day (Period 3).

[0349] treat:

[0350] Treatment sequence A:

[0351] Day 1 - Administer Test2A.

[0352] Day 2-3 - Wash out Test2A for at least 6 hours, then apply R.

[0353] Treatment sequence B:

[0354] Day 1 - Administer R

[0355] Day 2-3 - Wash out R for at least 6 hours, then apply Test2A.

[0356] The main purpose was solved using the following parameters:

[0357] - Maximum observed concentration (Cmax)

[0358] - Area under plasma concentration-time (AUC) from time 0 to the time of the last measurable plasma concentration (AUC0-t)

[0359] -AUC extrapolated to infinity (AUC0-∞)

[0360] -AUC from time 0 to 24 hours after dosing (AUC0-24h)

[0361] analyze

[0362] AUC0-t, AUC0-∞ and AUC0-24h were calculated using the trapezoidal rule. Before statistical analysis, Cmax, AUC0-t, AUC0-∞ and AUC0-24h data were natural logarithm transformed. A separate parameter analysis of variance (ANOVA) model was used to compare Cmax, AUC0-t, AUC0-∞ and AUC0-24h between treatments (T2A and R), with fixed effect terms for sequence, period, treatment group and random effects for subjects within the sequence. Based on the least squares mean of the ANOVA of logarithmic transformed Cmax, AUC0-t, AUC0-∞ and AUC0-24h, the difference between the reference preparation (R) and the test preparation (Test2A) was evaluated by constructing a 90% confidence interval for the test / reference ratio. Treatment differences and associated 90% confidence intervals estimated from log-scale ANOVA were back-transformed to obtain the estimated ratio of geometric means between treatment groups and the 90% confidence interval for that ratio.

[0363] Figure 3a and Figure 3b Results (mean concentration of deuterated tetrabenazine versus time) for the R treatment compared to the Test2A treatment are shown on a direct scale and a logarithmic scale, respectively. Table 14 below provides the assigned pK parameters for deuterated tetrabenazine observed for Test2A compared to R.

[0364] Table 14

[0365]

[0366]

[0367] Figure 4a and Figure 4bMetabolite data (mean concentration of total deuHTBZ versus time) for treatment with R compared to treatment with Test2A are shown on direct and logarithmic scales, respectively.

[0368] Table 15 below provides the assigned pK parameters for the total deuHTBZ observed for Test2A compared to R.

[0369] Table 15

[0370]

[0371] As shown in Tables 14 and 15, a once daily dose of Test2A provided acceptable deuHTBZ plasma concentrations observed for the reference. The osmotic dosage forms disclosed herein are administered once daily and provide Compared with the acceptable treatment effect, there are no safety issues.

[0372] The results of this study with a crossover design further demonstrate that patients can safely and effectively switch from twice daily (two divided doses) administration of deuterated tetrabenazine tablets to a once daily osmotic dosage form. The results of this study with a crossover design also demonstrate that patients can safely and effectively switch from a once daily osmotic dosage form to twice daily administration of deuterated tetrabenazine tablets (two divided doses).

[0373] Example 3 - Multiple-dose bioavailability evaluation

[0374] As disclosed in Example 1, an osmotic dosage form containing 24 mg of deuterated tetrabenazine was prepared and studied in healthy volunteers in an open-label, randomized, multiple-dose, two-way crossover study.

[0375] The primary objective was to evaluate the bioequivalence (BE) of Test2A administered once daily (qd) compared with R administered bid under fasting or fed conditions.

[0376] Treatment consisted of 7 days of repeated dosing of Test2A once daily and 7 days of repeated dosing of R bid.

[0377] Prediction of steady-state, AUCt, and C of deutetrabenazine and deuHTBZ concentrations using qualified models max ,t max , C min , C av .

[0378] Table 16 below provides simulation results for the steady state pK parameters for deuterated tetrabenazine for Test2A compared to R, and the pK parameters for total deuHTBZ for Test2A compared to R.

[0379] Table 16

[0380]

[0381] Study Results

[0382] Administration of treatments Test2A and R resulted in reproducible concentration-time profiles for all analytes.

[0383] The primary objective was achieved, namely to demonstrate the AUC of deutetrabenazine and deuHTBZ (alone and as a sum) between Test2A and R formulations 0-24h,ss Bioequivalence (BE) of deuterated tetrabenazine AUC 0-24h,ss The geometric LS mean ratio was 115.15% and the total deuHTBZ was 95.05%.

[0384] The results of this study with a crossover design further demonstrate that patients can safely and effectively switch from twice-daily administration of deuterated tetrabenazine tablets to a once-daily osmotic dosage form. The results of this study with a crossover design further demonstrate that patients can safely and effectively switch from a once-daily osmotic dosage form to a twice-daily administration of deuterated tetrabenazine tablets.

[0385] Example 4: Food Effect Study

[0386] As disclosed in Example 1, osmotic dosage forms containing 24 mg of deutetrabenazine were prepared and studied in an open-label, randomized, 3-period, 3-treatment, 6-sequence, crossover study to evaluate the comparative bioavailability of deutetrabenazine and deuHTBZ in the fed state compared to the fasted state following a single administration of 24 mg once daily (qd) of the osmotic formulation.

[0387] Treatment includes:

[0388] Subjects were randomized to receive 3 treatments: Test2A in the fed state (QD fed), Test2A in the fasted state (QD fasted), and R in the fed state [twice daily (BID) fed] separated by 12 hours in 1 of 6 treatment sequences, e.g. Figure 5 shown.

[0389] There was a washout period of at least 6 days between the first administration in one phase and the first administration in the next phase. In the morning of the first day (Day 1) of each administration period, subjects were orally administered treatment in a sitting position. The second dose of R in the BID fed group was administered exactly 12 hours after the morning administration.

[0390] All subjects fasted overnight for at least 10 hours before the first dose in each period. Subjects receiving either the R BID meal or the Test2A tablet meal were provided with a standardized high-calorie, high-fat breakfast (containing 800 to 1000 kilocalories [kcal] and 50% fat) 30 minutes before the first dose. A standardized dinner was provided 30 minutes before the second dose for the R BID meal or at the corresponding time for the Test2A tablet meal.

[0391] During all treatment periods, blood samples were collected before and up to 96 hours after dosing for pharmacokinetic analysis.

[0392] The AUCt, Cmax, tmax, Cmin, and Cav of deutetrabenazine and deuHTBZ were analyzed.

[0393] result

[0394] For all analytes, the variability of the Test2A fed treatment was generally similar to the variability of the Test2A fasted treatment, indicating that administration of a single 24 mg tablet in the fed state does not significantly increase the pharmacokinetic variability of the metabolites compared to a single 24 mg tablet in the fasted state.

[0395] Following oral administration of a single 24 mg QD osmotic tablet, all analytes met BE criteria under both fed and fasted conditions. Food apparently had no significant effect on PK, and thus the 24 mg QD tablet can be administered with or without food.

[0396] In healthy subjects, a single dose of 24 mg deutetrabenazine QD osmotic tablets in the fed or fasted state and twice daily administration of 12 mg deutetrabenazine tablets (fed state) appeared to be safe and well tolerated.

Claims

1. A method of converting a human subject treated with a total daily dose of twice daily (bid) deutetrabenazine to said total daily dose of once daily deutetrabenazine for control of abnormal involuntary movements, comprising: a) administering to said human subject a final dose of said twice daily deuterated tetrabenazine; and b) the next day, administering to said human subject said total daily dose of once-daily deuterated tetrabenazine.

2. The method of claim 1, wherein the total daily dose of deuterated tetrabenazine 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 of claim 1, wherein the once-daily deutetrabenazine is administered as an extended release osmotic dosage form.

4. The method of claim 3, wherein the osmotic dosage form comprises: a. a tablet core comprising an active layer and a push layer, wherein the active layer comprises an amount of deuterated tetrabenazine microparticles and an active layer controlled-release agent, and wherein the push layer comprises an osmotic agent and a push layer controlled-release agent, and an optional tablet seal coating on the outer surface of the tablet core; b. a semipermeable layer surrounding the core; c. a port extending through said semipermeable layer into said core; and d. an optional immediate release coating on the exterior of the semipermeable layer comprising a second amount of deuterated tetrabenazine microparticles.

5. The method of claim 4, wherein about 70%-80% of the total amount of deuterated tetrabenazine microparticles present in the osmotic dosage form are present in the active layer, and wherein about 20%-30% of the total amount of deuterated tetrabenazine microparticles present in the osmotic dosage form are present in the immediate release coat.

6. The method of claim 1, wherein the deuterated tetrabenazine microparticles have a 90 15μm, D 50 10μm and / or D 10 The particle size is 3 μm.

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

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

9. A method of converting a human subject treated with a total daily dose of once-daily deutetrabenazine to the same total daily dose of twice-daily (bid) deutetrabenazine for control of abnormal involuntary movements, comprising: a) administering the last dose of deutetrabenazine once daily; and b) on the second day, administering to the subject the total daily dose of deutetrabenazine twice daily.

10. The method of claim 9, wherein the total daily dose of deuterated tetrabenazine is from 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.

11. The method of claim 9, wherein the once daily dose of deuterated tetrabenazine is administered as an extended release osmotic dosage form.

12. The method of claim 11, wherein the osmotic dosage form comprises: a. a tablet core comprising an active layer and a push layer, wherein the active layer comprises an amount of deuterated tetrabenazine microparticles and an active layer controlled-release agent, and wherein the push layer comprises an osmotic agent and a push layer controlled-release agent, and an optional tablet seal coating on the outer surface of the tablet core; b. a semipermeable layer surrounding the core; c. a port extending through said semipermeable layer into said core; and d. an optional immediate release coating on the exterior of the semipermeable layer comprising a second amount of deuterated tetrabenazine microparticles.

13. The method of claim 12, wherein about 70%-80% of the total amount of deuterated tetrabenazine microparticles present in the osmotic dosage form are present in the active layer, and wherein about 20%-30% of the total amount of deuterated tetrabenazine microparticles present in the osmotic dosage form are present in the immediate release coat.

14. The method of claim 12, wherein the deuterated tetrabenazine microparticles have a 90 15μm, D 50 10μm and / or D 10 The particle size is 3 μm.

15. The method of claim 9, wherein the abnormal involuntary movement is chorea, akathisia, dyskinesia, tremor, tics, chorea associated with Huntington's disease, tardive dyskinesia, tics associated with Tourette's syndrome, levodopa-induced dyskinesia in Parkinson's disease, or dyskinesia in cerebral palsy.

16. The method of claim 9, wherein the total daily dose of once-daily deutetrabenazine is administered with or without food.

17. A method of converting a human subject treated with a daily dose of tetrabenazine to a once-daily dose of deuterated tetrabenazine to control abnormal involuntary movements, comprising: a) administration of the last dose of tetrabenazine; and b) on the second day, administering to the subject a once-daily osmotic dosage form of deuterated tetrabenazine, wherein: The daily dose of tetrabenazine is 12.5 mg, and the once daily dose of deuterated tetrabenazine is 6 mg; or wherein the daily dose of tetrabenazine is 25 mg, and the once daily dose of deuterated tetrabenazine is 12 mg; or wherein the daily dose of tetrabenazine is 37.5 mg, and the once daily dose of deuterated tetrabenazine is 18 mg; or wherein the daily dose of tetrabenazine is 50 mg, and the once-daily dose of deuterated tetrabenazine is 24 mg; or wherein the daily dose of tetrabenazine is 62.5 mg, and the once daily dose of deuterated tetrabenazine is 30 mg; or wherein the daily dose of tetrabenazine is 75 mg, and the once daily dose of deuterated tetrabenazine is 36 mg; or wherein the daily dose of tetrabenazine is 87.5 mg, and the once daily dose of deuterated tetrabenazine is 42 mg; or wherein the daily dosage of tetrabenazine is 100 mg, and the once-daily dosage of deuterated tetrabenazine is 48 mg; and wherein The osmotic dosage form comprises: a. a tablet core comprising an active layer and a push layer, wherein the active layer comprises an amount of deuterated tetrabenazine microparticles and an active layer controlled-release agent, and wherein the push layer comprises an osmotic agent and a push layer controlled-release agent, and an optional tablet seal coating on the outer surface of the tablet core; b. a semipermeable layer surrounding the core; c. a port extending through the semipermeable layer into the core; and d. an optional immediate release coating on the exterior of the semipermeable layer comprising a second amount of deuterated tetrabenazine microparticles.

18. The method of claim 17, wherein about 70%-80% of the total amount of deuterated tetrabenazine microparticles present in the osmotic dosage form are present in the active layer, and wherein about 20%-30% of the total amount of deuterated tetrabenazine microparticles present in the osmotic dosage form are present in the immediate release coat.

19. The method of claim 17, wherein the deuterated tetrabenazine microparticles have a 90 15μm, D 50 10μm and / or D 10 The particle size is 3 μm.

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

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

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