KR20250019144A - Osmotic formulations containing deutetrabenazine and methods of using the same - Google Patents

Abstract

Provided herein are osmotic dosage forms containing deutetrabenazine for use in the treatment of, for example, hyperkinesia. The dosage forms provide a favorable pharmacokinetic profile for the active agent, which provides therapeutic efficacy over an extended period of time when administered orally to a subject on a once daily basis.

Description

Osmotic formulations containing deutetrabenazine and methods of using the same

Cross-reference to related applications

This application claims the benefit of U.S. Provisional Application No. 63/037,369, filed June 10, 2020, U.S. Provisional Application No. 63/037,953, filed June 11, 2020, and U.S. Provisional Application No. 63/044,451, filed June 26, 2020, which is a continuation-in-part of U.S. Application No. 17/835,435, filed June 8, 2022, which is a continuation-in-part of U.S. Application No. 17/344,271, filed June 10, 2021, which claims the benefit of U.S. Provisional Application No. 63/037,369, filed June 10, 2020, U.S. Provisional Application No. 63/037,953, filed June 11, 2020, and U.S. Provisional Application No. 63/044,451, filed June 26, 2020, which are incorporated herein by reference in their entirety.

Technical field

The present disclosure relates to osmotic formulations and methods of using such formulations for treating hyperkinesias resulting from conditions such as Huntington's disease, tardive dyskinesia, Tourette syndrome, levodopa-induced dyskinesias and dyskinesias in cerebral palsy.

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) receptor. The biologically active metabolites formed from deutetrabenazine (alpha-dihydrodeutetrabenazine [α-deuHTBZ] and beta-dihydrodeutetrabenazine [β-deuHTBZ]) (together identified as "deuHTBZ") are potent inhibitors of VMAT2 binding. Deutetrabenazine exhibits active metabolites with increased half-lives compared to tetrabenazine (see, e.g., U.S. Patent No. 8,524,733).

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

One factor that affects the gastrointestinal absorption of an oral drug is the rate at which the drug is released from the dosage form. The rate of drug release from an oral dosage form is typically measured by the in vitro dissolution rate, i.e., the amount of drug released from the dosage form per unit time, in systems such as those approved by the FDA. Such systems include, for example, the United States Pharmacopeia (USP) Dissolution Devices I and II.

The therapeutic window of a drug is the period of time 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 formulation should be administered at appropriate intervals so that the plasma drug concentration is maintained within the therapeutic window or increases again. However, at the same time, it is necessary to avoid or minimize plasma drug concentrations that cause undesirable side effects.

Several formulations containing deutetrabenazine are disclosed in U.S. Patent No. 9,296,739. Formulations capable of delivering deutetrabenazine in a controlled manner over an extended period of time would allow for a more advantageous dosing regimen, such as once daily (qd) administration, while maintaining the therapeutic effect currently achieved by AUSTEDO®. There is a need for such alternative formulations.

a. A tablet core comprising an active layer and a push layer containing a certain amount of deutetrabenazine microparticles;

b. a semipermeable layer surrounding the purified core; and

c. A port extending into the purified core through the semi-permeable layer.

Disclosed herein is an osmotic dosage form for administering deutetrabenazine once daily to a subject in need thereof.

Further disclosed herein is a method of treating hyperkinesia in a subject, comprising administering to the subject an osmotic formulation disclosed herein once daily.

Figure 1 provides an example of an osmotic formulation in cross section.
Figures 2a and 2b provide a flow diagram of a general manufacturing process for an osmotic formulation according to the present disclosure.
Figures 3a and 3b are graphs showing the concentration of deutetrabenazine (pg/mL) versus time (hours, "h") in subjects administered 12 mg AUSTEDO® tablets bid ("R") or 24 mg deutetrabenazine osmotic formulation qd ("T2A"). Figure 3a shows a direct scale for mean concentration, and Figure 3b shows a log scale for mean concentration.
Figures 4a and 4b are graphs showing the concentration (pg/mL) of α- and β- deuHTBZ (total deuHTBZ) versus time (hours, “h”) in subjects administered 12 mg AUSTEDO® tablets bid (“R”) or 24 mg deutetrabenazine containing osmotic formulation qd (“T2A”). Figure 4a shows a direct scale for mean concentration, and Figure 4b shows a log scale for mean concentration.
Figure 5 is a drawing summarizing the food effect study described in Example 4.

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

Unless otherwise defined herein, scientific and technical terms used in connection with this application shall have the meanings commonly understood by those of ordinary skill in the art. Furthermore, unless the context requires otherwise, singular terms include plurals, and plural terms include the singular.

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

In this disclosure, the singular form includes plural references, and reference to a particular value includes at least that particular value unless the context clearly indicates otherwise. Thus, for example, reference to "a compound" refers to one or more of such compounds and equivalents thereof known to those skilled in the art, etc. The term "plurality" as used herein means more than one. When a range of values is expressed, another embodiment includes from the one particular value and/or to the other particular value. Likewise, when values are expressed as approximations, the use of the antecedent "about" is to be understood that the particular value forms another embodiment. All ranges are inclusive and combinable.

As used herein, the terms "compound", "drug", "pharmacologically active agent", "active agent" or "medicine" are used interchangeably herein to refer to a compound or composition of compounds or substances that, when administered to a subject (human or animal), induces a desired pharmacological and/or physiological effect by local and/or systemic action. The active agent is preferably deutetrabenazine as disclosed herein.

As used herein, "dosage form" refers to a drug form having osmotic properties and capable of releasing an active agent over an extended period of time, for example, the dosage form refers to a drug capable of releasing an active agent over an extended period of time, wherein the dosage form releases no more than 60 wt% of the active agent in the dosage form over a period of 8 hours after administration. The active agent is preferably deutetrabenazine as disclosed herein.

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

The terms "port" or "exit port", which are used interchangeably, refer to a means and method suitable for the exit of a drug or drug formulation from the core of the dosage form, such as any hole, passage, channel or similar opening within the core of the dosage form through which the drug or drug formulation may exit. Other expressions of these terms include, for example, an exit means, an orifice or a hole.

As used herein, the term "treatment" or "therapy" (and its different forms) includes preventive (e.g., prophylactic), curative or palliative treatment. As used herein, the term "treating" includes alleviating or reducing at least one adverse or negative effect or symptom of a condition, disease or disorder. Such a condition, disease or disorder can refer to a hyperkinesia movement disorder, such as, without limitation, Huntington's disease, tardive dyskinesia, Tourette's syndrome, dystonia, dyskinesia in cerebral palsy and levodopa-induced dyskinesia in Parkinson's disease.

The term “administering” means providing to a patient a pharmaceutical composition or formulation disclosed herein (used interchangeably herein).

The terms “subject,” “individual,” and “patient” are used interchangeably herein and refer to a human being to whom treatment, including prophylactic treatment, is provided in a formulation disclosed herein.

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

The presently disclosed formulations may include "derivatives" of particular formulation 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, the derivative may refer to semi-synthetic cellulose products such as cellophane, rayon, cellulose acetate, cellulose esters, and cellulose ethers.

"Particulate" refers to particles having a particle size (i.e., diameter) less than 1 mm, such as deutetrabenazine particles. In one embodiment, the microparticles have a median diameter (D ₅₀ ) of from about 0.05 to about 100 μm. In another embodiment, the microparticles have a D ₅₀ of from about 0.05 to about 50 μm. In another embodiment, the microparticles have a D ₅₀ of from about 1 μm to about 30 μm, or from about 1 μm to about 25 μm, or from about 5 μm to about 30 μm, or from about 1 μm to about 20 μm, or from about 5 μm to about 25 μm, or from about 10 μm to about 20 μm. In one embodiment, the deutetrabenazine microparticles have a particle size distribution from about 1 μm to about 30 μm in diameter. In another embodiment, the deutetrabenazine microparticles have a D ₉₀ of 15 μm (i.e., 90% of the particles have a diameter less than or equal to 15 μm). In another embodiment, the deutetrabenazine microparticles have a D ₅₀ of 10 μm (i.e., 50% of the particles have a diameter greater than 10 μm and 50% of the particles have a diameter less than or equal to 10 μm). In another embodiment, the deutetrabenazine microparticles have a D ₁₀ of 3 μm (i.e., 10% of the particles have a diameter less than 3 μm).

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

In general, osmotic dosage forms utilize osmotic pressure to create a driving force for the absorption of fluid into a compartment formed at least in part by a semipermeable wall, layer or membrane, such as the gastrointestinal (GI) tract, through which fluid can freely diffuse but the drug or osmotic agent(s), if present, cannot. A constant rate of drug release can be achieved by designing the system to provide a relatively constant osmotic pressure and having an appropriate outlet means such that the drug formulation is released at a rate corresponding to the rate of fluid absorbed as a result of the relatively constant osmotic pressure. Without being limited by theory, the osmotic system can operate independently of pH, and thus continue to operate at an osmotically determined rate for extended periods of time even as the dosage form passes through the GI tract and encounters different microenvironments having significantly different pH values.

An example of one type of osmotic device comprises two component layers within a compartment (referred to herein as a core and used interchangeably with core) defined by a semipermeable wall. One component layer (referred to herein as the active layer) comprises a drug (i.e., deutetrabenazine) mixed with excipient(s), and a second component layer (referred to herein as the push layer) comprises an osmotic active agent(s), optionally mixed with excipients that do not contain drug. The core is further coated by a semipermeable wall that allows entry of an aqueous fluid, i.e., from the GI system, into the core. Without being limited by theory, as the fluid is absorbed into the dosage form, the active layer forms a drug formulation and the osmotic agent(s) within the push layer swell and push the drug formulation, thereby facilitating release of the drug formulation at a substantially constant rate. See, e.g., U.S. Pat. Nos. 4,327,725; 4,612,008; 4,783,337; and see 5,082,668.

Although constant release formulations have proven effective for many different drug therapies, there are clinical situations where they are not entirely satisfactory. In some patients, it has been observed that the therapeutic effect of the drug decreases below the therapeutic threshold before the end of the desired treatment period, despite the maintenance of a substantially constant drug release that would be expected to provide a sustained effect.

It has surprisingly been discovered that oral dosage forms comprising deutetrabenazine can be achieved which exhibit a desirable release rate and thus a desirable pharmacokinetic profile over an extended period of time. In some embodiments, the presently disclosed osmotic dosage forms, when administered orally to a subject on a once daily (qd) basis, provide a pharmacokinetic profile that is comparable, e.g., bioequivalent, to that of an AUSTEDO® formulation administered bid. In certain embodiments, the osmotic dosage forms provide an in vivo plasma profile for total deuHTBZ at steady state comprising a mean AUC _0-24 of about 410,000 to 800,000 h*pg/mL and a mean C _max of less than about 40,000 pg/mL.

The osmotic dosage form of the present disclosure comprises a tablet core containing at least a push layer and an active layer, the active layer comprising deutetrabenazine and one or more excipients for forming a drug formulation when hydrated, and the push layer comprising at least one osmagent and one or more excipients. Both the push layer and the active layer are contained within a tablet core at least partially surrounded by a semipermeable layer having a port that functions as an exit means for releasing the drug formulation from the tablet core. In some embodiments, the two layers are compressed into a bilayer tablet core surrounded by a semipermeable membrane and further having an orifice suitable for releasing the drug therethrough.

An embodiment of the oral osmotic dosage form disclosed herein is illustrated in the cross-sectional view of FIG. 1. The components are not drawn to scale. The dosage form (2) comprises a bilayer tablet core. The core comprises an active layer (4) containing a drug, such as deutetrabenazine, and one or more active layer excipients, and a push layer (6) containing at least one osmagent together with one or more push layer excipients. At least a portion of the active layer forms a drug formulation upon exposure to an aqueous medium. Suitable active layer and push layer excipients are known in the art and include diluents, carriers, binders, fillers, controlled release agents, and processing aids. A semipermeable membrane (8) surrounds the bilayer tablet core and has 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 within the tablet core. As illustrated, the dosage form is compressible longitudinally, and the port (10) is on a side of the dosage form comprising the active layer. In another embodiment, the formulation is compressed along the lateral axis of the formulation, and the port is present at one end of the formulation. In all embodiments, more than one port may be present. Through the cooperation of the osmotic formulation components, in the presence of an aqueous medium, the drug formulation is released from the active layer through the port at a desired release rate over an extended period of time. Although not shown in FIG. 1 , an optional immediate release layer (immediate release coating) outside the semipermeable layer comprising an additional drug (i.e., deutetrabenazine microparticles) may additionally be provided, if desired, as described elsewhere herein.

In one embodiment, the present invention comprises:

a. A tablet core comprising an active layer and a push layer containing a certain amount of deutetrabenazine microparticles;

b. a semipermeable layer surrounding the purified core; and

c. Ports within the semipermeable layer extending into the purified core.

Provided is an osmotic formulation for once-daily administration to a subject in need thereof, comprising:

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

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

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

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

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

In one embodiment, the active layer further comprises at least one active layer antioxidant. Preferably, the active layer antioxidant comprises tert-butyl-4-methoxyphenol (a mixture of 2 and 3 isomers), 2,6-ditert-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 one specific embodiment, the active layer comprises a mixture of butylated hydroxyanisole and butylated hydroxytoluene. In one embodiment, the active layer antioxidant can be present in the active layer in an amount from about 0.001 wt. % to about 1 wt. %, based on the total weight of the active layer.

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

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

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

The push layer contained within the purified core comprises an osmotic agent which, without being bound by theory, swells when exposed to an aqueous medium and acts as a fluid attractant to allow the drug formulation to flow from within the dosage form to the external environment against the active layer. An osmotic agent is, for example, generally defined as a nonvolatile species that is soluble in water and creates an osmotic gradient to allow the osmotic influx of water. Species falling within the category of osmotic agents include inorganic salts or carbohydrates. Non-limiting examples of osmotic agents are well known in the art and include magnesium sulfate, magnesium chloride, potassium sulfate, sodium chloride, sodium sulfate, lithium sulfate, sodium phosphate, potassium phosphate, d-mannitol, sorbitol, inositol, urea, magnesium succinate, tartaric acid, raffinose, and various monosaccharides, oligosaccharides and polysaccharides such as sucrose, glucose, lactose, fructose and dextran, as well as mixtures of any one of these various species.

In one embodiment, the osmagent is present in the push layer in an amount from about 5 wt % to about 50 wt %, based on the total weight of the dosage form. In one embodiment, the osmagent is present in the push layer in an amount from about 5 wt % to about 20 wt %, based on the total weight of the dosage form. In another embodiment, the osmagent is present in the push layer in an amount from about 8 wt % to about 10 wt %, based on the total weight of the dosage form.

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

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

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

In one embodiment, the push layer controlled release agent is present in the push layer in an amount from about 50 wt % to about 80 wt %, 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 from about 60 wt % to about 70 wt %, based on the total weight of the push layer.

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

The push layer optionally further 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 skilled in the art.

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

The lubricant within the push layer may include any of the exemplary materials described above with respect to the active layer. The push layer may also include a disintegrant such as cross-linked polyvinylpyrrolidone, corn starch, potato starch, smectite clay (e.g., magnesium aluminum silicate such as Veegum®), bentonite, and citrus pulp. It may also be desirable to include a stabilizer for the drug. These include, without limitation, sodium bisulfite and histidine HCl.

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

The present osmotic dosage form comprises a semipermeable layer surrounding a tablet core, thereby allowing the influx of fluid from an external fluid environment (e.g., the gastrointestinal tract of a subject) into the tablet core while preventing the outflow of drug from the core. The semipermeable layer is preferably formed of a material that is not detrimental to a patient and is permeable to external fluids, such as water and biological fluids. The selectively permeable material forming the semipermeable layer is insoluble in body fluids and is non-erodible or capable of bioeroding after a predetermined period of time with bioerosion corresponding to the end of the drug release period. As used herein, "semipermeable layer," "semipermeable wall," and "semipermeable membrane" are interchangeable.

In general, semipermeable materials useful in forming the semipermeable layer can have a fluid permeability of from 10 ^-5 to 10 ^-1 (cc mil/cm ² hr atm) expressed per atmosphere of hydrostatic or osmotic pressure difference across the wall at the temperature of use. Suitable materials are known in the art; see, e.g., U.S. Patent Nos. 3,845,770 and 3,916,899.

Typical materials useful for forming the semipermeable layer are cellulose acetate, cellulose triacetate, agar acetate, amylose triacetate, beta-glucan acetate, cellulose diacetate, acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate, polyamides, polyurethanes, sulfonated polystyrene, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, cellulose acetate ethyl carbamate, cellulose acetate chloroacetate, cellulose dipalmitate, cellulose dioctanoate, cellulose dicaprylate, cellulose dipentanate, cellulose acetate valerate, cellulose acetate succinate, cellulose propionate succinate, methyl cellulose, cellulose acetate p-toluene sulfonate, cellulose acetate butyrate, Materials known in the art include selectively permeable polymers formed by co-precipitation of polycations and polyanions as disclosed in U.S. Patent Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006; and 3,546,142.

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 ethyl cellulose, agar acetate, amylose triacetate, beta-glucan acetate, poly(vinyl methyl) ether copolymers, poly(orthoesters), polyacetals, and selectively permeable poly(glycolic acid), poly(lactic acid) derivatives, and mixtures of any of these. The cellulose acetate comprises a cellulose acetate polymer (e.g., Eudragit®). In one embodiment, the semipermeable layer comprises the water-insoluble polymer present in an amount from about 80 wt % to about 99.9 wt %, based on the weight of the semipermeable layer. In another embodiment, the water-insoluble polymer is from about 85 wt % to about 95 wt %, based on the weight of the semipermeable layer. Preferably, the semipermeable layer comprises the water-insoluble polymer, which is cellulose acetate having an acetyl content of from about 32% to 40%.

The semipermeable layer may further comprise a pore former or "pore former." The pore former comprises a biocompatible material that dissolves, disperses or decomposes when contacted with a body fluid to form pores or channels in the semipermeable layer material. Typically, water-soluble organic and inorganic materials such as sugars (e.g., sucrose, dextrose), water-soluble salts (e.g., sodium chloride, sodium phosphate, potassium chloride and sodium carbonate), N-methyl-2-pyrrolidone and polyethylene glycol, and water-soluble solvents and water-soluble polymers (e.g., carboxymethylcellulose, hydroxypropylcellulose and the like) can be conveniently used as pore formers. In one embodiment, the semipermeable layer comprises a pore former selected from a water-soluble sugar, a water-soluble salt, a water-soluble solvent and a water-soluble polymer or mixtures thereof, in addition to the water-soluble polymer or water-insoluble polymer. In a particular embodiment, the pore former is a water-soluble solvent that is polyethylene glycol. In one embodiment, the pore former comprises from about 0.1 wt % to about 20 wt % of the semipermeable layer. Preferably, the pore former comprises from about 8 wt % to about 15 wt % of the semipermeable layer. In one embodiment, the weight ratio of the semipermeable layer to the tablet core is 1:8-1:10.

In one particular embodiment, the semipermeable layer comprises cellulose acetate and polyethylene glycol.

The present formulation comprises port(s), independently or in addition to the pore-forming agent. The ports are present within the semipermeable layer and extend outside the semipermeable layer into the tablet core to provide a means of egress for the drug formulation from the active layer within the tablet core to the environment outside the dosage form. The egress port(s) are formed by any means known in the art, including mechanical drilling, laser drilling, erosion by erosive elements, extraction, dissolution, rupture, or leaching. For example, the port(s) may be formed after coating by mechanical or thermal means, or by a light beam (e.g., a laser), particle beam, or other high energy source, or may be formed in situ by rupture of a small portion of the coating. Such rupture may be controlled by intentionally incorporating a relatively small, weak portion into the coating. The egress port(s) may also be formed in situ by erosion of a plug of water-soluble material, or by rupture of a thinner portion of the coating across a recess in the core. The exit port(s) may be formed by coating the core such that one or more small areas are left uncoated. Additionally, the exit port(s) may be a plurality of holes or pores that may be formed during coating. The exit port(s) may be pores formed by leaching sorbitol, lactose, or the like from a wall or layer as disclosed in U.S. Patent No. 4,200,098. That patent discloses pores of controlled size porosity formed by dissolving, extracting, or leaching sorbitol from a material, such as cellulose acetate, from the wall. A preferred form of laser drilling is the use of a pulsed laser to incrementally remove material from the semipermeable layer to a desired depth to form the exit ports. In certain embodiments, the port or ports can be formed by leaching a member selected from the group consisting of, for example, sorbitol, lactose, fructose, glucose, mannose, galactose, talose, sodium chloride, potassium chloride, sodium citrate, and mannitol to provide an outlet port of uniform release size. The outlet means can have any shape, such as circular, triangular, square, oval, and the like, for uniform metered dose release of the drug formulation from the dosage form. The osmotic dosage form can be configured to have one or more outlet ports in a spaced apart relationship or one or more surfaces of the osmotic dosage form. Such outlets and equipment for forming such outlets are disclosed, for example, in U.S. Patent Nos. 3,916,899 and 4,088,864.

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.

In some embodiments, the formulation further comprises one or more seal coatings, for example to ensure the integrity of one or more of the sub-portions of the formulation. In one embodiment, the tablet core comprises a seal coating immediately outside the tablet core. For example, the tablet core seal coating may be applied to the exterior surface of the compressed layered tablet core prior to applying the semipermeable layer. In certain embodiments, the tablet core comprises a semipermeable layer immediately outside the tablet core and a seal coating immediately outside the semipermeable layer. For example, the semipermeable layer seal coating may be applied to the exterior surface of the formulation after applying the semipermeable membrane to the tablet core. The seal coating material may comprise a binder, many types of which are disclosed above. In embodiments comprising a seal coating between the core and the semipermeable membrane immediately outside, the port will extend from outside the seal coating through all layers into the core.

In one embodiment, the tablet core sealing coat is applied to the outer surface of the tablet core.

In one embodiment, a semipermeable layer sealing coat is applied to the outer surface of the semipermeable layer.

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

In one embodiment, the total amount of binder in the formulation is from about 0 to about 20 wt %, based on the total weight of the formulation. In another embodiment, the total amount of binder in the formulation is from about 5 wt % to about 20 wt %, based on the total weight of the formulation. In another embodiment, the total amount of binder in the formulation is from about 8 wt % to about 10 wt %, based on the total weight of the formulation, or from about 10 wt % to about 20 wt %, based on the total weight of the formulation.

The absolute amount of deutetrabenazine within the active layer of the present osmotic dosage form will vary depending on the dosage strength of the particular embodiment. As described in more detail below, the dosage form may additionally comprise an immediate release amount of deutetrabenazine microparticles that are external to the active layer, preferably external to the semipermeable membrane layer.

In one embodiment, the formulation disclosed herein further comprises an immediate release coating comprising a second quantity of deutetrabenazine microparticles external to the semipermeable membrane or external to the semipermeable layer seal coating applied thereto.

In one embodiment, the immediate release coating comprises from about 0.1 wt % to about 25 wt % of deutetrabenazine microparticles, based on the total weight of the formulation. In another embodiment, the immediate release coating comprises from about 0.2 wt % to about 5 wt % of deutetrabenazine microparticles, based on the total weight of the formulation. In another embodiment, the immediate release coating comprises from about 0.3 wt % to about 2 wt % of deutetrabenazine microparticles, based on the total weight of the formulation. In another embodiment, the formulation comprises a total of 24 mg of deutetrabenazine microparticles, and the immediate release coating comprises from about 1 wt % to about 2 wt % of deutetrabenazine microparticles, based on the total weight of the formulation. In another embodiment, the formulation comprises a total of 12 mg of deutetrabenazine microparticles, and the immediate release coating comprises from about 0.5 wt % to about 1 wt % of deutetrabenazine microparticles, based on the total weight of the formulation. In another embodiment, the formulation comprises a total of 6 mg of deutetrabenazine microparticles and the immediate release coating comprises from about 0.1 wt % to about 0.5 wt % of the deutetrabenazine microparticles, based on the total weight of the formulation.

In one embodiment, at least 70% of the total amount of deutetrabenazine microparticles in the formulation are present in the active layer. In another embodiment, from 70% to 100% of the total amount of deutetrabenazine microparticles in the formulation are present in the active layer. In another embodiment, from about 70% to 80% of the total amount of deutetrabenazine microparticles in the formulation are present in the active layer. In some embodiments of the osmotic dosage form, deutetrabenazine is present only in the active layer.

In one embodiment, the osmotic dosage form comprises an immediate release coating comprising up to about 30% of the total weight of deutetrabenazine microparticles in the dosage form. In one embodiment, from about 8% to about 30% of the total weight of deutetrabenazine microparticles in the dosage form are present in the immediate release coating. In one embodiment of the invention, from about 70% to about 80% of the total weight of deutetrabenazine microparticles in the dosage form are present in the active layer, and from about 20% to about 30% of the total weight of deutetrabenazine microparticles in the dosage form are present in the immediate release coating.

The formulation of any embodiment of the present invention comprises a total amount of deutetrabenazine microparticles from about 6 mg to about 48 mg. In one embodiment, the total amount of deutetrabenazine microparticles in the formulation is about 6 mg. In one embodiment, the total amount of deutetrabenazine microparticles in the formulation is about 12 mg. In another embodiment, the total amount of deutetrabenazine microparticles in the formulation is about 24 mg. In another embodiment, the total amount of deutetrabenazine microparticles in the formulation is about 36 mg. In another embodiment, the total amount of deutetrabenazine microparticles in the formulation is about 48 mg.

According to the present disclosure, the total amount of deutetrabenazine or the total daily dose of deutetrabenazine, as used interchangeably herein, is administered to a subject in one dose per day (QD). Depending on the total daily dose, one or more than one (multiple) formulations may be administered to the subject in one dose. Preferably, a single formulation is administered in one dose. In one embodiment, the total daily dose of deutetrabenazine is from 12 mg to 48 mg. In one embodiment, the total daily dose of deutetrabenazine is 12 mg. In one embodiment, the total daily dose of deutetrabenazine is 18 mg. In one embodiment, the total daily dose of deutetrabenazine is 24 mg. In one embodiment, the total daily dose of deutetrabenazine is 30 mg. In one embodiment, the total daily dose of deutetrabenazine is 36 mg. In one embodiment, the total daily dose of deutetrabenazine is 42 mg. In one embodiment, the total daily dose of deutetrabenazine is 48 mg.

Patients treated with deutetrabenazine twice daily (bid) may be switched to deutetrabenazine once daily (qd) on the day following the last dose of deutetrabenazine bid, at the same total daily dose.

Patients treated with deutetrabenazine once daily (qd) may be switched to deutetrabenazine twice daily (bid) on the day following the last dose of deutetrabenazine qd, at the same total daily dose.

Patients treated with tetrabenazine may be switched to the once-daily (qd) osmotic formulation of deutetrabenazine disclosed herein on the day following the last dose of tetrabenazine.

In one embodiment, the total amount of deutetrabenazine microparticles present in the formulation is from about 0.5 wt % to about 15 wt %, based on the total weight of the osmotic dosage form. In another embodiment, the total amount of deutetrabenazine microparticles present in the formulation is from about 1 wt % to about 10 wt %, based on the total weight of the dosage form. In another embodiment, the formulation comprises 6 mg of deutetrabenazine microparticles, and the total amount of deutetrabenazine microparticles present in the formulation is from about 0.5 wt % to about 3 wt %, based on the total weight of the dosage form. In another embodiment, the formulation comprises 12 mg of deutetrabenazine microparticles, and the total amount of deutetrabenazine microparticles present in the formulation is from about 1 wt % to about 5 wt %, based on the total weight of the dosage form. In another embodiment, the formulation comprises a total of 24 mg of deutetrabenazine microparticles, and the total amount of deutetrabenazine microparticles present in the formulation is from about 5 wt % to about 10 wt %, based on the total weight of the formulation.

In addition to the quantity of deutetrabenazine microparticles, the immediate release coating can further comprise one or more pharmaceutically acceptable excipients, such as an antioxidant, a binder and a surfactant or any combination thereof. The antioxidants, binders and surfactants can be selected from a wide variety of options known to those skilled in the art. Exemplary antioxidants and binders are disclosed above in connection with the other components of the present formulation. Surfactants can include, but are not limited to, esters of polyhydric alcohols, such as glycerol monolaurate, ethoxylated castor oil, polysorbates, esters or ethers of saturated alcohols, such as myristyl lactate (e.g., Ceraphyl®50), and polyoxyethylene/polyoxypropylene block copolymers, such as Pluronic®.

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

In one embodiment, an osmotic dosage form for administering deutetrabenazine once daily to a subject in need thereof is provided, comprising:

a. A purified core comprising:

i. An active layer comprising an active layer controlled-release agent, an active layer antioxidant, and an active layer binder, comprising a certain amount of deutetrabenazine microparticles and a polymer having a viscosity of about 55-90 mPa s;

ii. A push layer comprising a push layer controlled release agent and a push layer binder comprising an osmotic agent and a polymer having a viscosity of about 5500-7500 mPa s;

b. A tablet core sealing coat comprising a binder on the outer surface of the tablet core;

c. A semipermeable layer comprising a water-insoluble polymer and a pore-forming agent surrounding a purified core sealing coat;

d. A semipermeable layer sealing coat comprising a binder on the outer surface of the semipermeable layer;

e. an immediate release coating comprising a second predetermined amount of deutetrabenazine microparticles and an immediate release coating antioxidant on the outer surface of the semipermeable layer sealing coat; and

f. Port within the semi-permeable layer sealing coat reaching the purified core.

In some embodiments, an osmotic dosage form is provided according to any one of the embodiments of the present invention, wherein when the dosage form is tested in 500 mL acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus, not more than 15% of the drug formulation is released within 2 hours, and/or not more than 60% of the drug formulation is released within 8 hours.

Additionally, provided herein is a method of treating hyperkinesia in a subject, comprising orally administering to the subject an osmotic formulation according to any one of the embodiments of the present invention on a once daily basis. Additionally, provided herein is an osmotic formulation according to any one of the embodiments disclosed herein for once daily oral use to treat hyperkinesia in a subject.

In some embodiments, the movement disorder is selected from chorea, ataxia, 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, Parkinson's disease levodopa-induced dyskinesia, or dyskinesia in cerebral palsy.

In certain embodiments, the osmotic formulation according to any one of the embodiments disclosed herein is administered with food.

In certain embodiments, the osmotic formulation according to any one of the embodiments disclosed herein is administered under fasting conditions.

In one embodiment, the invention provides a method of treating hyperkinesia in a subject in need thereof, comprising orally administering to a subject once daily an osmotic formulation according to any one of the embodiments of the invention, wherein a single dose of the osmotic formulation comprising a total amount of 6 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dehydrodeutetrabenazine comprising a geometric mean AUC _0-inf of about 91,250 to 142,750 h*pg/mL.

In one embodiment, the invention provides a method of treating hyperkinesia in a subject in need thereof, comprising orally administering to a subject once daily an osmotic formulation according to any one of the embodiments of the invention, wherein a single dose of the osmotic formulation comprising a total amount of 6 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dehydrodeutetrabenazine comprising a geometric mean C _max of less than about 4,600 pg/mL.

In one embodiment, the invention provides a method of treating hyperkinesia in a subject in need thereof, comprising orally administering to a subject once daily an osmotic formulation according to any one of the embodiments of the invention, wherein a single dose of the osmotic formulation comprising a total amount of 12 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dehydrodeutetrabenazine comprising a geometric mean AUC _0-inf of about 182,500 to 285,500 h*pg/mL.

In one embodiment, the invention provides a method of treating hyperkinesia in a subject in need thereof, comprising orally administering to a subject once daily an osmotic formulation according to any one of the embodiments of the invention, wherein a single dose of the osmotic formulation comprising a total amount of 12 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dehydrodeutetrabenazine comprising a geometric mean C _max of less than about 9,200 pg/mL.

In one embodiment, the invention provides a method of treating hyperkinesia in a subject in need thereof, comprising orally administering to a subject once daily an osmotic formulation according to any one of the embodiments of the invention, wherein a single dose of the osmotic formulation comprising a total amount of 24 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dehydrodeutetrabenazine comprising a geometric mean AUC _0-inf of about 365,000 to 571,000 h*pg/mL.

In one embodiment, the invention provides a method of treating hyperkinesia in a subject in need thereof, comprising orally administering to a subject once daily an osmotic formulation according to any one of the embodiments of the invention, wherein a single dose of the osmotic formulation comprising a total amount of 24 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dehydrodeutetrabenazine comprising a geometric mean C _max of less than about 18,400 pg/mL.

In one embodiment, the invention provides a method of treating hyperkinesia in a subject in need thereof, comprising orally administering to a subject once daily an osmotic formulation according to any one of the embodiments of the invention, wherein a single dose of the osmotic formulation comprising a total amount of 36 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dehydrodeutetrabenazine comprising a geometric mean AUC _0-inf of about 547,500 to 856,500 h*pg/mL.

In one embodiment, the invention provides a method of treating hyperkinesia in a subject in need thereof, comprising orally administering to a subject once daily an osmotic formulation according to any one of the embodiments of the invention, wherein a single dose of the osmotic formulation comprising a total amount of 36 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dehydrodeutetrabenazine comprising a geometric mean C _max of less than about 27,600 pg/mL.

In one embodiment, the invention provides a method of treating hyperkinesia in a subject in need thereof, comprising orally administering to a subject once daily an osmotic formulation according to any one of the embodiments of the invention, wherein a single dose of the osmotic formulation comprising a total amount of 48 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dehydrodeutetrabenazine comprising a geometric mean AUC _0-inf of about 730,000 to 1,142,000 h*pg/mL.

In one embodiment, the invention provides a method of treating hyperkinesia in a subject in need thereof, comprising orally administering to a subject once daily an osmotic formulation according to any one of the embodiments of the invention, wherein a single dose of the osmotic formulation comprising a total amount of 48 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dehydrodeutetrabenazine comprising a geometric mean C _max of less than about 36,800 pg/mL.

In one embodiment, the invention provides a method of treating hyperkinesia in a subject in need thereof, comprising orally administering to a subject once daily an osmotic dosage form according to any one of the embodiments of the invention, wherein the osmotic dosage form comprising a total amount of 6 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dehydrodeutetrabenazine at steady state comprising a mean AUC _0-24 of about 102,500 to 200,000 h*pg/mL.

In one embodiment, the invention provides a method of treating hyperkinesia in a subject in need thereof, comprising orally administering to a subject once daily an osmotic dosage form according to any one of the embodiments of the invention, wherein the osmotic dosage form comprising a total amount of 6 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dehydrodeutetrabenazine at steady state comprising a mean C _max of less than about 10,000 pg/mL.

In one embodiment, the invention provides a method of treating hyperkinesia in a subject in need thereof, comprising orally administering to a subject once daily an osmotic dosage form according to any one of the embodiments of the invention, wherein the osmotic dosage form comprising a total amount of 12 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dehydrodeutetrabenazine at steady state comprising a mean AUC _0-24 of about 205,000 to 400,000 h*pg/mL.

In one embodiment, the invention provides a method of treating hyperkinesia in a subject in need thereof, comprising orally administering to a subject once daily an osmotic dosage form according to any one of the embodiments of the invention, wherein the osmotic dosage form comprising a total amount of 12 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dehydrodeutetrabenazine at steady state comprising a mean C _max of less than about 20,000 pg/mL.

In one embodiment, the invention provides a method of treating hyperkinesia in a subject in need thereof, comprising orally administering to the subject once daily an osmotic dosage form according to any one of the embodiments of the invention, wherein the osmotic dosage form comprising a total amount of 24 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising a mean AUC _0-24 of about 410,000 to 800,000 h*pg/mL.

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

In one embodiment, the invention provides a method of treating hyperkinesia in a subject in need thereof, comprising orally administering to a subject once daily an osmotic dosage form according to any one of the embodiments of the invention, wherein the osmotic dosage form comprising a total amount of 36 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dehydrodeutetrabenazine at steady state comprising a mean AUC _0-24 of about 615,000 to 1,200,000 h*pg/mL.

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

In one embodiment, the invention provides a method of treating hyperkinesia in a subject in need thereof, comprising orally administering to a subject once daily an osmotic dosage form according to any one of the embodiments of the invention, wherein the osmotic dosage form comprising a total amount of 48 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dehydrodeutetrabenazine at steady state comprising a mean AUC _0-24 of about 820,000 to 1,600,000 h*pg/mL.

In one embodiment, the invention provides a method of treating hyperkinesia in a subject in need thereof, comprising orally administering to a subject once daily an osmotic dosage form according to any one of the embodiments of the invention, wherein the osmotic dosage form comprising a total amount of 48 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dehydrodeutetrabenazine at steady state comprising a mean C _max of less than about 80,000 pg/mL.

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

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

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

Additionally, a method of transitioning a human subject treated with a total daily dose of deutetrabenazine twice daily (bid) for the control of abnormal involuntary movements to a total daily dose of deutetrabenazine once daily,

a) administering a final dose of deutetrabenazine twice daily (bid) to a human subject; and

b) The next day, administering a total daily dose of deutetrabenazine once daily (qd) to the human subject.

A method including:

Deutetrabenazine once daily is, for example, an extended release osmotic formulation of deutetrabenazine disclosed herein.

Deutetrabenazine twice daily can refer to, for example, AUSTEDO® bid tablets or any equivalent thereof. As used herein, the term "last dose" refers to discontinuation of current treatment, for example, discontinuation of treatment with deutetrabenazine twice daily. In certain embodiments, the last dose of deutetrabenazine twice daily can refer to the second daily dose of deutetrabenazine twice daily administered to a human subject, for example, in the afternoon or evening.

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

In another embodiment, the human subject is treated with deutetrabenazine twice daily tablets at a total daily dose of 18 mg, and then transitions to a total daily dose of 18 mg deutetrabenazine once daily.

In another embodiment, the human subject is treated with deutetrabenazine twice daily tablets at a total daily dose of 24 mg, and then transitions to a total daily dose of 24 mg deutetrabenazine once daily.

In another embodiment, the human subject is treated with deutetrabenazine twice daily tablets at a total daily dose of 30 mg, and then transitions to a total daily dose of 30 mg deutetrabenazine once daily.

In another embodiment, the human subject is treated with deutetrabenazine twice daily tablets at a total daily dose of 36 mg, and then transitions to a total daily dose of 36 mg deutetrabenazine once daily.

In another embodiment, the human subject is treated with deutetrabenazine twice daily tablets at a total daily dose of 42 mg, and then transitions to a total daily dose of 42 mg deutetrabenazine once daily.

In another embodiment, the human subject is treated with deutetrabenazine twice daily tablets at a total daily dose of 48 mg, and then transitions to a total daily dose of 48 mg deutetrabenazine once daily.

In one particular embodiment, the once daily deutetrabenazine is an extended release osmotic dosage form, preferably a deutetrabenazine osmotic dosage form according to any one of the embodiments of the present invention.

In another specific embodiment, the once-daily osmotic formulation of deutetrabenazine is

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

b. A semipermeable layer surrounding the purified core;

c. a port extending into the purified core through the semipermeable layer; and

d. An optional immediate release coating on the outside of the semipermeable layer comprising a second quantity of deutetrabenazine microparticles.

Includes.

In one embodiment, the once-daily extended-release formulation of deutetrabenazine is administered with or without food.

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

Additionally, a method of transitioning a human subject being treated with a total daily dose of deutetrabenazine once daily for the control of abnormal involuntary movements to deutetrabenazine twice daily (bid) tablets at the same total daily dose,

a) administering the last dose of deutetrabenazine once daily; and

b) The next day, administering a total daily dose of deutetrabenazine twice a day to the human subject.

A method including:

As detailed above, human subjects are administered the same total daily dose, for example, 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg or 48 mg.

In one embodiment, the human subject is treated with a once daily dose of deutetrabenazine at a total daily dose of 12 mg, transitioning to a total daily dose of 12 mg deutetrabenazine tablets twice daily.

In one embodiment, the human subject is treated with a once daily dose of deutetrabenazine at a total daily dose of 18 mg, transitioning to a total daily dose of 18 mg deutetrabenazine tablets twice daily.

In one embodiment, the human subject is treated with a once daily dose of deutetrabenazine at a total daily dose of 24 mg, transitioning to a total daily dose of 24 mg deutetrabenazine tablets twice daily.

In one embodiment, the human subject is treated with a once daily dose of deutetrabenazine at a total daily dose of 30 mg, transitioning to a total daily dose of 30 mg deutetrabenazine tablets twice daily.

In one embodiment, the human subject is treated with a once daily dose of deutetrabenazine at a total daily dose of 36 mg, transitioning to a total daily dose of 36 mg deutetrabenazine tablets twice daily.

In one embodiment, the human subject is treated with a once daily dose of deutetrabenazine at a total daily dose of 42 mg, transitioning to a total daily dose of 42 mg deutetrabenazine tablets twice daily.

In one embodiment, the human subject is treated with a once daily dose of deutetrabenazine at a total daily dose of 48 mg, transitioning to a total daily dose of 48 mg deutetrabenazine tablets twice daily.

In one particular embodiment, the once daily deutetrabenazine is an extended release formulation, preferably an osmotic formulation according to any one of the embodiments of the present invention. In one embodiment, the once daily extended release formulation of deutetrabenazine is administered with or without food.

In one embodiment, the human subject is treated with a once daily osmotic formulation of deutetrabenazine and transitioned to a twice daily formulation of deutetrabenazine.

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

Additionally, a method is provided for transitioning a human subject treated with a daily dose of tetrabenazine for the control of abnormal involuntary movements to a once-daily dose of deutetrabenazine, the method comprising:

a) administering the last dose of tetrabenazine; and

b) The next day, administering the deutetrabenazine osmotic formulation to the human subject once a day.

, including, where,

The daily dose of tetrabenazine is 12.5 mg, and the daily dose of deutetrabenazine is 6 mg;

The daily dose of tetrabenazine is 25 mg, and the daily dose of deutetrabenazine is 12 mg;

The daily dose of tetrabenazine is 37.5 mg, and the daily dose of deutetrabenazine is 18 mg;

The daily dose of tetrabenazine is 50 mg, and the daily dose of deutetrabenazine is 24 mg;

The daily dose of tetrabenazine is 62.5 mg, and the single daily dose of deutetrabenazine is 30 mg;

The daily dose of tetrabenazine is 75 mg, and the daily dose of deutetrabenazine is 36 mg;

The daily dose of tetrabenazine is 87.5 mg, and the single daily dose of deutetrabenazine is 42 mg;

The daily dose of tetrabenazine is 100 mg, and the daily dose of deutetrabenazine is 48 mg.

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

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

In one embodiment, the once daily deutetrabenazine extended-release formulation is administered with or without food.

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

aspect

1. An osmotic formulation for once-daily administration to a subject in need thereof, comprising:

a. A tablet core comprising an active layer and a push layer containing a certain amount of deutetrabenazine microparticles;

b. a semipermeable layer surrounding the purified core; and

c. A port extending from the periphery of the formulation into the purified core.

2. A formulation according to aspect 1, wherein the active layer further comprises an active layer-controlled release agent.

3. A formulation according to aspect 2, wherein the active layer controlled-release agent comprises a polymer having a viscosity of about 50-150 mPa s or about 55-90 mPa s.

4. A formulation according to aspect 2 or aspect 3, wherein the active layer controlled-release agent comprises at least one of a polyoxyethylene polymer, an ionic hydrogel, a hydrophilic polymer, a hydrophobic polymer, or any mixture thereof.

5. A formulation according to aspect 4, wherein the active layer controlled release agent comprises a polyoxyethylene polymer which is polyethylene oxide.

6. A formulation according to aspect 5, wherein the polyethylene oxide in the active layer has an average molecular weight of 100,000 to 500,000 daltons.

7. A formulation according to aspect 6, wherein the polyethylene oxide in the active layer has an average molecular weight of 200,000 daltons.

8. A formulation according to any one of aspects 2 to 7, wherein the active layer controlled release agent is present in the active layer in an amount of about 60 wt% to about 98 wt% based on the total weight of the active layer.

9. A formulation according to aspect 8, wherein the active layer controlled release agent is present in the active layer in an amount of from about 70 wt% to about 95 wt% based on the total weight of the active layer, or from about 80 wt% to about 90 wt%, or from about 85 wt% to about 95 wt% based on the total weight of the active layer.

10. A formulation according to any one of aspects 2 to 9, wherein the weight ratio of the amount of deutetrabenazine microparticles in the active layer and the active layer controlled-release agent is 2:3 to 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.

11. A formulation according to any one of aspects 1 to 10, wherein the active layer further comprises at least one active layer antioxidant.

12. A formulation according to 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-ditert-butyl-p-cresol, propyl gallate, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquin), nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole, butylated hydroxytoluene or any mixture thereof.

13. A formulation according to aspect 12, wherein the active layer antioxidant comprises a mixture of butylated hydroxyanisole and butylated hydroxytoluene.

14. A formulation according to any one of aspects 11 to 13, wherein the active layer antioxidant is present in the active layer in an amount of about 0.001 wt% to about 1 wt% based on the total weight of the active layer.

15. A formulation according to any one of aspects 1 to 14, wherein the active layer further comprises at least one of the active layer binders.

16. A formulation according to aspect 15, wherein the active layer binder comprises at least one of hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, natural or synthetic gum, or any mixture thereof.

17. A formulation according to aspect 16, wherein the active layer binder comprises hypromellose.

18. A formulation according to any one of aspects 15 to 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.

19. A formulation according to any one of aspects 1 to 18, wherein the active layer further comprises one or more pharmaceutically acceptable excipients.

20. A formulation according to any one of aspects 1 to 19, wherein the active layer comprises deutetrabenazine microparticles, and an active layer controlled-release agent that is a polymer having a viscosity of about 55-90 mPa s, and an antioxidant.

21. A formulation according to aspect 20, wherein the active layer comprises deutetrabenazine microparticles, butylated hydroxyanisole, butylated hydroxytoluene, polyethylene oxide, hypromellose, and magnesium stearate.

22. A formulation according to any one of aspects 1 to 21, wherein the push layer comprises an osmotic agent and a push layer controlled-release agent.

23. A formulation according to aspect 22, wherein the osmotic agent comprises an inorganic salt, a carbohydrate or any mixture thereof.

24. A formulation according to aspect 23, wherein the osmotic agent comprises a carbohydrate that is d-mannitol, sorbitol, inositol, a monosaccharide, an oligosaccharide, a polysaccharide or any mixture thereof.

25. A formulation according to aspect 23, wherein the osmotic agent comprises an inorganic salt such as magnesium sulfate, magnesium chloride, potassium sulfate, sodium chloride, sodium sulfate, lithium sulfate, sodium phosphate, potassium phosphate, or any mixture thereof.

26. A formulation according to aspect 25, wherein the osmotic agent is/contains sodium chloride.

27. A formulation according to any one of aspects 22 to 26, wherein the osmotic agent is present in the formulation in an amount of from about 5 wt % to about 50 wt % based on the total weight of the formulation.

28. A formulation according to aspect 27, wherein the osmotic agent is present in the formulation in an amount of about 5 wt% to about 20 wt% based on the total weight of the formulation.

29. A formulation according to aspect 27 or aspect 28, wherein the osmotic agent is present in the formulation in an amount of about 8 wt% to about 10 wt% based on the total weight of the formulation.

30. A formulation according to any one of aspects 27 to 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.

31. A formulation according to aspect 30, wherein the osmotic agent is present in the push layer in an amount of about 30 wt% based on the total weight of the push layer.

32. A formulation according to any one of aspects 22 to 31, wherein the push layer controlled release agent comprises a polymer having a viscosity of about 5500-7500 mPa s.

33. A formulation according to 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.

34. A formulation according to aspect 33, wherein the push layer controlled release agent is polyethylene oxide.

35. A formulation according to aspect 34, wherein the polyethylene oxide in the push layer has an average molecular weight of 1,000,000 to 7,000,000 daltons.

36. A formulation according to aspect 35, wherein the polyethylene oxide in the push layer has an average molecular weight of 5,000,000 daltons.

37. A formulation according to any one of aspects 32 to 36, wherein the push layer controlled release agent is present in the push layer in an amount of from about 50 wt % to about 80 wt %, based on the total weight of the push layer.

38. A formulation according to 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.

39. A formulation according to any one of aspects 22 to 38, wherein the weight ratio of the osmotic agent in the push layer and the push layer controlled-release agent is 1:2 to 1:3.5 or 1:2 to 1:2.5.

40. A formulation according to any one of aspects 22 to 39, wherein the push layer further comprises a push layer binder.

41. A formulation according to aspect 40, wherein the push layer binder comprises hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, natural or synthetic gum, or any mixture thereof.

42. A formulation according to aspect 41, wherein the push layer binder comprises hypromellose.

43. A formulation according to any one of aspects 40 to 42, wherein the push layer binder is present in the push layer in an amount of from about 2 wt% to about 10 wt%, based on the total weight of the push layer.

44. A formulation according to aspect 43, wherein the push layer binder is present in the push layer in an amount of from about 4 wt% to about 6 wt% based on the total weight of the push layer or from about 3 wt% to about 6 wt% based on the total weight of the push layer.

45. A formulation according to any one of aspects 22 to 44, wherein the push layer further comprises a pharmaceutically acceptable excipient.

46. A formulation according to any one of aspects 22 to 45, wherein the push layer comprises sodium chloride and a polymer having a viscosity of about 5500-7500 mPa s.

47. A formulation according to aspect 46, wherein the push layer comprises sodium chloride, polyethylene oxide, hydroxypropyl methylcellulose, a colorant, and magnesium stearate.

48. A formulation according to any one of aspects 1 to 47, wherein the semipermeable layer comprises a water-soluble polymer, a water-insoluble polymer or any mixture thereof.

49. A formulation according to aspect 48, wherein the semipermeable layer comprises a water-insoluble polymer selected from cellulose ethers such as cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate butyrate, ethyl cellulose, agar acetate, 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.

50. A formulation according to aspect 49, wherein the water-insoluble polymer is cellulose acetate having an acetyl content of 32% to 39.8%.

51. A formulation according to any one of aspects 1 to 50, wherein the semipermeable layer comprises cellulose acetate and polyethylene glycol.

52. A formulation according to any one of aspects 48 to 51, wherein the water-insoluble polymer is present in an amount of from about 80 wt % to about 99.9 wt %, based on the weight of the semipermeable layer, or from about 85 wt % to about 95 wt %, based on the weight of the semipermeable layer.

53. A formulation according to any one of aspects 1 to 52, wherein the semipermeable layer comprises a pore-forming agent.

54. A formulation according to aspect 53, wherein the pore forming agent comprises a water-soluble sugar, a water-soluble salt, a water-soluble solvent, a water-soluble polymer or any mixture thereof.

55. A formulation according to aspect 54, wherein the pore-forming agent is a water-soluble solvent that is polyethylene glycol.

56. A formulation according to any one of aspects 53 to 55, wherein the pore forming agent is present in the semipermeable layer in an amount of from about 0.1 wt % to about 20 wt % of the semipermeable layer.

57. A formulation according to aspect 56, wherein the pore forming agent is present in the semipermeable layer in an amount of about 8 wt% to about 15 wt% of the semipermeable layer.

58. A formulation according to any one of aspects 1 to 57, wherein the weight ratio of the semipermeable layer and the tablet core is 1:8 to 1:10.

59. A formulation according to any one of aspects 1 to 58, wherein the port has a diameter of about 0.1 mm to about 1 mm.

60. A formulation according to aspect 59, wherein the port has a diameter of about 0.4 mm to about 0.8 mm.

61. A formulation according to any one of aspects 1 to 60, further comprising a tablet core sealing coat on the outer surface of the tablet core.

62. A formulation according to any one of aspects 1 to 61, further comprising a semipermeable layer sealing coat on the outer surface of the semipermeable layer.

63. A formulation according to aspect 61 or aspect 62, wherein the purified core sealing coat and/or the semipermeable layer sealing coat comprises a binder.

64. A formulation according to aspect 63, wherein the purified core seal coat binder and/or the semipermeable layer seal coat binder comprises hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, natural gum, synthetic gum and any mixture thereof.

65. A formulation according to aspect 64, wherein the purified core seal coat binder and/or the semipermeable layer seal coat binder is hypromellose.

66. A formulation according to any one of aspects 63 to 65, wherein the total amount of binder in the formulation is from about 0 wt % to about 20 wt % based on the total weight of the formulation; from 5 wt % to about 15 wt % based on the total weight of the formulation; or from 5 wt % to about 20 wt % based on the total weight of the formulation.

67. A formulation according to aspect 66, wherein the total amount of the binder in the formulation is from about 8 wt% to about 10 wt% based on the total weight of the formulation, or from about 10 wt% to about 20 wt% based on the total weight of the formulation, or from about 10 wt% to about 20 wt% based on the total weight of the formulation.

68. A formulation according to any one of aspects 1 to 67, further comprising an immediate release coating on the outside of the semipermeable membrane, wherein the immediate release coating comprises a second predetermined amount of deutetrabenazine microparticles.

69. A formulation according to aspect 68, wherein the immediate release coating comprises from about 0.1 wt % to about 25 wt % of deutetrabenazine microparticles based on the total weight of the formulation, or from about 0.2 wt % to about 5 wt % of deutetrabenazine microparticles based on the total weight of the formulation, or from about 0.3 wt % to about 2 wt % of deutetrabenazine microparticles based on the total weight of the formulation.

70. A formulation according to aspect 69, wherein the formulation comprises a total of 24 mg of deutetrabenazine microparticles and the immediate release coating comprises about 1 wt % to about 2 wt % of the deutetrabenazine microparticles, based on the total weight of the formulation, or wherein the formulation comprises a total of 12 mg of deutetrabenazine microparticles and the immediate release coating comprises about 0.5 wt % to about 1 wt % of the deutetrabenazine microparticles, based on the total weight of the formulation, or wherein the formulation comprises a total of 6 mg of deutetrabenazine microparticles and the immediate release coating comprises about 0.1 wt % to about 0.5 wt % of the deutetrabenazine microparticles, based on the total weight of the formulation.

71. A formulation according to any one of aspects 1 to 70, wherein about 70% to 99% of the total amount of deutetrabenazine microparticles in the formulation are in the active layer.

72. A formulation according to any one of aspects 1 to 71, wherein about 5% to 30% of the total amount of deutetrabenazine microparticles in the formulation are within the immediate release coating.

73. A formulation according to any one of aspects 1 to 72, wherein about 70% to 80% of the total amount of deutetrabenazine microparticles in the formulation are in the active layer, and about 20% to 30% of the total amount of deutetrabenazine microparticles in the formulation are in the immediate release coating.

74. A formulation according to any one of aspects 68 to 73, wherein the immediate release coating further comprises an immediate release coating antioxidant.

75. A formulation according to aspect 74, wherein the immediate release coating antioxidant comprises tert-butyl-4-methoxyphenol (a mixture of 2 and 3 isomers), 2,6-ditert-butyl-p-cresol, propyl gallate, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquin), nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole, butylated hydroxytoluene and any mixture thereof.

76. A formulation according to aspect 75, wherein the immediate release coating comprises a mixture of butylated hydroxyanisole and butylated hydroxytoluene.

77. A formulation according to any one of aspects 68 to 76, wherein the immediate release coating further comprises an additional pharmaceutically acceptable excipient.

78. A formulation according to any one of aspects 68 to 77, wherein the immediate release coating comprises deutetrabenazine microparticles, butylated hydroxyanisole, butylated hydroxytoluene, hypromellose and polysorbate 80.

79. A formulation according to any one of aspects 1 to 78, wherein the total amount of deutetrabenazine microparticles in the formulation is from about 6 mg to about 48 mg.

80. A formulation according to any one of aspects 1 to 79, wherein the total amount of deutetrabenazine microparticles in the formulation is about 6 mg.

81. A formulation according to any one of aspects 1 to 80, wherein the total amount of deutetrabenazine microparticles in the formulation is about 12 mg.

82. A formulation according to any one of aspects 1 to 81, wherein the total amount of deutetrabenazine microparticles in the formulation is about 24 mg.

83. A formulation according to any one of aspects 1 to 82, wherein the total amount of deutetrabenazine microparticles in the formulation is about 48 mg.

84. A formulation according to any one of aspects 1 to 83, wherein the total amount of deutetrabenazine microparticles is from about 0.5 wt% to about 15 wt% based on the total weight of the formulation.

85. A formulation according to aspect 84, wherein the total amount of deutetrabenazine microparticles is about 1 wt% to about 10 wt% based on the total weight of the formulation.

86. A formulation according to aspect 85, wherein the formulation comprises a total of 6 mg of deutetrabenazine microparticles and the total amount of deutetrabenazine microparticles is from about 0.5 wt% to about 3 wt% based on the total weight of the formulation, or comprises a total of 12 mg of deutetrabenazine microparticles and the total amount of deutetrabenazine microparticles is from about 1 wt% to about 5 wt% based on the total weight of the formulation, or comprises a total of 24 mg of deutetrabenazine microparticles and the total amount of deutetrabenazine microparticles is from about 5 wt% to about 10 wt% based on the total weight of the formulation.

87. A formulation according to any one of aspects 1 to 86, wherein the deutetrabenazine microparticles have a particle size of about 1 μm to about 30 μm in diameter.

88. A formulation according to aspect 87, wherein the deutetrabenazine microparticles have a particle size providing a D ₉₀ of 15 μm.

89. A formulation according to aspect 87 or aspect 88, wherein the deutetrabenazine microparticles have a particle size providing D ₅₀ 10 μm.

90. A formulation according to any one of aspects 87 to 89, wherein the deutetrabenazine microparticles have a particle size providing a D ₁₀ of 3 μm.

91. A method for treating hyperkinesia in a subject in need of treatment of hyperkinesia, comprising the step of orally administering to a subject in need of treatment of hyperkinesia an osmotic formulation according to any one of aspects 1 to 90 once daily.

92. A method according to aspect 91, wherein the movement disorder is selected from chorea, ataxia, dyskinesia, tremor, and tics.

93. A method according to aspect 92, wherein 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, and dyskinesia in cerebral palsy.

94. A method according to any one of aspects 91 to 93, comprising orally administering to a subject once daily an osmotic formulation according to any one of aspects 1 to 90, wherein a single dose of the osmotic formulation comprising a total amount of 6 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine comprising a geometric mean AUC _0-inf of about 91,250 to 142,750 h*pg/mL.

95. A method according to any one of aspects 91 to 94, comprising orally administering to a subject once daily an osmotic formulation according to any one of aspects 1 to 90, wherein a single dose administration of the osmotic formulation comprising a total amount of 6 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine comprising a geometric mean C _max of less than about 4,600 pg/mL.

96. A method according to any one of aspects 91 to 93, comprising orally administering to a subject once daily an osmotic formulation according to any one of aspects 1 to 90, wherein a single dose of the osmotic formulation comprising a total amount of 12 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine comprising a geometric mean AUC _0-inf of about 182,500 to 285,500 h*pg/mL.

97. A method according to any one of aspects 91 to 93 and 96, comprising orally administering to a subject once daily an osmotic formulation according to any one of aspects 1 to 90, wherein a single dose administration of the osmotic formulation comprising a total amount of 12 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine comprising a geometric mean C _max of less than about 9,200 pg/mL.

98. A method according to any one of aspects 91 to 93, comprising orally administering to a subject once daily an osmotic formulation according to any one of aspects 1 to 90, wherein a single dose of the osmotic formulation comprising a total amount of 24 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine comprising a geometric mean AUC _0-inf of about 365,000 to 571,000 h*pg/mL.

99. A method according to any one of aspects 91 to 93 and 98, comprising orally administering to a subject once daily an osmotic formulation according to any one of aspects 1 to 90, wherein a single dose administration of the osmotic formulation comprising a total amount of 24 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine comprising a geometric mean C _max of less than about 18,400 pg/mL.

100. A method according to any one of aspects 91 to 93, comprising orally administering to a subject once daily an osmotic formulation according to any one of aspects 1 to 90, wherein a single dose of the osmotic formulation comprising a total amount of 36 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine comprising a geometric mean AUC _0-inf of about 547,500 to 856,500 h*pg/mL.

101. A method according to any one of aspects 91 to 93 and 100, comprising orally administering to a subject once daily an osmotic formulation according to any one of aspects 1 to 90, wherein a single dose administration of the osmotic formulation comprising a total amount of 36 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine comprising a geometric mean C _max of less than about 27,600 pg/mL.

102. A method according to any one of aspects 91 to 93, comprising orally administering to a subject once daily an osmotic formulation according to any one of aspects 1 to 90, wherein a single dose of the osmotic formulation comprising a total amount of 48 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine comprising a geometric mean AUC _0-inf of about 730,000 to 1,142,000 h*pg/mL.

103. A method according to any one of aspects 91 to 93 and 102, comprising orally administering to a subject once daily an osmotic formulation according to any one of aspects 1 to 90, wherein a single dose administration of the osmotic formulation comprising a total amount of 48 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine comprising a geometric mean C _max of less than about 36,800 pg/mL.

104. A method according to any one of aspects 91 to 93, comprising orally administering to a subject once daily an osmotic formulation according to any one of aspects 1 to 90, wherein the osmotic formulation comprising a total amount of 6 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising a mean AUC _0-24 of about 102,500 to 200,000 h*pg/mL.

105. A method according to any one of aspects 91 to 93 and 104, comprising orally administering to a subject once daily an osmotic formulation according to any one of aspects 1 to 90, wherein the osmotic formulation comprising a total amount of 6 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising a mean C _max of less than about 10,000 pg/mL.

106. A method according to any one of aspects 91 to 93, comprising orally administering to a subject once daily an osmotic formulation according to any one of aspects 1 to 90, wherein the osmotic formulation comprising a total amount of 12 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising a mean AUC _0-24 of about 205,000 to 400,000 h*pg/mL.

107. A method according to any one of aspects 91 to 93 and 106, comprising orally administering to a subject once daily an osmotic formulation according to any one of aspects 1 to 90, wherein the osmotic formulation comprising a total amount of 12 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising a mean C _max of less than about 20,000 pg/mL.

108. A method according to any one of aspects 91 to 93, comprising orally administering to a subject once daily an osmotic formulation according to any one of aspects 1 to 90, wherein the osmotic formulation comprises a total amount of 24 mg of deutetrabenazine microparticles, providing an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising a mean AUC _0-24 of about 410,000 to 800,000 h*pg/mL.

109. A method according to any one of aspects 91 to 93 and 108, comprising orally administering to a subject once daily an osmotic formulation according to any one of aspects 1 to 90, wherein the osmotic formulation comprising a total amount of 24 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising a mean C _max of less than about 40,000 pg/mL.

110. A method according to any one of aspects 91 to 93, comprising orally administering to a subject once daily an osmotic formulation according to any one of aspects 1 to 90, wherein the osmotic formulation comprising a total amount of 36 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising a mean AUC _0-24 of about 615,000 to 1,200,000 h*pg/mL.

111. A method according to any one of aspects 91 to 93 and 110, comprising orally administering to a subject once daily an osmotic formulation according to any one of aspects 1 to 90, wherein the osmotic formulation comprising a total amount of 36 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising a mean C _max of less than about 60,000 pg/mL.

112. A method according to any one of aspects 91 to 93, comprising orally administering to a subject once daily an osmotic formulation according to any one of aspects 1 to 90, wherein the osmotic formulation comprising a total amount of 48 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising a mean AUC _0-24 of about 820,000 to 1,600,000 h*pg/mL.

113. A method according to any one of aspects 91 to 93 and 112, comprising orally administering to a subject once daily an osmotic formulation according to any one of aspects 1 to 90, wherein the osmotic formulation comprising a total amount of 48 mg of deutetrabenazine microparticles provides an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine at steady state comprising a mean C _max of less than about 80,000 pg/mL.

114. In any one of aspects 91 to 113, A method comprising administering an osmotic dosage form according to any one of aspects 1 to 90, wherein not more than 15% of the drug formulation is released after 2 hours when tested in 500 mL acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus.

115. A method according to any one of aspects 91 to 113, comprising administering an osmotic dosage form according to any one of aspects 1 to 90, wherein when tested in 500 mL acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus, not more than 60% of the drug formulation is released after 8 hours.

116. A formulation or method according to any one of aspects 1 to 115, wherein the formulation is administered together with food.

117. A formulation or method according to any one of aspects 1 to 115, wherein the formulation is administered under fasting conditions.

All patents, patent applications, and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. The invention illustratively described herein may be practiced without any element(s) not specifically disclosed herein. The terms and expressions which have been employed are used in the sense of description and not of limitation, and there is no intention in the use of such terms and expressions to exclude any equivalents of the features or portions thereof indicated and described, and it is recognized that various modifications are possible within the scope of the claimed invention. Accordingly, while the invention has been specifically disclosed by preferred embodiments and optional features, it should be understood that modifications and variations of the concepts disclosed herein may be made by those skilled in the art, and that such modifications and variations are considered to be within the scope of the invention as defined by the appended claims.

For the embodiments described above, each embodiment disclosed herein is contemplated to be applicable to each of the other disclosed embodiments. For example, elements recited in the method embodiments can be used in the pharmaceutical compositions, packages, and use/method embodiments described herein, and vice versa.

Example

The following examples are provided to supplement the prior disclosure and to provide a better understanding of the subject matter described herein. These examples should not be considered as limiting the subject matter described. It is to be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes will become apparent to those skilled in the art and are intended to fall within the true scope of the present disclosure, and may be made without departing from the true scope of the present disclosure.

Example 1 - Process for manufacturing osmotic tablets, 24 mg deutetrabenazine

Figures 2a and 2b provide a flow diagram of a general manufacturing process for osmotic dosage forms according to the present disclosure. Tables 1 to 13 below provide non-limiting examples of materials and their relative amounts used to produce the dosage forms described herein. The manufacturing method was as follows:

A: Active layer material treatment: Deutetrabenazine (micronized) and active layer controlled release agent were passed through a #30 mesh screen and combined with binder (previously passed through a #20 mesh screen). The mixture was introduced into a high shear granulator and dry mixed for approximately 5 minutes. While mixing, an antioxidant (pre-dissolved in alcohol) was added to the mixed powders to granulate the material. Additional mixing was continued until the desired granulation end point was reached. The resulting granules were wet screened to break up any large agglomerates. The material was fed to a diffusion mixer (V-blender) and blended for approximately 15 minutes. A lubricant passed through a #30 mesh screen was added to the blended material in the V-blender. The contents were lubricated for approximately 5 minutes.

B: Tablet core compression: The active layer material was released into a double-layer rotary tablet press. The push layer material (osmotic agent, push layer controlled-release agent and optionally binders, colorants and lubricants) was combined and further fed into a double-layer rotary tablet press. The tablet core was compressed.

C: Optional tablet core sealing coat: A tablet core sealing coat containing a binder solution was applied to the tablet core.

D: Semipermeable layer: A semipermeable layer comprising a solution of cellulose acetate and an optional pore-forming agent was applied to tablet cores or sealed tablet cores using a pan coater.

E: Optional semipermeable layer sealing coat: A semipermeable layer sealing coat containing a binder solution was applied to the tablet to compromise the semipermeable wall.

F: Creation of the exit means: The pores were laser drilled through the layers into the active layer.

A final immediate release coating comprising deutetrabenazine is optionally applied to the active layer using similar materials according to the treatment steps detailed above.

[Table 14]

[Table 15]

Example 2 - Single dose bioavailability evaluation

An osmotic formulation containing 24 mg deutetrabenazine was prepared as described in Example 1 and studied in a single-dose pharmacokinetic study.

The primary objective was to evaluate the comparative bioavailability (BA) of deutetrabenazine and deuterated α- and β-dihydrotetrabenazine (deuHTBZ) metabolites following a single dose of a 24 mg once daily (q.d.) osmotic formulation (test) compared to a single 12 mg AUSTEDO® tablet administered twice 12 hours apart (b.i.d.) in the fasting state.

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

Subject participation period: The study included a 4-week screening period (Period 1), an open-label treatment period with the investigational agent (Study 2A) and reference agent (R) (Period 2), and a follow-up visit at least 1 day later (Period 3).

therapy:

Treatment Sequence A:

Day 1 - Test 2A administration

Day 2-3 - Wash test 2A for at least 6 hours and then administer R

Treatment Sequence B:

Day 1 - R administration

Day 2-3 - Wash R for at least 6 hours and then administer Test 2A

The primary objective was addressed using the following parameters:

- Maximum observed concentration (Cmax)

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

- AUC extrapolated to infinity (AUC0-∞)

- AUC from time 0 to 24 hours after administration (AUC0-24h)

analyze

AUC0-t, AUC0-∞, and AUC0-24h were calculated using the trapezoidal rule. Cmax, AUC0-t, AUC0-∞, and AUC0-24h data were natural log-transformed prior to statistical analysis. Comparisons of Cmax, AUC0-t, AUC0-∞, and AUC0-24h between treatments (T2A vs R) were performed using separate parametric analysis of variance (ANOVA) models with fixed effects terms for sequence, period, treatment group, and the random effects of subject within sequence. Differences between the reference formulation (R) and test formulation (Trial 2A) were assessed by constructing 90% confidence intervals for the test/reference ratios based on the least squares means from the ANOVAs for the log-transformed Cmax, AUC0-t, AUC0-∞, and AUC0-24h. The estimated treatment differences and associated 90% confidence intervals from the ANOVA on a log scale were back-transformed to obtain the estimated ratio of geometric means between treatment groups and 90% confidence intervals for these ratios.

Figures 3a and 3b show the results of R treatment compared to the Trial 2A treatment (mean concentration of deutetrabenazine vs. time) on a direct and log scale, respectively. Table 14 below provides specific pK parameters observed for deutetrabenazine in relation to Trial 2A compared to R.

Figures 4a and 4b show metabolite data for treatment using R compared to direct and log scales, respectively, in Study 2A (mean concentration of total deuHTBZ vs. time).

Table 15 below provides specific pK parameters observed for total deuHTBZ for Test 2A compared to R.

As shown in Tables 14 and 15, the once daily dose in Study 2A provided acceptable deuHTBZ plasma concentrations observed for the reference. The osmotic formulations disclosed herein are administered once daily and provide acceptable therapeutic effects relative to those of USTEDO®, and also have no safety concerns.

The results of this crossover study further demonstrate that patients can be safely and effectively transitioned from twice-daily (in two divided doses) deutetrabenazine tablets to a once-daily osmotic formulation. The results of this crossover study further demonstrate that patients can be safely and effectively transitioned from once-daily osmotic formulation to twice-daily (in two divided doses) deutetrabenazine tablets.

Example 3 - Multi-dose bioavailability evaluation

An osmotic formulation containing 24 mg of deutetrabenazine was prepared as described in Example 1 and studied in an open-label, randomized, multiple-dose, two-way crossover study in healthy volunteers.

The primary objective was to assess the bioequivalence (BE) of once-daily (qd) Trial 2A dosing compared to bid administration of R under fasting or fed conditions.

Treatment included 7-day repeated doses of trial 2A once daily versus 7-day repeated doses of bid R.

Validated models were used to predict steady-state, AUCt, C _max , t _max , C _min , and C _av for deutetrabenazine and deuHTBZ concentrations.

Table 16 below provides simulation results for the steady-state pK parameters of deutetrabenazine for Test 2A compared to R, as well as the pK parameters of total deuHTBZ for Test 2A compared to R.

Research Results

Administration of treatments, trials 2A and R, resulted in reproducible concentration-time profiles for all analytes.

The primary objective of demonstrating bioequivalence (BE) for AUC _0-24h,ss of deutetrabenazine and deuHTBZ (individually and collectively) between Study 2A and R formulations was achieved. The geometric LS mean ratios for AUC _0-24h,ss were 115.15% for deutetrabenazine and 95.05% for total deuHTBZ.

The results of this study, which had a crossover design, additionally showed that patients were more likely to switch from twice-daily dosing of deutetrabenazine tablets to once-daily dosing. It shows that it can be safely and effectively implemented as an osmotic formulation. The results of this study with a crossover design additionally show that patients can be administered once daily It is shown that twice-daily administration of deutetrabenazine tablets from an osmotic formulation can be performed safely and effectively.

Example 4: Food Effect Study

An osmotic formulation containing 24 mg deutetrabenazine was prepared as described in Example 1 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 dose of 24 mg once daily (qd) osmotic formulation.

Treatment included:

Subjects were randomly assigned to receive the following three treatments: Trial 2A in the fed state (QD fed), Trial 2A in the fasted state (QD fasted), and R in the fed state with 12-hour intervals [twice daily (BID) feeding], in one of six treatment sequences, as depicted in Figure 5 .

There was a washout period of at least 6 days between the first dose in a period and the first dose in the next period. Treatment was administered orally to subjects in a sitting position on the morning of the first day (Day 1) of each dosing period. The second dose of R in the BID-fed group was administered exactly 12 hours after the morning dose.

All subjects fasted overnight for at least 10 hours prior to the first dose in each period. Subjects receiving the R BID diet or the Test 2A tablet diet were provided a standardized high-calorie, high-fat breakfast (containing 800 to 1000 kilocalories [kcal] with 50% fat) 30 minutes prior to the first dose. A standardized dinner was provided 30 minutes prior to the second dose for the R BID diet or at the corresponding time for the Test 2A tablet diet.

Blood samples for pharmacokinetic analysis were collected pre-dose and up to 96 hours post-dose during all treatment periods.

AUCt, Cmax, tmax, Cmin, and Cav for deutetrabenazine and deuHTBZ were analyzed.

result

For all analytes, the variability for the Trial 2A fed treatment was generally similar to that for the Trial 2A fasted treatment, indicating that administration of a single 24 mg tablet in the fed state, as opposed to a single 24 mg tablet in the fasted state, did not significantly increase the pharmacokinetic variability of metabolites.

Following oral administration of a single 24 mg QD osmotic tablet under fed and fasted conditions, all analytes met the BE criteria. No significant food effect on PK was observed, and therefore the 24 mg QD tablet can be administered with or without food.

Single doses of 24 mg deutetrabenazine QD osmotic tablets administered in the fed or fasted state, and also 12 mg deutetrabenazine tablets administered twice daily (in the fed state) were shown to be safe and well tolerated in healthy subjects.

Claims (21)

A method of transitioning a human subject being treated with a total daily dose of deutetrabenazine twice daily (bid) for the control of abnormal involuntary movements to a total daily dose of deutetrabenazine once daily,
a) administering the last dose of deutetrabenazine twice daily to the human subject; and
b) the following day, administering a total daily dose of deutetrabenazine once daily to the human subject;
A method including: A method in claim 1, wherein the total daily dose of deutetrabenazine is 12 mg to 48 mg; or 12 mg; or 18 mg; or 24 mg; or 30 mg; or 36 mg; or 42 mg; or 48 mg. A method in claim 1, wherein deutetrabenazine is administered once a day in an extended-release osmotic formulation. In the third paragraph, the osmotic formulation is
a. A tablet core comprising an active layer and a push layer, wherein the active layer comprises a predetermined amount of deutetrabenazine microparticles and an active layer controlled-release agent, and the push layer comprises an osmotic agent and a push layer controlled-release agent, and an optional tablet sealing coat on an outer surface of the tablet core;
b. A semipermeable layer surrounding the purified core;
c. a port extending into the purified core through the semipermeable layer; and
d. An optional immediate release coating outside the semipermeable layer comprising a second quantity of deutetrabenazine microparticles.
A method comprising: A method in claim 4, wherein about 70% to 80% of the total amount of deutetrabenazine microparticles present in the osmotic dosage form are present in the active layer, and about 20% to 30% of the total amount of deutetrabenazine microparticles present in the osmotic dosage form are present in the immediate release coating. A method in claim 1, wherein the deutetrabenazine microparticles have a particle size of D ₉₀ of 15 μm, and/or D ₅₀ of 10 μm, and/or D ₁₀ of 3 μm. In the first aspect, the abnormal involuntary movement is chorea, ataxia, 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. A method in claim 1, wherein the total daily dose of deutetrabenazine once a day is administered with or without food. A method of transitioning a human subject treated with a total daily dose of deutetrabenazine once daily for the control of abnormal involuntary movements to the same total daily dose of deutetrabenazine twice daily (bid),
a) administering the last dose of deutetrabenazine once daily; and
b) The next day, administering a total daily dose of deutetrabenazine to the subject twice a day.
A method including: A method according to claim 9, wherein the total daily dose of deutetrabenazine is 12 mg to 48 mg; or 12 mg; or 18 mg; or 24 mg; or 30 mg; or 36 mg; or 42 mg; or 48 mg. A method in claim 9, wherein the once-daily dose of deutetrabenazine is administered in a sustained-release osmotic formulation. In the 11th paragraph, the osmotic formulation is
a. A tablet core comprising an active layer and a push layer, wherein the active layer comprises a predetermined amount of deutetrabenazine microparticles and an active layer controlled-release agent, and the push layer comprises an osmotic agent and a push layer controlled-release agent, and an optional tablet sealing coat on an outer surface of the tablet core;
b. A semipermeable layer surrounding the purified core;
c. a port extending into the purified core through the semipermeable layer; and
d. An optional immediate release coating on the outside of the semipermeable layer comprising a second quantity of deutetrabenazine microparticles.
A method comprising: A method according to claim 12, wherein about 70% to 80% of the total amount of deutetrabenazine microparticles present in the osmotic dosage form are present in the active layer, and about 20% to 30% of the total amount of deutetrabenazine microparticles present in the osmotic dosage form are present in the immediate release coating. A method in claim 12, wherein the deutetrabenazine microparticles have a particle size of D ₉₀ of 15 μm, and/or D ₅₀ of 10 μm, and/or D ₁₀ of 3 μm. A method according to claim 9, wherein the abnormal involuntary movement is chorea, ataxia, 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. A method in claim 9, wherein the total daily dose of deutetrabenazine is administered once a day with or without food. A method of transitioning a human subject receiving a daily dose of tetrabenazine for the control of abnormal involuntary movements to a once daily dose of deutetrabenazine, the method comprising:
a) administering the last dose of tetrabenazine; and
b) The next day, administering the osmotic formulation of deutetrabenazine to the subject once a day.
, including, where,
The daily dose of tetrabenazine is 12.5 mg, and the single daily dose of deutetrabenazine is 6 mg;
The daily dose of tetrabenazine is 25 mg, and the daily dose of deutetrabenazine is 12 mg;
The daily dose of tetrabenazine is 37.5 mg, and the daily dose of deutetrabenazine is 18 mg;
The daily dose of tetrabenazine is 50 mg, and the daily dose of deutetrabenazine is 24 mg;
The daily dose of tetrabenazine is 62.5 mg, and the single daily dose of deutetrabenazine is 30 mg;
The daily dose of tetrabenazine is 75 mg, and the daily dose of deutetrabenazine is 36 mg;
The daily dose of tetrabenazine is 87.5 mg, and the single daily dose of deutetrabenazine is 42 mg;
The daily dose of tetrabenazine is 100 mg, and the single daily dose of deutetrabenazine is 48 mg;
Osmotic formulations are
a. A tablet core comprising an active layer and a push layer, wherein the active layer comprises a predetermined amount of deutetrabenazine microparticles and an active layer controlled-release agent, and the push layer comprises an osmotic agent and a push layer controlled-release agent, and an optional tablet sealing coat on an outer surface of the tablet core;
b. A semipermeable layer surrounding the purified core;
c. a port extending into the purified core through the semipermeable layer; and
d. An optional immediate release coating on the outside of the semipermeable layer comprising a second quantity of deutetrabenazine microparticles.
A method comprising: A method according to claim 17, wherein about 70% to 80% of the total amount of deutetrabenazine microparticles present in the osmotic dosage form are present in the active layer, and about 20% to 30% of the total amount of deutetrabenazine microparticles present in the osmotic dosage form are present in the immediate release coating. A method in claim 17, wherein the deutetrabenazine microparticles have a particle size of D ₉₀ of 15 μm, and/or D ₅₀ of 10 μm, and/or D ₁₀ of 3 μm. A method according to claim 17, wherein the abnormal involuntary movement is chorea, ataxia, 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. A method according to claim 17, wherein the once-daily deutetrabenazine formulation is administered with or without food.