Gastroretentive dosage forms comprising deuterated tetrabenazine

Abstract

Provided herein are controlled release gastroretentive dosage forms containing deuterated tetrabenazine for use in the treatment of e.g. Hyperactivity dyskinesia. The dosage form provides advantageous pharmacokinetic profiles when orally administered to a subject once a day.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 090,546, filed October 12, 2020, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0003] The present disclosure relates to gastric retentive dosage forms, methods of manufacture, and methods of using gastric retentive dosage forms to treat hyperkinetic movement disorders derived from conditions including Huntington’s disease, tardive dyskinesia, levodopa-induced dyskinesia, and dyskinesia in cerebral palsy. BACKGROUND

[0004] Deutetrabenazine ((RR,SS)-1,3,4,6,7,1 lb-hexahydro-9,10-di(methoxy-D3)-3-(2- methylpropyl)-2H-benzo[a]quinolizin-2-one) is a selective inhibitor of the vesicular monoamine transporter 2 (VMAT2). Bioactive metabolites formed from deutetrabenazine (a- dihydrodeutetrabenazine [a-deuHTBZ] and b-dihydrodeutetrabenazine [b-deuHTBZ]) together identified as “deuHTBZ” are potent inhibitors of VMAT2 binding. Deutetrabenazine shows an increase in the half-life of its active metabolites relative to tetrabenazine (e.g., U.S. Patent No. 8,524,733).

[0005] Deutetrabenazine (deu-TBZ) has been approved by the U.S. Food and Drug Administration under the trade name for the treatment of chorea (involuntary muscle movements) associated with Huntington’s disease (HD) and for the treatment of adult tardive dyskinesia (TD). The dosage form is administered orally twice daily (bid) at a total daily dose of 12 mg or more of deutetrabenazine.

[0006] Several factors affect the gastrointestinal absorption of orally administered drugs, including the solubility of the drug at different pH and the rate of drug release from the dosage form. The rate of drug release from an oral dosage form is typically measured as the in vitro dissolution rate, i.e., the amount of drug released from the dosage form per unit time in, for example, an FDA-approved system. Such systems include, for example, the United States Pharmacopeia (USP) dissolution apparatus I, II, and III.

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

[0008] Several dosage forms including deuterated tetrabenazine are disclosed in U.S. Patent No. 9,296,739. Dosage forms that can deliver deuterated tetrabenazine in a controlled manner over an extended period of time would enable more favorable dosing regimens, for example, allowing once-daily (“qd”) administration while maintaining the therapeutic effect currently achieved with the dosing regimen. There is a need for such alternative dosage forms. SUMMARY

[0009] Disclosed herein are controlled release gastro-retentive dosage forms for once-daily oral administration of deuterated tetrabenazine to a subject in need thereof.

[0010] The controlled release oral dosage form of the present invention includes an amount of deuterated tetrabenazine; at least two controlled release polymers, each independently having a viscosity of 2,000 cPs or more; and pharmaceutically acceptable excipients including at least one disintegrant, wherein the total amount of controlled release polymers is at least 30 wt.% relative to the total weight of the dosage form.

[0011] In other embodiments, the dosage form comprises pharmaceutically acceptable excipients including at least one disintegrant and at least one diluent, binder, gas generating agent, antioxidant, lubricant, or a combination thereof.

[0012] In some embodiments, the controlled release gastro-retentive dosage form includes deuterated tetrabenazine having a median particle size of 1 to 30 micrometers (pm).

[0013] In yet other embodiments, the present invention provides methods useful for treating VMAT2-mediated disorders. In some embodiments, the method of treating a VMAT2-mediated disorder includes orally administering to a patient in need thereof a controlled release dosage form disclosed herein. BRIEF DESCRIPTION OF DRAWINGS

[0014] Figure 1Dissolution profiles of samples 1, 2, and 3 in 500 mL acidic buffer at pH 3 in a USP II apparatus with sinker at 75 rpm. The co-milled and micro-milled particles exhibited slower dissolution profiles at pH 3 compared to the un-milled sample. The triangle represents the release profile of the micro-milled sample showing slow release (about 50% after 14 hours); the square represents the release profile of the co-milled deutero-trimebutine and the diamond represents the release profile of the un-milled deuterotrimenbutine.

[0015] Figure 2 is a graph showing dissolution profiles of samples 4-7 in phthalate buffer at pH 3.0 in a USP II with sinker at 75 rpm.

[0016] Figure 3 is a graph showing dissolution profiles of samples 8-9 in phthalate buffer at pH 3.0 in a USP II with sinker at 75 rpm.

[0017] Figure 4 is a graph showing dissolution profiles of samples 10-11 in phthalate buffer at pH 3.0 in a USP II with sinker at 75 rpm.

[0018] Figure 5 is a graph showing dissolution profiles of samples 12-13 in phthalate buffer at pH 3.0 in a USP II with sinker at 75 rpm.

[0019] Figure 6 is a graph showing dissolution profiles of samples 14-17 in phthalate buffer at pH 3.0 in a USP II with sinker at 75 rpm.

[0020] Figure 7 is a graph showing dissolution profiles of samples 18-19 in phthalate buffer at pH 3.0 in a USP II with sinker at 75 rpm.

[0021] Figure 8 is a graph showing dissolution profiles of samples 20-21 in phthalate buffer at pH 3.0 in a USP II with sinker at 75 rpm.

[0022] Figure 9 is a graph showing dissolution profiles of samples 22-23 in phthalate buffer at pH 3.0 in a USP II with sinker at 75 rpm. DETAILED DESCRIPTION

[0023] The inventive subject matter can be more easily understood by reference to the following detailed description taken in connection with the following drawings, which form a part of this disclosure. It is noted that the inventive subject matter is not limited to the specific methods, conditions or parameters described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed inventive subject matter.

[0024] Unless defined otherwise herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by ordinary

[0025] As employed above and throughout the disclosure, the following terms and abbreviations are understood to have the following meanings, unless indicated otherwise.

[0026] The singular forms "a," "an," and "the" can refer to both the singular and plural forms, unless otherwise specifically indicated.

[0027] As used herein, the term "about" is intended to qualify the numerical values to which it is applied, such that such values are variable within a ±10% margin of error.

[0028] When expressing a range of values, another embodiment includes from one particular value and / or to another particular value. Similarly, when a value is expressed as an approximation by use of the antecedent "about," it is understood that the particular value forms another embodiment. All ranges are inclusive and combinable.

[0029] As used herein, the terms "compound," "drug," "pharmacologically active agent," "active agent," or "medicament" are used interchangeably herein to refer to a composition of one or more compounds or substances that, when administered to a subject (human or animal), induces a desired pharmacological and / or physiological effect by local and / or systemic action. The active agent disclosed herein is preferably deuterated biperiden. "Deuterated biperiden" is a selectively deuterium-substituted stable non-radioactive isotope form of biperiden in which six hydrogen atoms on two O-linked methyl groups have been replaced with deuterium atoms (i.e., -OCD3 instead of -OCH3 moieties).

[0030] As used herein, "dosage form" refers to an oral pharmaceutical form having gastric retention properties, as described herein.

[0031] "Controlled release" refers to a dosage form capable of releasing the active agent over an extended period of time, such as up to about 12 hours, 15 hours, 18 hours, 21 hours, or up to about 24 hours. As disclosed herein, the active agent is preferably deuterated butylbenazine. In some embodiments, the dosage form releases about 20 wt.% to 40 wt.% of the active agent in the dosage form over two hours; and about 60 wt.% to 80 wt.% over eight hours, as measured in a USPII device at pH 3. In other embodiments, the dosage form releases about 40-60 wt% of the active agent in the dosage form over seven hours, as measured in a USPII device at pH 3. In other embodiments, the dosage form releases about 50 wt% of deuterated butylbenazine over seven hours, as measured in a USPII device at pH 3.

[0032] As used herein, the viscosity of a polymer refers to the viscosity measured in an aqueous solution containing 2 wt.% polymer at approximately 20–25 °C.

[0033] The controlled-release solid oral dosage forms of the present invention remain in the gastric region (i.e., the stomach) for several hours, for example up to 24 hours (preventing further movement through the gastrointestinal tract) and thus significantly prolong the gastric residence time of the active agent. Preferably, the controlled-release solid oral dosage forms of the present invention remain in the stomach for 6-20 hours. The prolonged gastric residence time improves bioavailability, reduces drug waste, and can improve the utilization of drugs with low solubility in high pH environments (i.e., the intestinal environment). Without being bound by any mechanism or theory, the prolonged gastric retention can be based at least in part on the mucosal adhesion properties of gases generated by one or more excipients within the dosage form and / or formulations. To obtain mucosal adhesion properties, a variety of bioadhesive polymers can be used. Such polymers swell in water and adhere to mucosal surfaces. The swelling of a particular polymer, optionally in combination with other excipients (i.e., disintegrants) within the dosage form, provides buoyancy properties upon contact with the gastric environment. The controlled-release solid oral dosage forms described herein preferably swell to at least about twice their unswollen volume upon contact with gastric juices.

[0034] As used herein, “floating” is used in conjunction with “floating gastric retention dosage form,” which exhibits a lower bulk density than the gastric juice [Timmermans, J. and Moes, AJ, (1990) How welldo floating dosage forms float? International Journal of Pharmaceutical Sciences (Int. JPharm.) 62: 207-216]. Such dosage forms are “floating” because they remain suspended in the gastric juice within the stomach for the target time period. The floating dosage form is then able to remain in the stomach while releasing the active agent.

[0035] As used herein, the terms “swellable” and “swellable” for polymers within a dosage form refer to the polymer’s ability to absorb fluid and increase in size, i.e., to swell when in contact with a fluid environment such as the stomach.

[0036] As used herein, the term “treatment” or “therapy” (and its various forms) includes preventative (e.g., preventive), curative, or palliative treatment. As used herein, the term “treatment” includes the reduction or alleviation of at least one adverse or negative effect or symptom of a symptom, disease, or condition. Such a symptom, disease, or condition may refer to hyperkinetic disorders, such as, but not limited to, chorea associated with Huntington's disease, tardive dyskinesia, Tourette syndrome, dystonia, dyskinesia (DCP) in cerebral palsy, and levodopa-induced dyskinesia (LID) in Parkinson's disease.

[0037] The term “administration” means to provide a patient with the pharmaceutical composition or dosage form of the present invention (these terms are used interchangeably herein).

[0038] The terms “subject,” “individual,” and “patient” are used interchangeably in this document and refer to a person to whom treatment is administered in the dosage form described herein, including prophylactic treatment.

[0039] "Pharmaceutical acceptable" means compounds, materials, compositions, and / or excipients that, within the bounds of reasonable medical judgment, are suitable for contact with human tissues without causing excessive toxicity, irritation, allergic reactions, or other problematic complications, in proportion to a reasonable benefit / risk ratio.

[0040] As used herein, the term "particle size distribution" refers to the statistical distribution of volume fractions associated with all particle sizes and is expressed by D90, D50, or D10 values. The D90 value of the overall volume distribution is defined in the context of this invention as the particle diameter at which 90% by volume of the particles have a diameter smaller than the diameter corresponding to the D90 value. For example, a D90 of 15 μm means that 90% (by volume) of the particles have a diameter less than or equal to 15 μm. A D50 of 10 μm means that 50% (by volume) of the particles have a diameter less than or equal to 10 μm. A D10 of 3 μm means that 10% (by volume) of the particles have a diameter less than or equal to 3 μm. Particle size distribution is determined by laser diffraction. More specifically, particle size distribution is determined using a Mastersizer 3000 from Malvern Instruments.

[0041] As used herein, “controlled release” and “release control” are used interchangeably and refer to the properties of the polymer used in the dosage form. Compared to immediate-release formulations, when such polymers are included in the dosage form with the API, they can slow the release of the API under physiological conditions and contribute to the release of the active agent over a prolonged period of time.

[0042] While constant-release formulations have proven effective for many different drug therapies, there are clinical situations where these formulations are not entirely satisfactory. It has been observed that in some patients, the therapeutic efficacy of the drug decreases below the therapeutic threshold before the expected end of the treatment period, but maintaining a substantially constant drug release is expected to provide sustained efficacy.

[0043] Surprisingly, oral dosage forms of deuterated butylbenazine can be achieved, exhibiting the desired release rate and thus the desired pharmacokinetic characteristics over a prolonged period. In some embodiments, the currently disclosed gastric retention dosage forms, when administered orally to subjects once daily (qd), provide the same level of benefit as when administered twice daily (bid). The pharmacokinetic characteristics of the dosage form are equivalent to those of the pharmacokinetic properties, such as bioequivalence.

[0044] This document provides a controlled-release gastric retention oral dosage form for once-daily administration of deuterated butylbenazine, the controlled-release gastric retention oral dosage form comprising: a certain amount of deuterated butylbenazine; at least two controlled-release polymers, each independently having a viscosity of 2,000 cPs or higher; and pharmaceutically acceptable excipients, the pharmaceutically acceptable excipients comprising at least one disintegrant, wherein the total amount of the controlled-release polymers is at least 30 wt.% relative to the total weight of the dosage form.

[0045] The dosage form disclosed herein comprises 2-15 wt.% of deuterated butylbenazine relative to the total weight of the dosage form. In some embodiments, the dosage form comprises 3-10 wt.% of deuterated butylbenazine relative to the total weight of the dosage form. In some embodiments, the dosage form comprises 4-7 wt.% of deuterated butylbenazine relative to the total weight of the dosage form. In some embodiments, the dosage form comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 wt.% of deuterated butylbenazine relative to the total weight of the dosage form.

[0046] The dosage form further comprises two or more controlled-release polymers. In some embodiments, each of the two controlled-release polymers independently has a viscosity in the range of 2,000 to 80,000 cPs. In some embodiments, each of the two controlled-release polymers independently has a viscosity of 2,000 to 60,000 cPs, 2,000 to 40,000 cPs, 2,000 to 20,000 cPs, 2,000 to 10,000 cPs, 2,000 to 8,000 cPs, 2,000 to 6,000 cPs, or 2,000 to 4,000 cPs. In one specific embodiment, each of the two controlled-release polymers independently has a viscosity of 2,000 to 4,000 cPs. In some embodiments, each of the two controlled-release polymers independently has a viscosity of 10,000 to 80,000 cPs, 20,000 to 80,000 cPs, 30,000 to 70,000 cPs, or 40,000 to 60,000 cPs. In one specific embodiment, each of the two controlled-release polymers independently has a viscosity of 40,000 to 60,000 cPs. In one specific embodiment, at least one of the controlled-release polymers has a viscosity of 2,000 to 4,000 cPs, and at least one of the controlled-release polymers has a viscosity of 40,000 to 60,000 cPs.

[0047] The dosage form may optionally further comprise one or more additional controlled-release polymers having a viscosity of about 3 to about 80,000 cPs. In some embodiments, the one or more additional controlled-release polymers independently have a viscosity of 3 to 60,000 cPs, 3 to 40,000 cPs, 3 to 20,000 cPs, or 3 to 15,000 cPs. In one specific embodiment, the dosage form comprises two controlled-release polymers, each independently having a viscosity in the range of 2,000 to 80,000 cPs, and an additional controlled-release polymer having a viscosity in the range of 3 to 15,000 cPs. In yet another specific embodiment, the dosage form comprises at least one controlled-release polymer having a viscosity in the range of 2,000 to 4,000 cPs and at least one controlled-release polymer having a viscosity in the range of 40,000 to 60,000 cPs, and further comprises at least one additional controlled-release polymer having a viscosity in the range of 3 to 15,000 cPs.

[0048] The release-controlled (also referred to herein as "controlled release") polymers of this disclosure include water-soluble polymers, water-insoluble polymers, or mixtures thereof. In some embodiments, the dosage form comprises a water-soluble polymer. In some embodiments, the water-soluble polymer is or includes hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymers, or mixtures thereof. In a preferred embodiment, the water-soluble polymer includes hydroxypropyl methylcellulose, polyacrylic acid polymers, or mixtures thereof. In another preferred embodiment, the polyacrylic acid polymer comprises, for example, hydroxypropyl methylcellulose, polyacrylic acid polymers, or mixtures thereof. The product is a cross-linked polyacrylic acid polymer. In yet another preferred embodiment, the dosage form comprises a water-insoluble polymer. In some embodiments, the water-insoluble polymer is or includes copovidone, cross-linked sodium carboxymethyl cellulose, starch, sodium glycolate starch, colloidal silica, silica, ethyl cellulose, polyvinyl acetate, or mixtures thereof. In another preferred embodiment, the water-insoluble polymer comprises copovidone or mixtures thereof. In one specific embodiment, copovidone is...

[0049] In some embodiments, the controlled-release polymer in the dosage form comprises a mixture of one or more water-soluble polymers and one or more water-insoluble polymers. In one embodiment, the dosage form comprises a release-controlled polymer mixture of copovidone, hydroxypropyl methylcellulose, and polyacrylic acid polymer.

[0050] The release control polymer is present in the dosage form in the range of 30 to 65 wt.% relative to the total weight of the solid oral dosage form. In some embodiments, the release control polymer is present in the dosage form in the range of 30 to 60 wt.% relative to the total weight of the solid oral dosage form. In some embodiments, the release control polymer is present in the dosage form in the range of 30 to 55 wt.% relative to the total weight of the solid oral dosage form. In some embodiments, the release control polymer is present in the dosage form in the range of 35 to 55 wt.% relative to the total weight of the solid oral dosage form. In some embodiments, the release control polymer is present in the dosage form in the range of 40 to 55 wt.% relative to the total weight of the solid oral dosage form. In some embodiments, the release control polymer is present in the dosage form in the range of 45 to 55 wt.% relative to the total weight of the solid oral dosage form. In some embodiments, the release control polymer is present in the dosage form in the range of 40 to 50 wt.% relative to the total weight of the solid oral dosage form. In some respects, the release control polymer is present in the dosage form at a weight of 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 or 65 wt.% relative to the total weight of the solid oral dosage form.

[0051] The dosage form further comprises pharmaceutically acceptable excipients, including at least one disintegrant. In one embodiment, the disintegrant is or includes croscarmellose sodium, alginate, microcrystalline cellulose, crospovidone, polacrilin potassium, sodium glycolate starch, low-substituted hydroxypropyl cellulose, starch, and mixtures thereof.

[0052] Pharmaceutically acceptable excipients may further include at least one of diluents, binders, gas generators, antioxidants, lubricants, or combinations thereof. Typically, combinations of pharmaceutically acceptable excipient materials are used.

[0053] The excipient may include a gas generating agent. In one embodiment, the gas generating agent includes a carbonate selected from sodium bicarbonate, a mixture of sodium bicarbonate and citric acid, calcium carbonate, a mixture of calcium carbonate and citric acid, and mixtures thereof. The gas generating agent is present in the dosage form in the range of 5 to 15 wt.% relative to the total weight of the solid oral dosage form. In some embodiments, the excipient comprises about (by wt.%) 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0, 14.0, or 15.0 wt.% relative to the total weight of the dosage form. In some embodiments, the excipient comprises about (by wt.%) 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 wt.% relative to the total weight of the dosage form.

[0054] The excipients may include antioxidants. In one embodiment, the antioxidant is or includes propyl gallate, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquinoline), nordihydroguaiacol (NDGA), butylated hydroxyanisole, butylated hydroxytoluene, or any mixture thereof. In a preferred embodiment, the antioxidant includes a mixture of butylated hydroxyanisole and butylated hydroxytoluene. The antioxidant is present in the dosage form at a weight of 0.1 to 1.0 wt.%, or about 0.2 to 1.0 wt.%, or about 0.5 to 0.8 wt.%, relative to the total weight of the solid oral dosage form. For example, the antioxidant is present in the dosage form at 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 wt.%, relative to the total weight of the solid oral dosage form.

[0055] Excipients may include adhesives. In some embodiments, the adhesive includes water-soluble adhesives, water-insoluble adhesives, or combinations thereof. In some embodiments, the adhesive includes a water-soluble adhesive, which may be a cellulose-based adhesive comprising hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymers, polyethers, carbohydrate polymers (natural or synthetic), or combinations thereof. In some embodiments, the adhesive is a cellulose-based adhesive selected from the group consisting of methylcellulose (MC), ethylcellulose (EC), propylcellulose (PC), hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose (INN), cellulose acetate, and combinations thereof. In some embodiments, the adhesive is a polyether. Suitable polyethers comprise polyethylene glycol (PEG) polymers. In another embodiment, the binder comprises a water-insoluble polymer, which is or includes crospovidone, copovidone, microcrystalline cellulose, croscarmellose sodium, starch, sodium glycolate starch, colloidal silica, silica, ethyl cellulose, lactic acid polymer, lactic acid and glutamic acid copolymer, polyvinyl acetate, or combinations thereof. In some embodiments, the binder comprises microcrystalline cellulose, gelatin, agar, natural and synthetic gums, or any mixture thereof. In one specific embodiment, the binder comprises microcrystalline cellulose. In some embodiments, the binder is present in the dosage form in the range of 5 to 50 wt.% relative to the total weight of the solid oral dosage form. In a preferred embodiment, the binder is present in the dosage form in the range of 30 to 50 wt.% relative to the total weight of the solid oral dosage form. For example, the binder is present in the dosage form in the range of 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 wt.% relative to the total weight of the solid oral dosage form.

[0056] In some embodiments, the excipient includes a diluent selected from the group consisting of sugars, disaccharides, polysaccharides, polyols, microcrystalline cellulose, natural and synthetic gums, gelatin, pregelatinized starch, polyvinylpyrrolidone, cellulose derivatives, dibasic calcium phosphate, kaolin, inorganic salts, calcium carbonate, sodium bicarbonate, sodium carbonate, and combinations thereof. Sugars may be, for example, glucose, galactose, dextrose, or fructose; disaccharides may be, for example, sucrose, lactose, lactose monohydrate, maltose, trehalose, or maltose; polysaccharides may be, for example, starch or maltodextrin; and polyols may be, for example, sorbitol, xylitol, inositol, lactitol, mannitol, or spray-dried mannitol. In some embodiments, the diluent is microcrystalline cellulose, lactose monohydrate, or a combination thereof.

[0057] Excipients may include lubricants. In some embodiments, lubricants include magnesium stearate, calcium stearate, glyceryl behenate, sodium stearoyl fumarate, stearic acid, talc, zinc stearate, and mixtures thereof.

[0058] In some embodiments, the dosage form includes 4-7 wt.% of deuterated butylbenazine relative to the total weight of the dosage form; 20-40 wt.% of cropovidone relative to the total weight of the dosage form; 20-50 wt.% of hydroxypropyl methylcellulose relative to the total weight of the dosage form; 15-45 wt.% of polyacrylic acid polymer relative to the total weight of the dosage form; and 0.3-2 wt.% of magnesium stearate relative to the total weight of the dosage form.

[0059] In some embodiments, the dosage form includes 4-7 wt.% of deuterated butylbenazine relative to the total weight of the dosage form; 10-30 wt.% of copovidone relative to the total weight of the dosage form; 20-40 wt.% of copovidone relative to the total weight of the dosage form; 20-50 wt.% of hydroxypropyl methylcellulose relative to the total weight of the dosage form; 2-15 wt.% of polyacrylic acid polymer relative to the total weight of the dosage form; and 0.3-2 wt.% of magnesium stearate relative to the total weight of the dosage form.

[0060] In some embodiments, the dosage form includes, by weight of 4-7 wt.% of deuterated butylbenazine; by weight of 5-20 wt.% of microcrystalline cellulose; by weight of 10-30 wt.% of copovidone; by weight of 20-40 wt.% of copovidone; by weight of 20-50 wt.% of hydroxypropyl methylcellulose; by weight of 2-15 wt.% of polyacrylic acid polymer; and by weight of 0.3-2 wt.% of magnesium stearate.

[0061] In some embodiments, the dosage form includes, by weight of 4-7 wt.% of deuterated butylbenazine; by weight of 0.2-0.5 wt.% of a mixture of butylated hydroxyanisole and butylated hydroxytoluene; by weight of 20-50 wt.% of microcrystalline cellulose; by weight of 4-8 wt.% of copovidone; by weight of 20-40 wt.% of cropovidone; by weight of 5-20 wt.% of hydroxypropyl methylcellulose; by weight of 2-15 wt.% of polyacrylic acid polymer; and by weight of 0.3-2 wt.% of magnesium stearate.

[0062] In some embodiments, the dosage form includes, by weight of 4-7 wt.% of deuterated butylbenazine; by weight of 0.2-0.5 wt.% of a mixture of butylated hydroxyanisole and butylated hydroxytoluene; by weight of 20-50 wt.% of microcrystalline cellulose; by weight of 4-8 wt.% of copovidone; by weight of 20-40 wt.% of cropovidone; by weight of 5-20 wt.% of hydroxypropyl methylcellulose; by weight of 2-15 wt.% of polyacrylic acid polymer; by weight of 0.1-0.7 wt.% of sodium bicarbonate; and by weight of 0.3-2 wt.% of magnesium stearate.

[0063] The relevant information now concerns the efficacy of the dosage form as disclosed when the median particle size of deuterated butylbenazine is 1 to 30 micrometers (μm), or 1 to 20 micrometers, or 1 to 10 micrometers, 1 to 9 micrometers, 1 to 8 micrometers, or about 1 to about 7 micrometers. The desired median particle size can be achieved, for example, by grinding the pharmaceutical material to a low micrometer size. In some embodiments, the deuterated butylbenazine has a D particle size of about 30 micrometers. 90 Characterized particle size distribution. In some embodiments, the deuterated butylbenazine has a particle size distribution of about 10 micrometers. 50 Characterized particle size distribution. In some embodiments, the deuterated butylbenazine has a particle size distribution of about 1 micrometer. 10 Characterized particle size distribution. In some embodiments, the deuterated butylbenazine has a particle size distribution of approximately 30 micrometers. 90 D, approximately 10 micrometers 50 and approximately 1 micrometer of D 10 The particle size distribution is characterized.

[0064] The dosage form may contain 4-7 wt.% of deuterated butylbenazine relative to the total weight of the dosage form. The dosage form may contain a total of 6 mg to 72 mg of deuterated butylbenazine. In one embodiment, the dosage form may contain a total of about 6 mg to 48 mg. In some embodiments, the dosage form comprises a total of 6 mg, or 12 mg, or 18 mg, or 24 mg, or 30 mg, or 36 mg, or 42 mg or 48 mg of deuterated butylbenazine.

[0065] This document further provides methods for treating VMAT2-mediated conditions. In some embodiments, the method of treating VMAT2-mediated conditions includes oral administration of the controlled-release formulation disclosed herein to a patient in need. VMAT2-mediated conditions can be hyperkinetic disorders. Hyperkinetic disorders can be chronic conditions such as dystonia, dyskinesia, Huntington's disease, tardive dyskinesia, and dyskinesia in cerebral palsy. In some embodiments, the method is effective in treating chorea associated with Huntington's disease. In some embodiments, the method is effective in treating tardive dyskinesia. An antipsychotic agent may be administered simultaneously to a subject with tardive dyskinesia. In some embodiments, the method is effective in treating dyskinesia in cerebral palsy.

[0066] In some embodiments, the dosage form according to any of the embodiments disclosed herein is administered together with food.

[0067] In some embodiments, the dosage form according to any of the embodiments disclosed herein is administered under fasting conditions.

[0068] Plasma profiles of the dosage form after administration are favorable for once-daily (“qd”) administration. In one embodiment, a single-dose administration of the oral dosage form comprising 6 mg of deuterated benzophenone provides in vivo plasma profiles of total α- and β-dihydrodeuterated benzophenone comprising a geometrically mean AUC of approximately 90,000 to 142,750 h*pico / mL. 0-inf and / or a geometric mean C of less than about 4,600 pg / mL max .

[0069] In one embodiment, a single-dose administration of the disclosed oral dosage form comprising 12 mg of deuterated butylbenazine provides an in vivo plasma profile of total α- and β-dihydrodeuterated butylbenazine, the in vivo plasma profile comprising a geometrically mean AUC of approximately 180,000 to 285,500 h*pico / mL. 0-inf And / or a geometric mean C of less than about 9,200 pg / mL max .

[0070] In one embodiment, a single-dose administration of the disclosed oral dosage form comprising 24 mg of deuterated butylbenazine provides an in vivo plasma profile of total α- and β-dihydrodeuterated butylbenazine, the in vivo plasma profile comprising a geometrically mean AUC of approximately 360,000 to 571,000 h*pico / mL. 0-inf And / or a geometric mean C of less than about 18,400 pg / mL max .

[0071] In one embodiment, a single-dose administration of the disclosed oral dosage form comprising 36 mg of deuterated butylbenazine provides an in vivo plasma profile of total α- and β-dihydrodeuterated butylbenazine, the in vivo plasma profile comprising a geometrically mean AUC of approximately 540,000 to 856,500 h*pico / mL. 0-inf and / or a geometric mean C of less than about 27,600 pg / mL max .

[0072] In one embodiment, a single-dose administration of the disclosed oral dosage form comprising 48 mg of deuterated butylbenazine provides an in vivo plasma profile of total α- and β-dihydrodeuterated butylbenazine, the in vivo plasma profile comprising a geometrically mean AUC of approximately 720,000 to 1,142,000 h*pico / mL. 0-inf and / or a geometric mean C of less than about 36,800 pg / mL max .

[0073] In one embodiment, administration of the disclosed oral dosage form comprising 6 mg of deuterated butylbenazine provides an in vivo plasma profile of total α- and β-dihydrodeuterated butylbenazine, the in vivo plasma profile comprising a geometrically mean AUC of approximately 102,500 to 200,000 h*pico / mL at steady state. 0-24 And / or an average Cg of less than about 10,000 pg / mL at steady state max .

[0074] In one embodiment, administration of the disclosed oral dosage form comprising 12 mg of deuterated butylbenazine provides in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, the in vivo plasma profiles comprising a geometrically mean AUC of approximately 205,000 to 400,000 h*pico / mL at steady state. 0-24 And / or an average Cg of less than about 20,000 pg / mL at steady state max .

[0075] In one embodiment, administration of the disclosed oral dosage form comprising 24 mg of deuterated butylbenazine provides an in vivo plasma profile of total α- and β-dihydrodeuterated butylbenazine, the in vivo plasma profile comprising a geometrically mean AUC of approximately 400,000 to 800,000 hours * picograms / mL at steady state. 0-24 And / or an average Cg of less than about 40,000 pg / mL at steady state max .

[0076] In one embodiment, administration of the disclosed oral dosage form comprising 36 mg of deuterated butylbenazine provides in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, the in vivo plasma profiles comprising a geometrically mean AUC of approximately 615,000 to 1,200,000 h*pico / mL at steady state.0-24 And / or an average Cg of less than about 60,000 pg / mL at steady state max .

[0077] In one embodiment, administration of the disclosed oral dosage form comprising 48 mg of deuterated butylbenazine provides in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, the in vivo plasma profiles comprising a geometrically mean AUC of approximately 800,000 to 1,600,000 hours * picograms / mL at steady state. 0-24 And / or an average Cg of less than about 80,000 pg / mL at steady state max .

[0078] In one embodiment, the present invention provides a method for treating hyperactivity disorder in a subject of need, the method comprising once daily oral administration to the subject of a gastric retention formulation according to any embodiment of the present invention, including a single-dose administration of a gastric retention formulation comprising a total amount of 6 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, the in vivo plasma profiles comprising a geometric mean AUC of approximately 90,000 to 142,750 h*pico / mL. 0-inf .

[0079] In one embodiment, the present invention provides a method for treating hyperactivity disorder in a subject of need, the method comprising once daily oral administration to the subject of a gastric retention formulation according to any embodiment of the present invention, comprising a single dose of a gastric retention formulation comprising a total amount of 6 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, the in vivo plasma profiles containing a geometric mean Cg of less than about 4,600 pg / mL. max .

[0080] In one embodiment, the present invention provides a method for treating hyperactivity disorder in a subject of need, the method comprising once daily oral administration to the subject of a gastric retention formulation according to any embodiment of the present invention, comprising a single dose of a gastric retention formulation comprising a total amount of 12 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, the in vivo plasma profiles comprising a geometrically mean AUC of approximately 180.00 to 285,500 h*pico / mL. 0-inf .

[0081] In one embodiment, the present invention provides a method for treating hyperactivity disorder in a subject of need, the method comprising once daily oral administration to the subject of a gastric retention formulation according to any embodiment of the present invention, comprising a single dose of a gastric retention formulation comprising a total amount of 12 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, the in vivo plasma profiles containing a geometric mean Cg of less than about 9,200 pg / mL. max .

[0082] In one embodiment, the present invention provides a method for treating hyperactivity disorder in a subject of need, the method comprising once daily oral administration to the subject of a gastric retention formulation according to any embodiment of the present invention, comprising a single dose of a gastric retention formulation comprising a total amount of 24 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, the in vivo plasma profiles comprising a geometric mean AUC of approximately 360,000 to 571,000 h*pico / mL. 0-inf .

[0083] In one embodiment, the present invention provides a method for treating hyperactivity disorder in a subject of need, the method comprising once daily oral administration to the subject of a gastric retention formulation according to any embodiment of the present invention, comprising a single dose of a gastric retention formulation comprising a total amount of 24 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, the in vivo plasma profiles containing a geometric mean Cg of less than about 18,400 pg / mL. max .

[0084] In one embodiment, the present invention provides a method for treating hyperactivity disorder in a subject of need, the method comprising once daily oral administration to the subject of a gastric retention formulation according to any embodiment of the present invention, including a single dose of a gastric retention formulation comprising a total amount of 36 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, the in vivo plasma profiles comprising a geometric mean AUC of approximately 540,000 to 856,500 h*pico / mL. 0-inf .

[0085] In one embodiment, the present invention provides a method for treating hyperactivity disorder in a subject of need, the method comprising once daily oral administration to the subject of a gastric retention formulation according to any embodiment of the present invention, comprising a single dose of a gastric retention formulation comprising a total amount of 36 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, the in vivo plasma profiles containing a geometric mean Cg of less than about 27,600 pg / mL. max .

[0086] In one embodiment, the present invention provides a method for treating hyperactivity disorder in a subject of need, the method comprising once daily oral administration to the subject of a gastric retention formulation according to any embodiment of the present invention, comprising a single dose of a gastric retention formulation comprising a total amount of 48 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, the in vivo plasma profiles comprising a geometric mean AUC of approximately 720,000 to 1,142,000 h*pico / mL. 0-inf .

[0087] In one embodiment, the present invention provides a method for treating hyperactivity disorder in a subject of need, the method comprising once daily oral administration to the subject of a gastric retention formulation according to any embodiment of the present invention, comprising a single dose of a gastric retention formulation comprising a total amount of 48 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, the in vivo plasma profiles containing a geometric mean Cg of less than about 36,800 pg / mL. max .

[0088] In one embodiment, the present invention provides a method for treating hyperactivity disorder in a subject of need, the method comprising orally administering once daily to the subject a gastric retention formulation according to any embodiment of the present invention, comprising a gastric retention formulation of a total amount of 6 mg of deuterated butylbenazine providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine at steady state, the in vivo plasma profiles comprising a mean AUC of approximately 102,500 to 200,000 h*pico / mL. 0-24 .

[0089] In one embodiment, the present invention provides a method for treating hyperactivity disorder in a subject of need, the method comprising orally administering once daily to the subject a gastric retention formulation according to any embodiment of the present invention, comprising a gastric retention formulation of a total amount of 6 mg of deuterated butylbenazine providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine at steady state, the in vivo plasma profile containing an average Cg of less than about 10,000 pg / mL.max .

[0090] In one embodiment, the present invention provides a method for treating hyperactivity disorder in a subject of need, the method comprising orally administering once daily to the subject a gastric retention formulation according to any embodiment of the present invention, comprising a gastric retention formulation comprising a total amount of 12 mg of deuterated butylbenazine providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine at steady state, the in vivo plasma profiles comprising a mean AUC of approximately 205,000 to 400,000 h*pico / mL. 0-24 .

[0091] In one embodiment, the present invention provides a method for treating hyperactivity disorder in a subject of need, the method comprising orally administering once daily to the subject a gastric retention formulation according to any embodiment of the present invention, comprising a gastric retention formulation comprising a total amount of 12 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine at steady state, the in vivo plasma profiles containing an average Cg of less than about 20,000 pg / mL. max .

[0092] In one embodiment, the present invention provides a method for treating hyperactivity disorder in a subject of need, the method comprising orally administering once daily to the subject a gastric retention formulation according to any embodiment of the present invention, comprising a gastric retention formulation of a total amount of 24 mg of deuterated butylbenazine providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine at steady state, the in vivo plasma profiles comprising a mean AUC of approximately 410,000 to 800,000 h*pico / mL. 0-24 .

[0093] In one embodiment, the present invention provides a method for treating hyperactivity disorder in a subject of need, the method comprising orally administering once daily to the subject a gastric retention formulation according to any embodiment of the present invention, comprising a gastric retention formulation comprising a total amount of 24 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine at steady state, the in vivo plasma profiles containing an average Cg of less than about 40,000 pg / mL. max .

[0094] In one embodiment, the present invention provides a method for treating hyperactivity disorder in a subject of need, the method comprising orally administering once daily to the subject a gastric retention formulation according to any embodiment of the present invention, comprising a gastric retention formulation of a total amount of 36 mg of deuterated butylbenazine providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine at steady state, the in vivo plasma profiles comprising a mean AUC of approximately 615,000 to 1,200,000 h*pico / mL. 0-24 .

[0095] In one embodiment, the present invention provides a method for treating hyperactivity disorder in a subject of need, the method comprising orally administering once daily to the subject a gastric retention formulation according to any embodiment of the present invention, comprising a gastric retention formulation of a total amount of 36 mg of deuterated butylbenazine providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine at steady state, the in vivo plasma profile containing an average Cg of less than about 60,000 pg / mL. max .

[0096] In one embodiment, the present invention provides a method for treating hyperactivity disorder in a subject of need, the method comprising orally administering once daily to the subject a gastric retention formulation according to any embodiment of the present invention, comprising a gastric retention formulation comprising a total amount of 48 mg of deuterated butylbenazine providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine at steady state, the in vivo plasma profiles comprising a mean AUC of approximately 820,000 to 1,600,000 h*pico / mL. 0-24 .

[0097] In one embodiment, the present invention provides a method for treating hyperactivity disorder in a subject of need, the method comprising orally administering once daily to the subject a gastric retention formulation according to any embodiment of the present invention, comprising a gastric retention formulation comprising a total amount of 48 mg of deuterated butylbenazine providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine at steady state, the in vivo plasma profile containing an average Cg of less than about 80,000 pg / mL. max .

[0098] In one embodiment, after administration of a gastric retention formulation according to the embodiments described herein, when tested using a USPII dissolution apparatus in 500 mL of acidic phosphate buffer at pH 3.0, no more than 40% of deuterated butylbenazine is released after 2 hours.

[0099] In one embodiment, after administration of the gastric retention formulation according to the embodiments described herein, when tested using a USPII dissolution apparatus in 500 mL of acidic phosphate buffer at pH 3.0, no more than 20% of deuterated butylbenazine is released after 2 hours.

[0100] In one embodiment, after administration of a gastric retention formulation according to the embodiments described herein, when tested using a USPII dissolution apparatus in 500 mL of acidic phosphate buffer at pH 3.0, no more than 80% of deuterated butylbenazine is released after 8 hours.

[0101] In one embodiment, after administration of a gastric retention formulation according to the embodiments described herein, when tested using a USPII dissolution apparatus in 500 mL of acidic phosphate buffer at pH 3.0, no more than 60% of deuterated butylbenazine is released after 8 hours.

[0102] In one embodiment, after administration of a gastric retention formulation according to the embodiments described herein, 40%–60% of deuterated butylbenazine was released after 7 hours when tested using a USPII dissolution apparatus in 500 mL of acidic phosphate buffer at pH 3.0.

[0103] In one embodiment, after administration of the gastric retention formulation according to the embodiments described herein, approximately 50% of deuterated butylbenazine was released after 7 hours when tested using a USPII dissolution apparatus in 500 mL of acidic phosphate buffer at pH 3.0.

[0104] This document further provides a method for manufacturing the gastric retention dosage form described herein, the method comprising dry and direct blending of a mixture of deuterated butylbenazine with at least two controlled-release polymers and pharmaceutically acceptable excipients, each controlled-release polymer independently having a viscosity of from 2,000 cps to about 80,000 cps. The dried blend can be further compressed into a monolayer tablet.

[0105] This document further provides a method for manufacturing the gastric retention dosage form described herein, the method comprising dry granulation of a mixture of deuterated butylbenazine and at least two controlled-release polymers and pharmaceutically acceptable excipients, each controlled-release polymer independently having a viscosity of about 2,000 cPs to about 80,000 cPs. The fine granules can be further compressed into monolayer tablets.

[0106] This document further provides micronized deuterated butylbenazine, wherein the median particle size of the micronized deuterated butylbenazine is 1 to 30 micrometers (μm), or 1 to 20 micrometers, or 1 to 10 micrometers, 1 to 9 micrometers, 1 to 8 micrometers, or about 1 to about 7 micrometers. In some embodiments, the deuterated butylbenazine has a particle size distribution characterized by a D90 of about 30 micrometers, a D50 of about 10 micrometers, and a D10 of about 1 micrometer.

[0107] Example

[0108] 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. It should be understood that the examples and embodiments described herein are for illustrative purposes only, and various modifications or changes made thereto will be apparent to those skilled in the art and are included within the true scope of this disclosure, and may be made without departing from the true scope of this disclosure.

[0109] Example 1 - Manufacturing Method Development

[0110] The method for manufacturing a gastric retention formulation includes the following steps:

[0111] a. Manufacturing deuterated butylbenazine blends;

[0112] b. Compressed tablets;

[0113] c. Optional packaging

[0114] Physical characterization of drug substances

[0115] Table 1 shows the particle size distribution of deuterated butylbenazine after manufacturing (untreated), grinding (four-time co-grinding), and micronization (air jet milling).

[0116] Table 1. Particle size distribution (PSD) of unground and ground pharmaceutical substances

[0117] PSD Unmilled Co-milled Micro-milled D10 (pm) 9.08 6.11 1.08 D50 (pm) 59.66 33.55 3.31 D90 (pm) 213.07 131.55 7.05

[0118] For dry measurements of ground and unground deuterated benzoxazine, the following settings are preferably used:

[0119] Analysis Model Mie Obstruction 1.12％ Sample Measurement Time 24 seconds

[0120] Deuterated butylbenazine is a weakly basic compound with relatively good solubility in acidic environments (pH < 4) and poor solubility at pH ≥ 4 (< 2.3 mg / mL). In a rat perfusion model, deuterated butylbenazine can penetrate the small intestine (SI). In humans, […]. 14In the C]-AME study, approximately 80% of the radioactive dose was recovered in the urine, with deuterated benzodiazepine administered as a powder capsule (PIC), indicating good absorption of the compound in the small and large / colon. Absorption levels of deuterated benzodiazepine in the lower GI of rats were shown as jejunum < mid-small intestine < colon < ileum, with ileal absorption at approximately 0.0006 cm / s.

[0121] The dosage form disclosed in this article achieves the same effect as two daily doses (bid) using a single daily dose (qd). Pharmacokinetics (PK) equivalent of 12 mg tablets. Drug solubility was tested in unground drug substance (DS) batches at pH > 3, compared to co-ground and micro-ground DS batches.

[0122] For all three batches, deuterated butylbenazine was dry-blended with a release-control polymer and a lubricant. For samples 1, 2, and 3, unground deuterated butylbenazine, deuterated butylbenazine with a particle size of D90 < 150 μm, and deuterated butylbenazine with a particle size of D90 < 10 μm were used, respectively. All three blends were compressed into tablets. Table 2 shows the composition of the deuterated butylbenazine tablets for samples 1, 2, and 3.

[0123] In all the examples below, dissolution of the formulation was performed in 500 mL of acidic buffer at pH 3 using a USP-II apparatus at 75 rpm for up to 14 hours. Samples were collected at 1, 2, 3, 4, 5, 6, 8, 10, 12, and 14 hours.

[0124] Table 2: Composition of Samples 1, 2 and 3.

[0125]

[0126] Figure 1 Dissolution profiles for samples 1, 2, and 3 are shown. Compared to the unground samples, both co-ground and micro-ground particles exhibited lower dissolution profiles at pH 3. Triangles represent the release profiles of the micro-ground samples, showing slow release (approximately 50% after 14 hours); squares represent the release profiles of the co-ground deuterated butylbenazine; and diamonds represent the release profiles of the unground deuterated butylbenazine. Without being bound by any theory, the lower dissolution profiles of the finer particles are believed to be attributable to better mixing with the controlled-release polymer.

[0127] Example 2 - Controlled-release gastric retention solid oral dosage form

[0128] A. Dry direct blending

[0129] The particle size of deuterated butylbenazine was reduced to micrometers (<10 micrometers) using an air jet milling process. The milled deuterated butylbenazine was then dry-blended with insoluble and water-soluble polymers. Lubricants were screened and further mixed with the blends. The blends were then compressed on a rotary tablet press. Additional sample dosage forms were prepared and dissolution was tested.

[0130] The composition of samples 4-7 is provided in Table 3 below.

[0131] Table 3

[0132] Drug release curves for samples 4-7 are provided as... Figure 2 The charts in the table are shown. Table 4 provides the composition of samples 8-9.

[0133] Table 4

[0134]

[0135] The drug release curves of samples 8-9 were provided as... Figure 3 The chart in the image.

[0136] The composition of samples 10-11 is provided in Table 5.

[0137] Table 5

[0138]

[0139] The drug release curves of samples 10-11 are provided as... Figure 4 The charts in the table are shown. Table 6 provides the composition of samples 12-13.

[0140] Table 6

[0141]

[0142] The drug release curves of samples 12-13 are provided as... Figure 5 The following samples were also produced in a dry-mix process, with antioxidants added to the dried mixture. The composition of samples 14-17 is provided in Table 7.

[0143] Table 7

[0144]

[0145] Drug release profiles for samples 14-17 were provided as... Figure 6 The chart in the image.

[0146] The composition of samples 18-19 is provided in Table 8.

[0147] Table 8

[0148]

[0149] Drug release profiles for samples 18-19 were provided as... Figure 7 The chart in the image.

[0150] The composition of samples 20-21 is provided in Table 9.

[0151] Table 9

[0152]

[0153]

[0154] The drug release curves of samples 20-21 are provided as... Figure 8 The chart in the image.

[0155] B. Granulation

[0156] Butylated hydroxytoluene and butylated hydroxyanisole were dissolved in ethanol (USP). Micronized active silanized microcrystalline cellulose, NF( SMCC 50 and sodium bicarbonate, USP (sample 23) were sieved through a #30 mesh and mixed with GMX-5 for 5 minutes. The dried blend was granulated using a solution of butylated hydroxyanisole and butylated hydroxytoluene. The granules were dried in a disc dryer at 60°C to reduce the LOD to less than 2%. The granules were sieved through a #20 mesh. After 15 minutes of sieving through a #20 mesh, the sieved granules were mixed with... SR, povidone, NF ( XL-10), hydroxypropyl methylcellulose 2208, USP and 71G and NF were blended, and then lubricated with magnesium stearate (#30 mesh sieve) for 5 minutes. The blend was then compressed using a 0.5512″ x 0.3937″ diamond punch.

[0157] The composition of samples 22-23 is provided in Table 10.

[0158] Table 10

[0159]

[0160] The drug release curves of samples 22-23 are provided as... Figure 9 The chart in the image.

[0161] Example 3 - Dog's internal release curve

[0162] The study was conducted as an open-label, randomized, single-dose, partially crossover bioavailability study. The study aimed to determine the AUC0-t, AUC0-24, Cmax, and Tmax of deuterated α- and β-dihydrobufotinazine (deuHTBZ) metabolites. The sample group consisted of four male beagle dogs. Each dog received two treatments. The first treatment, Treatment A, consisted of a single 12 mg dose. The first treatment is tablets, administered twice, 8 hours apart (bid); the second treatment, treatment B, is a single administration of the gastric retention formulation of sample 20. Maintain a 14-day clearance period before proceeding to the next treatment. Administer a single oral dose to each dog with 10 ml of water. Pre-treat the dog with pentagastrin (to stimulate gastric acid secretion) before each dose administration.

[0163] Blood samples were collected at predetermined time points before and 24 hours after administration. Plasma levels of deuterated butylbenazine and total deuHTBZ were analyzed using LC-MS / MS. Table 11 presents the pharmacokinetic (PK) characteristics after oral administration of the two treatments.

[0164] Table 11

[0165]

[0166] The * value is the mean (SD), except for the value for tmax, which is the median [range].

[0167] result

[0168] The tested gastric retention formulation (treatment B) was well tolerated in dogs after a single oral dose, with no adverse clinical signs or vomiting. The tested gastric retention formulation produced less than Peak plasma concentrations of deuterated benzophenone and total deuterated benzophenone (C max ) and total systemic exposure (AUC). These preliminary studies provide valuable indications about the design of formulations and their in vivo behavior. Observed C max The lower AUC values ​​can be attributed to differences between dogs and humans (deuterated benzodiazepine / deuHTBZ C) max The rate is approximately 10% in dogs and <1% in humans.

[0169] Example 4 - Human Single-Dose Bioavailability Assessment

[0170] Gastric retention formulations containing deuterated butylbenazine were produced as disclosed in Example 2 and investigated in single-dose pharmacokinetic studies.

[0171] The primary objective was to evaluate the effect of a single administration of the gastric retention formulation (“test”) compared to two single 12 mg administrations administered 12 hours apart under fasting conditions (bid). Comparative bioavailability (BA) of deuterated butylbenazine and total deuHTBZ metabolites compared to tablets (“Reference”).

[0172] Study population and number of participants: The study included healthy male and female non-smoking participants.

[0173] Duration of subject participation: The study included a screening period of 2–4 weeks (Phase 1), an open-label treatment period using a once-daily gastric retention test formulation (“Test”) and a reference formulation (“Reference”) (Phase 2), and a follow-up period of at least 1 day later (Phase 3).

[0174] treat:

[0175] Treatment Sequence A:

[0176] Day 1 - Application Test.

[0177] Days 2-3 - Clear test for at least 6 hours, then apply reference.

[0178] Treatment Sequence B:

[0179] Day 1 - Application Guidelines

[0180] Days 2-3 - Clear the reference for at least 6 hours, then apply the test.

[0181] The main objective was achieved using the following parameters:

[0182] -Maximum observed concentration (Cmax)

[0183] - The area under the plasma concentration-time curve (AUC) from time 0 to the final measurable plasma concentration (AUC0-t).

[0184] - Extrapolate AUC to infinity (AUC0-∞)

[0185] -AUC 0 to 24 hours after administration (AUC0-24h)

[0186] analyze

[0187] AUC0-t, AUC0-∞, and AUC0-24h were calculated using the trapezoidal rule. Cmax, AUC0-t, AUC0-∞, and AUC0-24h data were transformed using the natural logarithm prior to statistical analysis. Comparisons of Cmax, AUC0-t, AUC0-∞, and AUC0-24h between treatments (test vs. reference) were performed using separate parametric analysis of variance (ANOVA) models with fixed-effects terms for sequence, period, treatment group, and random effects for subjects within the sequence. Differences between reference and test were assessed based on the least-squares means of the log-transformed ANOVA of Cmax, AUC0-t, AUC0-∞, and AUC0-24h by constructing 90% confidence intervals for the test / reference ratio. The treatment differences estimated from ANOVA on a logarithmic scale and their associated 90% confidence intervals were inversely transformed to obtain an estimated ratio of the geometric mean between treatment groups and 90% confidence intervals for this ratio.

[0188] result

[0189] The once-daily test formulation provided similar deuHTBZ plasma concentrations as observed against a reference. The gastric retention formulation disclosed herein, administered once daily, provides similar... It has similar therapeutic effects and no safety issues.

[0190] Example 5 - Multi-dose bioavailability assessment

[0191] A gastric retention formulation containing 24 mg of deuterated benzoxine was produced as disclosed in Example 2 and investigated in an open-label, randomized, multiple-dose, 2-way crossover study in healthy volunteers.

[0192] The primary objective was to assess the bioequivalence (BE) of the qd administration test compared with the bid administration reference under fasting or fed conditions.

[0193] Treatment includes a 7-day repeat dosing test, once daily versus a 7-day repeat dosing reference, bid.

[0194] AUCt and C of deuterated butylbenazine and deuHTBZ were analyzed under steady-state conditions. max t max C min C av .

[0195] result

[0196] Multiple dosing tests conducted at steady state exhibited PK parameters comparable to those of a reference multiple dosing regimen. Therefore, a similar therapeutic response is expected with once-daily administration, and no safety concerns are anticipated.

[0197] Example 6 - Food Impact Study

[0198] Gastric retention formulations containing deuterated butylbenazine, as disclosed in Example 2, were developed and investigated in an open-label, randomized, two-way crossover study to evaluate the comparative bioavailability of deuterated butylbenazine and deuHTBZ during eating versus fasting following a single 24 mg dose of the gastric retention formulation once daily (qd).

[0199] Treatment includes:

[0200] A-Gastric Retention Compound, administered as a single oral dose with water after at least 10 hours of overnight fasting.

[0201] B-Gastric Retention Compound is administered as a single oral dose with water 30 minutes after the start of a standard high-calorie, high-fat breakfast following an overnight fast of at least 10 hours.

[0202] Subjects will receive treatment A / B with a clearance period of at least 6 days.

[0203] The AUCt, Cmax, tmax, Cmin, and Cav of deuterated butylbenazine and deuHTBZ will be analyzed.

[0204] result

[0205] Similar plasma concentrations of deuterated benzonazine and deuHTBZ after a single administration, with or without food, suggest that the gastric retention dose can be administered independently of food intake.

[0206] All patents, patent applications, and publications mentioned in this specification indicate the level of skill of one skilled in the art to which this invention pertains. All patents, patent applications, and publications are incorporated herein by reference to the extent that each individual publication is specifically and individually indicated to be incorporated by reference. The invention described herein may be practiced appropriately in the absence of any element not specifically disclosed herein. Therefore, for example, in each case herein, any one of the terms “comprising,” “substantially consisting of,” and “consisting of” may be replaced by any of the other two terms. The terms and expressions used are used as illustrative rather than restrictive terms and are not intended to be used without any equivalents of the features or portions thereof shown and described; however, it should be recognized that various modifications may be made within the scope of the claimed invention. Therefore, it should be understood that although the invention has been expressly disclosed by way of preferred embodiments and optional features, modifications and alterations to the concepts disclosed herein may be made by one skilled in the art, and such modifications and alterations are considered to be within the scope of the invention as defined by the appended claims.

[0207] With respect to the foregoing embodiments, each embodiment disclosed herein is contemplated to be applicable to each of the other disclosed embodiments. For example, elements described in the method embodiments may be used in the pharmaceutical composition, packaging, and use embodiments described herein, and vice versa.

[0208] aspect

[0209] Aspect 1. A controlled-release gastric retention solid oral dosage form for once-daily administration of deuterated butylbenazine, said controlled-release gastric retention solid oral dosage form comprising deuterated butylbenazine, at least one release-controlling polymer and a pharmaceutically acceptable excipient.

[0210] Aspect 2. The gastric retention solid oral dosage form according to aspect 1, wherein the release-controlling polymer comprises a water-soluble polymer, a water-insoluble polymer, or a mixture thereof.

[0211] Aspect 3. The gastric retention solid oral dosage form according to aspect 2, wherein the water-soluble polymer comprises hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymer or mixtures thereof.

[0212] Aspect 4. The gastric retention solid oral dosage form according to aspect 3, wherein the water-soluble polymer comprises hydroxypropyl methylcellulose, polyacrylic acid polymer, or a mixture thereof.

[0213] Aspect 5. The gastric retention solid oral dosage form according to aspect 4, wherein the polyacrylic acid polymer comprises, for example, Isocrosslinked polyacrylic acid polymers.

[0214] Aspect 6. The gastric retention solid oral dosage form according to aspect 2, wherein the water-insoluble polymer comprises crospovidone, copovidone, croscarmellose sodium, starch, sodium glycolate starch, colloidal silica, silica, ethyl cellulose, polyvinyl acetate, or mixtures thereof.

[0215] Aspect 7. The gastric retention solid oral dosage form according to aspect 6, wherein the water-insoluble polymer comprises cropovidone, copovidone, or a mixture thereof.

[0216] Aspect 8. The gastric retention solid oral dosage form according to aspect 7, wherein the copovidone is

[0217] Aspect 9. The gastric retention solid oral dosage form according to any one of the preceding aspects, comprising a release-control polymer mixture of cropovidone, copovidone, hydroxypropyl methylcellulose and polyacrylic acid polymer.

[0218] Aspect 10. The gastric retention solid oral dosage form according to any one of the preceding aspects, comprising, relative to the total weight of the solid oral dosage form, 5 to 65 wt.% of the release control polymer.

[0219] Aspect 11. The gastric retention solid oral dosage form according to any one of the preceding aspects, wherein the pharmaceutically acceptable excipients include diluents, disintegrants, binders, gas generators, antioxidants, lubricants, or combinations thereof.

[0220] Aspect 12. The gastric retention solid oral dosage form according to aspect 11, wherein the pharmaceutically acceptable excipient comprises a gas generator, and wherein the gas generator comprises a carbonate selected from the group consisting of: sodium bicarbonate, a mixture of sodium bicarbonate and citric acid, calcium carbonate, a mixture of calcium carbonate and citric acid, and mixtures thereof.

[0221] Aspect 13. The gastric retention solid oral dosage form according to aspect 12, wherein the gas generating agent is present in an amount of 5 to 15 wt.% relative to the total weight of the solid oral dosage form.

[0222] Aspect 14. The gastric retention solid oral dosage form according to any one of Aspects 11 to 13 above, wherein the pharmaceutically acceptable excipient comprises an antioxidant, and wherein the antioxidant comprises propyl gallate, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquinoline), nordihydroguaiacol (NDGA), butylated hydroxyanisole, butylated hydroxytoluene, or any mixture thereof.

[0223] Aspect 15. The gastric retention solid oral dosage form according to aspect 14, wherein the antioxidant comprises a mixture of butylated hydroxyanisole and butylated hydroxytoluene.

[0224] Aspect 16. The gastric retention solid oral dosage form according to any one of Aspects 11 to 15, wherein the antioxidant is present in an amount of 0.1 to 1 wt.% relative to the total weight of the solid oral dosage form.

[0225] Aspect 17. The gastric retention solid oral dosage form according to any one of Aspects 11 to 16, wherein the pharmaceutically acceptable excipient comprises a binder, and wherein the binder comprises microcrystalline cellulose, starch, gelatin, agar, natural and synthetic gums or any mixture thereof.

[0226] Aspect 18. A gastric retention solid oral dosage form according to any one of Aspects 11 to 17, wherein the binder is present in an amount of 5 to 50 wt.% relative to the total weight of the solid oral dosage form.

[0227] Aspect 19. The gastric retention solid oral dosage form according to any one of the preceding aspects, comprising 4-7 wt.% of deuterated butylbenazine relative to the total weight of the dosage form.

[0228] Aspect 20. The gastric retention solid oral dosage form according to any one of the preceding aspects, wherein the total amount of deuterated butylbenazine in the dosage form is about 6 mg to about 48 mg.

[0229] Aspect 21. The gastric retention solid oral dosage form according to aspect 20, wherein the total amount of deuterated butylbenazine in the dosage form is 6 mg.

[0230] Aspect 22. The gastric retention solid oral dosage form according to aspect 20, wherein the total amount of deuterated butylbenazine in the dosage form is 12 mg.

[0231] Aspect 23. The gastric retention solid oral dosage form according to aspect 20, wherein the total amount of deuterated butylbenazine in the dosage form is 24 mg.

[0232] Aspect 24. The gastric retention solid oral dosage form according to aspect 20, wherein the total amount of deuterated butylbenazine in the dosage form is 36 mg.

[0233] Aspect 25. The gastric retention solid oral dosage form according to aspect 20, wherein the total amount of deuterated butylbenazine in the dosage form is 48 mg.

[0234] Aspect 26. The gastric retention solid oral dosage form according to any one of the preceding aspects, wherein the deuterated butylbenazine is micronized deuterated butylbenazine, and the average particle size of the micronized deuterated butylbenazine is about 1 μm to about 30 μm in diameter.

[0235] Aspect 27. The gastric retention solid oral dosage form according to aspect 26, wherein the deuterated butylbenazine has a particle size distribution characterized by a D90 of 30 μm.

[0236] Aspect 28. The gastric retention solid oral dosage form according to aspect 26, wherein the deuterated butylbenazine has a particle size distribution characterized by a D50 of 10 μm.

[0237] Aspect 29. The gastric retention solid oral dosage form according to aspect 26, wherein the deuterated butylbenazine has a particle size distribution characterized by D10 of 1 μm.

[0238] Aspect 30. The gastric retention solid oral dosage form according to any one of the preceding aspects, comprising:

[0239] a. 4-7 wt.% of deuterated butylbenazine;

[0240] b. 20-40 wt.% of cross-pollination ketone;

[0241] c. 20-50 wt.% hydroxypropyl methylcellulose;

[0242] d. 15-45 wt.% microcrystalline cellulose;

[0243] e.0.3-2wt.% magnesium stearate.

[0244] Aspect 31. The gastric retention solid oral dosage form according to any one of Aspects 1 to 29 above, comprising:

[0245] a. 4-7 wt.% of deuterated butylbenazine;

[0246] b. 20-40 wt.% of cross-pollination ketone;

[0247] c. 20-50 wt.% hydroxypropyl methylcellulose;

[0248] d. 15-45 wt.% polyacrylic acid polymer;

[0249] e.0.3-2wt.% magnesium stearate.

[0250] Aspect 32. The gastric retention solid oral dosage form according to any one of Aspects 1 to 29 above, comprising:

[0251] a. 4-7 wt.% of deuterated butylbenazine;

[0252] b. 10-30 wt.% copolyvinylpyrrolidone;

[0253] c. 20-40 wt.% of cross-povidone;

[0254] d. 20-50 wt.% hydroxypropyl methylcellulose;

[0255] e. 2-15 wt.% polyacrylic acid polymer;

[0256] Magnesium stearate, f. 0.3-2 wt.%.

[0257] Aspect 33. The gastric retention solid oral dosage form according to any one of Aspects 1 to 29 above, comprising:

[0258] a. 4-7 wt.% of deuterated butylbenazine;

[0259] b. 5-20 wt.% microcrystalline cellulose;

[0260] c. 10-30 wt.% copolyvinylpyrrolidone;

[0261] d. 20-40 wt.% of crosspovidone;

[0262] e. 20-50 wt.% hydroxypropyl methylcellulose;

[0263] f. 2-15 wt.% polyacrylic acid polymer;

[0264] 0.3-2 wt.% magnesium stearate.

[0265] Aspect 34. The gastric retention solid oral dosage form according to any one of Aspects 1 to 29 above, comprising: a. 4-7 wt.% of deuterated butylbenazine;

[0266] b. A mixture of 0.2-0.5 wt.% butylated hydroxyanisole and butylated hydroxytoluene;

[0267] c. 20-50 wt.% microcrystalline cellulose;

[0268] d.4-8 wt.% copolyvinylpyrrolidone;

[0269] e. 20-40 wt.% of cross-linked viscosine;

[0270] f. 5-20 wt.% hydroxypropyl methylcellulose;

[0271] g.2-15wt.% of polyacrylic acid polymer;

[0272] 0.3-2 wt.% magnesium stearate.

[0273] Aspect 35. The gastric retention solid oral dosage form according to any one of Aspects 1 to 29 above, comprising: a. 4-7 wt.% of deuterated butylbenazine;

[0274] b. A mixture of 0.2-0.5 wt.% butylated hydroxyanisole and butylated hydroxytoluene;

[0275] c. 20-50 wt.% microcrystalline cellulose;

[0276] d.4-8 wt.% copolyvinylpyrrolidone;

[0277] e. 20-40 wt.% of cross-linked viscosine;

[0278] f. 5-20 wt.% hydroxypropyl methylcellulose;

[0279] g.2-15wt.% of polyacrylic acid polymer;

[0280] h. 0.1-0.7 wt.% sodium bicarbonate;

[0281] i. 0.3-2 wt.% magnesium stearate.

[0282] Aspect 36. The gastric retention solid oral dosage form according to any one of the preceding aspects, wherein the dosage form is a tablet.

[0283] Aspect 37. The gastric retention solid oral dosage form according to aspect 36, wherein the tablet is a single-layer tablet.

[0284] Aspect 38. A gastric retention solid oral dosage form according to any one of the preceding aspects, wherein when the dosage form is introduced into the gastric environment of a subject, the gastric retention of the subject is the result of one or more floating mechanisms of gas generation and swelling.

[0285] Aspect 39. The gastric retention solid oral dosage form according to aspect 38, wherein the dosage form swells to about 200 wt.% of the weight of the unswelled dosage form upon contact with gastric juice.

[0286] Aspect 40. A gastric retention solid oral dosage form according to any one of Aspects 38 to 39, wherein the dosage form floats in the gastric environment of the subject for up to 24 hours.

[0287] Aspect 41. The gastric retention solid oral dosage form according to any one of Aspects 38 to 40 above, wherein the dosage form floats in the gastric environment of the subject for 6-20 hours.

[0288] Aspect 42. The gastric retention solid oral dosage form according to any one of the preceding aspects, wherein when tested using a USP II dissolution apparatus in 500 mL of acidic phosphate buffer at pH 3.0, no more than 40 wt.% of the deuterated butylbenazine is released after 2 hours.

[0289] Aspect 43. The gastric retention solid oral dosage form according to aspect 42, wherein when tested using a USPII dissolution apparatus in 500 mL of acidic phosphate buffer at pH 3.0, no more than 20 wt.% of the deuterated butylbenazine is released after 2 hours.

[0290] Aspect 44. The gastric retention solid oral dosage form according to any one of Aspects 1 to 41, wherein when tested using a USPII dissolution apparatus in 500 mL of acidic phosphate buffer at pH 3.0, no more than 80 wt.% of the deuterated butylbenazine is released after 8 hours.

[0291] Aspect 45. The gastric retention solid oral dosage form according to aspect 44, wherein when tested using a USPII dissolution device in 500 mL of acidic phosphate buffer at pH 3.0, no more than 60 wt.% of the deuterated butylbenazine is released after 8 hours.

[0292] Aspect 46. The gastric retention solid oral dosage form according to any one of the preceding aspects, used for the treatment of VMAT2-mediated conditions.

[0293] Aspect 47. A method for treating VMAT2-mediated conditions in a subject in need, the method comprising orally administering, once daily, to the subject a gastric retention solid oral dosage form according to any one of Aspects 1 to 45.

[0294] Aspect 48. The dosage form according to aspect 46 or the method according to aspect 47, wherein the VMAT2-mediated condition is hyperactivity disorder.

[0295] Aspect 49. The dosage form or method according to aspect 48, wherein the hyperactivity disorder is chronic hyperactivity disorder.

[0296] Aspect 50. The dosage form or method according to aspect 49, wherein the chronic hyperactivity disorder is selected from Huntington's disease, tardive dyskinesia, and dyskinesia in cerebral palsy.

[0297] Aspect 51. A dosage form or method according to any one of Aspects 46 to 50, comprising a single-dose administration of a once-daily gastric retention solid oral dosage form of a total amount of 6 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles comprising a geometric mean AUC of about 91,250 to 142,750 hours * picograms / mL. 0-inf .

[0298] Aspect 52. A dosage form or method according to any one of Aspects 46 to 50, comprising a single-dose administration of a once-daily gastric retention solid oral dosage form of a total amount of 6 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles containing a geometric mean Cg of less than about 4,600 pg / mL. max .

[0299] Aspect 53. A dosage form or method according to any one of Aspects 46 to 50, comprising a single-dose administration of a once-daily gastric retention solid oral dosage form of a total amount of 12 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles comprising a geometrically mean AUC of about 182,500 to 285,500 h*pico / mL. 0-inf .

[0300] Aspect 54. A dosage form or method according to any one of Aspects 46 to 50, comprising a single-dose administration of a once-daily gastric retention solid oral dosage form of a total amount of 12 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles containing a geometric mean Cg of less than about 9,200 pg / mL. max .

[0301] Aspect 55. A dosage form or method according to any one of Aspects 46 to 50, comprising a single-dose administration of a once-daily gastric retention solid oral dosage form of a total amount of 24 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles comprising a geometric mean AUC of approximately 365,000 to 571,000 hours * picograms / mL. 0-inf .

[0302] Aspect 56. A dosage form or method according to any one of Aspects 46 to 50, comprising a single-dose administration of a once-daily gastric retention solid oral dosage form of a total amount of 24 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles containing a geometric mean Cg of less than about 18,400 pg / mL. max .

[0303] Aspect 57. A dosage form or method according to any one of Aspects 46 to 50, comprising a single-dose administration of a once-daily gastric retention solid oral dosage form of a total amount of 36 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles comprising a geometric mean AUC of approximately 547,500 to 856,500 h*pico / mL. 0-inf .

[0304] Aspect 58. A dosage form or method according to any one of Aspects 46 to 50, comprising a single-dose administration of a once-daily gastric retention solid oral dosage form of a total amount of 36 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles containing a geometric mean Cg of less than about 27,600 pg / mL. max .

[0305] Aspect 59. A dosage form or method according to any one of Aspects 46 to 50, comprising a single-dose administration of a once-daily gastric retention solid oral dosage form of a total amount of 48 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles comprising a geometric mean AUC of approximately 730,000 to 1,142,000 hours * picograms / mL. 0-inf .

[0306] Aspect 60. A dosage form or method according to any one of Aspects 46 to 50, comprising a single-dose administration of a once-daily gastric retention solid oral dosage form of a total amount of 48 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles containing a geometric mean Cg of less than about 36,800 pg / mL. max .

[0307] Aspect 61. A dosage form or method according to any one of Aspects 46 to 50, comprising administration of a once-daily gastric retention solid oral dosage form of a total amount of 6 mg of deuterated butylbenazine, providing steady-state in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles comprising an average AUC of about 102,500 to 200,000 h*pico / mL. 0-24 .

[0308] Aspect 62. A dosage form or method according to any one of Aspects 46 to 50, comprising the administration of a once-daily gastric retention solid oral dosage form of a total amount of 6 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine at steady state, said in vivo plasma profiles containing an average Cg of less than about 10,000 pg / mL. max .

[0309] Aspect 63. A dosage form or method according to any one of Aspects 46 to 50, comprising administration of a once-daily gastric retention solid oral dosage form of a total amount of 12 mg of deuterated butylbenazine, providing steady-state in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles comprising an average AUC of about 205,000 to 400,000 h*pico / mL. 0-24 .

[0310] Aspect 64. A dosage form or method according to any one of Aspects 46 to 50, comprising administration of a once-daily gastric retention solid oral dosage form of a total amount of 12 mg of deuterated butylbenazine, providing steady-state in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles containing an average Cg of less than about 20,000 pg / mL. max .

[0311] Aspect 65. A dosage form or method according to any one of Aspects 46 to 50, comprising administration of a once-daily gastric retention solid oral dosage form of a total amount of 24 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine at steady state, said in vivo plasma profiles comprising a mean AUC of about 410,000 to 800,000 h*pico / mL. 0-24 .

[0312] Aspect 66. A dosage form or method according to any one of Aspects 46 to 50, comprising administration of a once-daily gastric retention solid oral dosage form of a total amount of 24 mg of deuterated butylbenazine, providing steady-state in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles containing an average Cg of less than about 40,000 pg / mL. max .

[0313] Aspect 67. A dosage form or method according to any one of Aspects 46 to 50, comprising administration of a once-daily gastric retention solid oral dosage form of a total amount of 36 mg of deuterated butylbenazine, providing steady-state in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles comprising a mean AUC of about 615,000 to 1,200,000 h*pico / mL. 0-24 .

[0314] Aspect 68. A dosage form or method according to any one of Aspects 46 to 50, comprising administration of a once-daily gastric retention solid oral dosage form of a total amount of 36 mg of deuterated butylbenazine, providing steady-state in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles containing an average Cg of less than about 60,000 pg / mL. max .

[0315] Aspect 69. A dosage form or method according to any one of Aspects 46 to 50, comprising administration of a once-daily gastric retention solid oral dosage form of a total amount of 48 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine at steady state, said in vivo plasma profiles comprising an average AUC of about 820,000 to 1,600,000 h*pico / mL. 0-24 .

[0316] Aspect 70. A dosage form or method according to any one of Aspects 46 to 50, comprising administration of a once-daily gastric retention solid oral dosage form of a total amount of 48 mg of deuterated butylbenazine, providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine at steady state, said in vivo plasma profiles containing an average Cg of less than about 80,000 pg / mL. max .

[0317] Aspect 71. The dosage form or method according to any one of Aspects 46 to 50, wherein, after administration of the gastric retention solid oral dosage form according to any one of Aspects 1 to 45, when tested in 500 mL of acidic phosphate buffer at pH 3.0 using a USP II dissolution apparatus, no more than 40 wt.% of the deuterated butylbenazine is released after 2 hours.

[0318] Aspect 72. The dosage form or method according to any one of Aspects 46 to 50, wherein, after administration of the gastric retention solid oral dosage form according to any one of Aspects 1 to 45, when tested in 500 mL of acidic phosphate buffer at pH 3.0 using a USP II dissolution apparatus, no more than 20 wt.% of the deuterated butylbenazine is released after 2 hours.

[0319] Aspect 73. The dosage form or method according to any one of Aspects 46 to 50, wherein, after administration of the gastric retention solid oral dosage form according to any one of Aspects 1 to 45, when tested in 500 mL of acidic phosphate buffer at pH 3.0 using a USP II dissolution apparatus, no more than 80 wt.% of the deuterated butylbenazine is released after 8 hours.

[0320] Aspect 74. The dosage form or method according to any one of Aspects 46 to 50, wherein, after administration of the gastric retention solid oral dosage form according to any one of Aspects 1 to 45, when tested in 500 mL of acidic phosphate buffer at pH 3.0 using a USP II dissolution apparatus, no more than 60 wt.% of the deuterated butylbenazine is released after 8 hours.

[0321] Aspect 75. The dosage form or method according to any one of Aspects 46 to 74, wherein the dosage form is administered together with food.

[0322] Aspect 76. The dosage form or method according to any one of aspects 46 to 74, wherein the dosage form is administered independently of food intake.

Claims

1. A controlled-release gastric retention solid oral dosage form for once-daily administration of deutetrabenazine, the controlled-release gastric retention solid oral dosage form comprising: a. A certain amount of deuterated benzodiazepine; b. At least two controlled-release polymers, each independently having a viscosity of 2,000 cPs or higher; as well as c. Pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients include at least one disintegrant; The total amount of the controlled-release polymer is at least 30 wt.% relative to the total weight of the dosage form.

2. The gastric retention solid oral dosage form according to claim 1, wherein each of the controlled-release polymers independently has a viscosity of 2,000 to 80,000 cPs.

3. The gastric retention solid oral dosage form according to claim 1, wherein at least one of the two controlled-release polymers has a viscosity of 2,000 to 4,000 cPs.

4. The gastric retention solid oral dosage form according to any one of the preceding claims, wherein at least one of the two controlled-release polymers has a viscosity of 40,000 to 60,000 cPs.

5. The gastric retention solid oral dosage form according to any one of the preceding claims, further comprising at least one additional controlled-release polymer, each independently having a viscosity of 3 to 80,000 cPs or 3 to 15 cPs.

6. The gastric retention solid oral dosage form according to any one of the preceding claims, wherein the controlled-release polymer or the other controlled-release polymer comprises a water-soluble polymer, a water-insoluble polymer, or a mixture thereof.

7. The gastric retention solid oral dosage form according to claim 6, wherein the water-soluble polymer comprises hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymer or mixtures thereof.

8. The gastric retention solid oral dosage form according to any one of claims 6 to 7, wherein the water-soluble polymer comprises hydroxypropyl methylcellulose (HPMC), polyacrylic acid polymer, or a mixture thereof.

9. The gastric retention solid oral dosage form according to claim 8, wherein the polyacrylic acid polymer comprises Cross-linked polyacrylic acid polymer.

10. The gastric retention solid oral dosage form according to claim 6, wherein the water-insoluble polymer comprises copovidone, croscarmellose sodium, starch, sodium glycolate starch, colloidal silica, silica, ethyl cellulose, polyvinyl acetate, or mixtures thereof.

11. The gastric retention solid oral dosage form according to any one of claims 6 or 10, wherein the water-insoluble polymer comprises copovidone or a mixture thereof.

12. The gastric retention solid oral dosage form according to claim 11, wherein the copovidone is 13. The gastric retention solid oral dosage form according to any one of the preceding claims, comprising a controlled-release polymer mixture of copovidone, hydroxypropyl methylcellulose and polyacrylic acid polymer.

14. The gastric retention solid oral dosage form according to any one of the preceding claims, wherein the at least one disintegrant comprises: Crosslinked sodium carboxymethyl cellulose, alginate, microcrystalline cellulose, crosspovidone, polacrilinpotassium, sodium glycolate starch, low-substituted hydroxypropyl cellulose, starch, or mixtures thereof.

15. The gastric retention solid oral dosage form according to any one of the preceding claims, wherein the at least one disintegrant comprises cropovidone.

16. The gastric retention solid oral dosage form according to any one of the preceding claims, comprising, by weight of the solid oral dosage form, 30 to 65 wt.%, 35 to 55 wt.%, or 40 to 50 wt.%, of a release-controlled polymer.

17. The gastric retention solid oral dosage form according to any one of the preceding claims, wherein the pharmaceutically acceptable excipient further comprises a diluent, a binder, a gas generator, an antioxidant, a lubricant, or a combination thereof.

18. The gastric retention solid oral dosage form of claim 17, wherein the pharmaceutically acceptable excipient comprises a gas generator, and wherein the gas generator comprises a carbonate selected from the group consisting of: sodium bicarbonate, a mixture of sodium bicarbonate and citric acid, calcium carbonate, a mixture of calcium carbonate and citric acid, and mixtures thereof.

19. The gastric retention solid oral dosage form according to claim 18, wherein the gas generator is present in an amount of 5 to 15 wt.% relative to the total weight of the solid oral dosage form.

20. The gastric retention solid oral dosage form according to any one of the preceding claims, wherein the pharmaceutically acceptable excipient comprises an antioxidant, and wherein the antioxidant comprises propyl gallate, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquinoline), nordihydroguaiacol (NDGA), butylated hydroxyanisole, butylated hydroxytoluene, or any mixture thereof.

21. The gastric retention solid oral dosage form according to claim 20, wherein the antioxidant comprises a mixture of butylated hydroxyanisole and butylated hydroxytoluene.

22. The gastric retention solid oral dosage form according to any one of claims 17 to 21, wherein the antioxidant is present in an amount of 0.1 to 1.0 wt.% relative to the total weight of the solid oral dosage form.

23. The gastric retention solid oral dosage form according to any one of claims 17 to 22, wherein the pharmaceutically acceptable excipient comprises a binder, and wherein the binder comprises microcrystalline cellulose, starch, gelatin, agar, natural and synthetic gums or any mixture thereof.

24. The gastric retention solid oral dosage form according to claim 23, wherein the binder is present in an amount of 5 to 50 wt.% relative to the total weight of the solid oral dosage form.

25. The gastric retention solid oral dosage form according to any one of the preceding claims, comprising, by weight of the total weight of the dosage form, 2-15 wt.%, 3-10 wt.%, or 4-7 wt.% of deuterated butylbenazine.

26. The gastric retention solid oral dosage form according to any one of the preceding claims, wherein the total amount of deuterated butylbenazine in the dosage form is from 6 mg to 48 mg.

27. The gastric retention solid oral dosage form according to claim 26, wherein the total amount of deuterated butylbenazine in the dosage form is 6 mg.

28. The gastric retention solid oral dosage form according to claim 26, wherein the total amount of deuterated butylbenazine in the dosage form is 12 mg.

29. The gastric retention solid oral dosage form according to claim 26, wherein the total amount of deuterated butylbenazine in the dosage form is 24 mg.

30. The gastric retention solid oral dosage form according to claim 26, wherein the total amount of deuterated butylbenazine in the dosage form is 36 mg.

31. The gastric retention solid oral dosage form according to claim 26, wherein the total amount of deuterated butylbenazine in the dosage form is 48 mg.

32. The gastric retention solid oral dosage form according to any one of the preceding claims, wherein the deuterated butylbenazine is micronized deuterated butylbenazine, and the average particle size of the micronized deuterated butylbenazine is from 1 μm to 30 μm in diameter.

33. The gastric retention solid oral dosage form according to claim 32, wherein the deuterated butylbenazine has a D-value of 30 μm. 90 The particle size distribution is characterized.

34. The gastric retention solid oral dosage form according to claim 32, wherein the deuterated butylbenazine has a D-value of 10 μm. 50 The particle size distribution is characterized.

35. The gastric retention solid oral dosage form according to claim 32, wherein the deuterated butylbenazine has a D-value of 1 μm. 10 The particle size distribution is characterized.

36. The solid oral dosage form for gastric retention according to any one of claims 1 to 35, comprising: a. 4-7 wt.% of deuterated butylbenazine relative to the total weight of the dosage form; b. 20-40 wt.% of cropovidone relative to the total weight of the dosage form; c. 20-50 wt.% hydroxypropyl methylcellulose relative to the total weight of the dosage form; d. 15-45 wt.% polyacrylic acid polymer relative to the total weight of the dosage form; e. 0.3-2 wt.% magnesium stearate relative to the total weight of the dosage form.

37. The solid oral dosage form for gastric retention according to any one of claims 1 to 35, comprising: a. 4-7 wt.% of deuterated butylbenazine relative to the total weight of the dosage form; b. 10-30 wt.% copovidone relative to the total weight of the dosage form; c. 20-40 wt.% of cropovidone relative to the total weight of the dosage form; d. 20-50 wt.% of hydroxypropyl methylcellulose relative to the total weight of the dosage form; e. 2-15 wt.% of polyacrylic acid polymer relative to the total weight of the dosage form; f. 0.3-2 wt.% magnesium stearate relative to the total weight of the dosage form.

38. The solid oral dosage form for gastric retention according to any one of claims 1 to 35, comprising: a. 4-7 wt.% of deuterated butylbenazine relative to the total weight of the dosage form; b. 5-20 wt.% microcrystalline cellulose relative to the total weight of the dosage form; c. 10-30 wt.% copovidone relative to the total weight of the dosage form; d. 20-40 wt.% of cropovidone relative to the total weight of the dosage form; e. 20-50 wt.% of hydroxypropyl methylcellulose relative to the total weight of the dosage form; f. 2-15 wt.% polyacrylic acid polymer relative to the total weight of the dosage form; g. 0.3-2 wt.% magnesium stearate relative to the total weight of the dosage form.

39. The solid oral dosage form for gastric retention according to any one of claims 1 to 35, comprising: a. 4-7 wt.% of deuterated butylbenazine relative to the total weight of the dosage form; b. A mixture of butylated hydroxyanisole and butylated hydroxytoluene, relative to the total weight of the dosage form; c. 20-50 wt.% microcrystalline cellulose relative to the total weight of the dosage form; d. 4-8 wt.% copovidone relative to the total weight of the dosage form; e. 20-40 wt.% of cropovidone relative to the total weight of the dosage form; f. 5-20 wt.% hydroxypropyl methylcellulose relative to the total weight of the dosage form; g. 2-15 wt.% polyacrylic acid polymer relative to the total weight of the dosage form; h. 0.3-2 wt.% magnesium stearate relative to the total weight of the dosage form.

40. The solid oral dosage form for gastric retention according to any one of claims 1 to 35, comprising: a. 4-7 wt.% of deuterated butylbenazine relative to the total weight of the dosage form; b. A mixture of butylated hydroxyanisole and butylated hydroxytoluene, relative to the total weight of the dosage form; c. 20-50 wt.% microcrystalline cellulose relative to the total weight of the dosage form; d. 4-8 wt.% copovidone relative to the total weight of the dosage form; e. 20-40 wt.% of cropovidone relative to the total weight of the dosage form; f. 5-20 wt.% hydroxypropyl methylcellulose relative to the total weight of the dosage form; g. 2-15 wt.% polyacrylic acid polymer relative to the total weight of the dosage form; h. 0.1-0.7 wt.% sodium bicarbonate relative to the total weight of the dosage form; i. 0.3-2 wt.% magnesium stearate relative to the total weight of the dosage form.

41. The gastric retention solid oral dosage form according to any one of the preceding claims, wherein the dosage form is a tablet.

42. The gastric retention solid oral dosage form according to claim 41, wherein the tablet is a single-layer tablet.

43. The gastric retention solid oral dosage form according to any one of the preceding claims, wherein when the dosage form is introduced into the gastric environment of a subject, the gastric retention of the subject is the result of one or more of the floating mechanisms of gas generation and / or swelling.

44. The gastric retention solid oral dosage form according to claim 43, wherein the dosage form swells to about 200 wt.% of the weight of the unswelled dosage form upon contact with gastric juice.

45. The gastric retention solid oral dosage form according to any one of claims 43 to 44, wherein the dosage form floats in the gastric environment of the subject for up to 24 hours.

46. ​​The gastric retention solid oral dosage form according to any one of the preceding claims, wherein the dosage form floats in the gastric environment of the subject for 6-20 hours.

47. The gastric retention solid oral dosage form according to any one of the preceding claims, wherein when tested using a USPII dissolution apparatus in 500 mL of acidic phosphate buffer at pH 3.0, no more than 40 wt.% of the deuterated butylbenazine is released after 2 hours.

48. The gastric retention solid oral dosage form according to any one of claims 1 to 46, wherein when tested using a USPII dissolution apparatus in 500 mL of acidic phosphate buffer at pH 3.0, no more than 20 wt.% of the deuterated butylbenazine is released after 2 hours.

49. The gastric retention solid oral dosage form according to any one of claims 1 to 46, wherein when tested using a USPII dissolution apparatus in 500 mL of acidic phosphate buffer at pH 3.0, no more than 80 wt.% of the deuterated butylbenazine is released after 8 hours.

50. The gastric retention solid oral dosage form according to any one of claims 1 to 46, wherein when tested using a USPII dissolution apparatus in 500 mL of acidic phosphate buffer at pH 3.0, no more than 60 wt.% of the deuterated butylbenazine is released after 8 hours.

51. Use of the gastric retention solid oral dosage form according to any one of the preceding claims in the treatment of VMAT2-mediated conditions.

52. The use according to claim 51, wherein the gastric retention solid oral dosage form is administered orally to the subject once daily.

53. The use according to claim 51, wherein the VMAT2-mediated condition is hyperactivity disorder.

54. The use according to claim 53, wherein the hyperactivity disorder is chronic hyperactivity disorder.

55. The use according to claim 54, wherein the chronic hyperactivity disorder is selected from chorea associated with Huntington's disease, tardive dyskinesia, and dyskinesia in cerebral palsy.

56. The use according to any one of claims 51 to 55, comprising a single-dose administration of a once-daily gastric retention solid oral dosage form of 6 mg total amount of deuterated butylbenazine providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles comprising a geometric mean AUC of 91,250 to 142,750 h*pico / mL. 0-inf .

57. The use according to any one of claims 51 to 55, comprising a single-dose administration of a once-daily gastric retention solid oral dosage form of 6 mg total amount of deuterated butylbenazine to provide in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles containing a geometric mean C0 of less than 4,600 pg / mL. max .

58. The use according to any one of claims 51 to 55, comprising a single-dose administration of a once-daily gastric retention solid oral dosage form of 12 mg total amount of deuterated butylbenazine to provide in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles comprising a geometric mean AUC of 182,500 to 285,500 hours * picograms / mL. 0-inf .

59. The use according to any one of claims 51 to 55, comprising a single-dose administration of a once-daily gastric retention solid oral dosage form of 12 mg total amount of deuterated butylbenazine to provide in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles containing a geometric mean C0 of less than 9,200 pg / mL. max .

60. The use according to any one of claims 51 to 55, comprising a single-dose administration of a once-daily gastric retention solid oral dosage form of 24 mg total amount of deuterated butylbenazine providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles comprising a geometric mean AUC of 365,000 to 571,000 h*pico / mL. 0-inf .

61. The use according to any one of claims 51 to 55, comprising a single-dose administration of a once-daily gastric retention solid oral dosage form of 24 mg total amount of deuterated butylbenazine to provide in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles containing a geometric mean Cg of less than 18,400 pg / mL. max .

62. The use according to any one of claims 51 to 55, comprising a single-dose administration of a once-daily gastric retention solid oral dosage form of 36 mg total amount of deuterated butylbenazine providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles comprising a geometric mean AUC of 547,500 to 856,500 h*pico / mL. 0-inf .

63. The use according to any one of claims 51 to 55, comprising a single-dose administration of a once-daily gastric retention solid oral dosage form of 36 mg total amount of deuterated butylbenazine to provide in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles containing a geometric mean Cg of less than 27,600 pg / mL. max .

64. The use according to any one of claims 51 to 55, comprising a single-dose administration of a once-daily gastric retention solid oral dosage form of 48 mg total amount of deuterated butylbenazine providing in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles comprising a geometric mean AUC of 730,000 to 1,142,000 h*pico / mL. 0-inf .

65. The use according to any one of claims 51 to 55, comprising a single-dose administration of a once-daily gastric retention solid oral dosage form of 48 mg total amount of deuterated butylbenazine to provide in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles containing a geometric mean Cg of less than 36,800 pg / mL. max .

66. The use according to any one of claims 51 to 55, comprising the administration of a once-daily gastric retention solid oral dosage form of a total amount of 6 mg of deuterated butylbenazine to provide steady-state in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles comprising a mean AUC of 102,500 to 200,000 h*pico / mL. 0-24 .

67. The use according to any one of claims 51 to 55, comprising the administration of a once-daily gastric retention solid oral dosage form of 6 mg of deuterated butylbenazine to provide steady-state in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles containing an average Cg of less than 10,000 pg / mL. max .

68. The use according to any one of claims 51 to 55, comprising the administration of a once-daily gastric retention solid oral dosage form of a total amount of 12 mg of deuterated butylbenazine to provide steady-state in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles comprising a mean AUC of 205,000 to 400,000 h*pico / mL. 0-24 .

69. The use according to any one of claims 51 to 55, comprising the administration of a once-daily gastric retention solid oral dosage form of 12 mg of deuterated butylbenazine to provide steady-state in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles containing an average Cg of less than 20,000 pg / mL. max .

70. The use according to any one of claims 51 to 55, comprising the administration of a once-daily gastric retention solid oral dosage form of a total amount of 24 mg of deuterated butylbenazine to provide steady-state in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles comprising a mean AUC of 410,000 to 800,000 h*pico / mL. 0-24 .

71. The use according to any one of claims 51 to 55, comprising the administration of a once-daily gastric retention solid oral dosage form of a total amount of 24 mg of deuterated butylbenazine, providing steady-state in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles containing an average Cg of less than 40,000 pg / mL. max .

72. The use according to any one of claims 51 to 55, comprising the administration of a once-daily gastric retention solid oral dosage form of a total amount of 36 mg of deuterated butylbenazine to provide steady-state in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles comprising a mean AUC of 615,000 to 1,200,000 hours * picograms / mL. 0-24 .

73. The use according to any one of claims 51 to 55, comprising the administration of a once-daily gastric retention solid oral dosage form of a total amount of 36 mg of deuterated butylbenazine to provide steady-state in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles containing an average Cg of less than 60,000 pg / mL. max .

74. The use according to any one of claims 51 to 55, comprising the administration of a once-daily gastric retention solid oral dosage form of 48 mg of deuterated butylbenazine to provide steady-state in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles comprising a mean AUC of 820,000 to 1,600,000 hours * picograms / mL. 0-24 .

75. The use according to any one of claims 51 to 55, comprising the administration of a once-daily gastric retention solid oral dosage form of 48 mg of deuterated butylbenazine to provide steady-state in vivo plasma profiles of total α- and β-dihydrodeuterated butylbenazine, said in vivo plasma profiles containing an average Cg of less than 80,000 pg / mL. max .

76. The use according to any one of claims 51 to 55, wherein after administration of the gastric retention solid oral dosage form, approximately 50 wt.% of the deuterated butylbenazine is released after 7 hours when tested in vitro using a USPII dissolution apparatus in 500 mL of acidic phosphate buffer at pH 3.

0.

77. The use according to any one of claims 51 to 76, wherein the gastric retention solid oral dosage form is administered with food.

78. The use according to any one of claims 51 to 76, wherein the gastric retention solid oral dosage form is administered independently of food intake.

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