Valbenazine Composition

Abstract

The present application relates to pharmaceutical compositions and solid dosage forms of L-valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester (valbenazine) or a pharma- ceutically acceptable salt thereof, including processes for their preparation, which are useful in the treatment of neurological or psychiatric diseases or disorders (e.g., hyperkinetic movement disorders).

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 273,561, filed October 29, 2021, which is incorporated by reference in its entirety.

[0002] (Field) The present application relates to pharmaceutical compositions and solid dosage forms of L-valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester (valbenazine, or "VBZ"), or a pharma- ceutically acceptable salt thereof, including processes for their preparation, which are useful in the treatment of neurological or psychiatric diseases or disorders (e.g., hyperkinetic movement disorders). [Background technology]

[0003] (background) Dysregulation of the dopaminergic system is essential to several central nervous system (CNS) disorders, including neurological and psychiatric disorders. These neurological and psychiatric disorders include conditions such as hyperkinetic movement disorders, and schizophrenia and mood disorders. The transporter protein vesicular monoamine transporter 2 (VMAT2) plays an important role in presynaptic dopamine release, regulating monoamine uptake from the cytoplasm into synaptic vesicles for storage and release.

[0004] L-valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester (also known as valbenazine) is a selective VMAT2 inhibitor. A formulation of valbenazine:4-methylbenzenesulfonate (1:2) (also known as valbenazine tosylate or valbenazine ditosylate) is available as INGREZZA (登録商標) was previously reported in the FDA approved drug labeling for valbenazine. It is manufactured in size 1 hard gelatin capsules for a 40 mg unit dose when measured as the free base. Valbenazine readily hydrolyzes in the presence of heat and water. Due in part to its stability, attempts to formulate valbenazine have proven difficult, particularly for a formulation suitable for oral administration to patients who experience difficulty in swallowing tablets and capsules (e.g., patients with dysphagia or pediatric patients).

[0005] Many patients experience difficulty in swallowing tablets and capsules. This problem can lead to various adverse events and non-compliance of patients with treatment regimens. Surveys of adults regarding difficulty in swallowing tablets and capsules suggest that this problem may affect as many as 40 percent of Americans. Individuals who find it difficult to swallow tablets and capsules frequently cite their size as the main reason for their difficulty in swallowing.

[0006] Larger tablets and capsules have also been shown to affect the passage of drug products through the pharynx and esophagus. Larger tablets and capsules have been shown to have longer esophageal transit times, which can directly affect a patient's ability to swallow a particular drug product. This can result in the product's disintegration in the esophagus and / or cause damage to the esophagus. The United States Food and Drug Administration ("FDA") has indicated that "size should be considered as part of a single product risk / benefit profile." The FDA further recommends that "the maximum dimension of a tablet or capsule should not exceed 22 mm, and that capsules should not exceed standard 00 size."

[0007] Thus, there is a need for improved pharmaceutical compositions of valbenazine or a pharma- ceutically acceptable salt thereof (e.g., valbenazine ditosylate) suitable for oral administration in the treatment of neurological or psychiatric diseases or disorders. Summary of the Invention [Means for solving the problem]

[0008] (overview) A pharmaceutical dosage form is provided comprising a plurality of granules, each granule comprising: (a) an average diameter of at least 1 mm; (b) at least one pharma- ceutically acceptable carrier; (c) an amount of valbenazine or a pharma- ceutically acceptable salt thereof; and (d) Film Coating Includes.

[0009] Also provided is a unit dosage form comprising the pharmaceutical dosage form described herein, wherein the valbenazine or a pharma- ceutically acceptable salt thereof is present in an amount of about 10 mg to about 200 mg based on the weight of the free base.

[0010] Also provided is a method of administering valbenazine, or a pharma- ceutically acceptable salt thereof, to a patient in need thereof, the method comprising: (a) providing a pharmaceutical dosage form as described herein or a unit dosage form as described herein; (b) sprinkling the plurality of granules onto a soft food product; and (c) orally administering the soft food. Includes.

[0011] Also provided is a method of administering valbenazine or a pharma- ceutically acceptable salt thereof to a patient in need thereof, the method comprising orally administering a pharmaceutical dosage form described herein or a unit dosage form described herein.

[0012] Also provided is a method of administering valbenazine or a pharma- ceutically acceptable salt thereof to a patient in need thereof, the method comprising orally administering a capsule containing a pharmaceutical dosage form described herein or a capsule containing a unit dose described herein.

[0013] Also provided is a method for treating a neurological or psychiatric disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical dosage form as described herein or a unit dosage form as described herein.The present disclosure also provides the pharmaceutical dosage form as disclosed herein for use in therapy.The present disclosure also provides the use of the pharmaceutical dosage form as disclosed herein in the preparation of a medicament for treating a neurological or psychiatric disease or disorder.

[0014] These and other objects of the present disclosure are described in the following paragraphs, which should not be construed as narrowing the scope of the present disclosure. [Brief description of the drawings]

[0015] [Figure 1] FIG. 1 shows the oral dissolution profile of valbenazine ditosylate oral granules.

[0016] [Diagram 2] FIG. 2 shows a comparison of the dissolution profile of the final blended powder and the final blended powder compressed in a tablet press to obtain granules. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] (Detailed Description) The present disclosure relates to a pharmaceutical dosage form of valbenazine or its pharma- ceutically acceptable salt (e.g., valbenazine ditosylate) with improved properties for oral administration. In particular, the pharmaceutical dosage form can be prepared by a process involving high temperature and an aqueous environment, and the pharmaceutical dosage form can be easily administered orally, for example, to dysphagic and pediatric patients, using a vehicle (e.g., soft food). The pharmaceutical dosage form described herein can have a dissolution profile comparable to other dosage forms of valbenazine (e.g., powder-filled capsules), but can have physical properties (e.g., uniform size, weight, and / or hardness) that are better suited for administration by sprinkling on soft food. The pharmaceutical dosage form includes a plurality of granules, each of which includes a water-soluble film coating, which can further improve the organoleptic properties of the spread pharmaceutical composition.

[0018] Known dosage forms of valbenazine include powder-filled capsules. Due to the amount of lubricant in the powder-filled capsule formulation, the powder blended therein may have a tendency to over-lubricate due to shear. Thus, the powder blend filled in the capsule may experience release (dissolution rate) variability if not compressed into a slug by a dosing disk / dosator. Since the product intended for "sprinkle" is removed from the capsule shell of the capsule and disintegrated to facilitate swallowing, the variability resulting from shear impact may not be controlled when the powder is removed from the capsule shell.

[0019] In contrast, the granules described herein are prepared by compressing the final powder blend in an automated tablet press, thereby eliminating shear-related variability. Compression of the disintegrant component results in consistent and rapid dissolution, even in this spread format.

[0020] FIG. 2 shows that the granules described herein have a slower dissolution rate compared to the powder.

[0021] C for valbenazine in the fasting state max was reduced by approximately 28% when sprinkled on applesauce and administered as the granules described herein, compared to a commercially available powder-filled capsule of valbenazine (reference). This finding is consistent with a slightly reduced absorption rate but a similar degree of absorption. Advantageously, there was a slowing of the rate of valbenazine absorption and an associated C max The reduction did not affect the overall pharmacokinetics of valbenazine. Additionally, the oral granules described herein allow sufficient disintegration time to pass through a gastronomy tube without clogging the tube.

[0022] Compositions and Pharmaceutical Dosage Forms Pharmaceutical compositions of valbenazine and pharma- ceutically acceptable salts thereof are provided. The free base form of valbenazine has the formula: [ka] has.

[0023] Valbenazine may also be called [(2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-2,3,4,6,7,11b-hexahydro-1H-benzo[a]quinolizin-2-yl](2S)-2-amino-3-methylbutanoate, (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1a]isoquinolin-2-yl ester, or NBI-98854. Valbenazine may also be referred to as L-valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester. Specific active metabolites / decomposition products of valbenazine are shown below: [ka] .

[0024] Valbenazine ditosylate refers to the 4-methylbenzenesulfonate salt of valbenazine, which is also sold by INGREZZA (登録商標) It is also known as valbenazine tosylate, valbenazine:4-methylbenzenesulfonate (1:2), or L-valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester, 4-methylbenzenesulfonate (1:2).

[0025] A pharmaceutical dosage form is provided comprising a plurality of granules, each granule comprising: (a) at least one pharma- ceutically acceptable carrier; (b) an amount of valbenazine or a pharma- ceutically acceptable salt thereof (e.g., valbenazine ditosylate); and (c) Film Coating Includes.

[0026] A pharmaceutical dosage form is provided comprising a plurality of granules, each granule comprising: (a) an average diameter of at least 1 mm; (b) at least one pharma- ceutically acceptable carrier; and (c) an amount of valbenazine or a pharma- ceutically acceptable salt thereof (e.g., valbenazine ditosylate); Includes.

[0027] A pharmaceutical dosage form is provided comprising a plurality of granules, each granule comprising: (a) an average diameter of at least 1 mm; (b) at least one pharma- ceutically acceptable carrier; (c) an amount of valbenazine or a pharma- ceutically acceptable salt thereof (e.g., valbenazine ditosylate); and (d) Film coating, if necessary Includes.

[0028] A pharmaceutical dosage form is provided comprising a plurality of granules, each granule comprising: (a) an average diameter of at least 1 mm; (b) at least one pharma- ceutically acceptable carrier; (c) an amount of valbenazine or a pharma- ceutically acceptable salt thereof; and (d) Film Coating Includes.

[0029] In some embodiments, each granule comprises a film coating.

[0030] In some embodiments, each granule has an average diameter of about 1.5 mm to about 5 mm. In some embodiments, each granule has an average diameter of about 2 mm to about 3 mm. In some embodiments, each granule has an average diameter of about 2.15 mm to about 2.25 mm. In some embodiments, each granule has an average diameter of about 2.18 mm to about 2.23 mm. In some embodiments, each granule has an average diameter of about 2.19 mm to about 2.21 mm. In some embodiments, each granule has an average diameter of about 2.2 mm. In some embodiments, each granule has an average diameter of about 2 mm.

[0031] In some embodiments, each granule has an average diameter of about 1 mm to about 5 mm. In some embodiments, each granule has an average diameter of about 1 mm to about 4 mm. In some embodiments, each granule has an average diameter of about 1 mm to about 3.5 mm. In some embodiments, each granule has an average diameter of about 1.2 mm to about 5 mm. In some embodiments, each granule has an average diameter of about 1.2 mm to about 4 mm. In some embodiments, each granule has an average diameter of about 1.2 mm to about 3.5 mm.

[0032] In some embodiments, each granule has an average diameter of about 1.2 mm, about 1.4 mm, about 1.6 mm, about 1.8 mm, about 1.9 mm, about 2 mm, about 2.1 mm, about 2.2 mm, about 2.3 mm, about 2.4 mm, about 2.5 mm, about 2.6 mm, about 2.8 mm, or about 3 mm.

[0033] In some embodiments, each granule has a diameter variation of 20% or less from the average diameter. In some embodiments, each granule has a diameter variation of 15% or less, 10% or less, 7.5% or less, or 5% or less from the average diameter. In some embodiments, each granule has a d99 particle size distribution of up to about 2.8 mm. In some embodiments, each granule has a d99 particle size distribution of up to about 2.5 mm. In some embodiments, each granule has a d99 particle size distribution of about 1.2 to about 2.8 mm, about 1.2 mm to about 2.5 mm, about 1.6 mm to about 2.8 mm, about 1.6 mm to about 2.5 mm, about 1.8 mm to about 2.8 mm, or about 1.8 mm to about 2.5 mm.

[0034] In some embodiments, each granule has a density of at least about 0.5 g / cm 3 In some embodiments, each granule has an average density of at least about 0.75 g / cm 3 , at least about 1 g / cm 3 , at least about 1.25 g / cm 3 , or at least about 1.5 g / cm 3 In some embodiments, each granule has an average density of about 0.5 g / cm 3 ~Approx. 2.5g / cm 3In some embodiments, each granule has an average density of about 0.5 g / cm 3 ~About 2g / cm 3 , about 0.75g / cm 3 ~Approx. 2.5g / cm 3 , about 0.75g / cm 3 ~About 2g / cm 3 , about 1g / cm 3 ~Approx. 2.5g / cm 3 , or about 1 g / cm 3 ~About 2g / cm 3 In some embodiments, each granule has an average density of about 1 g / cm 3 , about 1.25g / cm 3 , about 1.5g / cm 3 , about 1.75g / cm 3 , about 2g / cm 3 , or about 2.25 g / cm 3 , or about 2.5 g / cm 3 has an average density of

[0035] In some embodiments, each granule has an average diameter of about 1.2 mm to about 4 mm, an average diameter variation of no more than 10% from the average diameter, and a density of about 0.5 g / cm 3 ~Approx. 2.5g / cm 3 In some embodiments, each granule has an average diameter of about 1.2 mm to about 4 mm, an average diameter variation of no more than 10% from the average diameter, and an average density of about 0.75 g / cm 3 ~Approx. 2.5g / cm 3 In some embodiments, each granule has an average diameter of about 1.2 mm to about 3.5 mm, an average diameter variation of no more than 10% from the average diameter, and an average density of about 0.75 g / cm 3 ~Approx. 2.5g / cm 3 In some embodiments, each granule has an average diameter of about 1.2 mm to about 3.5 mm, an average diameter variation of no more than 10% from the average diameter, and an average density of about 1 g / cm 3 ~About 2g / cm 3 has an average density of

[0036] In some embodiments, each granule has an average diameter of up to about 2.5 mm, a d99 particle size distribution of up to about 2.8 mm, and a particle size distribution of about 0.75 g / cm3 ~Approx. 2.5g / cm 3 In some embodiments, each granule has an average diameter of up to about 2.5 mm, a d99 particle size distribution of up to about 2.8 mm, and an average density of about 1 g / cm 3 ~Approx. 2.5g / cm 3 In some embodiments, each granule has an average diameter of up to about 2.2 mm, a d99 particle size distribution of up to about 2.5 mm, and an average density of about 0.75 g / cm 3 ~About 2g / cm 3 In some embodiments, each granule has an average diameter of up to about 2.2 mm, a d99 particle size distribution of up to about 2.5 mm, and an average density of about 1 g / cm 3 ~About 2g / cm 3 has an average density of

[0037] In some embodiments, each granule has an average hardness of about 0.5 kp to about 3 kp. In some embodiments, each granule has an average hardness of about 0.8 kp to about 2.6 kp. In some embodiments, each granule has an average hardness of about 1 kp to about 2.4 kp. In some embodiments, each granule has an average hardness of about 1.2 kp to about 2 kp. In some embodiments, each granule has an average hardness of about 1.4 kp to about 1.8 kp. In some embodiments, each granule has an average hardness of about 1.5 kp to about 1.7 kp. In some embodiments, each granule has an average hardness of about 1.6 kp.

[0038] In some embodiments, each granule has an average hardness of about 1 kp to about 2.5 kp. In some embodiments, each granule has an average hardness of about 1 kp to about 2 kp, about 1.2 kp to about 2.5 kp, or about 1.2 kp to about 2 kp. In some embodiments, each granule has an average hardness of about 1 kp, about 1.1 kp, about 1.2 kp, about 1.3 kp, about 1.4 kp, about 1.5 kp, about 1.6 kp, about 1.7 kp, about 1.8 kp, about 1.9 kp, or about 2 kp.

[0039] In some embodiments, each granule has an average weight of about 8 mg to about 11 mg. In some embodiments, each granule has an average weight of about 8 mg to about 10.2 mg. In some embodiments, each granule has an average weight of about 8 mg to about 10 mg. In some embodiments, each granule has an average weight of about 8.2 mg to about 10.1 mg. In some embodiments, each granule has an average weight of about 8.3 mg to about 9.9 mg. In some embodiments, each granule has an average weight of about 8.5 mg to about 9.7 mg. In some embodiments, each granule has an average weight of about 8.7 mg to about 9.5 mg. In some embodiments, each granule has an average weight of about 8.9 mg to about 9.3 mg. In some embodiments, each granule has an average weight of about 9 mg to about 9.2 mg. In some embodiments, each granule has an average weight of about 9.1 mg.

[0040] In some embodiments, each granule is stable to a film-coating process. In some embodiments, each granule is stable to a film-coating process at high temperatures (e.g., above 40°C) in the presence of water. Each granule is stable to a film-coating process that can undergo a film-coating process at high temperatures in the presence of water without significant degradation (e.g., by hydrolysis) of valbenazine or its pharma- ceutically acceptable salt. In some embodiments, less than about 10% by weight, less than about 7.5% by weight, less than about 5% by weight, less than about 2.5% by weight, or less than about 1% by weight of valbenazine or its pharma-ceutically acceptable salt is degraded by the film-coating process. Film-coating processes for which each granule is stable include, for example, the Wurster technique, which can include the use of high temperatures (e.g., above 40°C) in the presence of water.

[0041] In some embodiments, each granule comprises a film coating. The film coating described herein may comprise a film-forming polymer. In some embodiments, the film coating comprises a film-forming polymer. As used herein, the term "film-forming polymer" refers to a polymer that can be applied to the surface of each granule described herein (e.g., as a component of a film coating) using an aqueous coating technique (e.g., Wurster coating) to provide a pharma- ceutically acceptable film coating on each granule. Exemplary film-forming polymers include, but are not limited to, hydroxypropylmethylcellulose (also called hypromellose), sodium carboxymethylcellulose, poly(vinyl alcohol), and methacrylic acid copolymers. In some embodiments, the film-forming polymer is poly(vinyl alcohol).

[0042] In some embodiments, the film coating comprises a film-forming polymer, and the film-forming polymer is about 25% to about 55% by weight of the film coating. In some embodiments, the film coating comprises a film-forming polymer, and the film-forming polymer is about 25% to about 45% by weight of the film coating. In some embodiments, the film coating comprises a film-forming polymer, and the film-forming polymer is about 35% to about 55% by weight of the film coating. In some embodiments, the film coating comprises a film-forming polymer, and the film-forming polymer is about 35% to about 45% by weight of the film coating. In some embodiments, the film coating comprises a film-forming polymer, and the film-forming polymer is about 30%, about 35%, about 40%, about 45%, or about 50% by weight of the film coating. In some embodiments, the film-forming polymer is poly(vinyl alcohol).

[0043] In some embodiments, the film coating includes a plasticizer. As used herein, the term "plasticizer" refers to a compound that can be added to the film coating to reduce the glass transition temperature and minimum film-forming temperature of the film-forming polymer. Exemplary plasticizers include, but are not limited to, polyethylene glycol, glycerin, triethyl citrate, and diethyl phthalate. In some embodiments, the plasticizer is polyethylene glycol, glycerin, or a mixture thereof. In some embodiments, the plasticizer is polyethylene glycol. In some embodiments, the plasticizer is polyethylene glycol (e.g., having a molecular weight of about 1,000 g / mol to about 4,000 g / mol).

[0044] In some embodiments, the film coating comprises a plasticizer, and the plasticizer is about 5% to about 30% by weight of the film coating. In some embodiments, the film coating comprises a plasticizer, and the plasticizer is about 5% to about 25% by weight, about 10% to about 30% by weight, or about 10% to about 25% by weight of the film coating. In some embodiments, the film coating comprises a plasticizer, and the plasticizer is about 10%, about 15%, about 20%, or about 25% by weight of the film coating. In some embodiments, the plasticizer is polyethylene glycol.

[0045] The film coating may further include a filler. In some embodiments, the film coating includes a filler. As used herein, the term "filler" refers to a compound that can be added to the film coating to reduce the amount of other ingredients in the composition. Certain fillers can improve the flowability of the film coating. Exemplary fillers include, but are not limited to, talc, fumed silica, bentonite, and edible hydrogenated vegetable oil. In some embodiments, the filler is talc.

[0046] In some embodiments, the film coating comprises a filler, the filler being about 5% to about 45% by weight of the film coating. In some embodiments, the film coating comprises a filler, the filler being about 5% to about 20% by weight, about 10% to about 45% by weight, or about 10% to about 20% by weight of the film coating. In some embodiments, the film coating comprises a filler, the filler being about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40% by weight of the film coating. In some embodiments, the filler is talc.

[0047] The film coating may further comprise a pigment / opacifier. In some embodiments, the film coating comprises a pigment / opacifier. As used herein, the term "pigment / opacifier" refers to a compound that can be added to the film coating to increase opacity and / or provide color to the coating formed from the film coating. Exemplary pigment / opacifiers include, but are not limited to, aluminum flake, iron oxide, titanium dioxide, and natural pigments. In some embodiments, the pigment / opacifier is titanium dioxide.

[0048] In some embodiments, the film coating comprises a pigment / opacifier, the pigment / opacifier being up to about 40% by weight of the film coating. In some embodiments, the film coating comprises a pigment / opacifier, the pigment / opacifier being about 5% to about 40%, about 10% to about 40%, 20% to about 40%, or about 20% to about 30% by weight of the film coating. In some embodiments, the film coating comprises a pigment / opacifier, the pigment / opacifier being about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, or about 35% by weight of the film coating. In some embodiments, the pigment / opacifier is titanium dioxide.

[0049] In some embodiments, based on the weight of the film coating, the film coating comprises: (a) about 25% to about 55% by weight of a film-forming polymer; (b) about 5% to about 30% by weight of a plasticizer; (c) about 5% to about 45% by weight of a filler; and (d) up to about 40% by weight of a pigment / opacifier. In some embodiments, based on the weight of the film coating, the film coating comprises: (a) about 25% to about 55% by weight of a poly(vinyl alcohol); (b) about 5% to about 30% by weight of a polyethylene glycol; (c) about 5% to about 45% by weight of a talc; and (d) up to about 40% by weight of a titanium dioxide.

[0050] In some embodiments, the film coating comprises a pH independent water soluble polymeric film coating system, which comprises a polymer, a plasticizer, and optionally a pigment (e.g., OPADRY®). (登録商標) II). In some embodiments, the film coating comprises OPADRY (登録商標) In some embodiments, the film coating consists essentially of OPADRY II. (登録商標) II.

[0051] In some embodiments, the film coating comprises about 3.5% to about 15% by weight of each granule. In some embodiments, the film coating comprises about 3.5% to about 12.5%, about 5% to about 15%, or about 5% to about 12.5% ​​by weight of each granule. In some embodiments, the film coating comprises about 5%, about 7.5%, about 10%, or about 12.5% ​​by weight of each granule.

[0052] In some embodiments, the at least one pharma- ceutically acceptable carrier comprises a diluent. As used herein, the term "diluent" refers to a compound that can dilute a composition. A diluent may also be called a filler, dilutant, or thinner. Exemplary diluents include lactose, lactose monohydrate, spray-dried monohydrate lactose, lactose-316 Fast Flow ... (登録商標) , mannitol, isomalt, sucrose, dextrose, sorbitol, microcrystalline cellulose, silicified microcrystalline cellulose, acidified cellulose, starch 1500, prosolve MCC, colloidal silica, dicalcium phosphate dihydrate, and calcium carbonate, or any combination thereof.

[0053] In some embodiments, the diluent is silicified microcrystalline cellulose, isomalt, or a mixture thereof. In some embodiments, the diluent is a mixture of silicified microcrystalline cellulose and isomalt.

[0054] In some embodiments, each granule comprises about 25% to about 65% by weight of diluent. In some embodiments, each granule comprises about 30% to about 60% by weight of diluent. In some embodiments, each granule comprises about 35% to about 55% by weight of diluent. In some embodiments, each granule comprises about 40% to about 50% by weight of diluent. In some embodiments, each granule comprises about 45% by weight of diluent (e.g., a mixture of silicified microcrystalline cellulose and isomalt).

[0055] In some embodiments, each granule comprises about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 60% by weight of diluent (e.g., a mixture of silicified microcrystalline cellulose and isomalt).

[0056] In some embodiments, each granule contains a mixture of about 15% to about 40% by weight of silicified microcrystalline cellulose and about 10% to about 35% by weight of isomalt as a diluent. In some embodiments, each granule contains a mixture of about 20% to about 35% by weight of silicified microcrystalline cellulose and about 10% to about 35% by weight of isomalt as a diluent. In some embodiments, each granule contains a mixture of about 20% to about 30% by weight of silicified microcrystalline cellulose and about 10% to about 35% by weight of isomalt as a diluent.

[0057] In some embodiments, each granule contains a mixture of about 15% to about 40% by weight of silicified microcrystalline cellulose and about 15% to about 30% by weight of isomalt as a diluent. In some embodiments, each granule contains a mixture of about 20% to about 35% by weight of silicified microcrystalline cellulose and about 15% to about 30% by weight of isomalt as a diluent. In some embodiments, each granule contains a mixture of about 20% to about 30% by weight of silicified microcrystalline cellulose and about 15% to about 30% by weight of isomalt as a diluent.

[0058] In some embodiments, each granule contains a mixture of about 15% to about 40% by weight of silicified microcrystalline cellulose and about 15% to about 25% by weight of isomalt as a diluent. In some embodiments, each granule contains a mixture of about 20% to about 35% by weight of silicified microcrystalline cellulose and about 15% to about 25% by weight of isomalt as a diluent. In some embodiments, each granule contains a mixture of about 20% to about 30% by weight of silicified microcrystalline cellulose and about 15% to about 25% by weight of isomalt as a diluent.

[0059] In some embodiments, the at least one pharma- ceutically acceptable carrier comprises a disintegrant. As used herein, the term "disintegrant" refers to a compound that can cause the composition to disintegrate and release its drug substance (e.g., when contacted with moisture). Disintegrants, for example, facilitate the disintegration of the dosage form after oral administration. Exemplary disintegrants include, but are not limited to, croscarmellose sodium, crospovidone, starch (e.g., partially pregelatinized maize starch), cellulose, low-substituted hydroxypropyl cellulose, alginic acid, sodium starch glycolate, and acid-carbonate effervescent systems. In some embodiments, the disintegrant is partially pregelatinized maize starch.

[0060] In some embodiments, each granule comprises about 2% to about 12% by weight of disintegrant. In some embodiments, each granule comprises about 5% to about 10% by weight of disintegrant. In some embodiments, each granule comprises about 6% to about 9% by weight of disintegrant. In some embodiments, each granule comprises about 7% to about 8% by weight of disintegrant. In some embodiments, each granule comprises about 7.5% by weight of disintegrant. In some embodiments, each granule comprises about 0.5% to about 15% by weight, about 0.5% to about 12.5% ​​by weight, about 2.5% to about 15% by weight, or about 2.5% to about 12.5% ​​by weight of disintegrant (e.g., partially pregelatinized maize starch). In some embodiments, each granule comprises about 1.5%, about 2.5%, about 5%, about 7%, about 7.5%, about 8%, about 10%, or about 12.5% ​​by weight of a disintegrant (e.g., partially pregelatinized maize starch).

[0061] In some embodiments, the pharmaceutical dosage form comprises about 0.5% to about 15%, about 0.5% to about 12.5%, about 2.5% to about 15%, or about 2.5% to about 12.5% ​​by weight of a disintegrant (e.g., partially pregelatinized maize starch). In some embodiments, the pharmaceutical dosage form comprises about 1.5%, about 2.5%, about 5%, about 7%, about 7.5%, about 8%, about 10%, or about 12.5% ​​by weight of a disintegrant (e.g., partially pregelatinized maize starch).

[0062] In some embodiments, the at least one pharma- ceutically acceptable carrier comprises a binder.As used herein, the term "binder" refers to a compound that can cause the composition to hold together.Exemplary binders include, but are not limited to, hydroxypropylmethylcellulose (also called hypromellose), polyvinylpyrrolidone, natural gum (e.g., acacia gum), microcrystalline cellulose, methylcellulose, ethylcellulose, sucrose, starch, and gelatin.In some embodiments, the binder is hydroxypropylmethylcellulose.

[0063] In some embodiments, each granule comprises about 0.5% to about 10% by weight of binder. In some embodiments, each granule comprises about 2% to about 8% by weight of binder. In some embodiments, each granule comprises about 3% to about 7% by weight of binder. In some embodiments, each granule comprises about 4% to about 6% by weight of binder. In some embodiments, each granule comprises about 4.5% to about 5.5% by weight of binder. In some embodiments, each granule comprises about 5% by weight of binder. In some embodiments, each granule comprises about 0.5% to about 10% by weight, about 0.5% to about 7.5% by weight, about 2.5% to about 10% by weight, or about 2.5% to about 7.5% by weight of binder (e.g., hydroxypropyl methylcellulose). In some embodiments, each granule comprises about 1.5%, about 2.5%, about 4%, about 5%, about 6%, or about 7.5% by weight of a binder (eg, hydroxypropyl methylcellulose).

[0064] In some embodiments, the pharmaceutical dosage form comprises about 0.5% to about 10%, about 0.5% to about 7.5%, about 2.5% to about 10%, or about 2.5% to about 7.5% by weight of a binder (e.g., hydroxypropyl methylcellulose). In some embodiments, the pharmaceutical dosage form comprises about 1.5%, about 2.5%, about 4%, about 5%, about 6%, or about 7.5% by weight of a binder (e.g., hydroxypropyl methylcellulose).

[0065] In some embodiments, the at least one pharma- ceutically acceptable carrier comprises a lubricant.As used herein, the term "lubricant" refers to a compound (e.g., an organic compound) that can reduce the friction between materials in a composition.Exemplary lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid (stearin), talc, starch, fumed silica, hydrogenated oil, polyethylene glycol, sodium stearyl fumarate, and glyceryl behenate.In some embodiments, the lubricant is magnesium stearate.

[0066] In some embodiments, each granule contains about 0.5% to about 5% by weight of lubricant. In some embodiments, each granule contains about 1% to about 3% by weight of lubricant. In some embodiments, each granule contains about 2% to about 2.8% by weight of lubricant. In some embodiments, each granule contains about 2.2% to about 2.6% by weight of lubricant. In some embodiments, each granule contains about 2.3% to about 2.5% by weight of lubricant. In some embodiments, each granule contains about 2.4% to about 2.4% by weight of lubricant. In some embodiments, each granule contains about 2.5% by weight of lubricant.

[0067] In some embodiments, each granule comprises about 0.5% to about 5% by weight, about 0.5% to about 4% by weight, about 1% to about 5% by weight, or about 1% to about 4% by weight of a lubricant (e.g., magnesium stearate). In some embodiments, each granule comprises about 1% by weight, about 2% by weight, about 3% by weight, or about 4% by weight of a lubricant (e.g., magnesium stearate). In some embodiments, the pharmaceutical dosage form comprises about 0.5% by weight to about 5% by weight, about 0.5% by weight to about 4% by weight, about 1% by weight to about 5% by weight, or about 1% by weight to about 4% by weight of a lubricant (e.g., magnesium stearate). In some embodiments, the pharmaceutical dosage form comprises about 1% by weight, about 2% by weight, about 3% by weight, or about 4% by weight of a lubricant (e.g., magnesium stearate).

[0068] In some embodiments, each granule comprises about 5% to about 40% by weight of valbenazine or a pharma- ceutically acceptable salt thereof (e.g., valbenazine ditosylate) based on the weight of the free base. In some embodiments, each granule comprises about 10% to about 40% by weight of valbenazine or a pharma- ceutically acceptable salt thereof based on the weight of the free base. In some embodiments, each granule comprises about 15% to about 30% by weight of valbenazine or a pharma- ceutically acceptable salt thereof based on the weight of the free base. In some embodiments, each granule comprises about 19% to about 25% by weight of valbenazine or a pharma- ceutically acceptable salt thereof based on the weight of the free base. In some embodiments, each granule comprises about 20% to about 24% by weight of valbenazine or a pharma- ceutically acceptable salt thereof based on the weight of the free base. In some embodiments, each granule comprises about 21% to about 23% by weight of valbenazine or a pharma- ceutically acceptable salt thereof based on the weight of the free base. In some embodiments, each granule contains about 21.5% to about 22.5% by weight of valbenazine or a pharma- ceutically acceptable salt thereof based on the weight of the free base. In some embodiments, each granule contains about 21.9% to about 22.1% by weight of valbenazine or a pharma- ceutically acceptable salt thereof based on the weight of the free base. In some embodiments, each granule contains about 22% by weight of valbenazine or a pharma- ceutically acceptable salt thereof based on the weight of the free base.

[0069] In some embodiments, each granule contains about 5% to about 40% by weight of valbenazine or a pharma- ceutically acceptable salt thereof (e.g., valbenazine ditosylate) based on the weight of the free base. In some embodiments, each granule contains about 5% to about 35% by weight, about 5% to about 30% by weight, about 10% to about 40% by weight, about 10% to about 35% by weight, about 10% to about 30% by weight, about 15% to about 40% by weight, about 15% to about 35% by weight, or about 15% to about 30% by weight of valbenazine or a pharma- ceutically acceptable salt thereof (e.g., valbenazine ditosylate) based on the weight of the free base. In some embodiments, each granule contains about 10%, about 15%, about 20%, about 25%, about 30%, or about 35% by weight of valbenazine or a pharma- ceutically acceptable salt thereof (e.g., valbenazine ditosylate) based on the weight of the free base.

[0070] In some embodiments, each granule contains about 20% to about 50% by weight of valbenazine ditosylate. In some embodiments, each granule contains about 10% to about 60% by weight, about 25% to about 60% by weight, about 25% to about 50% by weight, about 10% to about 40% by weight, about 25% to about 35% by weight, or about 35% to about 55% by weight of valbenazine ditosylate. In some embodiments, each granule contains about 30% by weight, about 32% by weight, about 35% by weight, or about 40% by weight of valbenazine ditosylate.

[0071] In some embodiments, the pharmaceutical dosage form comprises about 5% to about 40% by weight of valbenazine or a pharma- ceutically acceptable salt thereof (e.g., valbenazine ditosylate) based on the weight of the free base. In some embodiments, the pharmaceutical dosage form comprises about 5% to about 35% by weight, about 5% to about 30% by weight, about 10% to about 40% by weight, about 10% to about 35% by weight, about 10% to about 30% by weight, about 15% to about 40% by weight, about 15% to about 35% by weight, or about 15% to about 30% by weight of valbenazine or a pharma- ceutically acceptable salt thereof (e.g., valbenazine ditosylate) based on the weight of the free base. In some embodiments, the pharmaceutical dosage form contains about 10%, about 15%, about 20%, about 25%, about 30%, or about 35% by weight of valbenazine or a pharma- ceutically acceptable salt thereof (e.g., valbenazine ditosylate) based on the weight of the free base.

[0072] In some embodiments, the pharmaceutical dosage form comprises about 20% to about 50% by weight of valbenazine ditosylate. In some embodiments, the pharmaceutical dosage form comprises about 10% to about 60% by weight, about 25% to about 60% by weight, about 25% to about 50% by weight, about 10% to about 40% by weight, about 25% to about 35% by weight, or about 35% to about 55% by weight of valbenazine ditosylate. In some embodiments, the pharmaceutical dosage form comprises about 30% by weight, about 32% by weight, about 35% by weight, or about 40% by weight of valbenazine ditosylate.

[0073] In some embodiments, the valbenazine or a pharma- ceutically acceptable salt thereof is valbenazine ditosylate.

[0074] In some embodiments, each granule contains (a) about 5% to about 40% by weight of valbenazine or a pharma- ceutically acceptable salt thereof, based on the weight of the free base; (b) about 25% to about 65% by weight of a diluent; (c) about 0.5% to about 15% by weight of a disintegrant; (d) about 0.5% to about 10% by weight of a binder; and (e) about 0.5% to about 5% by weight of a lubricant.

[0075] In some embodiments, each granule contains (a) about 30% to about 50% by weight of valbenazine ditosylate; (b) about 25% to about 65% by weight of a diluent; (c) about 0.5% to about 15% by weight of a disintegrant; (d) about 0.5% to about 10% by weight of a binder; and (e) about 0.5% to about 5% by weight of a lubricant.

[0076] In some embodiments, each granule contains (a) about 30% to about 50% by weight of valbenazine ditosylate; (b) about 15% to about 35% by weight of silicified microcrystalline cellulose; (c) about 10% to about 30% by weight of isomalt; (d) about 0.5% to about 15% by weight of partially pregelatinized maize starch; (e) about 0.5% to about 10% by weight of hydroxypropyl methylcellulose; and (f) about 0.5% to about 5% by weight of magnesium stearate.

[0077] In some embodiments, each granule comprises: (a) about 5% to about 40% by weight of valbenazine or a pharma- ceutically acceptable salt thereof, based on the weight of the free base; (b) about 25% to about 65% by weight of a diluent; (c) about 0.5% to about 15% by weight of a disintegrant; (d) about 0.5% to about 10% by weight of a binder; (e) about 0.5% to about 5% by weight of a lubricant; and (f) about 3.5% to about 15% by weight of a film coating.

[0078] In some embodiments, each granule comprises: (a) about 30% to about 50% by weight of valbenazine ditosylate; (b) about 25% to about 65% by weight of a diluent; (c) about 0.5% to about 15% by weight of a disintegrant; (d) about 0.5% to about 10% by weight of a binder; (d) about 0.5% to about 5% by weight of a lubricant; and (e) about 3.5% to about 15% by weight of a film coating comprising a film-forming polymer; a plasticizer; and a filler.

[0079] In some embodiments, each granule comprises: (a) about 30% to about 50% by weight of valbenazine ditosylate; (b) about 15% to about 35% by weight of silicified microcrystalline cellulose; (c) about 10% to about 30% by weight of isomalt; (d) about 0.5% to about 15% by weight of partially pregelatinized maize starch; (e) about 0.5% to about 10% by weight of hydroxypropyl methylcellulose; and (f) about 0.5% to about 5% by weight of magnesium stearate; and (g) about 3.5% to about 15% by weight of a film coating comprising poly(vinyl alcohol); polyethylene glycol; and talc.

[0080] In some embodiments, each granule comprises: (a) about 33% to about 40% by weight of valbenazine ditosylate; (b) about 20% to about 25% by weight of silicified microcrystalline cellulose; (c) about 16% to about 20% by weight of isomalt; (d) about 6% to about 8% by weight of partially pregelatinized maize starch; (e) about 4% to about 5% by weight of hydroxypropyl methylcellulose; (f) about 2% to about 2.5% by weight of magnesium stearate; and (g) about 8% to about 11% by weight of a film coating.

[0081] In some embodiments, each granule comprises: (a) about 33% to about 40% by weight of valbenazine ditosylate; (b) about 20% to about 25% by weight of silicified microcrystalline cellulose; (c) about 16% to about 20% by weight of isomalt; (d) about 6% to about 8% by weight of partially pregelatinized maize starch; (e) about 4% to about 5% by weight of hydroxypropyl methylcellulose; (f) about 2% to about 2.5% by weight of magnesium stearate; and (e) about 8% to about 11% by weight of a film coating comprising polyvinyl alcohol, polyethylene glycol, talc, and titanium dioxide.

[0082] In some embodiments, each granule contains: (a) about 33% to about 40% by weight of valbenazine ditosylate; (b) about 20% to about 25% by weight of silicified microcrystalline cellulose; (c) about 16% to about 20% by weight of isomalt; (d) about 6% to about 8% by weight of partially pregelatinized maize starch; (e) about 4% to about 5% by weight of hydroxypropyl methylcellulose; (f) about 2% to about 2.5% by weight of magnesium stearate; and (g) about 8% to about 11% by weight of OPADRY® II.

[0083] In some embodiments, each granule comprises: (a) about 34.5% to about 38.2% by weight of valbenazine ditosylate; (b) about 22.6% to about 24% by weight of silicified microcrystalline cellulose; (c) about 17.3% to about 19.2% by weight of isomalt; (d) about 6.5% to about 7.2% by weight of partially pregelatinized maize starch; (e) about 4.4% to about 5% by weight of hydroxypropyl methylcellulose; (f) about 2% to about 2.3% by weight of magnesium stearate; and (g) about 8.2% to about 10.5% by weight of a film coating.

[0084] In some embodiments, each granule comprises: (a) about 34.5% to about 38.2% by weight of valbenazine ditosylate; (b) about 22.6% to about 24% by weight of silicified microcrystalline cellulose; (c) about 17.3% to about 19.2% by weight of isomalt; (d) about 6.5% to about 7.2% by weight of partially pregelatinized maize starch; (e) about 4.4% to about 5% by weight of hydroxypropyl methylcellulose; (f) about 2% to about 2.3% by weight of magnesium stearate; and (g) about 8.2% to about 10.5% by weight of a film coating, the film coating comprising polyvinyl alcohol, polyethylene glycol, talc, and titanium dioxide.

[0085] In some embodiments, each granule contains: (a) about 34.5% to about 38.2% by weight of valbenazine ditosylate; (b) about 22.6% to about 24% by weight of silicified microcrystalline cellulose; (c) about 17.3% to about 19.2% by weight of isomalt; (d) about 6.5% to about 7.2% by weight of partially pregelatinized maize starch; (e) about 4.4% to about 5% by weight of hydroxypropyl methylcellulose; (f) about 2% to about 2.3% by weight of magnesium stearate; and (g) about 8.2% to about 10.5% by weight of OPADRY® II.

[0086] In some embodiments, the pharmaceutical dosage form comprises: (a) about 5% to about 40% by weight of valbenazine or a pharma- ceutically acceptable salt thereof, based on the weight of the free base; (b) about 25% to about 65% by weight of a diluent; (c) about 0.5% to about 15% by weight of a disintegrant; (d) about 0.5% to about 10% by weight of a binder; and (e) about 0.5% to about 5% by weight of a lubricant.

[0087] In some embodiments, the pharmaceutical dosage form comprises: (a) about 30% to about 50% by weight of valbenazine ditosylate; (b) about 25% to about 65% by weight of a diluent; (c) about 0.5% to about 15% by weight of a disintegrant; (d) about 0.5% to about 10% by weight of a binder; and (e) about 0.5% to about 5% by weight of a lubricant.

[0088] In some embodiments, the pharmaceutical dosage form comprises: (a) about 30% to about 50% by weight of valbenazine ditosylate; (b) about 15% to about 35% by weight of silicified microcrystalline cellulose; (c) about 10% to about 30% by weight of isomalt; (d) about 0.5% to about 15% by weight of partially pregelatinized maize starch; (e) about 0.5% to about 10% by weight of hydroxypropyl methylcellulose; and (f) about 0.5% to about 5% by weight of magnesium stearate.

[0089] In some embodiments, the pharmaceutical dosage form comprises: (a) about 5% to about 40% by weight of valbenazine or a pharma- ceutically acceptable salt thereof, based on the weight of the free base; (b) about 25% to about 65% by weight of a diluent; (c) about 0.5% to about 15% by weight of a disintegrant; (d) about 0.5% to about 10% by weight of a binder; (e) about 0.5% to about 5% by weight of a lubricant; and (f) about 3.5% to about 15% by weight of a film coating.

[0090] In some embodiments, the pharmaceutical dosage form comprises: (a) about 30% to about 50% by weight of valbenazine ditosylate; (b) about 25% to about 65% by weight of a diluent; (c) about 0.5% to about 15% by weight of a disintegrant; (d) about 0.5% to about 10% by weight of a binder; (d) about 0.5% to about 5% by weight of a lubricant; and (e) about 3.5% to about 15% by weight of a film coating comprising a film-forming polymer; a plasticizer; and a filler.

[0091] In some embodiments, the pharmaceutical dosage form comprises: (a) about 30% to about 50% by weight of valbenazine ditosylate; (b) about 15% to about 35% by weight of silicified microcrystalline cellulose; (c) about 10% to about 30% by weight of isomalt; (d) about 0.5% to about 15% by weight of partially pregelatinized maize starch; (e) about 0.5% to about 10% by weight of hydroxypropyl methylcellulose; and (f) about 0.5% to about 5% by weight of magnesium stearate; and (g) about 3.5% to about 15% by weight of a film coating comprising poly(vinyl alcohol); polyethylene glycol; and talc.

[0092] In some embodiments, the pharmaceutical dosage form comprises: (a) about 33% to about 40% by weight of valbenazine ditosylate; (b) about 20% to about 25% by weight of silicified microcrystalline cellulose; (c) about 16% to about 20% by weight of isomalt; (d) about 6% to about 8% by weight of partially pregelatinized maize starch; (e) about 4% to about 5% by weight of hydroxypropyl methylcellulose; (f) about 2% to about 2.5% by weight of magnesium stearate; and (g) about 8% to about 11% by weight of a film coating.

[0093] In some embodiments, the pharmaceutical dosage form comprises: (a) about 33% to about 40% by weight of valbenazine ditosylate; (b) about 20% to about 25% by weight of silicified microcrystalline cellulose; (c) about 16% to about 20% by weight of isomalt; (d) about 6% to about 8% by weight of partially pregelatinized maize starch; (e) about 4% to about 5% by weight of hydroxypropyl methylcellulose; (f) about 2% to about 2.5% by weight of magnesium stearate; and (e) about 8% to about 11% by weight of a film coating, the film coating comprising polyvinyl alcohol, polyethylene glycol, talc, and titanium dioxide.

[0094] In some embodiments, the pharmaceutical dosage form comprises: (a) about 33% to about 40% by weight of valbenazine ditosylate; (b) about 20% to about 25% by weight of silicified microcrystalline cellulose; (c) about 16% to about 20% by weight of isomalt; (d) about 6% to about 8% by weight of partially pregelatinized maize starch; (e) about 4% to about 5% by weight of hydroxypropyl methylcellulose; (f) about 2% to about 2.5% by weight of magnesium stearate; and (g) about 8% to about 11% by weight of OPADRY® II.

[0095] In some embodiments, the pharmaceutical dosage form comprises: (a) about 34.5% to about 38.2% by weight of valbenazine ditosylate; (b) about 22.6% to about 24% by weight of silicified microcrystalline cellulose; (c) about 17.3% to about 19.2% by weight of isomalt; (d) about 6.5% to about 7.2% by weight of partially pregelatinized maize starch; (e) about 4.4% to about 5% by weight of hydroxypropyl methylcellulose; (f) about 2% to about 2.3% by weight of magnesium stearate; and (g) about 8.2% to about 10.5% by weight of a film coating.

[0096] In some embodiments, the pharmaceutical dosage form comprises: (a) about 34.5% to about 38.2% by weight of valbenazine ditosylate; (b) about 22.6% to about 24% by weight of silicified microcrystalline cellulose; (c) about 17.3% to about 19.2% by weight of isomalt; (d) about 6.5% to about 7.2% by weight of partially pregelatinized maize starch; (e) about 4.4% to about 5% by weight of hydroxypropyl methylcellulose; (f) about 2% to about 2.3% by weight of magnesium stearate; and (g) about 8.2% to about 10.5% by weight of a film coating, the film coating comprising polyvinyl alcohol, polyethylene glycol, talc, and titanium dioxide.

[0097] In some embodiments, the pharmaceutical dosage form comprises: (a) about 34.5% to about 38.2% by weight of valbenazine ditosylate; (b) about 22.6% to about 24% by weight of silicified microcrystalline cellulose; (c) about 17.3% to about 19.2% by weight of isomalt; (d) about 6.5% to about 7.2% by weight of partially pregelatinized maize starch; (e) about 4.4% to about 5% by weight of hydroxypropyl methylcellulose; (f) about 2% to about 2.3% by weight of magnesium stearate; and (g) about 8.2% to about 10.5% by weight of OPADRY® II.

[0098] In some embodiments, each granule contains an average amount of valbenazine or a pharma- ceutically acceptable salt thereof of about 1.5 mg to about 2.5 mg based on the weight of the free base. In some embodiments, each granule contains an average amount of valbenazine or a pharma- ceutically acceptable salt thereof of about 1.8 mg to about 2.2 mg based on the weight of the free base. In some embodiments, each granule contains an average amount of valbenazine or a pharma- ceutically acceptable salt thereof of about 1.85 mg to about 2.15 mg based on the weight of the free base. In some embodiments, each granule contains an average amount of valbenazine or a pharma- ceutically acceptable salt thereof of about 1.9 mg to about 2.1 mg based on the weight of the free base. In some embodiments, each granule contains an average amount of valbenazine or a pharma- ceutically acceptable salt thereof of about 1.95 mg to about 2.05 mg based on the weight of the free base. In some embodiments, each granule contains an average amount of valbenazine or a pharma- ceutically acceptable salt thereof of about 2 mg based on the weight of the free base.

[0099] In some embodiments, each granule contains an average amount of about 3 mg to about 4.5 mg of valbenazine ditosylate. In some embodiments, each granule contains an average amount of about 3.4 mg to about 4 mg of valbenazine ditosylate. In some embodiments, each granule contains an average amount of about 3.5 mg to about 3.9 mg of valbenazine ditosylate. In some embodiments, each granule contains an average amount of about 3.6 mg to about 3.8 mg of valbenazine ditosylate. In some embodiments, each granule contains an average amount of about 3.7 mg of valbenazine ditosylate.

[0100] In some embodiments, the pharmaceutical dosage form is a capsule. In some embodiments, the capsule is size 00 or smaller. In some embodiments, the capsule is size 00. In some embodiments, the capsule is size 0 or smaller. In some embodiments, the capsule is size 0. In some embodiments, the capsule is size 1 or smaller. In some embodiments, the capsule is size 1. In some embodiments, the capsule is size 2. In some embodiments, the capsule is size 2 or smaller. In some embodiments, the capsule is a sprinkle capsule. As used herein, "capsule size" refers to the internationally accepted numbering system for capsule sizes used in U.S. approved drugs.

[0101] Also provided herein is a unit dosage form comprising the pharmaceutical dosage form described herein, wherein the valbenazine or a pharma- ceutically acceptable salt thereof is present in an amount of about 10 mg to about 200 mg based on the weight of the free base. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of an active agent calculated to produce a desired therapeutic effect, together with a suitable pharmaceutical carrier. In some embodiments, the valbenazine or a pharma- ceutically acceptable salt thereof in the unit dosage form is present in an amount of about 20 mg to about 100 mg based on the weight of the free base. In some embodiments, the valbenazine or a pharma- ceutically acceptable salt thereof in the unit dosage form is present in an amount of about 20 mg to about 80 mg based on the weight of the free base. In some embodiments, the valbenazine or a pharma- ceutically acceptable salt thereof in the unit dosage form is present in an amount of about 10 mg based on the weight of the free base. In some embodiments, the valbenazine or its pharmaceutically acceptable salt in the unit dosage form is present in an amount of about 20 mg based on the weight of the free base. In some embodiments, the valbenazine or its pharmaceutically acceptable salt in the unit dosage form is present in an amount of about 40 mg based on the weight of the free base. In some embodiments, the valbenazine or its pharmaceutically acceptable salt in the unit dosage form is present in an amount of about 60 mg based on the weight of the free base. In some embodiments, the valbenazine or its pharmaceutically acceptable salt in the unit dosage form is present in an amount of about 80 mg based on the weight of the free base. In some embodiments, the valbenazine or its pharmaceutically acceptable salt in the unit dosage form is present in an amount of about 100 mg based on the weight of the free base.

[0102] In some embodiments, the valbenazine or pharma- ceutically acceptable salt thereof in the unit dosage form is present in an amount of about 20 mg to about 200 mg, about 20 mg to about 160 mg, about 40 mg to about 200 mg, about 40 mg to about 160 mg, about 60 mg to about 200 mg, or about 60 mg to about 160 mg, based on the weight of the free base. In some embodiments, the valbenazine or pharma- ceutically acceptable salt thereof in the unit dosage form is present in an amount of about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, or about 160 mg, based on the weight of the free base.

[0103] In some embodiments, the unit dosage form is a capsule. In some embodiments, the capsule is size 00 or smaller. In some embodiments, the capsule is size 00. In some embodiments, the capsule is size 0 or smaller. In some embodiments, the capsule is size 0. In some embodiments, the capsule is size 1 or smaller. In some embodiments, the capsule is size 1. In some embodiments, the capsule is size 2 or smaller. In some embodiments, the capsule is size 2. In some embodiments, the capsule is a sprinkle capsule. As used herein, "capsule size" refers to the internationally accepted numbering system for capsule sizes used in U.S. approved drugs.

[0104] Process for Preparing Pharmaceutical Dosage Forms A process for preparing a granule containing an amount of valbenazine or a pharma- ceutically acceptable salt thereof is provided, the process comprising: (1) roller compacting a blend comprising milled isomalt (item 3), milled valbenazine ditosylate (item 1), milled silicified microcrystalline cellulose (item 2), milled partially pregelatinized maize starch (item 4), milled hypromellose (item 5) and sieved magnesium stearate (item 6) to obtain a roller compacted ribbon material; (2) milling the roller compacted ribbon material; (3) blending additional sieved magnesium stearate with the milled roller compacted ribbon material of step (2) to obtain a final blend; and (4) Pressing the final blend to obtain granules. Includes.

[0105] In some embodiments, a process for preparing a granule comprising an amount of valbenazine or a pharma- ceutically acceptable salt thereof is provided, the process comprising: (1) blending isomalt (item 3), valbenazine ditosylate (item 1), and silicified microcrystalline cellulose (item 2); (2) milling the mixture of step (1) and transferring the milled material to a bin; (3) blending the mixture of step (2); (4) milling partially pregelatinized corn starch (item 4) and hypromellose (item 5) and adding the milled mixture comprising items 4 and 5 to the mixture of step (3); (5) blending the mixture of step (4); (6) adding sieved magnesium stearate (Item 6) to the mixture of step (5); (7) blending the mixture of step (6); (8) roller compacting the mixture of step (7) to obtain a roller compacted ribbon material; (9) milling the roller compacted ribbon material; (10) blending additional sieved magnesium stearate with the milled roller compacted ribbon material of step (9) to obtain a final blend; and (11) pressing the final blend to obtain granules. Includes.

[0106] The roller compacting step may be carried out in any suitable equipment, such as, for example, a Fitzmill IR 220 Roller Compactor, to provide a ribbon material that is milled by passing through a Fitzmill to provide a granulated material.

[0107] The pressing of the final blend is carried out in a suitable tablet press, such as, for example, a Fette 52i Press. In some embodiments, after the final blend is pressed to obtain granules, the process further comprises coating the granules with a film coating.

[0108] The present disclosure further provides a process for preparing the film-coated granules of the pharmaceutical dosage form disclosed herein, which process comprises the step of coating a granule core with a film coating.

[0109] In some embodiments, the film coating comprises a film-forming polymer and one or more of a plasticizer, a filler, and a pigment / opacifier.

[0110] In some embodiments, the film coating comprises a film-forming polymer. In some embodiments, the film coating comprises a film-forming polymer, the film-forming polymer is about 25% to about 55%, about 25% to about 45%, about 35% to about 55%, or about 35% to about 45% by weight of the film coating. In some embodiments, the film coating comprises a film-forming polymer, the film-forming polymer is about 30%, about 35%, about 40%, about 45%, or about 50% by weight of the film coating. In some embodiments, the film-forming polymer is poly(vinyl alcohol).

[0111] In some embodiments, the film coating comprises a plasticizer. In some embodiments, the film coating comprises a plasticizer, and the plasticizer is about 5% to about 30%, about 5% to about 25%, about 10% to about 30%, or about 10% to about 25% by weight of the film coating. In some embodiments, the film coating comprises a plasticizer, and the plasticizer is about 10%, about 15%, about 20%, or about 25% by weight of the film coating. In some embodiments, the plasticizer is polyethylene glycol.

[0112] In some embodiments, the film coating comprises a filler, the filler being about 5% to about 45%, about 5% to about 20%, about 10% to about 45%, or about 10% to about 20% by weight of the film coating. In some embodiments, the film coating comprises a filler, the filler being about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40% by weight of the film coating. In some embodiments, the filler is talc.

[0113] In some embodiments, the film coating comprises a pigment / opacifier, the pigment / opacifier being about 5% to about 40%, about 10% to about 40%, 20% to about 40%, or about 20% to about 30% by weight of the film coating. In some embodiments, the film coating comprises a pigment / opacifier, the pigment / opacifier being about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, or about 35% by weight of the film coating. In some embodiments, the pigment / opacifier is titanium dioxide.

[0114] In some embodiments, based on the weight of the film coating, the film coating comprises: (a) about 25% to about 55% by weight of a film-forming polymer; (b) about 5% to about 30% by weight of a plasticizer; (c) about 5% to about 45% by weight of a filler; and (d) up to about 40% by weight of a pigment / opacifier. In some embodiments, based on the weight of the film coating, the film coating comprises: (a) about 25% to about 55% by weight of a poly(vinyl alcohol); (b) about 5% to about 30% by weight of a polyethylene glycol; (c) about 5% to about 45% by weight of a talc; and (d) up to about 40% by weight of a titanium dioxide.

[0115] In some embodiments, the film coating is OPADRY (登録商標) In some embodiments, the film coating comprises OPADRY II. (登録商標) In some embodiments, the film coating comprises OPADRY II. (登録商標) In some embodiments, the film coating consists essentially of OPADRY II. (登録商標) II.

[0116] In some embodiments, the film coating comprises about 3.5% to about 15% by weight of each granule. In some embodiments, the film coating comprises about 3.5% to about 12.5%, about 5% to about 15%, or about 5% to about 12.5% ​​by weight of each granule. In some embodiments, the film coating comprises about 5%, about 7.5%, about 10%, or about 12.5% ​​by weight of each granule.

[0117] In some embodiments, the step of coating the granule cores with a film coating comprises spraying a mixture comprising water and the film coating onto the surface of the granule cores and contacting the granules with a process gas having an elevated temperature (e.g., a temperature of at least about 40° C.). As used herein, the term "process gas" refers to a gas or mixture of gases suitable for use in the processes described herein.

[0118] In some embodiments, the step of coating the granules with a film coating comprises fluidizing the granules using a process gas having a temperature of at least about 40° C., at least about 45° C., or at least about 50° C., and spraying a mixture comprising water and the film coating onto the surface of the fluidized granules. In some embodiments, the temperature is from about 40° C. to about 65° C. In some embodiments, the temperature is from about 45° C. to about 60° C. In some embodiments, the temperature is from about 50° C. to about 54° C. In some embodiments, the process gas comprises one or more inert gases (e.g., nitrogen). In some embodiments, the process gas comprises air.

[0119] The granule cores may be formed by compressing a precursor composition comprising valbenazine or a pharma- ceutically acceptable salt thereof, the precursor composition comprising particles including particles having an average diameter of less than about 1 mm.

[0120] In some embodiments, compressing the precursor composition comprises pressing the precursor composition in a tablet press. Compressing the precursor composition can form a granule core as described herein.

[0121] In some embodiments, compressing the precursor composition forms granules having an average diameter of about 1.5 mm to about 5 mm, about 2 mm to about 3 mm, about 2.15 mm to about 2.25 mm, about 2.18 mm to about 2.23 mm, or about 2.19 mm to about 2.21 mm.

[0122] In some embodiments, compressing the precursor composition forms granules having an average diameter of about 1 mm to about 5 mm, about 1 mm to about 4 mm, about 1 mm to about 3.5 mm, about 1.2 mm to about 5 mm, about 1.2 mm to about 4 mm, or about 1.2 mm to about 3.5 mm. In some embodiments, compressing the precursor composition forms granules having an average diameter of about 1.2 mm, about 1.4 mm, about 1.6 mm, about 1.8 mm, about 2 mm, about 2.2 mm, about 2.4 mm, about 2.6 mm, about 2.8 mm, or about 3 mm.

[0123] In some embodiments, compressing the precursor composition provides a compressible composite having an average diameter of about 1.2 mm to about 4 mm, an average diameter variation of 10% or less from the average diameter, and an average density of about 0.5 g / cm 3 ~Approx. 2.5g / cm 3 In some embodiments, compressing the precursor composition forms granules having an average diameter of about 1.2 mm to about 4 mm, an average diameter variation of 10% or less from the average diameter, and an average density of about 0.75 g / cm 3 ~Approx. 2.5g / cm 3 In some embodiments, compressing the precursor composition forms granules having an average diameter of about 1.2 mm to about 3.5 mm, an average diameter variation of 10% or less from the average diameter, and an average density of about 0.75 g / cm 3 ~Approx. 2.5g / cm 3In some embodiments, compressing the precursor composition forms granules having an average diameter of about 1.2 mm to about 3.5 mm, an average diameter variation of 10% or less from the average diameter, and an average density of about 1 g / cm. 3 ~About 2g / cm 3 The mixture forms granules having the formula:

[0124] In some embodiments, compressing the precursor composition produces a particle having an average diameter of up to about 2.5 mm, a d99 particle size distribution of up to about 2.8 mm, and an average density of about 0.75 g / cm 3 ~Approx. 2.5g / cm 3 In some embodiments, compressing the precursor composition forms granules having an average diameter of up to about 2.5 mm, a d99 particle size distribution of up to about 2.8 mm, and an average density of about 1 g / cm 3 ~Approx. 2.5g / cm 3 In some embodiments, compressing the precursor composition forms granules having an average diameter of up to about 2.2 mm, a d99 particle size distribution of up to about 2.5 mm, and an average density of about 0.75 g / cm 3 ~About 2g / cm 3 In some embodiments, compressing the precursor composition forms granules having an average diameter of up to about 2.2 mm, a d99 particle size distribution of up to about 2.5 mm, and an average density of about 1 g / cm 3 ~About 2g / cm 3 The mixture forms granules having the formula:

[0125] In some embodiments, compressing the precursor composition forms granules having an average hardness of about 1 kp to about 2.5 kp. In some embodiments, compressing the precursor composition forms granules having an average hardness of about 1 kp to about 2 kp, about 1.2 kp to about 2.5 kp, or about 1.2 kp to about 2 kp. In some embodiments, compressing the precursor composition forms granules having an average hardness of about 1 kp, about 1.2 kp, about 1.4 kp, about 1.6 kp, about 1.8 kp, or about 2 kp.

[0126] The precursor composition may be formed by compressing a blend of valbenazine or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable carrier (e.g., a diluent, disintegrant, binder, or lubricant); and milling the compressed blend.

[0127] In some embodiments, the precursor composition comprises about 5% to about 40% by weight of valbenazine or a pharma- ceutically acceptable salt thereof (e.g., valbenazine ditosylate) based on the weight of the free base. In some embodiments, the precursor composition comprises about 5% to about 35%, about 5% to about 30%, about 10% to about 40%, about 10% to about 35%, about 10% to about 30%, about 15% to about 40%, about 15% to about 35%, or about 15% to about 30% by weight of valbenazine or a pharma- ceutically acceptable salt thereof (e.g., valbenazine ditosylate) based on the weight of the free base. In some embodiments, the precursor composition comprises about 10%, about 15%, about 20%, about 25%, or about 30% by weight of valbenazine or a pharma- ceutically acceptable salt thereof (e.g., valbenazine ditosylate) based on the weight of the free base.

[0128] In some embodiments, the precursor composition comprises at least one pharma- ceutically acceptable carrier, such as one or more of a diluent, a disintegrant, a binder, and a lubricant (e.g., selected to provide a granule core as described herein). In some embodiments, the precursor composition as described herein comprises, based on the weight of its free base, about 5% to about 40% by weight of valbenazine or a pharma- ceutically acceptable salt thereof, about 25% to about 65% by weight of a diluent, about 0.5% to about 15% by weight of a disintegrant, about 0.5% to about 10% by weight of a binder, and about 0.5% to about 5% by weight of a lubricant.

[0129] In some embodiments, the precursor compositions described herein comprise about 30% to about 50% by weight of valbenazine ditosylate, about 25% to about 65% by weight of a diluent, about 0.5% to about 15% by weight of a disintegrant, about 0.5% to about 10% by weight of a binder, and about 0.5% to about 5% by weight of a lubricant.

[0130] In some embodiments, the precursor compositions described herein include about 30% to about 50% by weight valbenazine ditosylate, about 15% to about 35% by weight silicified microcrystalline cellulose, about 10% to about 30% by weight isomalt, about 0.5% to about 15% by weight partially pregelatinized maize starch; about 0.5% to about 10% by weight hydroxypropyl methylcellulose, and about 0.5% to about 5% by weight magnesium stearate.

[0131] In some embodiments, the precursor compositions described herein include (a) about 33% to about 40% by weight of valbenazine ditosylate; (b) about 20% to about 25% by weight of silicified microcrystalline cellulose; (c) about 16% to about 20% by weight of isomalt; (d) about 6% to about 8% by weight of partially pregelatinized maize starch; (e) about 4% to about 5% by weight of hydroxypropyl methylcellulose; and (f) about 2% to about 2.5% by weight of magnesium stearate.

[0132] In some embodiments, the precursor compositions described herein comprise about 40% by weight valbenazine ditosylate, about 25% by weight silicified microcrystalline cellulose, about 20% by weight isomalt, about 7.5% by weight partially pregelatinized maize starch, about 5% by weight hydroxypropyl methylcellulose, and about 2.5% by weight magnesium stearate.

[0133] In some embodiments, the precursor compositions described herein include (a) about 34.5% to about 38.2% by weight of valbenazine ditosylate; (b) about 22.6% to about 24% by weight of silicified microcrystalline cellulose; (c) about 17.3% to about 19.2% by weight of isomalt; (d) about 6.5% to about 7.2% by weight of partially pregelatinized maize starch; (e) about 4.4% to about 5% by weight of hydroxypropyl methylcellulose; and (f) about 2% to about 2.3% by weight of magnesium stearate.

[0134] In some embodiments, the precursor composition comprises particles having an average particle size of up to about 0.9 mm. In some embodiments, the precursor composition comprises particles having an average particle size of about 1 μm to about 0.9 mm, about 10 μm to about 0.9 mm, about 50 μm to about 0.9 mm, about 1 μm to about 0.8 mm, about 10 μm to about 0.8 mm, or about 50 μm to about 0.8 mm. In some embodiments, the precursor composition comprises particles having an average particle size of about 50 μm, about 100 μm, about 200 μm, about 300 μm, about 400 μm, or about 500 μm.

[0135] In some embodiments, the precursor composition has a d99 particle size distribution of up to about 0.9 mm. In some embodiments, the precursor composition has a d99 particle size distribution of about 50 μm to about 0.9 mm, or about 50 μm to about 0.8 mm. In some embodiments, the precursor composition has a d90 particle size distribution of up to about 500 μm, up to about 250 μm, or up to about 100 μm. In some embodiments, the precursor composition has a d90 particle size distribution of about 10 μm to about 500 μm, about 10 μm to about 250 μm, or about 10 μm to about 100 μm.

[0136] (definition) As used herein, unless otherwise specified, the term "about" refers to a numerical value or range of values ​​provided to describe a particular composition, salt, or solid form (e.g., melting, hydration, or glass transition; mass change (e.g., mass change as a function of temperature or humidity, etc.); solvent or water content (e.g., in terms of mass or percentage); or (e.g., 13 When used in conjunction with a particular size measurement, such as describing a peak position, a particular temperature or a particular temperature range, such as in analysis by C NMR, DSC, TGA and XRPD, it indicates that the value or range of values ​​may vary as would be reasonable for one of ordinary skill in the art while still describing that particular solid form. In particular, the term "about" when used in this context indicates that the numerical value or range of values ​​may vary by 5%, 4%, 3%, 2%, or 1% of the described value or range of values ​​while still describing that particular solid form. In some embodiments, the term "about" indicates that the numerical value or range of values ​​may vary by 5%. As used herein, the terms "blend", "blending" and "blended" refer to combining or mixing various materials to obtain a mixture. The resulting blended mixture may be homogeneous.

[0137] As used herein, the diameter of a granule described herein refers to its largest dimension (e.g., the diameter of a spherical particle, the length of an ovoid particle, the height and diameter of a cylindrical particle, etc.). As used herein, d99 particle size distribution refers to the particle size (e.g., the diameter of a granule) value at which about 99% of the particles in a sample have a value lower than the d99 value and about 1% of the particles in a sample have a value higher than the d99 value. The average diameter particle size distribution of the granules described herein can be measured using conventional particle size analysis techniques (e.g., sieve analysis, laser diffraction analysis, or microscopic counting). Further measurement methods are described in the United States Pharmacopeia ("USP") 905 (Uniformity of Dosage Units (2016)) and USP429 (Light Diffraction Measurement of Particle Size (2016)), each of which is incorporated herein by reference for all purposes.

[0138] As used herein, the term "diameter variation" refers to the maximum amount that the diameter of particles in a distribution varies from the average diameter of the distribution. For example, for a sample of granules having a diameter variation of 20% or less, the diameter of each granule in the sample is 20% or more and 20% or less than the average diameter of the granules.

[0139] As used herein, the "average hardness" of a granule refers to the breaking point and structural integrity measure of the granule. In particular, the average hardness refers to the average amount of force that needs to be applied to the granule to cause it to begin to break apart. The average hardness can be measured using conventional practices in the field (e.g., compression testing) or using devices such as Monsanto tester or Pfizer tester.

[0140] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, immunogenicity, other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0141] A variety of pharma- ceutically acceptable carriers can be used in the formulations described herein. As used herein, a "pharma- ceutically acceptable carrier" refers to Refers to a pharma- ceutically acceptable material, composition, or vehicle (e.g., a liquid or solid filler, diluent, solvent, or encapsulating material). A pharma- ceutically acceptable carrier is also known as a "pharmaceutically acceptable excipient." Carriers are generally safe, non-toxic, and not biologically or otherwise undesirable, and include carriers that are acceptable for veterinary use as well as for human pharmaceutical use. In one embodiment, each component is "pharmaceutically acceptable" as defined herein. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash, eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson, ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0142] The present application also includes pharma- ceutically acceptable salts of the compounds described herein. As used herein, "pharma- ceutically acceptable salts" refers to derivatives of the disclosed compounds, whose parent compounds are modified by converting existing acidic or basic moieties into their salt forms. Examples of pharma- ceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines); alkali or organic salts of acidic residues (e.g., carboxylic acids); and the like. The pharma- ceutically acceptable salts of the present application include, for example, conventional non-toxic salts of the parent compounds formed from non-toxic inorganic or organic acids. The pharma- ceutically acceptable salts of the present application can be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base forms of these compounds with a stoichiometric amount of a suitable base or acid in water or in an organic solvent or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition (Mack Publishing Company, Easton, 1985), p.1418; Berge et al., J.Pharm.Sci., 1977, 66(1), 1-19; and Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002).

[0143] As used herein, the terms "individual," "patient," or "subject," used interchangeably, refer to any animal, including a mammal, preferably a mouse, rat, monkey, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, and most preferably a human.

[0144] As used herein, the phrase "therapeutically effective amount" refers to an amount of an active compound or drug that elicits the biological or medical response sought in a tissue, system, animal, individual or human by a researcher, veterinarian, physician, or other clinician. The therapeutically effective amount varies depending on the compound, the disease, disorder or condition and its severity, as well as the age of the mammal being treated, the weight of the mammal being treated, etc. The dosage can be administered conventionally, for example, in divided doses up to four times a day, or in sustained release form.

[0145] As used herein, the term "treat" or "treatment" refers to inhibiting a disease (e.g., inhibiting a disease, condition or disorder in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder (i.e., halting further development of the pathology and / or symptoms)); or ameliorating the disease (e.g., ameliorating a disease, condition or disorder in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder (i.e., reversing the pathology and / or symptoms) (e.g., reducing the severity of the disease)).

[0146] (How to use) The present disclosure also relates to a method of treating a neurological or psychiatric disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical dosage form described herein or a unit dosage form described herein.

[0147] In some embodiments, the patient suffers from dysphagia or other swallowing disorder. In some embodiments, the patient suffers from a swallowing disorder. In some embodiments, the patient has a swallowing disorder.

[0148] In some embodiments, the patient is a pediatric patient, e.g., a child under 12 years of age, under 6 years of age, under 5 years of age, under 4 years of age, under 3 years of age, under 2 years of age, or under 1 year of age. In some embodiments, the pediatric patient is between about 6 months and about 5 years of age, between about 6 months and about 4 years of age, between about 6 months and about 3 years of age, between about 6 months and about 2 years of age, or between about 6 months and about 1 year of age.

[0149] In some embodiments, the patient is a geriatric patient, e.g., a geriatric patient suffering from dysphagia or other swallowing disorder, hi some embodiments, the geriatric patient is at least 50 years old, at least 60 years old, at least 70 years old, or at least 80 years old.

[0150] A method of administering valbenazine, or a pharma- ceutically acceptable salt thereof, to a patient in need thereof is disclosed, the method comprising: (a) providing a pharmaceutical dosage form as described herein or a unit dosage form as described herein; (b) sprinkling the plurality of granules onto a soft food product; and (c) orally administering the soft food. Includes.

[0151] In some embodiments, the soft food is selected from applesauce, yogurt, pudding, ice cream, baby food, and soy-based or grain-based products.

[0152] A method of administering valbenazine or a pharma- ceutically acceptable salt thereof to a patient in need thereof is disclosed, the method comprising orally administering a pharmaceutical dosage form described herein or a unit dosage form described herein.

[0153] A method of administering valbenazine or a pharma- ceutically acceptable salt thereof to a patient in need thereof is disclosed, the method comprising orally administering a capsule containing a pharmaceutical dosage form described herein or a capsule containing a unit dose described herein.

[0154] In some embodiments, each granule is suitable for oral administration.

[0155] In some embodiments, the step of orally administering a pharmaceutical composition described herein comprises sprinkling the composition on food (eg, soft food).

[0156] In some embodiments, the neurological disease or disorder or psychiatric disease or disorder is hyperactivity disorder, a mood disorder, a bipolar disorder, schizophrenia, schizoaffective disorder, mania in a mood disorder, depression in a mood disorder, treatment-resistant obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor ataxia syndrome, autism spectrum disorder, Rett syndrome, or choreoacanthocytosis.

[0157] In some embodiments, the neurological disease or disorder or psychiatric disease or disorder is a hyperkinetic movement disorder. In some embodiments, the hyperkinetic movement disorder is tardive dyskinesia. In some embodiments, the hyperkinetic movement disorder is Tourette's syndrome. In some embodiments, the hyperkinetic movement disorder is Huntington's disease (also called Huntington's disease). In some embodiments, the hyperkinetic movement disorder is tics. In some embodiments, the hyperkinetic movement disorder is chorea associated with Huntington's disease (i.e., Huntington's chorea, Huntington's chorea, or Huntington's chronic progressive hereditary chorea). In some embodiments, the hyperkinetic movement disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless legs syndrome, or tremor.

[0158] In some embodiments, the pharmaceutical compositions of the present disclosure may be useful in preventing a disease or reducing the risk of developing a disease (e.g., preventing a disease, condition, or disorder or reducing the risk of developing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but has not yet experienced or exhibited the pathology or symptoms of the disease).

[0159] In some embodiments, the patient has 22q11.2 deletion syndrome. In some embodiments, the patient is predisposed to developing a psychiatric disorder due to the patient having 22q11.2 deletion syndrome.

[0160] In some embodiments, the patient has a catechol-O-methyltransferase ("COMT") haploinsufficiency. In some embodiments, the patient is predisposed to developing a psychiatric disorder due to the patient having a COMT haploinsufficiency.

[0161] Hyperkinetic movement disorders refer to a class of neurological disorders characterized by unwanted, uncontrollable or poorly controlled involuntary movements. The symptoms of these disorders are highly variable and include chorea, tremors, dystonia, myoclonus, tics, other dyskinesias, spasms and shakes. Hyperkinetic movement disorders include ataxia, chorea, dystonia, hemifacial spasm, Huntington's disease, chorea associated with Huntington's disease, myoclonus, restless legs syndrome, tardive dyskinesia, tics, Tourette's syndrome, and tremors.

[0162] Mood disorders refer to a class of mental disorders in which the underlying problem primarily affects a person's persistent emotional state (their mood). Mood disorders include major depressive disorder (also called major depression), bipolar disorder, persistent depressive disorder (persistent mild depression), cyclothymia (a milder form of bipolar disorder), catatonic depression, postpartum depression, mania, and seasonal affective disorder (SAD). Mood disorders include substance-induced mood disorders, and mood disorders resulting from medical conditions (e.g., hypothyroidism or Parkinson's disease).

[0163] Bipolar disorder (also known as bipolar affective disorder or manic depression) is a mental disorder characterized by periods of elevated mood and periods of depression. The elevated periods are known as mania or hypomania, depending on their severity or whether psychosis is present. Symptoms of a manic or manic episode include long periods of "high" or excessive happiness or sociable mood, extreme irritability, talking very quickly, racing thoughts, jumping from one idea to another, being easily distracted, increased activity, excessive restlessness, little sleep, having unrealistic confidence in one's own talents, impulsive behavior, and preoccupation with hedonic, high-risk behavior. Symptoms of depression or depressive episodes include excessively prolonged sadness or hopelessness, lack of interest in activities, fatigue, problems with concentration or memory, difficulty making decisions, being restless or irritable, changes in eating habits or sleep patterns, and suicidal ideation. Patients with bipolar disorder are at high risk for suicide and self-harm.

[0164] Schizoaffective disorder is a mental health condition characterised primarily by symptoms of schizophrenia (e.g., hallucinations or delusions) and symptoms of a mood disorder (e.g., mania and depression).

[0165] Obsessive-compulsive disorder (OCD) is an anxiety disorder characterized by recurrent and persistent anxiety-provoking thoughts (obsessions) that result in repetitive behaviors (compulsions) that focus on reducing the distress caused by the obsessive thoughts. Patients may or may not recognize that their obsessions and compulsions are irrational and that these thoughts and behaviors can be time-consuming and impair functioning.

[0166] Lesch-Nyhan syndrome is characterized by neurological dysfunction, cognitive and behavioral disorders, and uric acid overproduction, and has a prevalence of 1:380,000. Patients with the condition suffer from cognitive impairment, motor disorders, and self-injurious behaviors. The most common presenting symptom of Lesch-Nyhan syndrome is developmental delay during the first year of life; hypotonia and delayed motor skills are usually evident by 3 to 6 months of age. Children with Lesch-Nyhan syndrome are typically unable to sit, crawl, and walk, and are eventually restricted to wheelchairs. Even with effective management of symptoms, most affected individuals survive only into their 20s or 30s.

[0167] Agitation in Alzheimer's disease refers to a group of several behavioral symptoms associated with the disease. Agitation develops as the disease progresses and occurs in addition to cognitive loss. The group of symptoms includes anxiety, depression, irritability, and motor restlessness (e.g., pacing, wandering, constant movement). Other symptoms that may occur include sleep disorders, delusions, hallucinations, obsessive behavior, aggression, and general emotional distress. Agitation may occur in half of all individuals with Alzheimer's disease. Agitation is associated with patients having poor quality of life, impairing family relationships and professional caregivers, and ultimately leading to admission to residential care facilities.

[0168] Fragile X syndrome (also known as Martin-Bell syndrome) is a genetic condition that causes a range of developmental problems, including learning disabilities and cognitive impairments. Males are usually more severely affected than females. Fragile X syndrome is inherited in an X-linked dominant pattern. Affected individuals usually have speech and language developmental delays by age 2. Most males with fragile X syndrome have mild to moderate intellectual disability, while approximately one-third of affected females have intellectual disability. Children with fragile X syndrome may also exhibit behavioral problems, including anxiety, attention deficits, anxiety, and hyperactive behaviors (e.g., fidgeting or impulsive behaviors).

[0169] Autism spectrum disorder (ASD) is a range of complex neurodevelopmental disorders characterized by social impairments; communication difficulties; and restricted, repetitive, and stereotyped patterns of behavior (stereotypies). Autistic disorder (sometimes called autism or classic ASD) is the most severe form of ASD. Other conditions include a milder form known as Asperger syndrome, childhood disintegrative disorder, and pervasive developmental disorder, not otherwise specified (usually called PDD-NOS). Although ASD varies significantly in characteristics and severity, ASD occurs in all ethnic and socioeconomic groups and affects all age groups.

[0170] Major depressive disorder is one of the most common mental illnesses. Depression causes people to lose enjoyment from daily life, can complicate other medical conditions, and can even be severe enough to lead to suicide. Depression can happen to anyone, at any age, and in people of any race or ethnicity.

[0171] Rett syndrome (RTT), originally called cerebroatrophic hyperammonemia, is a rare genetic postnatal neurological disorder of the gray matter of the brain that affects both female and male patients, with a female predominance. Rett syndrome causes problems in brain functions responsible for cognitive, sensory, emotional, motor, and autonomic functions. The most frequent problems that arise include problems with learning, speech, sensory function, mood, movement, breathing, cardiac function, chewing, swallowing, and digestion. It may be characterized by normal early growth and development, followed by slowing of development, loss of purposeful use of the hands, characteristic hand movements, slowing of brain and hand growth, problems with walking, seizures, and intellectual disability.

[0172] Chorea acanthocytosis (ChAc) is a neurological disorder that affects movement in many parts of the body. Chorea refers to the involuntary jerking movements performed by people with the disorder. People with the condition also have abnormal star-shaped red blood cells (acanthocytosis). The disorder is one of a group of conditions called neuroacanthocytosis, which involves neurological problems and abnormal red blood cells.

[0173] As used herein, "22q11.2 deletion syndrome" (22q11.2 DS) is also known as velotharyngocardiofacial syndrome ("VCFS"), DiGeorge syndrome, or CATCH22, and less frequently referred to as DiGeorge sequence, microdeletion 22q11.2, monosomy 22q11, conotruncal anomaly face syndrome, Sedlacova syndrome, Shprintzen syndrome, Takao syndrome, or Cayler cardiofacial syndrome.

[0174] As used herein, "COMT" is an important enzyme for regulating catechol compounds, including dopamine, epinephrine and norepinephrine.Compared to normal subjects, individuals with VCFS have about 50% less COMT mRNA, COMT protein expression and enzyme activity.The characteristic behavioral manifestations of VCFS may be related to dopamine dysregulation resulting from COMT haploinsufficiency. EXAMPLES

[0175] (Example) The present disclosure further provides specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present disclosure in any manner. Those skilled in the art will readily recognize various non-critical parameters that can be changed or modified to produce essentially the same results. Example 1. Preparation of Granules (material) [Table 1A]

[0176] (Pre-blended, 30L bottle, Comil, and Fitzmil) To a 30 L bin blender, the following ingredients were added in order: Isomalt (GalenIQ (商標) 720, 1.820 kg, item 3), valbenazine ditosylate (3.640 kg, item 1), and silicified microcrystalline cellulose (PROSOLV (登録商標) 90, 2.275 kg, Item 2). A lid was secured to the bottle and the ingredients were blended for 4 minutes at 20 rpm. A conical screen mill (COMIL) configured with a 0.8 mm screen and 0.150 inch spacers at approximately 1500 rpm was used. (登録商標) The blended ingredients were transferred to a jar (100 ml) of water. The milled ingredients were added to the jar and the lid was secured. With the blender speed set at 20 rpm, the ingredients were blended for 25 minutes and 30 seconds.

[0177] The following ingredients were transferred, in order, to a conical screen mill equipped with a 0.8 mm screen and 0.150 inch spacers at approximately 1500 rpm: partially pregelatinized corn starch (STARCH 1500®, 0.683 kg, item 4) and hypromellose (METHOCEL (商標) E5 Premium LV, 0.455 kg, item 5). The milled material was transferred to the jar and the lid was secured. With the blender speed set at 20 rpm, the ingredients were blended for 10 minutes and 15 seconds.

[0178] Magnesium stearate (Ligamed MF-2-V, 0.136 kg, item 6) was hand sieved through an 18 mesh screen. The sieved material was added to the 30 L bottle and the lid was secured. With the blender rotation speed set at 20 rpm, the ingredients were blended for 3 minutes. After blending, the blended ingredients (i.e., items 1-6) were discharged into a polyethylene-lined in-process container.

[0179] (Roller compaction and Fitzmill processing) A Fitzmill IR 220 Roller Compactor (with a polyethylene-lined container secured to the discharge of the roller compactor) was set with the following operating parameters: 1) roll speed of 3.0 rpm, 2) VFS screw speed of 250 rpm, 3) HFS screw speed of 55 rpm, and 4) roll force of 2710 lb / in. The roller compactor and hopper vibrator were started and the blended ingredients (i.e., Items 1-6) were gradually charged into the roller compactor.

[0180] A Model M5A Fitzmill in knife configuration was equipped with a 20 mesh screen and set at 1200 rpm. The roller compacted ribbon was moved slowly through the Fitzmill to yield 7.448 kg of granulated material, which was placed into a polyethylene-lined in-process vessel.

[0181] (Final blend, 30L bin blender) The following ingredients were added to a 30 L bin blender in order: milled ribbon material prepared as above, and sieved magnesium stearate (Ligamed MF-2-V, adjusted to 1.0% based on intragranular yield, 0.075 kg added, item 7). A lid was secured to the bin and the ingredients were blended for 3 minutes at 20 rpm. The final blend was discharged into a double polyethylene lined container (containing two 4-unit desiccant bags between the two liners) to yield 7.345 kg of the final blend.

[0182] (Press batch settings) The Fette 52i Press was configured with a 6mm fill cam, dosing shim, and multi-tip punch (2.2mm). A polyethylene trash bag was placed under the tablet discharge chute for collection during setup. The press was set up with the following operating parameters: 1) turret speed of 35 rpm, 2) fill depth setting at 3.42mm, 3) preload setting at 1.83mm, 4) preload setting at 0.70kN, 5) main compression setting at 1.66mm, 6) main compression setting at 5.00kN, 7) Feeder 1 setting at 50 rpm, and 8) punch count 16 with 10 tips each. The hopper of the Fette 52i Press was filled with the final blend and the press started. After collecting approximately 5g of tablets, the press was stopped, the tablets were examined, and the press was adjusted as needed. The targets and target ranges for the granules are as follows: weight of each granule, 9.12 mg, range 8.21 mg to 10.03 mg; total weight for the 10 granules, 91.20 mg, range 86.64 mg to 95.76 mg; hardness, 1.6 kilopounds (kp); friability, less than or equal to 1.0% (NMT); and appearance, no defects.

[0183] (Granular compression) Once the press was adjusted to provide granule properties in the target range, the trash bag was removed and a new polyethylene bag was placed under the tablet discharge chute to collect acceptable granules. The press was started and the granules were collected.

[0184] (Metal Inspection) The granules were passed through a metal detector. All granules that passed and were deemed acceptable were collected in a double polyethylene lined container containing one 8 unit desiccant to yield 6.904 kg (excluding the weight of the in-process test material of 0.109 kg); the total weight for the finished granules (uncoated) was 7.013 kg (77% yield). The average weight for the granules was determined to be 9.195 mg (3.7 mg of valbenazine ditosylate or 2.0 mg of valbenazine free base), with a theoretical number of granules produced from this process of 750,843 (6.904 kg / 9.195 mg x 1,000,000). Example 2. Preparation of coated granules (material) [Table 2]

[0185] (Preparation of Coating Solution) A stainless steel container (NLT 20-L) was charged with 10.312 kg of purified water (USP) (Article No. 2). Gentle agitation was initiated to create a vortex and the OPADRY (登録商標) II White (1.820 kg, item no. 3) was slowly added. (登録商標) After addition of II White was complete, the contents were mixed for 30 minutes or more until a solution was obtained (34 minutes). The agitation was reduced so that the solution was still moving and a slight vortex was noted. This solution was used within 24 hours of preparation.

[0186] (Preparing the spray system) The GPCG-5 Wurster Spray System was configured as follows: partition length, 18 inches; air distribution plate, D; product support screen, 100 mesh; partition height from distribution plate, 25+ / -2mm; nozzle tip port size, 1.0mm; nozzle cap height, same height as nozzle tip; solution tubing size, MASTERFLEX. (登録商標) 14mm; process, aqueous; filter bag shaking interval / duration, 30 seconds / 5 seconds. The nozzle was manually tested with purified water (USP) using the following settings: 6mL / min for spray rate, and 1.0 bar for atomization air pressure. (Coating process parameters) [Table 3]

[0187] It is understood that the coating process parameters in Table 3 are representative and other parameters may also be used. For example, during this coating process, the process air temperature (°C) may range from 55°C to 72°C without any effect on product quality; the process air volume (cfm) may range from 600 cfm to 900 cfm without any effect on product quality; spray rates of up to 170 g / min may be used without any effect on product quality; product temperature excursions of more than 48°C may occur for up to 5 minutes to 8 minutes (up to a maximum of 51°C to 52°C) without any effect on product quality.

[0188] (Preparation of equipment and filling of granules) A GPCG-5 Wurster Spray System was preconditioned to the following processing parameters: process air temperature of about 60° C.; process air volume of 140 cfm; and dew point of about 6° C. Once the product temperature reached 50° C., the GPCG-5 was shut down and the uncoated granules of Example 1 (Item No. 1) were loaded into the product chamber. The back of the chamber was inserted into the GPCG-5 unit, and then the spray delivery line, temperature probe, and atomization air line were attached to the nozzle inlet. The product bowl was compressed to preheat the granules, and the dryer blower was started.

[0189] (coating) After fluidization was achieved, 40 granules were collected from the GPCG-5 sample port and the average weight was determined (9.125 mg). Based on the average granule weight, the target 10% coating weight was calculated to be 10.038 mg. The spray rate was started at 8 mL / min and increased by 4 mL / min every 10 minutes until a spray rate of 20 mL / min was achieved. Once the 20 mL / min spray rate was achieved, the product at the sample port was checked for agglomeration every 15 minutes thereafter. The temperature, air flow, and product bed temperature were adjusted as necessary to fall within the target range. Once the target coating weight was achieved, the solution pump was stopped, flow reversed, and the pump was restarted to clear the lines. At the same time, fluidization of the granules continued for an additional drying time until the product temperature increased by 2° C. and the unit was shut down. The coated granules were discharged from the product bowl and sieved through dedicated US standard size 7 mesh and 10 mesh sieves. Material sized <7 mesh and >10 mesh was retained. No oversize (>7 mesh) or undersize (<10 mesh) material was identified. The coated granules were placed into a double polyethylene lined container containing one 8 unit desiccant, 7.523 kg (including an analytical sample weighing 0.020 kg) (99% yield).

[0190] (Encapsulation) The coated granules were then pelleted into a sprinkle capsule (i.e., CAPSUGEL) designed to be open, using an IMA Adapta encapsulator configured with a pellet dosator configured with a Size 00 pellet doser and a piston from the Size 0 pellet doser. (登録商標) Size 0 CONI-SNAP (登録商標) Sprinkle capsules) to achieve target dosage strengths of 20 mg, 40 mg, 60 mg, and 80 mg of valbenazine. Granule dosing was volumetrically controlled to achieve the 80 mg strength. Granules were also counted and filled by hand to achieve lower strengths.

[0191] Additional batches (utilizing equivalent upstream processes) used an IMA Adapta encapsulator configured with a counting wheel and vacuum. A dosator and a wheel with holes were used to control dosing by counting, providing automated encapsulation and better control over unit dosing. The coated granules therefore have the composition shown in Table 1B: [Table 1B]

[0192] Example 3. Dissolution profile of coated granules (material) [Table 4]

[0193] (General method) The following dissolution standards and sample preparations were analyzed by HPLC. Instrument parameters were as listed in Table 5 below: [Table 5]

[0194] The mobile phase gradient was as set forth in Table 6 below: [Table 6]

[0195] The column was equilibrated at initial conditions before each sample sequence and equilibrated after each sample sequence with acetonitrile and H flowing at 1.0 mL / min at a column temperature of 50 °C. 2 Washing was performed using a gradient of O / acetonitrile (90 / 10 (v / v)).

[0196] For each sample preparation below, at each time point below, a % valbenazine (free base) release value was calculated as follows:

number

[0197] (Preparation of Dissolution Standards for Valbenazine) (80mg dose) 40.5±4.0 mg of valbenazine ditosylate standard (equivalent to 22.22 mg of valbenazine free base) was added to a 250 mL volumetric flask. Diluent (0.1 N HCl dissolution medium) was added to the flask to approximately 75% of the flask's volume. The contents of the flask were mixed thoroughly and sonicated if necessary to provide a standard solution containing 0.0889 mg / mL of valbenazine free base. This standard was stable for 17 days when stored at ambient laboratory conditions.

[0198] (20mg and 40mg doses) 10.12±1.0 mg of valbenazine ditosylate standard (equivalent to 5.55 mg of valbenazine free base) was added to a 250 mL volumetric flask. Diluent (0.1 N HCl dissolution medium) was added to the flask to approximately 75% of the flask's volume. The contents of the flask were mixed thoroughly and sonicated if necessary to provide a standard solution containing 0.0222 mg / mL of valbenazine free base. This standard was stable for 7 days when stored at ambient laboratory conditions. (Dissolution test) (Test Standards) [Table 7]

[0199] Stage S 1 So, six units were tested in Tier I media (0.1N HCl).

[0200] Stage S 1 If the criteria were not met but there was no evidence of bridging (no pellicles observed), Stage S 2 Testing was performed in Tier I media on an additional 6 units, and results from these 12 units tested in Tier I media were evaluated and reported. 2 If criteria are not met, stage S 3 Testing was performed on an additional 12 units in Tier I media, and results from these 24 units tested in Tier I media were evaluated and reported.

[0201] Stage S 1 If the criteria are not met and evidence of bridging is present (film is observed), proceed to Stage S. 1 The test was repeated in Tier II medium (0.1N HCl containing pepsin, 700,000-750,000 activity units per liter of medium). 1 If the criteria are not met for Tier II media, Stage S 2Testing was performed in Tier II media on an additional 6 units, and results from these 12 units tested in Tier II media were evaluated and reported. 2 If criteria are not met, stage S 3 Testing was performed on an additional 12 units in Tier II media, and results from these 24 units tested in Tier II media were evaluated and reported.

[0202] (Test parameters) 80 mg, 40 mg, and 20 mg doses of coated oral granules prepared according to Example 2 were removed from their capsules and tested according to Table 8 below: [Table 8]

[0203] Coated oral granules of 80 mg, 40 mg, and 20 mg doses prepared according to Example 2 were tested as whole capsules according to Table 9 below: [Table 9]

[0204] (Test Procedure - 80mg dose, capsule removed) Each dissolution vessel was filled with 900 mL of degassed dissolution medium. The temperature of the medium for each vessel was recorded prior to beginning the dissolution run.

[0205] Six valbenazine sprinkle capsules were weighed and their weights recorded. The contents of each capsule were carefully removed and transferred to their respective baskets. The weight of each empty capsule shell was recorded.

[0206] Dissolution was measured according to Table 8 above. After the dissolution was complete, the end temperature and findings for each container were recorded. The dissolution samples were stable for 12 days when stored at ambient laboratory conditions.

[0207] Dissolution in Tier I media, as shown in Figure 1, is stage S 1 The acceptance criteria were met.

[0208] (Test Procedure - 40mg and 20mg doses, capsule removed) Each dissolution vessel was filled with 900 mL of degassed dissolution medium. The temperature of the medium for each vessel was recorded prior to beginning the dissolution run.

[0209] Six valbenazine sprinkle capsules were weighed and their weights recorded. The contents of each capsule were carefully removed and transferred to their respective baskets. The weight of each empty capsule shell was recorded.

[0210] Dissolution was measured according to Table 8 above. After the dissolution was complete, the end temperature and findings for each container were recorded. The dissolution samples were stable for 7 days when stored at ambient laboratory conditions.

[0211] Dissolution in Tier I media, as shown in Figure 1, is stage S 1 The acceptance criteria were met.

[0212] (Test Procedure - 80mg Dose, Whole Capsule) Each dissolution vessel was filled with 900 mL of degassed dissolution medium. The temperature of the medium for each vessel was recorded before starting the dissolution run. Six valbenazine sprinkle capsules were weighed and their weights recorded. Each capsule was fitted with a wire helix sinker and introduced into its respective vessel.

[0213] Dissolution was measured according to Table 9 above. After the dissolution was complete, the ending temperature and findings for each container were recorded. The dissolution samples were stable for 12 days in Tier I media stored at ambient laboratory conditions. The dissolution samples were stable for 7 days in Tier II media stored at ambient laboratory conditions.

[0214] Dissolution in Tier II media, as shown in Figure 1, is stage S 1The acceptance criteria were met.

[0215] (Test Procedure - 40mg and 20mg Doses, Whole Capsules) Each dissolution vessel was filled with 900 mL of degassed dissolution medium. The temperature of the medium for each vessel was recorded before starting the dissolution run. Six valbenazine sprinkle capsules were weighed and their weights recorded. Each capsule was fitted with a wire helix sinker and introduced into its respective vessel.

[0216] Dissolution was measured according to Table 9 above. After the dissolution was complete, the ending temperature and findings for each container were recorded. The dissolution samples were stable for 7 days in Tier I media stored at ambient laboratory conditions. The dissolution samples were stable for 7 days in Tier II media stored at ambient laboratory conditions.

[0217] Dissolution in Tier II media, as shown in Figure 1, is stage S 1 The acceptance criteria were met.

[0218] Example 4. G-tube compatibility evaluation of oral granules for sprinkle capsules The purpose of this study was to determine the suitability of valbenazine oral granules for sprinkle capsules for administration via a gastrostomy tube (G-tube) for clinical use. The doses for this study were 20 mg, 40 mg, 60 mg, and 80 mg.

[0219] (Selection of Gastrostomy Tube) Silicone material was chosen because it is a commonly used gastrostomy tube material, and the size range of 12 Fr to 18 Fr was chosen based on the needs of the patient population. A gastrostomy tube length of 8 inches was used throughout this study.

[0220] (Preparation of Dispersion Medium and Dispersion) Water was selected as the dispersion medium because of ease and availability to the caregiver / patient. Water is readily available and compatible with all meals. Warm water (warm to the touch) is necessary for administration of the product through a gastrostomy tube. The warm water ensures that an adequate dose is delivered and prevents clogging of the gastrostomy tube because it dissolves the product in the dispersion medium rather than suspending it.

[0221] A caregiver / patient typically administers medication through the gastrostomy tube by mixing the drug with a dispersion medium, then drawing it up into a syringe and forcing it through the gastrostomy tube, after which a flush is performed with the dispersion medium to remove any remaining material from the gastrostomy tube.

[0222] (Gastrostomy tube compatibility assessment) This suitability assessment was performed by conducting a recovery study. The recovery study was performed by determining the % recovery at the minimum and maximum doses administered through a G-tube. The acceptance criteria were set at a % recovery of 90.0% to 110.0%.

[0223] Ambient temperature tap water soak times (30 and 45 minutes) were initially evaluated for bracketing gastrostomy tube size dimensions 12Fr and 18Fr, and bracketing doses 20mg and 80mg. The 80mg test failed for the 30 and 45 minutes ambient temperature tap water soak times, so it was decided to proceed with warm tap water (warm to the touch). It is possible that ambient temperature tap water could be used for soak times longer than 45 minutes. However, this route was not explored further due to the inconvenience it would cause the caregiver / patient long preparation times.

[0224] Table 10 shows the results from this % recovery test. [Table 10]

[0225] An evaluation of the first dose (10 mL) was performed with warm water and no cup rinsing to determine whether rinsing of the cup was necessary to deliver the intended dose. This evaluation was performed using a 12Fr gastrostomy tube and a cohort of doses of 20 mg and 80 mg. This evaluation determined that rinsing the cup with 5 mL after administration was necessary to achieve adequate recovery.

[0226] Example 5. Stability Test The dosage forms were stored for 3 months at 25° C. / 60% relative humidity (RH), 30° C. / 75% RH, and 40° C. / 75% RH. A 60 mg powder-filled capsule was compared to a 60 mg oral granule in a sprinkle capsule. Results from the stability study are shown in Table 11. Under the test conditions, the oral granules described herein have acceptable stability at 3 months. [Table 11]

[0227] In addition to the modifications described herein, various modifications will be apparent to those skilled in the art from the above description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, and publications) is hereby incorporated by reference in its entirety.

Claims

1. 1. A pharmaceutical dosage form comprising a plurality of granules, each granule comprising: (a) an average diameter of at least 1 mm; (b) at least one pharmaceutically acceptable carrier; (c) an amount of valbenazine, or a pharmaceutically acceptable salt thereof; and (d) Film coating 1. A pharmaceutical dosage form comprising:

2. 2. The pharmaceutical dosage form of claim 1, wherein each granule has an average diameter of about 2 mm to about 3 mm.

3. 2. The pharmaceutical dosage form of claim 1, wherein each granule has a diameter variation of no more than 20% from said average diameter.

4. 2. The pharmaceutical dosage form of claim 1, wherein each granule has a d99 particle size distribution of up to about 2.8 mm.

5. Each granule has an average density of about 1 g / cm ３ ~Approx. 2g / cm ３ 2. The pharmaceutical dosage form of claim 1, having:

6. Each granule is (a) an average diameter of up to about 2.5 mm; (b) a d99 particle size distribution of up to about 2.8 mm; and (c) Average density is approximately 0.75 g / cm³ ３ ~ Approximately 2.5 g / cm ３ 2. The pharmaceutical dosage form of claim 1, having:

7. 10. The pharmaceutical dosage form of claim 1, wherein each granule has an average hardness of about 0.5 kp to about 3 kp.

8. 10. The pharmaceutical dosage form of claim 1, wherein each granule has an average hardness of about 1.6 kp.

9. 10. The pharmaceutical dosage form of claim 1, wherein each granule has an average weight of about 8 mg to about 10.2 mg.

10. 10. The pharmaceutical dosage form of claim 1, wherein each granule has an average weight of about 9.1 mg.

11. 10. The pharmaceutical dosage form of claim 1, wherein each granule is stable to a film-coating process.

12. 10. The pharmaceutical dosage form of claim 1, wherein each granule is suitable for oral administration.

13. 10. The pharmaceutical dosage form of claim 1, wherein the film coating comprises a film-forming polymer.

14. 14. The pharmaceutical dosage form of claim 13, wherein the film-forming polymer is poly(vinyl alcohol).

15. 10. The pharmaceutical dosage form of claim 1, wherein the film coating comprises a film-forming polymer, and the film-forming polymer is about 25% to about 55% by weight of the film coating.

16. 10. The pharmaceutical dosage form of claim 1, wherein the film coating comprises a plasticizer.

17. 17. The pharmaceutical dosage form of claim 16, wherein the plasticizer is polyethylene glycol, glycerin, or a mixture thereof.

18. 17. The pharmaceutical dosage form of claim 16, wherein the plasticizer is polyethylene glycol.

19. 10. The pharmaceutical dosage form of claim 1, wherein the film coating comprises a plasticizer, the plasticizer being from about 5% to about 30% by weight of the film coating.

20. 10. The pharmaceutical dosage form of claim 1, wherein the film coating comprises a filler.

21. 21. The pharmaceutical dosage form of claim 20, wherein the filler is talc.

22. 10. The pharmaceutical dosage form of claim 1, wherein the film coating comprises a filler, the filler being from about 5% to about 45% by weight of the film coating.

23. 10. The pharmaceutical dosage form of claim 1, wherein the film coating comprises a pigment / opacifier.

24. 24. The pharmaceutical dosage form of claim 23, wherein the pigment / opacifier is titanium dioxide.

25. 10. The pharmaceutical dosage form of claim 1, wherein the film coating comprises a pigment / opacifier, the pigment / opacifier being up to about 40% by weight of the film coating.

26. The film coating comprises, based on the weight of the film coating: (a) from about 25% to about 55% by weight of a film-forming polymer; (b) about 5% to about 30% by weight of a plasticizer; (c) about 5% to about 45% by weight of a filler; and (d) up to about 40% by weight of a pigment / opacifier 2. The pharmaceutical dosage form of claim 1, comprising:

27. 10. The pharmaceutical dosage form of claim 1, wherein the film coating comprises OPADRY® II.

28. 2. The pharmaceutical dosage form of claim 1, wherein the film coating is OPADRY® II.

29. 10. The pharmaceutical dosage form of claim 1, wherein the film coating comprises from about 3.5% to about 15% by weight of each granule.

30. 10. The pharmaceutical dosage form of claim 1, wherein the at least one pharmaceutically acceptable carrier comprises a diluent.

31. 31. The pharmaceutical dosage form of claim 30, wherein the diluent is silicified microcrystalline cellulose, isomalt, or a mixture thereof.

32. 31. The pharmaceutical dosage form of claim 30, wherein the diluent is a mixture of silicified microcrystalline cellulose and isomalt.

33. 31. The pharmaceutical dosage form of claim 30, wherein each granule comprises from about 25% to about 65% by weight of said diluent.

34. 31. The pharmaceutical dosage form of claim 30, wherein each granule comprises about 45% by weight of said diluent.

35. 10. The pharmaceutical dosage form of claim 1, wherein the at least one pharmaceutically acceptable carrier comprises a disintegrant.

36. 36. The pharmaceutical dosage form of claim 35, wherein the disintegrant is partially pregelatinized corn starch.

37. 36. The pharmaceutical dosage form of claim 35, wherein each granule comprises from about 5% to about 10% by weight of said disintegrant.

38. 36. The pharmaceutical dosage form of claim 35, wherein each granule comprises about 7.5% by weight of the disintegrant.

39. 10. The pharmaceutical dosage form of claim 1, wherein the at least one pharmaceutically acceptable carrier comprises a binder.

40. 40. The pharmaceutical dosage form of claim 39, wherein the binder is hydroxypropyl methylcellulose.

41. 40. The pharmaceutical dosage form of claim 39, wherein each granule comprises from about 2% to about 8% by weight of said binder.

42. 40. The pharmaceutical dosage form of claim 39, wherein each granule comprises about 5% by weight of the binder.

43. 10. The pharmaceutical dosage form of claim 1, wherein the at least one pharmaceutically acceptable carrier comprises a lubricant.

44. 44. The pharmaceutical dosage form of claim 43, wherein the lubricant is magnesium stearate.

45. 44. The pharmaceutical dosage form of claim 43, wherein each granule comprises from about 0.5% to about 5% by weight of said lubricant.

46. 44. The pharmaceutical dosage form of claim 43, wherein each granule contains about 2.5% by weight of said lubricant.

47. 10. The pharmaceutical dosage form of claim 1, wherein each granule contains about 15% to about 30% by weight of valbenazine, or a pharmaceutically acceptable salt thereof, based on the weight of the free base.

48. 2. The pharmaceutical dosage form of claim 1, wherein each granule contains about 22% by weight of valbenazine, or a pharmaceutically acceptable salt thereof, based on the weight of the free base.

49. 2. The pharmaceutical dosage form of claim 1, wherein the valbenazine or a pharmaceutically acceptable salt thereof is valbenazine ditosylate.

50. Each granule is (a) about 5% to about 40% by weight of valbenazine, or a pharmaceutically acceptable salt thereof, based on the weight of the free base; (b) about 25% to about 65% by weight of a diluent; (c) about 0.5% to about 15% by weight of a disintegrant; (d) about 0.5% to about 10% by weight of a binder; and (e) about 0.5% to about 5% by weight of a lubricant 2. The pharmaceutical dosage form of claim 1, comprising:

51. 10. The pharmaceutical dosage form of claim 1, wherein each granule contains an average amount of about 1.5 mg to about 2.5 mg of valbenazine, or a pharmaceutically acceptable salt thereof, based on the weight of the free base.

52. 2. The pharmaceutical dosage form of claim 1, wherein each granule contains an average amount of about 2 mg of valbenazine, or a pharmaceutically acceptable salt thereof, based on the weight of the free base.

53. 2. The pharmaceutical dosage form of claim 1, wherein each granule contains an average amount of about 3 mg to about 4.5 mg of valbenazine ditosylate.

54. 2. The pharmaceutical dosage form of claim 1, wherein each granule contains an average amount of about 3.7 mg of valbenazine ditosylate.

55. 10. The pharmaceutical dosage form of claim 1, which is a capsule.

56. 56. The pharmaceutical dosage form of claim 55, wherein the capsule is size 00 or smaller.

57. 56. The pharmaceutical dosage form of claim 55, wherein the capsule is a sprinkle capsule.

58. 10. A unit dosage form comprising the pharmaceutical dosage form of claim 1, wherein the valbenazine, or a pharmaceutically acceptable salt thereof, is present in an amount of about 10 mg to about 200 mg, based on the weight of the free base.

59. 59. The unit dosage form of claim 58, wherein the valbenazine, or a pharmaceutically acceptable salt thereof, is present in an amount of about 20 mg to about 80 mg based on the weight of the free base.

60. 60. A pharmaceutical dosage form according to any one of claims 1 to 57 or a unit dosage form according to claim 58 or 59 for use in a method of administering valbenazine, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, said method comprising: (a) providing said pharmaceutical dosage form or said unit dosage form; (b) sprinkling a plurality of granules onto the soft food; and (c) orally administering the soft food 10. A pharmaceutical dosage form or unit dosage form comprising:

61. 61. The pharmaceutical dosage form or unit dosage form of claim 60, wherein the soft food is selected from applesauce, yogurt, pudding, ice cream, baby food, and soy or grain-based products.

62. 60. A pharmaceutical dosage form according to any one of claims 1 to 57 or a unit dosage form according to claim 58 or 59 for use in a method of administering valbenazine, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, said method comprising orally administering said pharmaceutical dosage form or said unit dosage form.

63. 60. A capsule comprising the pharmaceutical dosage form of any one of claims 1 to 57 or the unit dosage form of claim 58 or 59 for use in a method of administering valbenazine, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, said method comprising orally administering the capsule.

64. 58. A pharmaceutical dosage form according to any one of claims 1 to 57 for the treatment of a neurological disease or disorder or a psychiatric disease or disorder in a patient in need thereof.

65. 65. The pharmaceutical dosage form of claim 64, wherein the patient has a swallowing disorder.

66. 65. The pharmaceutical dosage form of claim 64, wherein the patient is a pediatric patient.

67. 65. The pharmaceutical dosage form of claim 64, wherein the neurological disease or disorder or psychiatric disease or disorder is hyperactivity, a mood disorder, a bipolar disorder, schizophrenia, schizoaffective disorder, mania in a mood disorder, depression in a mood disorder, treatment-resistant obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor ataxia syndrome, autism spectrum disorder, Rett syndrome, or choreoacanthocytosis.

68. 65. The pharmaceutical dosage form of claim 64, wherein the neurological disease or disorder or psychiatric disease or disorder is a hyperkinetic movement disorder.

69. 69. The pharmaceutical dosage form of claim 68, wherein the hyperkinetic movement disorder is tardive dyskinesia.

70. 69. The pharmaceutical dosage form of claim 68, wherein the hyperkinetic movement disorder is Tourette's syndrome.

71. 69. The pharmaceutical dosage form of claim 68, wherein the hyperkinetic movement disorder is Huntington's disease.

72. 69. The pharmaceutical dosage form of claim 68, wherein the hyperkinetic movement disorder is a tic.

73. 69. The pharmaceutical dosage form of claim 68, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

74. 69. The pharmaceutical dosage form of claim 68, wherein the hyperkinetic movement disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless legs syndrome, or tremor.

75. 65. The pharmaceutical dosage form of claim 64, wherein the patient has 22q11.2 deletion syndrome.

76. 65. The pharmaceutical dosage form of claim 64, wherein the patient is predisposed to developing a psychiatric disorder due to the patient having 22q11.2 deletion syndrome.

77. 65. The pharmaceutical dosage form of claim 64, wherein the patient has a COMT haploinsufficiency.

78. 65. The pharmaceutical dosage form of claim 64, wherein the patient is predisposed to developing a psychiatric disorder due to the patient having a COMT haploinsufficiency.

79. 1. A process for preparing granules containing a quantity of valbenazine, or a pharmaceutically acceptable salt thereof, comprising: (1) roller compacting a blend comprising milled isomalt (item 3), milled valbenazine ditosylate (item 1), milled silicified microcrystalline cellulose (item 2), milled partially pregelatinized corn starch (item 4), milled hypromellose (item 5), and sieved magnesium stearate (item 6) to obtain a roller compacted ribbon material; (2) milling the roller-compacted ribbon material; (3) blending additional sieved magnesium stearate with the milled roller-compacted ribbon material of step (2) to obtain a final blend; and (4) Pressing the final blend to obtain granules. The process includes:

80. 1. A process for preparing granules containing a quantity of valbenazine, or a pharmaceutically acceptable salt thereof, comprising: (1) blending isomalt (item 3), valbenazine ditosylate (item 1), and silicified microcrystalline cellulose (item 2); (2) milling the mixture of step (1) and transferring the milled material to a bin; (3) blending the mixture of step (2); (4) milling partially pregelatinized corn starch (item 4) and hypromellose (item 5) and adding the milled mixture comprising items 4 and 5 to the mixture of step (3); (5) blending the mixture of step (4); (6) adding sieved magnesium stearate (Item 6) to the mixture of step (5); (7) blending the mixture of step (6); (8) roller compacting the mixture of step (7) to obtain a roller compacted ribbon material; (9) milling the roller-compacted ribbon material; (10) blending additional sieved magnesium stearate with the milled roller-compacted ribbon material of step (9) to obtain a final blend; and (11) Pressing the final blend to obtain granules. The process includes:

81. 81. The process of claim 79 or 80, further comprising coating the granules with a film coating.

82. 82. The process of claim 81, wherein the film coating comprises OPADRY® II.

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