Liquid compositions of valbenazine for oral administration

Abstract

The present invention relates to a stable pharmaceutical composition comprising valbenazine or its pharmaceutically acceptable salts or derivatives thereof, and a pharmaceutically acceptable carrier for the treatment of patients suffering from tardive dyskinesia, and chorea associated with Huntington disease. The invention further relates to oral liquid stable compositions of valbenazine or its pharmaceutically acceptable salts or derivatives thereof. These compositions demonstrate stability throughout both the manufacturing process and their shelf life. Oral liquid compositions of the present invention are advantageous due to their straightforward manufacturing process and consistent functionality. Furthermore, the said liquid oral compositions are designed to provide a pleasant taste, thereby promoting better patient compliance and facilitating administration. The compositions of the present invention are suitable to administer via nasogastric, gastrostomy, or other enteral tubes.

Description

[0001] LIQUID COMPOSITIONS OF VALBENAZINE FOR ORAL ADMINISTRATION

[0002] FILED OF INVENTION:

[0003] The present disclosure relates, in general, to the pharmaceutical field, and more precisely it relates to the pharmaceutical compositions comprising VMAT2 inhibitors. In particular, the present invention relates to liquid pharmaceutical compositions of S)-2-amino-3-methyl-butyric acid (2R,3R,l lbR)-3-isobutyl-9,10- dimethoxy-l,3,4,6,7,l lb-hexahydro-2H-pyrido[2,l-a]isoquinolin-2-yl ester or its pharmaceutically acceptable salts or derivatives thereof.

[0004] BACKGROUND:

[0005] Valbenazine, chemically identified as (S)-2-amino-3-methyl-butyric acid (2R,3R,l lbR)-3-isobutyl-9,10-dimethoxy-l,3,4,6,7,l lb-hexahydro-2H- pyrido[2,l-a]isoquinolin-2-yl ester, is also referred to as NB 1-98854. Its chemical structure is illustrated in Formula I.

[0006] Valbenazine ditosylate, chemically designated as (S)-(2R,3R,l lbR)-3-isobutyl-

[0007] 9,10-dimethoxy-2,3,4,6,7,l lb-hexahydro-lH-pyrido[2,l-a]isoquinolin-2-yl-2- amino-3-methylbutanoate di(4-methylbenzenesulfonate), is illustrated by the chemical structure shown in Formula II.

[0008]

[0009] (Formula II)

[0010] Valbenazine and its method of synthesis, and its pharmaceutical compositions for the treatment of hyperkinetic disorder thereof have been described in WO 2008 / 058261. Different solid-state forms of Valbenazine or salts thereof have been described in various patent publications including WO 2017 / 075340, WO 2018 / 001335, WO 2018 / 067945, WO 2018 / 130345 and WO 2018 / 153632.

[0011] Dysregulation of dopaminergic systems is a key factor in numerous central nervous system disorders, such as hyperkinetic movement disorders including tardive dyskinesia (TD), schizophrenia, Huntington's disease and bipolar disorder. The vesicular monoamine transporter 2 (VMAT2) protein is crucial for presynaptic dopamine release, as it regulates the uptake of monoamines from the cytoplasm into synaptic vesicles for storage and subsequent release. Inhibitors of vesicular monoamine transporter 2 (VMAT2) have demonstrated efficacy in the treatment of various movement disorders.

[0012] Tardive dyskinesia (TD), is a neurological disorder marked by involuntary movements affecting the orofacial area, including the tongue, lips, jaw, and face, as well as choreoathetoid movements in the limbs and trunk. Individuals with mild TD often remain unaware of these involuntary movements and typically do not pursue treatment. However, as the severity of symptoms escalates, these hyperkinetic movements can interfere with essential functions such as speech, chewing, breathing, facial expressions, limb coordination, walking, and maintaining balance. In the most extreme instances, TD can lead to self-inflicted injuries, abrasions, lacerations, and an inability to perform basic activities such as dressing, eating, or drinking. Patients with TD can show chorea (quick, irregular movements of the extremities) indistinguishable from that seen in cases of Huntington's disease.

[0013] Huntington's disease is a genetic disorder characterized by the progressive degeneration of brain cells, leading to a gradual loss of their functionality. This condition primarily impacts the areas of the brain responsible for voluntary movement and memory. Individuals with Huntington's disease often experience involuntary movements, as well as alterations in cognition, behavior, and personality. The severity of these symptoms tends to increase over time.

[0014] The condition affects regions of the brain responsible for regulating voluntary movements, among other functions. Individuals diagnosed with Huntington's disease exhibit involuntary, dance-like movements known as chorea, alongside unusual body postures. Additionally, they may experience difficulties related to behavior, emotions, cognitive processes, and personality traits. Uncontrolled movements may manifest in various parts of the body, including the fingers, feet, face, or torso. Such movements are indicative of chorea. They tend to intensify when the individual experiences nervousness or distraction; as Huntington's disease advances, these movements can become increasingly pronounced and noticeable.

[0015] Valbenazine has received approval from the U.S. Food and Drug Administration under the brand name INGREZZA® and INGREZZA® SPRINKLE for the treatment of tardive dyskinesia, Huntington disease and the chorea associated with Huntington disease in adult patients. It functions as an inhibitor of vesicular monoamine transporter 2 (VMAT2).

[0016] Valbenazine capsules, marketed under the brand name INGREZZA®, are available in size 1 hard gelatin capsules. Each capsule contains 40 mg, 60 mg, or 80 mg, of equivalent valbenazine as the free base. Treatment of tardive dyskinesia involves the administration of an initial 40 mg dosage of INGREZZA once daily. After one week, the dose is increased to the recommended dosage of 80 mg once daily. Treatment of Chorea associated with Huntington’ s Disease involves administration of the initial dosage of 40 mg INGREZZA once daily. The dose is increased in 20 mg increments every two weeks to the recommended dosage of 80 mg once daily. A dosage of 40 mg or 60 mg once daily may be considered depending on response and tolerability.

[0017] Valbenazine capsules, marketed under the brand name INGREZZAOSPRINKLE. Each capsule contains 40 mg, 60 mg, or 80 mg, of equivalent valbenazine as the free base. Administration of INGREZZA® SRINKLE involves sprinkling the entire content of capsule over a bowl containing a small amount (1 tablespoonful) of soft food such as applesauce, yogurt, or pudding. INGREZZA® SPRINKLE cannot be administered via nasogastric, gastrostomy, or other enteral tubes because it may cause obstruction of enteral tube.

[0018] Numerous patients encounter challenges when attempting to swallow tablets and capsules. This issue can result in various negative outcomes and may contribute to non-adherence to prescribed treatment plans. Research conducted among adults indicates that up to 40% of Americans may be affected by difficulties in swallowing these forms of medication. Those who struggle with swallowing often identify the size of the tablets and capsules as the main factor contributing to their difficulties.

[0019] It has been demonstrated that larger tablets and capsules can impact the transit of drug formulations through the pharynx and esophagus. These larger dosage forms tend to have extended esophageal transit times, which can adversely affect a patient's capacity to swallow certain medications. This situation may lead to the disintegration of the drug within the esophagus or result in injury to the esophageal tissue. At present, valbenazine is offered exclusively in solid dosage forms, including immediate-release capsules and sprinkles for oral administration. This limitation can be problematic for patients who struggle with swallowing solid medications. Furthermore, solid dosage forms may not provide the necessary convenience for those requiring ongoing treatment.

[0020] Consequently, there is a necessity for enhanced pharmaceutical formulations of valbenazine or a pharmaceutically acceptable salt thereof that are appropriate for oral administration in the management of neurological or psychiatric conditions.

[0021] Thus, the introduction of liquid formulations of valbenazine would be preferable over currently available solid forms, as they would improve patient compliance, convenience, and offer a more flexible dosing regimen.

[0022] The inventors of the current application have successfully prepared oral liquid stable compositions of valbenazine. These compositions demonstrate stability throughout both the manufacturing process and their shelf life. Consequently, this invention represents a notable improvement over existing solid dosage forms of valbenazine, addressing the longstanding need to enhance patient adherence by offering a stable oral liquid composition. Additionally, these oral liquid compositions are advantageous due to their straightforward manufacturing process and consistent functionality. Furthermore, the compositions are designed to provide a pleasant taste, thereby promoting better patient compliance and facilitating administration. Moreover, the compositions are also designed to administer via nasogastric, gastrostomy, or other enteral tubes.

[0023] These pharmaceutical compositions may be classified as immediate-release compositions. Such pharmaceutical compositions enhance patient compliance and allow for dosing flexibility according to the age and body weight of the patients. Additionally, the current pharmaceutical composition pertains to methods for preparing these oral liquid compositions. SUMMARY OF THE INVENTION:

[0024] The following aspects and embodiments thereof described and illustrated below are meant to be exemplary and illustrative, not limiting in scope.

[0025] In one aspect, the invention provides liquid pharmaceutically compositions that are adapted for oral administration and that comprises a therapeutically effective amount of valbenazine or a pharmaceutically acceptable salt or derivative thereof.

[0026] In another aspect the invention provides liquid pharmaceutically compositions comprising valbenazine or a pharmaceutically acceptable salt or derivative thereof effective for the treatment of hyperkinetic movement disorders.

[0027] In another aspect the invention provides liquid pharmaceutically compositions comprising valbenazine or a pharmaceutically acceptable salt or derivative thereof effective for the treatment of tardive dyskinesia, huntington disease, and chorea associated with huntington disease.

[0028] In another aspect the invention provides liquid pharmaceutically compositions comprising valbenazine or a pharmaceutically acceptable salt or derivative thereof in an amount from about 5 mg to about 120 mg.

[0029] In another aspect the invention provides liquid pharmaceutically compositions comprising valbenazine or a pharmaceutically acceptable salt or derivative thereof in an amount about 20 mg / mL.

[0030] In another aspect the invention provides administration of the liquid pharmaceutically compositions from about 2 mL to about 4 mL for the treatment of tardive dyskinesia and chorea associated with Huntington disease. In another aspect the invention provides liquid pharmaceutically compositions comprising valbenazine or a pharmaceutically acceptable salt or derivative thereof that is administered once daily.

[0031] In some embodiment the pharmaceutical compositions described in this invention pertain to a liquid composition comprising a therapeutically effective amount of valbenazine or its pharmaceutically acceptable salts or derivative thereof and atleast one pharmaceutically acceptable carrier.

[0032] In some embodiment the pharmaceutical compositions comprising valbenazine or its pharmaceutically acceptable salts or derivative thereof and atleast one pharmaceutically acceptable carrier wherein the pharmaceutically acceptable carrier is selected from group comprising solvents, co-solvents, wetting agents, emulsifying agents, pH modifying agents, viscosity modifying agents, isotonizing agents, surfactant components, solubilizing agents, thickening agents, colorant agents, sweeteners, flavoring agents, taste masking agents, and antioxidant components.

[0033] In some embodiment the invention relates to pharmaceutical compositions comprising valbenazine or its pharmaceutically acceptable salts or derivative thereof in the form of solutions, suspensions, emulsions, powder for oral solution, powder for oral suspension, powder for oral emulsion, liquid filled capsules, tablet for oral solution, and tablet for oral suspension.

[0034] In some embodiment the invention provides process for the preparation of the liquid pharmaceutical composition wherein said process comprises adding valbenazine or its pharmaceutically acceptable salts or derivative thereof to pharmaceutically acceptable excipients not limited to vehicle or liquid vehicle, surfactant, wetting agents, emulsifying agents, viscosity modifying agents, pH modifying agents, stabilizers, preservatives, antioxidants, taste masking agents. In some embodiment the invention relates to a process for the preparation of the liquid pharmaceutical composition comprises adding valbenazine or its pharmaceutically acceptable salts or derivative thereof in powder form to a liquid vehicle or diluent and then mixing by stirring, shaking, swirling, agitation, inversion, or a combination thereof.

[0035] In some embodiment the invention provides pharmaceutical compositions that are in the form of ready-to-use liquid compositions and said ready-to-use compositions are administered directly to the patients in required doses without any prior preparation e.g. reconstitution in suitable diluent or liquid vehicle such as water.

[0036] In some embodiment the invention offers better patient compliance to the patient suffering from tardive dyskinesia, Huntington disease, and chorea associated with Huntington disease. Additionally, pharmaceutical compositions of the present invention provide dosing flexibility based on age and body weight of the patients.

[0037] In some embodiment the invention provides distinct benefits related to dose titration of valbenazine or its pharmaceutically acceptable salts or derivative thereof during treatment initiation.

[0038] In some embodiment the pharmaceutical compositions described herein can be prepared in various dosage forms appropriate for oral administration such as solutions, suspensions, emulsions, powder for oral solution, powder for oral suspension, powder for oral emulsion, liquid filled capsules, tablet for oral solution, and tablet for oral suspension. The preparation of these dosage forms can be accomplished using standard methods recognized by professionals in the field of pharmaceutical science.

[0039] In some embodiment the pharmaceutical compositions of the present invention are immediate release compositions and may be presented in the form of a solution. Such a solution may consist of water for injection and may optionally incorporate antioxidants, buffers, preservatives, and various other standard additives. The pharmaceutical compositions of the present invention may be aqueous or nonaqueous or hydro-alcoholic.

[0040] In some embodiment the compositions of the present invention provide liquid oral composition comprising about 20 mg / mL valbenazine or its pharmaceutically acceptable salts or derivative thereof for the treatment of tardive dyskinesia and chorea associated with Huntington disease.

[0041] DETAILED DESCRIPTION OF INVENTION:

[0042] The invention will now be described in detail in connection with certain preferred and optional aspects, so that various aspects thereof may be more fully understood and appreciated.

[0043] The present invention relates to the pharmaceutical compositions comprising valbenazine or its pharmaceutically acceptable salts or derivatives thereof, and a pharmaceutically acceptable carrier for the treatment of patients suffering from tardive dyskinesia, Huntington disease, and chorea associated with Huntington disease.

[0044] The present invention relates to the pharmaceutical compositions that provide from about 5 mg to about 120 mg valbenazine or its pharmaceutically acceptable salts or derivatives thereof.

[0045] The present invention relates to the once daily oral administration of the pharmaceutical composition comprising from about 5 mg to about 120 mg valbenazine or its pharmaceutically acceptable salts or derivatives thereof for the treatment of tardive dyskinesia, Huntington disease, and chorea associated with Huntington disease. The compositions of the present invention provide 20 mg / mL valbenazine or its pharmaceutically acceptable salts or derivatives thereof for the treatment of tardive dyskinesia and chorea associated with Huntington disease.

[0046] The compositions of the present invention provide liquid oral composition comprising 20 mg / mL valbenazine or its pharmaceutically acceptable salts or derivatives thereof for the treatment of tardive dyskinesia and chorea associated with Huntington disease.

[0047] The composition of the present invention provides administration of the said liquid oral composition from about 2 mL to about 4 mL for the treatment of tardive dyskinesia and chorea associated with Huntington disease.

[0048] The present invention relates to an immediate release pharmaceutical compositions comprising valbenazine or its pharmaceutically acceptable salts or derivatives thereof, and a pharmaceutically acceptable carrier.

[0049] The present invention relates to the pharmaceutical composition comprising liquid dosage form, powder for oral solution, powder for oral suspension, powder for oral emulsion, liquid filled capsules, tablet for oral solution, and tablet for oral suspension (dispersible tablet).

[0050] In one embodiment, the pharmaceutical compositions described herein can be prepared in various dosage forms appropriate for oral administration.

[0051] In another embodiment, said pharmaceutical composition includes solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems. The preparation of these dosage forms can be accomplished using standard methods recognized by professionals in the field of pharmaceutical science. In another embodiment, the pharmaceutical compositions of the present invention may be presented in the form of a solution.

[0052] In another embodiment, said solution comprises of water for injection and optionally incorporate antioxidants, buffers, preservatives, and various other standard additives. In some embodiment, the pharmaceutical compositions of the present invention may be aqueous or non-aqueous or hydro-alcoholic.

[0053] In another embodiment, the pharmaceutical compositions are selected from the group consisting of a syrup, a drop, a solution, a dispersion, a suspension, and an emulsion.

[0054] In another embodiment, the pharmaceutical compositions of the present invention comprise liquid vehicle and may include one or more additional excipients selected from the group comprising wetting agents, emulsifying agents, suspending agents, pH modifying agents, viscosity modifying agents, isotonizing agents, surfactant, solubilizing agents, thickening agents, coloring agents, sweeteners, flavoring agents, preservative, taste masking agents, and antioxidant components.

[0055] Definitions:

[0056] As used herein, the term “active pharmaceutical ingredient” or “drug” refers to valbenazine or its pharmaceutically acceptable salts thereof or it’s a derivative thereof.

[0057] Valbenazine, chemically identified as (S)-2-amino-3-methyl-butyric acid (2R,3R,l lbR)-3-isobutyl-9,10-dimethoxy-l,3,4,6,7,l lb-hexahydro-2H- pyrido[2,l-a]isoquinolin-2-yl ester, is also referred to as NB 1-98854. Its chemical structure is illustrated in Formula I.

[0058]

[0059] Valbenazine ditosylate, chemically designated as (S)-(2R,3R,l lbR)-3-isobutyl-

[0060] 9,10-dimethoxy-2,3,4,6,7,l lb-hexahydro-lH-pyrido[2,l-a]isoquinolin-2-yl-2- amino-3-methylbutanoate di(4-methylbenzenesulfonate), is illustrated by the chemical structure shown in Formula II. (Formula II)

[0061] As used herein, the term “a derivative thereof’ refers to an ester thereof, a free acid form thereof, a solvate thereof, a deuterated derivative thereof, a hydrate thereof, an N-oxide thereof, a clathrate thereof, a prodrug thereof, a polymorph thereof, a stereoisomer thereof, a geometric isomer thereof, a tautomer thereof, a mixture of tautomers thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a mixture of stereoisomers thereof, an isotope thereof (e.g., tritium, deuterium), or a combination thereof. In some embodiments, the active pharmaceutical ingredient may be administered as a derivative thereof. In some embodiments, reference to a derivative, e.g. a salt thereof, shall be interchangeable with the active pharmaceutical ingredient or any other derivative thereof. For example, unless otherwise stated, valbenazine and / or valbenazine tosylate and / or deuterated valbenazine may be used interchangeably herein. A suitable amount of said active pharmaceutical ingredient or drug present in the pharmaceutical composition of the present invention about 1% w / w to about 75% w / w of the total composition.

[0062] As used herein, “hyperkinetic movement disorder” refers to disorders or diseases characterized by excessive, abnormal, involuntary movements. These disorders include but are not limited to Huntington’s disease, tardive dyskinesia, Tourette syndrome, dystonia, hemiballismus, chorea, senile chorea, or tics.

[0063] As used herein, the term “tardive dyskinesia” (TD) refers to a neurological disorder marked by involuntary movements affecting the orofacial area, including the tongue, lips, jaw, and face, as well as choreoathetoid movements in the limbs and trunk. Individuals with mild TD often remain unaware of these involuntary movements and typically do not pursue treatment. However, as the severity of symptoms escalates, these hyperkinetic movements can interfere with essential functions such as speech, chewing, breathing, facial expressions, limb coordination, walking, and maintaining balance. In the most extreme instances, TD can lead to self-inflicted injuries, abrasions, lacerations, and an inability to perform basic activities such as dressing, eating, or drinking.

[0064] As used herein, the term “Huntington disease” refers to a genetic disorder characterized by the progressive degeneration of brain cells, leading to a gradual loss of their functionality. This condition primarily impacts the areas of the brain responsible for voluntary movement and memory. Individuals with Huntington's disease often experience involuntary movements, as well as alterations in cognition, behavior, and personality. The severity of these symptoms tends to increase over time. As used herein, the term “about” refers to all numerical values relating to amounts, weights, and the like, wherein each particular value is plus or minus 10%.

[0065] The term “pharmaceutically acceptable excipients” as used herein refers to such pharmaceutically acceptable excipients which are known to those skilled in the art for the purposes of preparing liquid pharmaceutical compositions of the present invention. Such pharmaceutically acceptable excipients, without limitation include, vehicles, solvents / co-solvents, solubilizers, solubility enhancing agents, tonicity agents / isotonizing agents, permeation / penetration enhancers, mucoadhesives, viscosity modifying agents, bulking agents / auxiliary suspending agents, wetting agents, anti-foaming agents, anti-caking agents, stabilizing agents, antioxidants, chelating agents, buffering agents / pH modifying agents / pH adjusting agents, surfactants, preservatives, sweetening agents, flavoring agents and the like or any combination thereof. Such pharmaceutically acceptable excipients can be used in an amount which provides the liquid pharmaceutical compositions of the present disclosure desired property for which they are intended or desired to use.

[0066] As used herein, the term “liquid dosage form” refers to a combination or mixture of active pharmaceutical ingredient(s) and non-pharmaceutical components (excipients) is either dissolved or suspended in an appropriate solvent or a blend of solvents. These compositions can be administered through various routes, including oral and parenteral methods such as injection, inhalation, ophthalmic applications, ear canal, nasal cavity, and topical administration.

[0067] As used herein, the term “solution” refers to a homogeneous mixture at the molecular or ionic level, consisting of one or more pharmaceutical active ingredients (the solute) combined with one or more additional substances (the solvent). Under standard ambient conditions, this solution maintains a physical state that allows for easy dispensing from a container through pouring. As used herein, the term “suspension” refers to a composition that contains of finely dispersed drug particles uniformly distributed within vehicles that exhibit low solubility for the drugs. These biphasic liquid dosage forms contain solid particles. Suspensions can be taken orally, as well as administered intravenously and topically. Suspensions are classified as follows based on the particle size of the dispersed phase such as a coarse suspension consists of dispersed particles and a colloidal suspension is a distribution of particles.

[0068] As used herein, the term “emulsion” refers to a liquid dispersive system that comprises tiny droplets of a liquid (the dispersed phase) that are suspended within another liquid that is immiscible with it. The phase that is dispersed is termed the internal or discontinuous phase, while the medium in which this phase is dispersed is referred to as the external or continuous phase.

[0069] As used herein, the term “syrup” refers to concentrated solutions of sugar dissolved in water or other aqueous mediums. In the context of medicine, a medicinal syrup refers to a nearly saturated aqueous solution that contains a dissolved active pharmaceutical ingredient.

[0070] As used herein, the terms “powder for oral suspension” or “powder for oral solution” or “powder for oral emulsion” refers to a powder or granules obtained by conventional techniques known to the skilled artisan when admixed or reconstituted with suitable diluent or aqueous phase such as a water forms an aqueous oral suspension or oral solution or oral emulsion.

[0071] The liquid pharmaceutical compositions of the present invention may also be prepared by reconstitution of dry powder in suitable diluent or media such as water. The dry powder for reconstitution may be in the form of immediate release forms and comprise active pharmaceutical ingredient and one or more suitable excipients selected form the group comprising of fillers, binders, diluents, disintegrants, pore formers, lubricants, glidants, sweeteners, stabilizing agents, suspending agents, emulsifying agents, solubilizing agents, antioxidants, flavoring agents, viscosity modifying agents, surfactants, preservatives and plasticizers. In some embodiments, pharmaceutical composition of the present invention may be reconstituted with suitable diluent, wherein said diluent includes but not limited to one or more a surfactant, a suspending agent, emulsifying agents, solubilizing agents, a viscosity modifying agent, a pH modifying agent, a flavoring agent, a preservative, an antioxidant, a taste masking agent.

[0072] As herein, the term “tablet for oral suspension” or “tablet for oral solution” refers to dispersible tablet which disperses in aqueous phase, e.g. in water, before administration.

[0073] One or more pharmaceutically acceptable excipients may be present in the tablet for oral suspension or tablet in solution, for example, those conventionally used, for example, at least one filler not limited to lactose, ethyl cellulose, microcrystalline cellulose, sugar alcohols not limited to mannitol, sorbitol in an amount of about 1% w / w to 50% w / w of the total composition; at least one disintegrant not limited to cross-linked polyvinylpyrrolidinone (Crospovidone®), sodium starch glycolate, starch, croscarmellose in an amount of about 1% w / w to 35% w / w of the total composition; at least one binder not limited to polyvinylpyridone, hydroxypropylmethyl cellulose in an amount of about 1% w / w to 10% w / w of the total composition; optionally at least one surfactant not limited to sodium lauryl sulfate in an amount of about 1% w / w to 50% w / w of the total composition; at least one glidant not limited to colloidal silicon dioxide, talc in an amount of about 0.01% w / w to 5% w / w of the total composition; at least one lubricant not limited to magnesium stearate, sodium stearyl fumarate in an amount of about 0.01% w / w to 5% w / w of the total composition; at least one pH modifier not limited to citric acid in an amount of about 0.01% w / w to 5% w / w of the total composition; at least one flavor not limited to orange, banana, and strawberry flavor in an amount of about 0.01% w / w to 2% w / w of the total composition. In another embodiment tablet for oral suspension may be prepared by convention techniques known to the skilled artisan not limited to wet granulation, dry granulation, and direct compression.

[0074] As used herein, the term “liquid vehicle” refers to any solvent or carrier fluid in a pharmaceutical product that has no pharmacological role. Liquid vehicles may be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active pharmaceutical agent of the invention can be dissolved, dispersed or suspended in a pharmaceutically acceptable liquid vehicle such aqueous, non-aqueous solvent. The characteristics of the liquid vehicle may be hydrophilic or lipophilic. In certain embodiments, the liquid vehicle may include a combination of hydrophilic and lipophilic materials. Typically, the pharmaceutical composition of the present invention includes a pharmaceutical ingredients mixed, dissolved, dispersed, suspended, or emulsified with a liquid vehicle.

[0075] The liquid vehicle may be an aqueous liquid, such as water, a non-aqueous liquid, such as glycols, e.g., propylene glycol or polyethylene glycol, vegetable oil, triglycerides e.g., medium chain triglycerides, long chain triglycerides, and medium chain partial glycerides, an oil-in-water emulsion or a water-in-oil liquid emulsion, or an aqueous dispersion, such as in glycol, liquid polyethylene glycol, vegetable oil and mixture thereof. The preferred liquid carrier is water.

[0076] In some embodiments, the liquid pharmaceutical compositions in accordance with the invention are provided as substantially non-aqueous. In some embodiments, the vehicle comprises a non-aqueous hydrophobic lipid. In some embodiments, the non-aqueous liquid vehicle comprises a hydrophilic organic compound.

[0077] The pharmaceutical compositions of the present invention may incorporate various liquid vehicles. Liquid vehicles serve as the liquid bases that facilitate the delivery of drugs and other excipients, either in a dissolved or dispersed form. These vehicles can be aqueous, non-aqueous, or a combination of both. The inclusion of nonaqueous solvents or co-solvents in the liquid compositions can enhance the solubility of poorly soluble compounds and improve the chemical stability of the drug. Appropriate solvents, co-solvents, solubilizers, or vehicles that may be utilized in the liquid compositions of the embodiments include, but are not limited to, dichloromethane, acetonitrile, ethyl acetate, acetone, propylene carbonate, water, glycerin, coconut fatty acid diethanolamide, medium and long-chain fatty acids or glycerides, monoglycerides, diglycerides, triglycerides, structured triglycerides, soybean oil, peanut oil, com oil, corn oil monoglycerides, com oil diglycerides, corn oil triglycerides, polyethylene glycol, caprylocaproylmacro glycerides, caproyl 90, propylene glycol, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene castor oil derivatives, castor oil, cottonseed oil, olive oil, safflower oil, peppermint oil, coconut oil, palm seed oil, beeswax, oleic acid, methanol, ethanol, isopropyl alcohol, butanol, methyl isobutyl ketone, methyl ethyl ketone, and similar substances, as well as any combinations thereof.

[0078] A suitable amount of the liquid vehicle, if present, is about 5% w / w to about 50% w / w of the total weight of the composition.

[0079] As used herein, the term “wetting agents” refers to a surface-active agent. Suitable wetting agents are selected from the group comprising anionic, cationic, nonionic, or zwitterionic surfactants, or combinations thereof.

[0080] Suitable examples of wetting agents are sodium lauryl sulphate; cetrimide; polyethylene glycols; polyoxyethylene-polyoxypropylene block copolymers such as poloxamers; polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate; sorbitan fatty acid esters such as sorbitan monostearate; polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan monooleate; polyethylene glycol fatty acid ester such as polyoxyethylene monostearate; polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether; polyoxyethylene castor oil; polaxomers and mixtures thereof. Wetting agents, as referenced in this context, are commonly employed in pharmaceutical compositions, particularly in liquid dosage forms, to achieve a uniform dispersion of solid particles within a liquid medium. This task can be complicated by the presence of a layer of adsorbed air on the surface of the particles. Consequently, even particles with considerable density may remain buoyant on the liquid's surface until the air is entirely displaced. The application of a wetting agent facilitates the elimination of this adsorbed air, allowing the liquid medium to penetrate the particle's pores swiftly. For aqueous vehicles, substances such as alcohol, glycerin, and propylene glycol are often utilized to aid in the removal of adsorbed air from particle surfaces. In contrast, mineral oil is typically employed as a wetting agent for non-aqueous liquid vehicles. Examples of wetting agents include, but are not limited to, Benzalkonium chloride, Benzethonium chloride, Cetylpyridinium chloride, Docusate sodium, Nonoxynol 9, Octoxynol, Poloxamer (including Poloxamer 124, 188, 237, 338, and 407), Polyoxyl 35 castor oil, Polyoxyl 40 hydrogenated castor oil, Polyoxyl 10 oleyl ether, Polyoxyl 20 cetylstearyl ether, Polyoxyl 40 stearate, Polysorbate (20, 40, 60, and 80), Sodium lauryl sulfate, Sorbitan derivatives (monolaurate, monooleate, monopalmitate, and monostearate), Tyloxapol, and various combinations thereof.

[0081] A suitable amount of the wetting agent, if present, is about 5% w / w to about 10% w / w of the total composition.

[0082] As used herein, the term “emulsifying agents” refers to compounds containing both oil-soluble hydrophobic (nonpolar) and water-soluble hydrophilic (polar) portions that act as a stabilizer of the droplets (globules) of the internal phase of an emulsion, by inhibiting flocculation, creaming, and coalescence.

[0083] Suitable examples of emulsifying agents are Potassium laurate, Triethanolamine stearate, Sodium lauryl sulfate, Alkyl polyoxyethylene sulfates, sodium dodecyl sulfate, and Dioctyl sodium sulfosuccinate, Quaternary ammonium compounds, Cetyltrimethyllammonium bromide, and Lauryldimethylbenzylammonium chloride etc. Nonionic: Polyoxyethylene fatty acid derivatives of the sorbitan esters (for example, Tween series), Polyoxyethylene fatty alcohol ethers Sorbitan fatty acid esters Polyoxyethylene alkyl ethers (macrogols) Polyoxyethylene sorbitan fatty acid esters, Polyoxyethylene polyoxypropylene block copolymers (poloxamers), polyethylene glycol 400 monostearate, lanolin alcohols, and ethoxylated lanolin, Hydrophilic colloids, Alginates, Acacia, Tragacanth, Xanthan, and Pectin, Gelatin, Casein, Egg yolk, Wool fat, Cholesterol, Wax, and Lecithin, Colloidal clays (such as attapulgite), Bentonite, and Veegum / Magnesium Aluminum Silicate, Cetyl alcohol, Glyceryl monostearate, Methylcellulose, Sodium carboxymethylcellulose, and Stearic acid and combination thereof.

[0084] A suitable amount of the emulsifying agent, if present, is about 5% w / w to about 10% w / w of the total composition.

[0085] As used herein, the term “suspending agents” refers to compounds added to disperse systems to ensure that any solid particles in the formulation are kept uniformly distributed within the continuous phase, thereby maintaining physical stability of the product.

[0086] Suitable suspending agents are selected from the group comprising cellulose derivatives such as co-processed spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, carboxymethyl cellulose and its salts / derivatives, and microcrystalline cellulose; carbomers; gums such as locust bean gum, xanthan gum, tragacanth gum, arabinogalactan gum, agar gum, gellan gum, guar gum, apricot gum, karaya gum, sterculia gum, acacia gum, gum arabic, and carrageenan; pectin; dextran; gelatin; polyethylene glycols; polyvinyl compounds such as polyvinyl acetate, polyvinyl alcohol, and polyvinyl pyrrolidone; sugar alcohols such as xylitol and mannitol; colloidal silica; and mixtures thereof. Co-processed spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium have been marketed under the trade names Avicel® RC-501, Avicel® RC-581, Avicel® RC-591, and Avicel® CL-611. The suspending agent is present in an amount of not more than about 20% w / w, based on the total weight of the suspension base.

[0087] As used herein, the term “pH modifying agents” refers to agents which buffer the pH to maintain a physiologically compatible pH range to enhance the solubility and stability of the active pharmaceutical agent present in the pharmaceutical composition.

[0088] Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid, sodium hydroxide, sodium citrate, sodium dihydrogen phosphate, trometamol (Tris), hydrochloric acid, ascorbic acid, sodium ascorbate, and glutamic acid, any of the abovementioned sodium salts replaced with potassium salts and / or the like.

[0089] A suitable amount of the pH modifiers, if present, is about 0.01% w / w to about 5% w / w of the total composition.

[0090] As used herein, the term “viscosity modifying agents” refers to agents that are designed to change the thickness or texture of pharmaceutical composition.

[0091] Suitable viscosity modifying agents include but are not limited to polyvinylpyrrolidone (povidone or PVP), carboxymethyl cellulose sodium, chitosan, xanthan, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), galactomannans such as guar, konjac, locust bean gum and mannan, for example, microcrystalline cellulose and combinations thereof. viscosity modifiers including, for example, cellulose or cellulose derivatives such as ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, caboxymethylcellulose, sodium hydroxypropylmethylcellulose, methylcellulose, methylethylcellulose, sodium carboxymethylcellulose, Aerosil (silicon dioxide), cetostearyl alcohol, cetyl alcohol, stearyl alcohol, Gelucires 33 / 01, 39 / 01 and 43 / 01, glyceryl behenate (Compritol 888 A TO), glyceryl palmitostearate (Precirol AT05), Softisans 100, 142, 378 and 649, stearyl alcohol carbomer, xanthan gum, maltodextrin, acacia, tragacanth, povidone and polyvinyl alcohol.

[0092] Other viscosity modifying agents that may be used include but are not limited to carrageenan, cellulose gel, colloidal silicon dioxide, gelatin, propylene carbonate, carbonic acid, alginic acid, agar, carboxyvinyl polymers or carbomers and polyacrylamides, acacia, ester gum, guar gum, gum arabic, ghatti, gum karaya, tragacanth, terra, pectin, tamarind seed, larch arabinogalactan, alginates, locust bean, xanthan gum, starch, veegum, tragacanth, polyvinyl alcohol, gellan gum, hydrocolloid blends, and povidone. Other viscosity modifying agents known in the art can also be used, including but not limited to sodium carboxymethyl cellulose, algin, carageenans, galactomannans, hydropropyl methyl cellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone, sodium carboxymethyl chitin, sodium carboxymethyl dextran, sodium carboxymethyl starch, xanthan gum, and zein.

[0093] A suitable amount of the viscosity modifying agent, if present, is about 5% w / w to about 70% w / w of the total weight of the composition.

[0094] As used herein, the term “tonicity agent or isotonizing agents” refers to compounds that ensures the isotonicity of the pharmaceutical composition.

[0095] In certain embodiments, an isotonic agent or tonicity agent includes, by way of nonlimiting example, dextrose, glycerin, mannitol, sodium chloride, potassium chloride and combinations thereof.

[0096] A suitable amount of the isotonizing agent or tonicity agent, if present, is about 2% w / w to about 50% w / w of the total composition. As used herein, the term “solubilizing agents” refers to agents that aid to solubilize or dissolves the active pharmaceutical ingredient in the pharmaceutical composition.

[0097] Solubilizing agents include but not limited to Capryol 90; Cremophor RH40; Labrafil M 1944 CS; Labrafil M 2125 CS; Lauroglycol 90; PEG MW>4000; Plurol Oleique CC 497 ; poloxamer 124; poloxamer 188; Softigen 701; Softigen 767; Tagat TO; Tween 80; triacetin; triethylcitrate; tributylcitrate; acetyl triethylcitrate; acetyl tributyl citrate; ethyl oleate; ethyl caprylate; ethyl butyrate; triacetin; 2-pyrrolidone; 2-piperidone; N-methylpyrrolidone; M-ethylpyrrolidone; N-hydroxyethyl pyrrolidone; N-octylpyrrolidone; N-laurylpyrrolidone; dimethylacetamide; Miglyol, lanolin, petrolatum, mineral oil and mixtures thereof, solubilizing agents include Capryol 90; Cremophor RH40; Labrafil M 1944 CS; Labrafil M 2125 CS; Lauroglycol 90; PEG MW>4000; Plurol Oleique CC 497; poloxamer 124; poloxamer 188; Softigen 701; Softigen 767; Tagat TO; Tween 80; triacetin; triethylcitrate; tributylcitrate; acetyl triethylcitrate; acetyl tributyl citrate; ethyl oleate; ethyl caprylate; ethyl butyrate; triacetin; 2-pyrrolidone; 2-piperidone; N- methylpyrrolidone; M-ethylpyrrolidone; N-hydroxyethyl pyrrolidone; N- octylpyrrolidone; N-laurylpyrrolidone; dimethylacetamide; Miglyol, lanolin, petrolatum, mineral oil and mixtures thereof.

[0098] A suitable amount of the solubilizing agent, if present, is about 0.01 wt.% to about 50 wt. %, preferably about 0.05 wt. % to about 10 wt. %, of the total weight of the composition.

[0099] As used herein, the term “thickening agents” refers to agents generally thicken the liquid composition which typically improves the mouth-feel of the pharmaceutical composition.

[0100] Suitable thickening agent includes one or more of acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, glycerin, gelatin guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum, and any combination thereof. More preferred thickening agents are glycerin, hydroxypropylmethylcellulose, and xanthan gum, and any combination thereof. Such a thickening agent, if present, will typically form about 0.1 wt.-% to 20 wt.- %, preferably about 0.3 wt.-% to about 15 wt.-%, and more preferably about 0.5 wt.-% to 4 wt.-%, of the total weight of the composition.

[0101] As used herein, the term “taste masking agent” refers to agents that are useful to avoid unpleasant taste effects, such as bitterness, often associated with the active pharmaceutical ingredients. Taste masking agents imparts an unexpected improvement in a taste profile.

[0102] Suitable taste masking agents include but not limited to polymeric and / or non- polymeric pharmaceutically acceptable excipients, cyclodextrins, ion exchange resins including but not limited to Polacriline potassium, Sodium polystyrene sulphonate, carbomers, adsorbents, sugar substitutes, or any combinations thereof. The bitter or unpleasant taste of active pharmaceutical ingredient is masked using pharmaceutically acceptable taste-masking agents by methods including, but not limited to, coating, physical mixing, melt granulation, complexation, adsorption, salt formation or the like.

[0103] A suitable amount of the taste masking agent, if present, is about 10% w / w to 80% w / w of the total weight of the composition

[0104] As used herein, the term “sweeteners” refers to agents that sweeten and mask taste of the pharmaceutical composition to make them palatable to the patient.

[0105] Suitable sweeteners include but not limited to sucrose, fructose, sucralose, sorbitol, xylitol, saccharin, saccharin sodium, aspartame or combinations thereof as a sweetening agent. In certain exemplary embodiments, the aqueous-based pharmaceutical composition contain a pharmaceutically acceptable sweetener such as sucralose. Other exemplary embodiments may include sweeteners such as xylitol, saccharin, and saccharin sodium.

[0106] As used herein, the term “flavoring agents” refers to compounds that provides a desired taste and / or smell. The flavoring agent can be a natural or artificial compound, and it can, but does not have to be, oil-soluble.

[0107] Flavorants include but not limited to isoamyl acetate (or other banana flavorant), benzaldehyde (or other almond flavorant), cinnamic aldehyde (or other cinnamon flavorant), citric acid or ethyl propionate (or other fruity flavorant), methyl anthranilate (or other grape flavorant), limonene (or other orange flavorant), ethyl decadienoate (or other pear flavorant), allyl hexanoate (or other pineapple flavorant), ethyl maltol (or other sugar or cotton candy flavorant), ethylvanillin (or other vanilla flavorant), methyl salicylate (or other wintergreen flavorant), glyceryl monoacetate (E1516 food additive), glyceryl diacetate (E1517 food additive), lemon flavorant, and combinations thereof.

[0108] As used herein, the term “antioxidant” refers to agents that improves the stability of the pharmaceutical composition by preventing or delaying the oxidation of the active pharmaceutical ingredient and / or other excipients.

[0109] The antioxidant component provides long term stability to the liquid compositions. Addition of the antioxidant component can help enhance and ensure the stability of the compositions and renders the compositions stable even after three months at 40° C.

[0110] Suitable antioxidants include but not limited to butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, lecithin, Vitamin E tocopherol, sesamin, sesamol, sesamolin, alpha tocopherol, ascorbic acid, ascorbyl palmitate, fumaric acid, malic acid, sodium ascorbate, citric acid and sodium metabisulphite A suitable amount of the antioxidant, if present, is about 2% w / w to 30% w / w of the total weight of the composition.

[0111] As used herein, the term “preservative” refers to compounds which are used to prevent the growth of bacteria, fungi, mold and other microbes. They are used for their individual antibacterial (destroying and inhibiting the growth of bacteria), antifungal (destroying and inhibiting the growth of fungus), anti-microbial, anti- mycoplasmal, anti-viral and / or anti -prion properties.

[0112] Suitable preservatives can include, but are not limited to, at least one of a benzalkonium chloride, a benzethonium chloride, a chlorohexidine, a phenol, a m- cresol, a benzyl alcohol, an alkyl paraben (methylparaben, ethylparaben, propylparaben, butylparaben, and the like), sodium dehydroacetate, an o-cresol, a p-cresol, a chlorocresol, a phenylmercuric nitrate, a thimerosal, a benzoic acid and any mixture thereof of one or more preservatives. In certain embodiments, preservatives may include the parabens, such as methylparaben, propylparaben, isopropylparaben, butylparaben, and isobutylparaben, and their salts such as sodium butylparaben, benzoic acid and its salts and esters, benzyl alcohol, urea derivatives such as diazofidinyl urea, imidazolidinyl urea, and DMDM hydantoin, sorbic acid and its salts, and the like.

[0113] A suitable amount of the preservative, if present, is about 0.0001% w / w to 0.2% w / w of the total weight of the composition.

[0114] In another embodiment, the pharmaceutical compositions of the present invention may provide preservative-free pharmaceutical compositions.

[0115] As used herein, the term “stabilizer” refers to agent that promote the stability of the active pharmaceutical ingredient and other excipients of the pharmaceutical composition against unacceptable degradation. Suitable stabilizers include, but are not limited to, saturated, monoenoic, polyenoic, branched, ring-containing, acetylenic, dicarboxylic and functional-group- containing fatty acids such as oleic acid, caprylic acid, capric acid, caproic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, linoleic acid, linolenic acid, eicosapentaenoic acid (EPA), DHA; fatty alcohols such as stearyl alcohol, cetyl alcohol, ceteryl alcohol; other alcohols such as ethanol, isopropyl alcohol, butanol; long chain fatty acid esters, ethers or amides such as glyceryl stearate, cetyl stearate, oleyl ethers, stearyl ethers, cetyl ethers, oleyl amides, stearyl amides; hydrophilic derivatives of fatty acids such as polyglyceryl fatty acids, polyethylene glycol fatty acid esters; polyvinylpyrrolidones, polyvinylalcohols (PVAs), waxes, docosahexaenoic acid and de -hydroabietic acid, fatty acids, fatty alcohols, alcohols, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidones, polyvinylethers, polyvinyl alcohols, hydrocarbons, hydrophobic polymers, moisture-absorbing polymers etc.

[0116] A suitable amount of the stabilizer, if present, is about 5% w / w to about 20% w / w of the total weight of the composition.

[0117] As used herein, the term “coloring agents” refers to compositions or compounds, such as, but not limited to, pigments, dyes and tints, which impart color.

[0118] Typical coloring agents may include but not limited to carotenoids (E160, E161, E164), chlorophyllin (E140, E141), anthocyanins (E163), and betanin (E162). Other colorants such as, annatto (E160b), a reddish-orange dye made from the seed of the achiote, caramel coloring (E150a-d), made from caramelized sugar, carmine (E120), a red dye derived from the cochineal insect, Dactylopius coccus, elderberry juice (E163), lycopene (E160d), paprika (E160c), and turmeric (E100) may also be used.

[0119] As used herein, the terms “stable” or “stability” encompass any characteristic of the liquid compositions of the present invention which may be affected by storage conditions including, without limitation, potency, total impurities, degradation products, specific optical rotation, optical purity, water content, appearance, viscosity, sterility, and color and clarity. The storage conditions which may affect stability include, for example, duration of storage, temperature, humidity, and / or light exposure.

[0120] In another embodiment, the liquid pharmaceutical compositions of the present invention are stable for prolonged time when stored under storage conditions. The term “storage conditions” as used herein without limitation include typical storage conditions such as 2° C.-80C., RH, 30° C.±2° C. / 65±5% RH, 25° C.±2° C. / 40±5% RH, 25° C.±2° C. / 60±5% RH, and 25% RH (NMT=not more than) and accelerated conditions such as RH. The term “prolonged time” as used herein indicates that the liquid pharmaceutical compositions of the present disclosure are stable for at least 1 month, at least 3 months, at least 6 months or at least 12 months or at least 18 months or at least 24 months when stored under storage conditions.

[0121] The methods of use and administration of medicinal products necessitate a significant variation in packaging materials, closures, and containers, which must comply with a diverse array of requirements. The liquid pharmaceutical formulations described herein can be contained in any pharmaceutically acceptable packaging, including but not limited to containers, pumps, spray bottles, dropper bottles, collapsible tubes, glass ampoules, stoppered vials, and pre-filled syringes. These may be constructed from low-density polyethylene (LDPE), high-density polyethylene (HDPE), polyolefin, or polypropylene, depending on the volume of the final dosage form. The containers may consist of clear, transparent, opaque, or amber-colored glass or plastic, utilizing materials such as polyethylene, polyamide, polycarbonate, acrylic multipolymers, polypropylene, polyethylene terephthalate, and polystyrene. The design of closures for these containers may vary in shape and size, and they can also be manufactured from materials including polyethylene, polyamide, polycarbonate, acrylic multipolymers, polypropylene, polyethylene terephthalate, polyvinyl chloride, and polystyrene. The following examples are meant to illustrate the present invention and should not be construed as limiting its scope. EXAMPLES

[0122] Example 1: Valbenazine Liquid oral composition

[0123] Table 1: Valbenazine Liquid oral composition Example 2: Valbenazine liquid oral composition

[0124] Tablet 2: Valbenazine liquid oral composition

[0125]

[0126] Example 3: Valbenazine liquid oral composition

[0127] Tablet 3: Valbenazine liquid oral composition

[0128] Example 4: Valbenazine liquid oral composition

[0129] Tablet 4: Valbenazine liquid oral composition Example 5: Valbenazine liquid oral composition

[0130] Tablet 5: Valbenazine liquid oral composition

[0131] Example 6: Valbenazine liquid oral composition

[0132] Tablet 6: Valbenazine liquid oral composition Example 7: Valbenazine liquid oral composition

[0133] Tablet 7: Valbenazine liquid oral composition

[0134] Example 8: Valbenazine liquid oral capsules

[0135] Tablet 8: Valbenazine liquid oral capsules

[0136] Example 9: Valbenazine liquid oral capsules

[0137] Tablet 9: Valbenazine liquid oral capsules Example 10: Valbenazine liquid oral capsules

[0138] Tablet 10: Valbenazine liquid oral capsules

[0139] Example 11: Valbenazine liquid oral capsules

[0140] Tablet 11: Valbenazine liquid oral capsules Example 12: Valbenazine liquid oral capsules

[0141] Tablet 12: Valbenazine liquid oral capsules

[0142] Example 13: Valbenazine liquid oral suspension

[0143] Tablet 13: Valbenazine liquid oral suspension Example 15: Valbenazine powder for oral solution

[0144] Tablet 15: Valbenazine powder for oral suspension

[0145] Example 16: Valbenazine liquid oral suspension

[0146] Tablet 14: Valbenazine liquid oral suspension Example 17: Valbenazine liquid oral suspension

[0147] Table 17: Valbenazine liquid oral suspension

[0148] Example 18: Valbenazine powder for oral suspension Table 18: Valbenazine powder for oral suspension

[0149] Example 19: Valbenazine liquid oral emulsion

[0150] Table 19: Valbenazine liquid oral emulsion

[0151] Example 20: Valbenazine powder for oral emulsion

[0152] Table 20: Valbenazine powder for oral emulsion Example 21: Valbenazine tablets for oral suspension (dispersible tablets)

[0153] Table 21: Valbenazine tablets for oral suspension (dispersible tablets)

[0154] Example 22: Valbenazine powder for oral liquid composition

[0155] Table 22: Valbenazine powder for oral liquid composition Degradation product study:

[0156] Example 23: Degradation product data for reconstituted oral composition (Example 22 reconstituted with purified water with 20 mg / mL concentration)

[0157] Table 23: Degradation product data for reconstituted oral composition (Example 22 reconstituted with purified water with 20 mg / mL concentration)

[0158] VLBRC-3 is the active metabolite for Valbenazine NMT: Not More Than

[0159] Example 24: Degradation product data for reconstituted oral composition (Example 22 reconstituted with purified water with 20 mg / mL concentration and stored in ambered colored glass bottle)

[0160] Table 24: Degradation product data for reconstituted oral composition (Example 22 reconstituted with purified water with 20 mg / mL concentration and stored in ambered colored glass bottle)

[0161] VLBRC-3 is the active metabolite for Valbenazine

[0162] NMT: Not More Than

[0163] Nasogastric Compatibility Study:

[0164] Example 25: Assay for reconstituted oral liquid composition of Valbenazine 20 mg / mL passed through Nasogastric Tube. (Reconstituted composition of

[0165] Example 22)

[0166] Table 25: Assay for reconstituted oral liquid composition of Valbenazine 20 mg / mL passed through Nasogastric Tube. (Reconstituted composition of Example 22 with 20 mg / mL concentration)

Claims

CLAIMSClaim 1. A stable pharmaceutical composition comprising (i) valbenazine or its pharmaceutically acceptable salts thereof or it’s a derivative thereof; (ii) at least one pharmaceutically acceptable excipient.Claim 2. The stable pharmaceutical composition according to claim 1, wherein said composition is suitable for oral administration.Claim 3. The stable pharmaceutical composition according to claim 1, wherein said composition comprises about 5 mg to about 120 mg dose of valbenazine or its pharmaceutically acceptable salts or derivatives thereof.Claim 4. The stable pharmaceutical composition according to claim 1, wherein said composition comprises about 5 mg to about 120 mg dose of valbenazine or its pharmaceutically acceptable salts or derivatives thereof for the treatment of tardive dyskinesia, and chorea associated with Huntington disease.Claim 5. The stable pharmaceutical composition according to claim 1, wherein said composition is suitable for liquid dosage form, powder for oral solution, powder for oral suspension, liquid filled capsules, tablet for oral solution, tablet for oral suspension, dispersible tablet.Claim 6. The stable pharmaceutical composition according to claim 5, wherein said liquid dosage form is selected from groups comprising of solutions, suspensions, and emulsions.Claim 7. The stable pharmaceutical composition according to claim 5 and claim 6, wherein said composition provides 20 mg / mL valbenazine or its pharmaceutically acceptable salts or derivatives thereof for the treatment of tardive dyskinesia and chorea associated with Huntington disease.Claim 8. The stable pharmaceutical composition according to claim 5 and claim 6, wherein said composition provides oral administration from about 2 mL to about 4 mL for the treatment of tardive dyskinesia and chorea associated with Huntington disease.Claim 9. The stable pharmaceutical composition according to claim 1, wherein said at least one excipient selected from group comprising of liquid vehicles, solvents, co-solvents, solubilizers, solubility enhancing agents, tonicity agents, permeation enhancers, viscosity modifying agents, , suspending agents, wetting agents, stabilizing agents, antioxidants, chelating agents, buffering agents, pH modifying agents, surfactants, preservatives, sweetening agents, flavoring agents or any combination thereof.Claim 10. The stable pharmaceutical composition according to claim 1 and claim 5, wherein said powder for oral solution, powder for oral suspension tablet for oral solution, tablet for oral suspension, dispersible tablet is in the form of immediate release forms, and said at least one excipient selected from group comprising of fillers, binders, diluents, disintegrants, lubricants, glidants, sweeteners, stabilizing agents, suspending agents, emulsifying agents, solubilizing agents, antioxidants, flavoring agents, viscosity modifying agents, surfactants, preservatives and combination thereof.Claim 11. The stable pharmaceutical composition according to claim 10, wherein said composition is reconstituted with suitable diluent or liquid vehicle.Claim 12. The stable pharmaceutical composition according to preceding claims, wherein administration of the said composition is suitable via nasogastric, gastrostomy, or other enteral tubes.

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