DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to and the benefit of Indian Patent Application No. 20242102561 filed on Mar 21, 2024.

FIELD OF THE INVENTION:
The present invention relates to compositions of Deutetrabenazine having enhanced bioavailability, more specifically stable extended release compositions comprising Deutetrabenazine and pharmaceutically acceptable excipients and method of manufacturing thereof. The invention also relates to the use of said stable composition for the treatment of hyperkinetic movement disorders deriving from conditions such as Huntington's disease, tardive dyskinesia, Tourette syndrome, levodopa-induced dyskinesia and dyskinesia in cerebral palsy.

BACKGROUND OF THE INVENTION:
Deutetrabenazine ((RR, SS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2- methylpropyl)-2H-benzo[a]quinolizin-2-one) is a vesicular monoamine transporter type 2 (VMAT2). The biologically active metabolites formed from deutetrabenazine (alpha- dihydrodeutetrabenazine [a-deuHTBZ] and beta-dihydrodeutetrabenazine [ß-deuHTBZ]), together identified as “deuHTBZ”, are potent inhibitors of VMAT2 binding.

The molecular formula for deutetrabenazine is C19H21D6NO3. Deutetrabenazine is a racemic mixture containing the following structures:

Deutetrabenazine is commercially available United States as twice daily product and once daily products. Twice daily product is available under the brand name AUSTEDO® in 6mg, 9mg and 12mg tablets. Once daily product is available under the brand name AUSTEDO® XR in 6mg, 12mg and 24mg extended-release tablets.
U.S. Patent No 8,524,733 discloses compound deutetrabenazine or a pharmaceutically acceptable salt thereof, method of treatment of chronic hyperkinetic disorders and pharmaceutical compositions thereof.
US Patent No. 9,550,780 discloses crystalline form I and crystalline form II of deutetrabenazine. Also discloses pharmaceutical composition comprising a pharmaceutically acceptable carrier and crystalline deutetrabenazine form I having deuterium enrichment of no less than about 90%, and having different X-ray diffractogram peaks.
US Patent No. 9,233,959 discloses oral pharmaceutical composition comprising about 2% and about 18% of d6-tetrabenazine; between about 60% and about 70% mannitol; between about 15% and about 25% microcrystalline cellulose; between about 1% and about 10% of a polyvinylpyrrolidone; between about 0.5% and about 2% of a polysorbate; between about 5% and about 20% of a poly (ethylene oxide) polymer; and between about 0.5% and about 2% of magnesium stearate.
US Patent No. 10,959,996 discloses method of transitioning a human from tetrabenazine to deutetrabenazine for the treatment of chorea associated with Huntington's disease.
US Patent No. 11,311,488 discloses osmotic dosage forms for once daily administration of deutetrabenazine to a subject in need thereof comprising a. a tablet core comprising an active layer comprising an amount of deutetrabenazine microparticles and a push layer; b. a semipermeable layer surrounding the tablet core; and c. a port extending through the semipermeable layer into the tablet core.
Indian patent application No. 202141028671 discloses pharmaceutical composition comprising Deutetrabenazine and suitable pharmaceutical excipients. The invention also relates to the methods of preparation of the composition having improved stability and dissolution profile. It also discloses 1-4% w/w of Deutetrabenazine, 2-10% of rate controlling polymers comprising hypromellose and xanthan 30 gum and 1-10% w/w of binder comprising povidone.
Nitrosamine impurities are possible in the synthesis of deutetrabenazine or its pharmaceutical salt thereof and manufacturing of the pharmaceutical composition comprising deutetrabenazine and pharmaceutically acceptable excipients. The Nitrosamine impurities may originate from any or all of the active pharmaceutical ingredient, excipients, pharmaceutical packaging materials, and/or manufacturing process and equipment. Examples of deutetrabenazine impurities include, but are not limited to, N-Nitroso deutetrabenazine, N-Nitrosodimethyl amine (“NDMA”), N-Nitrosodiethyl amine (“NDEA”), N-Nitrosodiisopropylamine (“NDIPA”), NNitrosoethylisopropylamine (“NIPEA”), N-nitroso-N-methyl-4-aminobutyric acid (“NMBA”), N-Nitrosodibutylamine (“NDBA”), and N-Methyl-N phenylnitrosamine (“NMPA”). Nitrosamines are generally formed when a secondary or tertiary amine reacts with a nitrosating agent. While the amounts of the Nitrosamine impurities in drugs is generally low, some levels have been above the U.S. Food and Drug Administration’s acceptable daily limit, potentially exposing many people to a slightly increased risk of cancer. Because of the aforementioned health-related effects, stringent limitations have been placed upon the permissible amounts of nitrosamine impurities in drug products. Because of the exceptionally low allowable limits for nitrosamine impurities in these products it become important to control the nitrosamine impurities during synthesis of active pharmaceutical ingredient or drug formulation.
There is still a need to develop to stable composition comprising deutetrabenazine which exhibits prolonged stability and also convenient to manufacture at large scale. The present inventors have developed solid pharmaceutical composition of Deutetrabenazine and unexpectedly found that said composition have improved stability and dissolution profile coupled with simple manufacturing process and it is bioequivalence to commercially available AUSTEDO® XR. Additionally, there is a need to develop pharmaceutically acceptable deutetrabenazine compositions wherein the amount of nitrosamine impurity is less than the FDA acceptable intake limit of the nitrosamine impurity based on maximum daily dose of deutetrabenazine.

SUMMARY OF THE INVENTION:

In one aspect, the present invention relates to a pharmaceutical composition comprising Deutetrabenazine and one or more pharmaceutically acceptable excipient(s).
In another aspect, the present invention relates to a pharmaceutical composition comprising Deutetrabenazine and one or more pharmaceutically acceptable excipient diluents, release modifiers, binder, antioxidants, solvents, lubricants, glidants, plasticizer, coating materials.
In another aspect, the present invention relates to an extended release dosage forms for once daily administration of deutetrabenazine to a subject in need thereof comprising: a) a tablet core comprising deutetrabenazine, diluent, binder, antioxidant, solvent and lubricant; b) a seal coating of tablet core using film forming agent, plasticizer and solvent c) an extended release coating surrounding the tablet core; d) a port extending through the extended release coating into the tablet core; e) an optional external coating of deutetrabenazine surrounding the extended release coating; and f) a film coating.
In another aspect, the present invention relates to an extended release dosage forms for once daily administration of deutetrabenazine to a subject in need thereof comprising: a) a tablet core comprising deutetrabenazine, diluent, binder, antioxidant, solvent and lubricant; b) a seal coating of tablet core using film forming agent, plasticizer and solvent; c) an extended release coating surrounding the tablet core; d) a port extending through the extended release coating into the tablet core; and e) an optional external coating of deutetrabenazine surrounding the extended release coating; wherein about 60% w/w to about 80% w/w of the total amount of deutetrabenazine present in the dosage form is present within the tablet core and wherein about 20 % w/w to about 40% w/w of the total amount of deutetrabenazine present in the dosage form, is present in the external coating.
In another aspect, the present invention relates to an extended release dosage forms for once daily administration of deutetrabenazine to a subject in need thereof comprising: a) a tablet core comprising deutetrabenazine, diluent, binder, antioxidant, solvent and lubricant; b) a seal coating of tablet core using film forming agent, plasticizer and solvent c) an extended release coating surrounding the tablet core; d) a port extending through the extended release coating into the tablet core; e) an optional external coating of deutetrabenazine surrounding the extended release coating; and f) a film coating; wherein said extended release dosage forms for once daily administration of deutetrabenazine is in the form of osmotic dosage form.
In another aspect, the present invention relates to an extended release dosage forms for once daily administration of deutetrabenazine to a subject in need thereof comprising: a) a tablet core comprising about 0.5 % w/w to about 10 % w/w of Deutetrabenazine; about 20 % w/w to about 80 % w/w of one or more diluents selected from the group consisting of dextrates, lactose, dicalcium phosphate, mannitol; about 2 % w/w to about 20 % w/w of one or more binders selected from the group consisting of hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, copovidone, polyvinyl pyrrolidone; about 0.01 % w/w to about 1 % w/w of one or more antioxidants selected from the group consisting of butylated hydroxyanisole, butylated hydroxytoluene; about 0.5 % w/w to about 2 % w/w of one or more lubricants selected from the group consisting of magnesium stearate, sodium stearyl fumarate; and solvent system; b) a seal coating of tablet core comprises about 1% w/w to about 5 % w/w of one or more film forming agent selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose; about 0.05 % w/w to about 1 % w/w of one or more plasticizer selected from the group consisting of polyethylene glycol, triacetin, acetylated monoglycerides, citrate esters (e.g., triethyl citrate), or phthalate esters (e.g., diethyl phthalate) and solvent system; c) an extended release coating surrounding the tablet core comprises about 1 % w/w to about 15 % w/w of one or more extended release polymers selected from the group consisting of cellulose acetate, hydroxypropyl methyl cellulose; about 0.1 % w/w to about 1 % w/w of one or more plasticizer selected from the group consisting of polyethylene glycol, triacetin, acetylated monoglycerides, citrate esters (e.g., triethyl citrate), or phthalate esters (e.g., diethyl phthalate) and solvent system; d) a port extending through the extended release coating into the tablet core; and e) an external coating of deutetrabenazine surrounding the extended release coating comprises about 0.1 % w/w to about 5 % w/w of Deutetrabenazine; about 1 % w/w to about 10 % w/w of one or more film former selected from the group consisting of hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose; about 0.1 % w/w to about 2 % w/w of one or more plasticizer selected from the group consisting of polyethylene glycol, triacetin and solvent system; f) about 1 % w/w to about 5 % w/w of film coating material comprises polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide.
In another aspect, the present invention relates to an extended release tablet composition comprising: a) a tablet core comprising about 1 % w/w to about 10 % w/w of Deutetrabenazine; about 10 % w/w to about 40 % w/w of mannitol; ; about 10 % w/w to about 40 % w/w of dextrate; about 5 % w/w to about 12 % w/w of hydroxypropyl methyl cellulose; about 3 % w/w to about 12 % w/w of hydroxyethyl cellulose; about 0.05 % w/w to about 0.2 % w/w of butylated hydroxyanisole; about 0.05 % w/w to about 0.2 % w/w of butylated hydroxytoluene; about 0.5 % w/w to about 1.2 % of magnesium stearate, and solvent system; b) a seal coating of tablet core (a) comprises about 1 % w/w to about 5 % w/w of hydroxypropyl cellulose; about 0.05 % w/w to about 0.1 % w/w of polyethylene glycol, and solvent system; c) an extended release coating surrounding the seal coated tablet core (b) comprises about 1 % w/w to about 15 % w/w of cellulose acetate; about 0.1 % w/w to about 0.85 % w/w of polyethylene glycol, and solvent system; wherein the extended release coating comprises about 10 % w/w to about 15 % w/w of the total composition comprises combination of cellulose acetate; and polyethylene glycol; d) a port extending through the extended release coating into the tablet core; and e) an external coating of deutetrabenazine surrounding the extended release coating comprises about 0.2 % w/w to 4 % w/w of Deutetrabenazine; about 2 % w/w to about 8 % w/w of hydroxypropyl methylcellulose; about 0.02 % w/w to 0.1 % w/w of butylated hydroxyanisole, and solvent system; f) about 2 % w/w to about 5 % w/w of film coating material.
In another aspect, the present invention relates to an extended release tablet composition comprising: a) a tablet core comprising about 1.2 % w/w of Deutetrabenazine; about 30 % w/w of mannitol; about 30 % w/w of dextrate; about 9 % w/w of hydroxypropyl methyl cellulose; about 7 % w/w of hydroxyethyl cellulose; about 0.1 % w/w of butylated hydroxyanisole; about 0.1 % w/w of butylated hydroxytoluene; about 0.8 % w/w of magnesium stearate, and solvent system; b) a seal coating of tablet core (a) comprises about 2.2 % w/w of hydroxypropyl cellulose; about 0.12 % w/w of polyethylene glycol, and solvent system; c) an extended release coating surrounding the seal coated tablet core (b) comprises about 1 % w/w to about 15 % w/w of cellulose acetate; about 0.1 % w/w to about 0.85 % w/w of polyethylene glycol, and solvent system; wherein the extended release coating comprises about 10 % w/w to about 15 % w/w of the total composition comprises combination of cellulose acetate; and polyethylene glycol; d) a port extending through the extended release coating into the tablet core; and e) an external coating of deutetrabenazine surrounding the extended release coating comprises about 0.5 % w/w of Deutetrabenazine; about 6 % w/w of hydroxypropyl methylcellulose; about 0.04 % w/w of butylated hydroxyanisole, and solvent system; f) about 3 % w/w of film coating material.
In another aspect, the present invention relates to an extended release tablet composition comprising: a) a tablet core comprising about 5 % w/w of Deutetrabenazine; about 26 % w/w of mannitol; about 26 % w/w of dextrate; about 9 % w/w of hydroxypropyl methyl cellulose; about 9 % w/w of hydroxyethyl cellulose; about 0.11 % w/w of butylated hydroxyanisole; about 0.11 % w/w of butylated hydroxytoluene; about 0.8 % w/w of magnesium stearate, and solvent system; b) a seal coating of tablet core (a) comprises about 2.2 % w/w of hydroxypropyl cellulose; about 0.12 % w/w of polyethylene glycol, and solvent system; c) an extended release coating surrounding the seal coated tablet core (b) comprises about 1 % w/w to about 15 % w/w of cellulose acetate; about 0.1 % w/w to about 0.85 % w/w of polyethylene glycol, and solvent system; wherein the extended release coating comprises about 10 % w/w to about 15 % w/w of the total composition comprises combination of cellulose acetate; and polyethylene glycol; d) a port extending through the extended release coating into the tablet core; and e) an external coating of deutetrabenazine surrounding the extended release coating comprises about 2 % w/w of Deutetrabenazine; about 6 % w/w of hydroxypropyl methylcellulose; about 0.03 % w/w of butylated hydroxyanisole, and solvent system; f) about 3 % w/w of film coating material.
In yet another aspect, the present invention further relates to stable pharmaceutical composition of deutetrabenazine which is substantially free of nitrosamine impurity.
In yet another aspect of the present invention provides a stable pharmaceutical composition comprising deutetrabenazine, wherein the amount of nitrosamine impurity after exposure of the pharmaceutical composition to 40°C/75% RH is less than the FDA acceptable limit based on maximum daily dose of deutetrabenazine.
In another aspect, the present invention relates to an extended release dosage forms for once daily administration of deutetrabenazine to a subject in need thereof comprising: a) a push layer comprising dry mix which contains about 15 % w/w to about 40 % w/w of Polyethylene Oxide; about 1 % w/w to about 5 % w/w of Sodium Chloride; about 0.5 % w/w to about 5 % w/w of hydroxypropylmethyl cellulose; about 0.02 % w/w to about 2 % w/w of Magnesium Stearate; and solvent system; b) a pull layer comprising dry mix which contains about 1% w/w to about 10 % w/w of deutetrabenazine; about 30 % w/w to about 60 % w/w of Polyethylene Oxide; about 0.5 % w/w to about 5 % w/w of hydroxypropylmethyl cellulose; about 1 % w/w to about 5 % w/w of Sodium Chloride; about 0.01 % w/w to about 1.5 % w/w of one or more preservatives selected from the group consisting of Butylated Hydroxyanisole, Butylated Hydroxytoluene; about 0.1 % w/w to about 1 % w/w of Magnesium Stearate; and solvent system; c) a seal coating of bilayer tablet comprises about 0.5% w/w to about 5 % w/w of hydroxypropyl cellulose; about 0.05% w/w to about 1 % w/w of Polyethylene Glycol; and solvent system; d) an extended release coating surrounding the tablet core comprises about 1 % w/w to about 15 % w/w of cellulose acetate; about 0.1% w/w to about 1 % w/w of Polyethylene Glycol; and solvent system; e) a port extending through the extended release coating into the tablet core; and f) an external coating of deutetrabenazine surrounding the extended release coating comprises about 0.1 % w/w to about 5 % w/w of Deutetrabenazine; about 1 % w/w to about 10 % w/w of hydroxypropyl methyl cellulose; about 0.5 % w/w to about 2 % w/w of polyethylene glycol; and solvent system; g) about 1 % w/w to about 5 % w/w of film coating material comprises polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide.
In yet another aspect, the blend or tablet composition obtained in present invention are subjected for tests such as dissolution, assay, impurity profiling, related Substances, content uniformity, Hardness, thickness, Friability, Bulk density, tapped density, Hausner ratio (HR), Compressibility Index, Particle Size Distribution, Loss on drying (LOD), etc.
In yet another aspect, the present invention relates to a pharmaceutical composition comprising Deutetrabenazine used for the treatment of hyperkinetic movement disorders deriving from conditions such as Huntington's disease, tardive dyskinesia, Tourette syndrome, levodopa-induced dyskinesia and dyskinesia in cerebral palsy.
In yet another aspect, the present invention relates to method of treating of hyperkinetic movement disorders deriving from conditions such as Huntington's disease, tardive dyskinesia, Tourette syndrome, levodopa-induced dyskinesia and dyskinesia in cerebral palsy by a pharmaceutical composition comprising Deutetrabenazine.
In yet another aspect, the present invention relates to a use of pharmaceutical composition comprising Deutetrabenazine for the treatment of hyperkinetic movement disorders deriving from conditions such as Huntington's disease, tardive dyskinesia, Tourette syndrome, levodopa-induced dyskinesia and dyskinesia in cerebral palsy by a pharmaceutical composition comprising Deutetrabenazine.
DESCRIPTION OF THE INVENTION:

The present invention can be more readily understood by reading the following description of the invention and study of the included examples.
The term “active ingredient” or “active agent” or “drug” used interchangeably, is defined to mean active drug i.e. Deutetrabenazine and its salt, solvate, esters, isomers, polymorphs that induce a desired pharmacological or physiological effect.
By the term “pharmaceutical composition” or “solid oral pharmaceutical composition" or "composition" or "formulation" as used herein refers to a solid dosage form comprising Deutetrabenazine suitable for administration such as a tablet, capsule, mini-tablets, pellets, granules, pills and the like.
The term ‘‘w/w’’ refers to total weight of substance/excipients with respect to total composition weight or the proportion of a particular substance within a mixture, as measured by weight or mass.
The term "about" as used herein means a deviation within 10%, more preferably within 5%, and even more preferably, within 2% of the numbers reported.
The term ‘‘stable’’ refers to formulations that substantially retain the labelled amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug- related impurity contents in the formulations remain within acceptable limits.
The term “impurity” refers to undesired contents present or produced in a pharmaceutical composition.
The term “therapeutically effective amount” is defined to mean the amount or quantity of the active drug is sufficient to elicit an appreciable pharmacological response, when administered to the patient.
As used herein, the term "bioavailability" denotes the degree to which a drug or other substance becomes available to the target tissue after administration.
The use of the word "a" or "an" when used in conjunction with the term "comprising" in the claims and/or the specification may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one."
The term modified-release drug product as used herein is to describe products that alter the timing and/or the rate of release of the drug substance.
The pattern of drug release from modified-release (MR) dosage forms is deliberately changed from that of a conventional (immediate-release) dosage formulation to achieve a desired therapeutic objective or better patient compliance. Types of MR drug products include delayed release (e. g, enteric coated), extended release (ER), and orally disintegrating tablets (ODT).
Extended-release drug products is a dosage form that allows at least a twofold reduction in dosage frequency as compared to that drug presented as an immediate-release (conventional) dosage form. Examples of extended-release dosage forms include controlled-release, matrix release, osmotic system, sustained-release, long- acting drug products and the like. The term "extended release" used herein refer to a dosage form that provides gradual release of Deutetrabenazine over an extended period of time.
Osmotic system dosage form includes various types such as Single chamber osmotic system (e.g. Elementary osmotic pump), Multi chambered osmotic pumps (e.g. Push-pull osmotic pumps, sandwiched osmotic pump and osmotic pump with non-expanding second chamber), Specific types (e.g. Controlled-porosity osmotic pumps, Monolithic osmotic pumps tablet, Colon targeted Oral Osmotic System, Osmotically Brusting Osmotic Pump, Asymmetrical Membrane Osmotic Tablet, Liquid Oral Osmotic System, Effervescent Osmotic pump Tablet, Multiparticulate Delayed-Release System, Self-Emulsified Osmotic Tablet, Telescopic capsule for Delayed-Release).
Delayed-release drug products is a dosage form that releases a discrete portion or portions of drug at a time other than promptly after administration. An initial portion may be released promptly after administration. Enteric-coated dosage forms are common delayed-release products.
Targeted-release drug products is a dosage form that releases drug at or near the intended physiologic site of action. Targeted-release dosage forms may have either immediate- or extended- release characteristics.
In one aspect, the present invention relates to a pharmaceutical composition comprising Deutetrabenazine and one or more pharmaceutically acceptable excipient(s).
In another aspect, the present invention relates to a pharmaceutical composition comprising Deutetrabenazine and one or more pharmaceutically acceptable excipient selected from but not limited to diluents, release modifiers, binder, antioxidants, solvents, lubricants, glidants, plasticizer, coating materials.
“Pharmaceutically acceptable excipient(s)” are components that are added to the pharmaceutical composition other than the active ingredient. Pharmaceutically acceptable excipient(s) includes, but are not limited to, diluents, release modifiers, binder, antioxidants, solvents, lubricants, glidants, plasticizer, coating materials and any other excipient known to the art for making pharmaceutical composition for oral administration, e. g. such as a tablet, capsule, mini-tablets, pellets, granules, pills and the like.
Diluents according to the present invention are selected from, but are not limited to, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, light magnesium oxide, silicon dioxide, titanium dioxide, talc, celluloses, microcrystalline cellulose, mannitol (e.g. Pearlitol 50c, Pearlitol 25 C, Ramritol 60 IP, Pearlitol 160 C ), sorbitol or other sugar alcohols, sucrose, lactose, dextrates (e.g. emdex), dextrin, starch, pregelatinized starch, and the like used either alone or in combinations thereof. Diluent may be present in an amount of about 10 % w/w to about 80 % w/w, preferably about 20 % w/w to about 80% w/w.
Release modifiers or extended release polymers or swellable polymers according to the present invention are selected from, but are not limited to, water soluble polysaccharide gums such as carrageenan, fucoidan, gum ghatti, tragacanth, arabinogalactan, pectin, and xanthan; water- soluble salts of polysaccharide gums such as sodium alginate, sodium tragacanth, and sodium gum ghattate; water-soluble hydroxyalkylcellulose wherein the alkyl member is straight or branched of 1 to 7 carbons such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; synthetic water-soluble cellulose-based lamina formers such as methyl cellulose and its hydroxyalkyl methylcellulose cellulose derivatives such as a member selected from the group consisting of hydroxyethyl methylcellulose, hydroxypropyl methylcellulose such as hydroxypropyl methylcellulose (Hypromellose) (e.g. Methocel®. E, F and K, the 4,000 cps grades of Methocel E, Methocel E 6 PREMIUM LV, the 4,000 cps grades of Methocel® F, the 4,000, 15,000 and 100,000 cps grades of Methocel® K; and the Metho.K100 PREM.L VCR, Methocel K4M PREM. CR), and hydroxybutyl methylcellulose; other cellulose polymers such as sodium carboxymethylcellulose, cellulose acetate (e.g. CA- 398-10, CA-398-6, CA-398-3, CA320-S), cellulose acetate butyrate, polyethylene oxide (e.g. Polyox WSR 303/ Polyox WSR Coagulant/ Polyox WSR N80, PEO-4, PEO-3, Polyox WSR COAGU LEO, Polyox WSR N80 LEO), and ethyl cellulose; and other materials known to those of ordinary skill in the art. Swellable polymers such as polyalkylene oxide, polyethylene oxide (Polyox WSR N80, PEO-4, PEO-3, Polyox WSR COAGU LEO), and poly (alkalicarboxymethylcellulose) are also included in the push layer of certain osmotic systems. Release modifiers or extended release polymers may be present in an amount of about 1 % w/w to about 80 % w/w, preferably about 2 % w/w to about 70% w/w.
Osmogen according to the present invention are selected from, but are not limited to, magnesium sulfate, magnesium chloride, potassium sulfate, sodium chloride, sodium sulfate, lithium sulfate, sodium phosphate, potassium phosphate, mannitol, sorbitol, inositol, urea, magnesium succinate, tartaric acid, raffinose, and various monosaccharides, oligosaccharides and polysaccharides such as dextrates, sucrose, glucose, lactose, fructose, and dextran or combinations thereof. Osmogen may be present in an amount of about 0.5 % w/w to about 20
% w/w, preferably about 1 % w/w to about 10% w/w.
Binder according to the present invention are selected from, but not limited to microcrystalline cellulose, polyvinylpyrrolidone (PVP), eg, PVP K 30, PVP-K value 25, hydroxypropylmethyl cellulose (e.g. HPMC 3cps, 5 cps, 10 cps, Methocel E 5 premium LV), hydroxypropyl cellulose, hydroxyethyl cellulose (e.g. Natrosol 250H), copovidone, or combinations thereof. Binder may be present in an amount of about 0.5 % w/w to about 20 % w/w, preferably about 1 % w/w to about 15% w/w.
Antioxidants according to the present invention are selected from, but not limited to selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid (vitamin C), propyl gallate, or combinations thereof. Antioxidants may be present in an amount of about 0.01 % w/w to about 2 % w/w, preferably about 0.01 % w/w to about 1 % w/w.
Solvents according to the present invention are selected from, but are not limited to, isopropyl alcohol, methanol, ethanol, methylene chloride, chloroform, ethylacetate, dichloromethane, purified water, ketones such as acetone, propanone, ethers such as dimethylether, diethylether, methyltertiarybutylether, ethylmethylether, diisopropylether, and dioxane or mixtures thereof.
Lubricants according to the present invention are selected from, but are not limited to, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, and the like used either alone or in combinations thereof. Lubricants may be present in an amount of about 0.05
% w/w to about 2 % w/w, preferably about 0.07 % w/w to about 1.5 % w/w.
Glidants according to the present invention are selected from, but are not limited to, colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, and the like used either alone or in combinations thereof. Glidants may be present in an amount of about 0.05 % w/w to about 2 % w/w, preferably about 0.5 % w/w to about 1.5 % w/w.
Plasticizer according to the present invention are selected from, but are not limited to, polyethylene glycol (e.g. Kollisolv PEG 400, PEG 3350, PEG 6000) triacetin, acetylated monoglycerides, citrate esters (e.g., triethyl citrate), phthalate esters (e.g., diethyl phthalate), and the like used either alone or in combinations thereof. Plasticizer may be present in an amount of about 0.01 % w/w to about 2 % w/w, preferably about 0.05 % w/w to about 1 % w/w.
Tablet coating refers to the phenomenon of application of coating to the tablet, which involves some coating agents like plasticizer, polymers, colorants and solvent. Coating material for film coating purpose according to the present invention are selected from, but are not limited to, polyvinyl alcohol, hydroxypropyl cellulose (e.g. HPC SSL, Klucel HPC), hydroxypropylmethyl cellulose, polyethylene glycol, talc, titanium dioxide. Coating material may be present in an amount of about 1 % w/w to about 5 % w/w, preferably about 2 % w/w to about 4 % w/w.
Colorants is a substance that is preferably added to the coating agent for coating of the tablet. Pharmaceutically acceptable colorants include but are not limited to red iron oxide, non- irradiated, iron oxide black, Ferrosoferric oxide, Neelikol Ponceau 4R, tartrazine, erythrosine, amaranth lake, opadry systems, titanium dioxide, and iron oxide yellow.
Deutetrabenazine or pharmaceutically acceptable salt thereof may be present in an amount of about 0.5 to about 20 % w/w, preferably about 0.5 to about 10 % w/w, more preferably about 1 to 8 % w/w of the composition e.g. particularly about 1.75 % w/w, , about 3 % w/w, about 3.50 % w/w, about 6 % w/w, about 6.80 % w/w, about 7 % w/w.
The present invention provides a pharmaceutical composition comprising Deutetrabenazine in an amount of about 1 to about 100 mg, preferably about 3 to about 50mg, more preferably about 6 mg, 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, or 48 mg.
The present invention provides a Deutetrabenazine having D90 particle size in the range of 1 to 50 µm. Preferably, the D90 particle size can be between 3 and 40 µm, more preferably not more than 30 µm.
In another aspect, the present invention relates to an extended release dosage forms for once daily administration of deutetrabenazine to a subject in need thereof comprising: a tablet core comprising deutetrabenazine, diluent, binder, solvent and lubricant; a) a seal coating of tablet core using film forming agent, plasticizer and solvent b) an extended release coating surrounding the tablet core; c) a port extending through the extended release coating into the tablet core; d) an optional external coating of deutetrabenazine surrounding the extended release coating; and e) a film coating.
In another aspect, the present invention relates to an extended release dosage forms for once daily administration of deutetrabenazine to a subject in need thereof comprising: a) a tablet core comprising deutetrabenazine, diluent, binder, antioxidant, solvent and lubricant; b) a seal coating of tablet core using film forming agent, plasticizer and solvent c) an extended release coating surrounding the tablet core; d) a port extending through the extended release coating into the tablet core; and e) an optional external coating of deutetrabenazine surrounding the extended release coating; wherein about 60% w/w to about 80% w/w of the total amount of deutetrabenazine present in the dosage form is present within the tablet core and wherein about 20 % w/w to about 40% w/w of the total amount of deutetrabenazine present in the dosage form, is present in the external coating.
In another aspect, the present invention relates to an extended release dosage forms for once daily administration of deutetrabenazine to a subject in need thereof comprising: a) a tablet core comprising deutetrabenazine, diluent, binder, antioxidant, solvent and lubricant; b) a seal coating of tablet core using film forming agent, plasticizer and solvent c) an extended release coating surrounding the tablet core; d) a port extending through the extended release coating into the tablet core; e) an optional external coating of deutetrabenazine surrounding the extended release coating; and f). a film coating; wherein said extended release dosage forms for once daily administration of deutetrabenazine is in the form of osmotic dosage form.
In another aspect, the present invention relates to an extended release dosage forms for once daily administration of deutetrabenazine to a subject in need thereof comprising: a) a tablet core comprising about 0.5 % w/w to about 10 % w/w of Deutetrabenazine; about 20 % w/w to about 80 % w/w of one or more diluents selected from the group consisting of dextrates, lactose, dicalcium phosphate, mannitol; about 2 % w/w to about 20 % w/w of one or more binders selected from the group consisting of hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, copovidone, polyvinyl pyrrolidone; about 0.01 % w/w to about 1 % w/w of one or more antioxidants selected from the group consisting of butylated hydroxyanisole, butylated hydroxytoluene; about 0.5 % w/w to about 2 % w/w of one or more lubricants selected from the group consisting of magnesium stearate, sodium stearyl fumarate; and solvent system; b) a seal coating of tablet core comprises about 1% w/w to about 5 % w/w of one or more film forming agent selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose; about 0.05 % w/w to about 1 % w/w of one or more plasticizer selected from the group consisting of polyethylene glycol, triacetin, acetylated monoglycerides, citrate esters (e.g., triethyl citrate), or phthalate esters (e.g., diethyl phthalate) and solvent system; c) an extended release coating surrounding the tablet core comprises about 1 % w/w to about 15 % w/w of one or more extended release polymers selected from the group consisting of cellulose acetate, hydroxypropyl methyl cellulose; about 0.1 % w/w to about 1 % w/w of one or more plasticizer selected from the group consisting of polyethylene glycol, triacetin, acetylated monoglycerides, citrate esters (e.g., triethyl citrate), or phthalate esters (e.g., diethyl phthalate) and solvent system; d) a port extending through the extended release coating into the tablet core; and e) an external coating of deutetrabenazine surrounding the extended release coating comprises about 0.1 % w/w to about 5 % w/w of Deutetrabenazine; about 1 % w/w to about 10 % w/w of one or more film former selected from the group consisting of hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose; about 0.1 % w/w to about 2 % w/w of one or more plasticizer selected from the group consisting of polyethylene glycol, triacetin and solvent system; f) about 1 % w/w to about 5 % w/w of film coating material comprises polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide.
In another aspect, the present invention relates to an extended release tablet composition comprising: a) a tablet core comprising about 1 % w/w to about 10 % w/w of Deutetrabenazine; about 10 % w/w to about 40 % w/w of mannitol; ; about 10 % w/w to about 40 % w/w of dextrate; about 5 % w/w to about 12 % w/w of hydroxypropyl methyl cellulose; about 3 % w/w to about 12 % w/w of hydroxyethyl cellulose; about 0.05 % w/w to about 0.2 % w/w of butylated hydroxyanisole; about 0.05 % w/w to about 0.2 % w/w of butylated hydroxytoluene; about 0.5 % w/w to about 1.2 % of magnesium stearate, and solvent system; b) a seal coating of tablet core (a) comprises about 1 % w/w to about 5 % w/w of hydroxypropyl cellulose; about 0.05 % w/w to about 0.1 % w/w of polyethylene glycol, and solvent system; c) an extended release coating surrounding the seal coated tablet core (b) comprises about 1 % w/w to about 15 % w/w of cellulose acetate; about 0.1 % w/w to about 0.85 % w/w of polyethylene glycol, and solvent system; wherein the extended release coating comprises about 10 % w/w to about 15 % w/w of the total composition comprises combination of cellulose acetate; and polyethylene glycol; d) a port extending through the extended release coating into the tablet core; and e) an external coating of deutetrabenazine surrounding the extended release coating comprises about 0.2 % w/w to 4 % w/w of Deutetrabenazine; about 2 % w/w to about 8 % w/w of hydroxypropyl methylcellulose; about 0.02 % w/w to 0.1 % w/w of butylated hydroxyanisole, and solvent system; f) about 2 % w/w to about 5 % w/w of film coating material.
In another aspect, the present invention relates to an extended release tablet composition comprising: a) a tablet core comprising about 1.2 % w/w of Deutetrabenazine; about 30 % w/w of mannitol; about 30 % w/w of dextrate; about 9 % w/w of hydroxypropyl methyl cellulose; about 7 % w/w of hydroxyethyl cellulose; about 0.11 % w/w of butylated hydroxyanisole; about 0.11 % w/w of butylated hydroxytoluene; about 0.8 % w/w of magnesium stearate, and solvent system; b) a seal coating of tablet core (a) comprises about 2.2 % w/w of hydroxypropyl cellulose; about 0.12 % w/w of polyethylene glycol, and solvent system; c) an extended release coating surrounding the seal coated tablet core (b) comprises about 1 % w/w to about 15 % w/w of cellulose acetate; about 0.1 % w/w to about 0.85 % w/w of polyethylene glycol, and solvent system; wherein the extended release coating comprises about 10 % w/w to about 15 % w/w of the total composition comprises combination of cellulose acetate; and polyethylene glycol; d) a port extending through the extended release coating into the tablet core; and e) an external coating of deutetrabenazine surrounding the extended release coating comprises about 0.5 % w/w of Deutetrabenazine; about 6 % w/w of hydroxypropyl methylcellulose; about 0.04 % w/w of butylated hydroxyanisole, and solvent system; f) about 3 % w/w of film coating material.
In another aspect, the present invention relates to an extended release tablet composition comprising: a) a tablet core comprising about 5 % w/w of Deutetrabenazine; about 26 % w/w of mannitol; about 26 % w/w of dextrate; about 9 % w/w of hydroxypropyl methyl cellulose; about 9 % w/w of hydroxyethyl cellulose; about 0.11 % w/w of butylated hydroxyanisole; about 0.11 % w/w of butylated hydroxytoluene; about 0.8 % w/w of magnesium stearate, and solvent system; b) a seal coating of tablet core (a) comprises about 2.2 % w/w of hydroxypropyl cellulose; about 0.12 % w/w of polyethylene glycol, and solvent system; c) an extended release coating surrounding the seal coated tablet core (b) comprises about 1 % w/w to about 15 % w/w of cellulose acetate; about 0.1 % w/w to about 0.85 % w/w of polyethylene glycol, and solvent system; wherein the extended release coating comprises about 10 % w/w to about 15 % w/w of the total composition comprises combination of cellulose acetate; and polyethylene glycol; d) a port extending through the extended release coating into the tablet core; and e) an external coating of deutetrabenazine surrounding the extended release coating comprises about 2 % w/w of Deutetrabenazine; about 6 % w/w of hydroxypropyl methylcellulose; about 0.03 % w/w of butylated hydroxyanisole, and solvent system; f) about 3 % w/w of film coating material.
In yet another aspect, the present invention further relates to stable pharmaceutical composition of deutetrabenazine which is substantially free of nitrosamine impurity.
In yet another aspect of the present invention provides a stable pharmaceutical composition comprising deutetrabenazine, wherein the amount of nitrosamine impurity after exposure of the pharmaceutical composition to 40°C/75% RH is less than the FDA acceptable limit based on maximum daily dose of deutetrabenazine.
In another aspect, the present invention relates to an extended release dosage forms for once daily administration of deutetrabenazine to a subject in need thereof comprising: a) a push layer comprising dry mix which contains about 15 % w/w to about 40 % w/w of Polyethylene Oxide; about 1 % w/w to about 5 % w/w of Sodium Chloride; about 0.5 % w/w to about 5 % w/w of hydroxypropylmethyl cellulose; about 0.02 % w/w to about 2 % w/w of Magnesium Stearate; and solvent system; b) a pull layer comprising dry mix which contains about 1% w/w to about 10 % w/w of deutetrabenazine; about 30 % w/w to about 60 % w/w of Polyethylene Oxide; about 0.5 % w/w to about 5 % w/w of hydroxypropylmethyl cellulose; about 1 % w/w to about 5 % w/w of Sodium Chloride; about 0.01 % w/w to about 1.5 % w/w of one or more preservatives selected from the group consisting of Butylated Hydroxyanisole, Butylated Hydroxytoluene; about 0.1 % w/w to about 1 % w/w of Magnesium Stearate; and solvent system; c) a seal coating of bilayer tablet comprises about 0.5% w/w to about 5 % w/w of hydroxypropyl cellulose; about 0.05% w/w to about 1 % w/w of Polyethylene Glycol; and solvent system; d) an extended release coating surrounding the tablet core comprises about 1 % w/w to about 15 % w/w of cellulose acetate; about 0.1% w/w to about 1 % w/w of Polyethylene Glycol; and solvent system; e) a port extending through the extended release coating into the tablet core; and f) an external coating of deutetrabenazine surrounding the extended release coating comprises about 0.1 % w/w to about 5 % w/w of Deutetrabenazine; about 1 % w/w to about 10 % w/w of hydroxypropyl methyl cellulose; about 0.5 % w/w to about 2 % w/w of polyethylene glycol; and solvent system; g) about 1 % w/w to about 5 % w/w of film coating material comprises polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide.
In yet another aspect, the present invention relates to the process for preparation of an extended release tablet dosage form, wherein process comprises steps of a) Mix intra granular portion i.e. deutetrabenazine, hydroxypropyl methylcellulose, hydroxyethyl cellulose, dextrate hydrated, mannitol in rapid mixture granulator b) Granulating of the material of step (a) using required quantity of Butylated Hydroxyanisole, Butylated Hydroxy toluene, Isopropyl alcohol and/or purified water c) Milling of the material of step (b), followed by drying. d) Add the magnesium stearate in step (c) extragranularly, followed by compression of the lubricated blend to form tablet e) Seal coating of tablet (d) using Hydroxypropyl Cellulose and Polyethylene Glycol with Isopropyl alcohol f) Extended Release coating (e) using extended release polymer solution containing Cellulose Acetate, Polyethylene Glycol, Acetone, and Purified Water g) Laser drilling of extended release tablet (f). h) Dissolving of remaining portion of deutetrabenazine, Polyethylene Glycol (optionally) and Butylated Hydroxyanisole (optionally) in solvent such as acetone, purified water, isopropyl alcohol or mixture. Then hydroxypropyl methylcellulose added to the solution to form drug layering solution, then drug layering of step (g) using drug layering solution, followed by film coating.
In yet another aspect, the present invention relates to the process for preparation of an extended release tablet dosage form, wherein process comprises steps of a) Milling of osmogen, followed by sifting of Swelling agent, colorant, binder, and loaded in Mixer Granulator and mixed for 5 minutes b) Granulating of the material of step (a) using required quantity of solvent, followed by drying c) The dry mix of step (b) granulated by adding binder solution, followed by drying d) The dried granules of step (c) sifted using 20 mesh sieve and milled using co-mill, followed by lubrication e) Mixing of remaining quantity of deutetrabenazine, polymer, binder, osmogen, further, addition of preservative solution, purified water under continuous stirring. f) Drying of the material in RMG to obtain dry mix, then dry mix granulated by adding binder solution, and the wet mass dried using Fluid bed dryer, followed by milling. g) Add the lubricant in step (f) extragranularly, followed by compression of the lubricated blend to form tablet. h) Seal coating of tablet (g) using film former and plasticizer with suitable solvents. i) Extended Release coating (e) using extended release polymer solution j) Laser drilling of extended release tablet (i) k) Drug layering of step (g) using remaining portion of solution containing deutetrabenazine and plasticizer, followed by film coating.
In yet another aspect, the blend or tablet composition obtained in present invention are subjected for tests such as dissolution, assay, impurity profiling, related Substances, content uniformity, Hardness, thickness, Friability, Bulk density, tapped density, Hausner ratio (HR), Compressibility Index, Particle Size Distribution, Loss on drying (LOD), etc.
In yet another aspect, the present invention relates to a pharmaceutical composition comprising Deutetrabenazine used for the treatment of hyperkinetic movement disorders deriving from conditions such as Huntington's disease, tardive dyskinesia, Tourette syndrome, levodopa-induced dyskinesia and dyskinesia in cerebral palsy.
The term “hyperkinetic movement disorders” refers to disorders characterized by non- purposeful, repetitive, disordered motor acts, variously termed “compulsive”, “rhythmical”, or “stereotyped.” In humans, chronic hyperkinetic movement disorders can be psychogenic (e.g., tics), idiopathic (as in, e.g., Tourette's syndrome and Parkinson's Disease, genetic (as in, e.g., the chorea characteristic of Huntington's Disease), infectious (as in, e.g., Sydenham's Chorea), or, as in tardive dyskinesia, drug-induced. Unless otherwise stated, “chronic hyperkinetic movement disorders” refers to and includes all psychogenic, idiopathic, genetic, and drug-induced movement disorders.
In yet another aspect, the present invention relates to method of treating of hyperkinetic movement disorders deriving from conditions such as Huntington's disease, tardive dyskinesia, Tourette syndrome, levodopa-induced dyskinesia and dyskinesia in cerebral palsy by a pharmaceutical composition comprising Deutetrabenazine.
The composition of the Deutetrabenazine extended release tablet can be packed into suitable packaging system e. g. Blister packs, strip packs, alu-alu packs, bottles such as glass and plastic bottles, etc.

EXAMPLES
Example - 1: Deutetrabenazine extended release tablet

Sr. Ingredients % w/w
Dry mix
1 Deutetrabenazine 0.5-10
2 Dextrate 10-40
3 Mannitol 10-40
4 Hypromellose 2-20
5 Hydroxyethyl cellulose 1-10
6 BHA/BHT 0.01-1
7 Purified Water/Isopropyl alcohol q.s.
Lubrication
8 Magnesium Stearate 0.5-2
Core tablet weight 70-80
Seal coating
9 Hydroxypropyl Cellulose 1-5
10 Polyethylene glycol 0.05 -1
11 Isopropyl alcohol q.s.
Seal Coated Tablet Weight 75-85
Extended Release Coating
12 Cellulose Acetate 1-15
13 Polyethylene Glycol 0.1-1
14 Acetone q.s.
15 Purified Water q.s.
Extended Release Coated Tablet Weight 85-95
Drug layer
16 Deutetrabenazine 0.1-5
17 Hypromellose 1-5
18 Polyethylene glycol 0.1-2
19 Acetone q.s.
20 Water q.s.
Drug layered tablet weight 90-99
Film coating
21 Film coating material 1-5
22 Purified Water q.s.
Film Coated Tablet Weight 100

Manufacturing process: Example 1 manufactured by using below steps:
Wet granulation
1. Deutetrabenazine, diluents, binders were co-sifted through #20.
2. Sifted materials were loaded to rapid mixture granulator.
3. The material obtained in step 2) were dry mixed for appropriate time.
4. Dry mix were granulated by adding granulation fluid to get desired granules and then the material was unloaded.
5. Wet mass was milled through appropriate sieve.

Drying
6. Wet mass was loaded into fluid bed dryer bowl.
7. Wet mass was dried at appropriate process parameters to get desired LOD.
8. The dried granules were sifted using 24 mesh sieve and milled using co-mill fitted with 1 mm screen.
Lubrication
9. Lubricant was sifted through #60.
10. Sifted Lubricant was added in blender containing granules.
11. Allowed to mix for 05 minutes.
Compression
12. Lubricated blend was compressed using suitable punches.
Seal coating
13. Solvent was taken in a solution vessel and plasticizer added into it under gently stirring.
14. Film forming agent was added to the above step under continuous stirring to get a clear solution.
15. Core tablets was coated with seal coating solution at appropriate parameters to achieve target weight gain.

Preparation of extended Release coating solution
16. Required quantity of solvents was taken in a solution mixing vessel and mixed under stirring.
17. Extended release polymer was slowly added in step 16 mixture under continuous stirring. Stir the mixture for 60 minutes to get a clear solution.
18. Then plasticizer was added to the above step solution under continuous stirring and Stir the mixture for 10 minutes to get a clear solution.
Extended Release coating
19. The seal coated tablets were loaded in coating pan and pre-warm them for 5-10 minutes at 25-28°C.
20. Then pre-warmed core tablets were coated using extended release coating solution at of appropriate process parameters to achieve target weight build up as mentioned below.
Laser drilling
21. The laser hole drilling was performed on tablet
Drug layering
22. Required quantity of solvent was taken to dissolve batch quantity of Deutetrabenazine under continuous stirring to get clear solution.
23. The purified water was added in above step under continuous stirring to get clear solution.
24. Then batch quantity of film former was added under continuous stirring to get clear solution.
25. Then the extended release tablets were coated using drug layering solution at appropriate process parameters to achieve target weight build up.
Film coating
26. Film coating material was dispersed in purified water to obtain 15% w/w dispersion & mix for 45 min.
27. The drug layered tablets were coated with respective film coating material coating dispersion to achieve target weight gain.

Example - 2: Deutetrabenazine extended release tablet

Sr. Ingredients % w/w
Push Layer
Dry mix
1 Polyethylene Oxide 15-40
2 Sodium Chloride 1-5
3 Hypromellose 0.5-5
4 Colorants 0.1-1
5 Iso-propyl Alcohol (IPA) q.s.
6 Purified Water q.s.
Lubrication
7 Magnesium Stearate 0.02-2
Push Layer Weight 15-50
Dry mix (70% drug portion)
8 Deutetrabenazine 1-10
9 Polyethylene Oxide 30-60
10 Hypromellose 0.5-5
11 Sodium Chloride 1-5
12 Butylated Hydroxyanisole (BHA) 0.5-0.5
13 Butylated Hydroxytoluene (BHT) 0.01-0.5
14 Isopropyl Alcohol (IPA) q.s.
15 Purified Water q.s.
Lubrication
16 Magnesium Stearate 0.1-1
17 Hydroxypropyl Cellulose 0.5-5
18 Polyethylene Glycol 0.05-1
19 Isopropyl alcohol q.s.
Seal Coated Tablet Weight 80-90
Extended Release Coating
20 Cellulose Acetate 1-15
21 Polyethylene Glycol 0.1-1
Sr. Ingredients % w/w
22 Acetone q.s.
23 Purified Water q.s.
Extended Release Coated Tablet
Weight 85-95
Drug layer (30% drug portion)
24 Deutetrabenazine 0.1-5
25 Hypromellose 1-10
26 Polyethylene glycol 0.5-2
27 Acetone q.s.
28 Water q.s.
Drug Layered Tablet Weight 90-99
Laser Drilling
Film coating
29 Film coating material 1-5
30 Purified Water q.s.
Film Coated Tablet Weight 100

Manufacturing process: Example 2 manufactured by using below steps:

Push Layer-Wet granulation
1. Sodium Chloride was milled using Co-mill fitted with 0.5 mm screen.
2. Then milled Sodium Chloride was sifted through # 40.
3. Polyethylene Oxide was sifted through #20.
4. Colorant, Hypromellose was co-sifted through #60.
5. Load sifted materials in Rapid Mixer Granulator and mixed for 5 minutes.
6. The iso-propyl alcohol (IPA), and purified water were taken in a solution vessel and gently mixed.
Drying
7. The obtained material was dry mixed in RMG at appropriate parameters.
8. The dry mix was granulated by adding hypromellose solution at appropriate parameters to get granulation end point.
9. The wet mass was dried using Fluid bed dryer.
Sizing and milling
10.The dried granules were sifted using 20 mesh sieve and milled using co-mill fitted with 1 mm screen.
Lubrication
11. Magnesium stearate was sifted through #60.
12. Sifted magnesium stearate was added in blender containing granules.
13. Mixed for 05 minutes.
Drug (Pull) Layer-Wet granulation
14. Deutetrabenazine and polyethylene oxide co-sifted through #20.
15. Hypromellose was sifted through #20.
16. Sodium Chloride was milled using Co-mill fitted with 0.5 mm screen.
17. Milled sodium chloride was sifted through # 40.
18. Sifted materials were charged in Rapid Mixer Granulator and mix for 5 minutes.
19. The BHA, BHT was dissolved in IPA under continuous stirring to get clear solution and then purified water was added under continuous stirring.

Drying
20. The material was dry mixed in RMG at appropriate parameters.
21. The dry mix was granulated by adding hypromellose solution at appropriate parameters to get granulation end point.
22. The wet mass was dried using Fluid bed dryer.
Sizing and milling
23. The dried granules were sifted using #20 sieve and milled using co-mill fitted with 1 mm screen.
Lubrication
24. Magnesium stearate was sifted through #60.
25. Sifted magnesium stearate was added in blender containing granules.
26. Mixed for 05 minutes.
Compression
27. The lubricated blend was compressed to form bilayer tablets using suitable punches.
Seal coating
28. IPA was taken in a solution vessel and PEG was added with gentle stirring.
29. Hydroxypropyl Cellulose was added to the above step under continuous stirring to get a clear solution.
30.The core tablets coated with seal coating solution at appropriate parameters to achieve target weight gain.
Extended Release coating
31.Purified water and acetone were taken in a solution vessel under continuous stirring.
32.PEG was added to the above step under continuous stirring to get a clear solution.
33.Cellulose Acetate was added to above solution and the mixture stirred for 60 min.
34. The seal coated tablets were coated with extended release coating solution at appropriate parameters to achieve target weight gain.

Laser drilling
35.Perform the laser orifice drilling on extended release coated tablets.
Drug layering
36. Required quantity of Deutetrabenazine was dissolved in acetone under continuous stirring to get clear solution.
37.Required quantity of PEG was added into above step to get clear solution.
38.Required quantity of purified water was added into above step under continuous stirring to get clear solution.
39.Required quantity of hypromellose was added under continuous stirring to get clear solution.
40.The extended release coated tablets were coated using drug layering solution at appropriate process parameters to achieve target weight build up.
Film coating
41.Film coating material was dispersed in purified water to obtain 15% w/w dispersion & mix for 45 min.
42. The tablets obtained in above step coated with respective film coating material to achieve target weight gain.

Example - 3: Deutetrabenazine extended release tablet- 6mg

Sr. Ingredients Quantity (% w/w)
Ex. 3A Ex. 3B Ex. 3C
Intra-granular
1 Deutetrabenazine 1.28 1.28 1.28
2 Mannitol 26.32 29.32 27.64
3 Dextrate Hydrated 32.32 29.32 31
4 Hydroxypropyl methylcellulose 6.92 8.92 8.35
5 Hydroxyethyl cellulose 9.43 7.43 8
6 Butylated Hydroxyanisole 0.12 0.11 0.09
7 Butylated Hydroxytoluene 0.1 0.11 0.13
8 Isopropyl alcohol/ Purified Water q.s. q.s. q.s.
Extragranular
9 Magnesium Stearate 0.79 0.79 0.79
Seal coating
10 Hydroxypropyl Cellulose 2.27 2.26 2.25
11 Polyethylene Glycol 0.11 0.12 0.13
12 Isopropyl alcohol
Extended Release Coating (%) 13.50% 13.50% 13.50%
13 Cellulose Acetate 7.8 8.09 8.29
14 Cellulose Acetate 2.31 2.02 1.82
15 Polyethylene Glycol 0.65 0.65 0.65
16 Acetone (Acetone: Water 80:20) q.s. q.s. q.s.
17 Purified Water q.s. q.s. q.s.
Orifice Drilling
Drug Layering
18 Deutetrabenazine 0.5 0.5 0.5
19 Hydroxypropyl methylcellulose 6.15 5.99 5.75
20 Butylated Hydroxyanisole 0.04 0.04 0.04
21 Isopropyl alcohol q.s. q.s. q.s.
22 Purified Water q.s. q.s. q.s.
Film Coating
23 OPADRY II 85F575060 GREY 2.89 3.05 3.29
24 Purified Water q.s. q.s. q.s.
Final Tablet Weight (%) 100 100 100

Manufacturing process: Example 3 manufactured by using process as mentioned in example 1 with the addition of Butylated Hydroxyanisole and appropriate solvent (isopropyl alcohol and water) in drug layering.

Example - 4: Deutetrabenazine extended release tablet- 24mg
Sr. Ingredient Quantity (% w/w)
Ex. 4A Ex. 4B Ex. 4C
Intra-granular
1 Deutetrabenazine 5.01 5.01 5.01
2 Mannitol 27.94 25.97 24.99
3 Dextrate Hydrated 24 25.97 26.95
4 Hydroxypropyl methylcellulose 8.5 8.69 8.99
5 Hydroxyethyl cellulose 8.88 8.69 8.39
6 Butylated Hydroxyanisole 0.12 0.11 0.1
7 Butylated Hydroxytoluene 0.1 0.11 0.12
8 Isopropyl alcohol/ Purified Water q.s. q.s. q.s.
Extragranular
9 Magnesium Stearate 0.77 0.77 0.77
Seal coating
10 Hydroxypropyl Cellulose 2.22 2.2 2.21
11 Polyethylene Glycol 0.1 0.12 0.11
12 Isopropyl alcohol q.s. q.s. q.s.
Extended Release Coating 15% 15% 15%
13 Cellulose Acetate 8.66 8.76 8.86
14 Cellulose Acetate 2.24 2.19 2.14
15 Polyethylene Glycol 0.75 0.7 0.65
16 Acetone (Acetone: Water 80:20) q.s. q.s. q.s.
17 Purified Water q.s. q.s. q.s.
Orifice Drilling
Drug Layering
18 Deutetrabenazine 1.95 1.95 1.95
19 Hydroxypropyl methylcellulose 6.17 5.84 5.64
20 Butylated Hydroxyanisole 0.03 0.03 0.03
21 Isopropyl alcohol q.s. q.s. q.s.
22 Purified Water q.s. q.s. q.s.
Film Coating
23 OPADRY II 85F500164 PURPLE 2.6 2.9 3.1
24 Purified Water q.s. q.s. q.s.
Final Tablet Weight (%) 100 100 100

Manufacturing process: Same as given in example 3.
Deutetrabenazine Extended Release Tablets obtained in example 4 was subjected to testing and results obtained as below:

Stability condition
Initial 1 Month 2 Months 1 Month 2 Months
40°C/75% RH 40°C/75% RH 40°C/75% RH 40°C/75% RH
Pack details HDPE bottle Alu_Blister
Assay (%) 99.9 99.2 99.0 98.9 99.7
Water content (%) 2.44 2.19 2.14 3.73 3.77
BHA Assay (%) 87.8 87.5 89.3 89.1 89.7
BHT Assay (%) 84.3 84.6 82.1 84.9 82.1
Nitrosamine impurity Not detected Not detected Not detected Not detected Not detected
Related substances (%)
Didehydro impurity 0.112 0.236 0.421 0.229 0.407
Diasteriomer impurity 0.263 0.410 0.551 0.501 0.659
Max. unspecified impurity. Not detected Not detected Not detected Not detected Not detected
Total impurity 0.418 0.695 0.972 0.782 1.066
Dissolution data
Time (hr) % Drug Release
1 29 29 30 29 29
2 29 29 30 30 28
4 34 34 34 35 34
6 47 45 45 48 45
8 61 59 57 62 57
10 71 70 68 72 66
12 78 78 75 80 73
16 85 85 83 88 81
20 90 91 88 93 86
24 93 94 92 97 91

Although the inventions herein have been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described.

All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

,CLAIMS:WE CLAIM:
1. An extended release tablet composition comprising: a) a tablet core comprising about 1 % w/w to about 10 % w/w of Deutetrabenazine; about 10 % w/w to about 40 % w/w of mannitol; ; about 10 % w/w to about 40 % w/w of dextrate; about 5 % w/w to about 12 % w/w of hydroxypropyl methyl cellulose; about 3 % w/w to about 12 % w/w of hydroxyethyl cellulose; about 0.05 % w/w to about 0.2 % w/w of butylated hydroxyanisole; about 0.05 % w/w to about 0.2 % w/w of butylated hydroxytoluene; about 0.5 % w/w to about 1.2 % of magnesium stearate; b) a seal coating of tablet core (a) comprises about 1 % w/w to about 5 % w/w of hydroxypropyl cellulose; about 0.05 % w/w to about 0.2 % w/w of polyethylene glycol; c) an extended release coating surrounding the seal coated tablet core (b) comprises about 1 % w/w to about 15 % w/w of cellulose acetate; about 0.1 % w/w to about 0.85 % w/w of polyethylene glycol; d) a port extending through the extended release coating into the tablet core; and e) an external coating of deutetrabenazine surrounding the extended release coating comprises about 0.2 % w/w to 4 % w/w of Deutetrabenazine; about 2 % w/w to about 8 % w/w of hydroxypropyl methylcellulose; about 0.02 % w/w to 0.1 % w/w of butylated hydroxyanisole; about 2 % w/w to about 5 % w/w of film coating material.
2. The pharmaceutical composition as claimed in claim 1, wherein deutetrabenazine is present in an amount of about 6 mg, 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, or 48 mg.
3. The pharmaceutical composition as claimed in claim 1, wherein the extended release coating comprises about 10 % w/w to about 15 % w/w of the total composition comprises combination of cellulose acetate; and polyethylene glycol.
4. The pharmaceutical composition as claimed in claim 1, wherein water content of the composition is less than about 5 %.
5. The pharmaceutical composition as claimed in claim 1, wherein the composition releases more than 90 % of deutetrabenazine at 24 hours.
6. The pharmaceutical composition as claimed in claim 1, wherein the composition is stable for at least 2 months when stored at 40° C. and 75% relative humidity.
7. The pharmaceutical composition as claimed in claim 1, wherein stable pharmaceutical composition of deutetrabenazine is substantially free of nitrosamine impurity.
8. The pharmaceutical composition as claimed in claim 1, wherein the tablet composition having particle size distribution D90 of deutetrabenazine is not more than 30 µm.
9. An extended release tablet composition comprising: a) a tablet core comprising about 1.2 % w/w of Deutetrabenazine; about 30 % w/w of mannitol; about 30 % w/w of dextrate; about 9 % w/w of hydroxypropyl methyl cellulose; about 7 % w/w of hydroxyethyl cellulose; about 0.1 % w/w of butylated hydroxyanisole; about 0.1% w/w of butylated hydroxytoluene; about 0.8 % w/w of magnesium stearate; b) a seal coating of tablet core (a) comprises about 2.2 % w/w of hydroxypropyl cellulose; about 0.1 % w/w of polyethylene glycol; c) an extended release coating surrounding the seal coated tablet core (b) comprises about 1 % w/w to about 15 % w/w of cellulose acetate; about 0.1 % w/w to about 0.85 % w/w of polyethylene glycol; wherein the extended release coating comprises about 10 % w/w to about 15 % w/w of the total composition comprises combination of cellulose acetate; and polyethylene glycol; d) a port extending through the extended release coating into the tablet core; and e) an external coating of deutetrabenazine surrounding the extended release coating comprises about 0.5 % w/w of Deutetrabenazine; about 6 % w/w of hydroxypropyl methylcellulose; about 0.04 % w/w of butylated hydroxyanisole; f) about 3 % w/w of film coating material.
10. An extended release tablet composition comprising: a) a tablet core comprising about 5 % w/w of Deutetrabenazine; about 25 % w/w of mannitol; about 25 % w/w of dextrate; about 8% w/w of hydroxypropyl methyl cellulose; about 8 % w/w of hydroxyethyl cellulose; about 0.1 % w/w of butylated hydroxyanisole; about 0.1 % w/w of butylated hydroxytoluene; about 0.8 % w/w of magnesium stearate; b) a seal coating of tablet core (a) comprises about 2.2 % w/w of hydroxypropyl cellulose; about 0.1 % w/w of polyethylene glycol; c) an extended release coating surrounding the seal coated tablet core (b) comprises about 1 % w/w to about 15 % w/w of cellulose acetate; about 0.1 % w/w to about 0.85 % w/w of polyethylene glycol; wherein the extended release coating comprises about 10 % w/w to about 15 % w/w of the total composition comprises combination of cellulose acetate; and polyethylene glycol; d) a port extending through the extended release coating into the tablet core; and e) an external coating of deutetrabenazine surrounding the extended release coating comprises about 2 % w/w of Deutetrabenazine; about 6 % w/w of hydroxypropyl methylcellulose; about 0.03 % w/w of butylated hydroxyanisole; f) about 3 % w/w of film coating material.