This invention in general relates to a pharmaceutical composition comprising Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof with pharmaceutically acceptable excipients. In particular, the present invention discloses a pharmaceutical composition comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts thereof with pharmaceutically acceptable excipients, wherein the composition is free of Hydroxypropylcellulose (HPC) and/or heterocyclic amide-group containing polymeric compound.
BACKGROUND OF THE INVENTION
Tolvaptan, is a small, synthetic, non-peptide vasopressin antagonist that
specifically blocks the binding of arginine vasopressin (AVP) at the V2 receptors
of the distal nephron. Chemically it is N-(4-(7-Chloro-5-hydroxy-2,3,4,5-
tetrahydro-lH-benzo[b]azepine-l-carbonyl)-3-methylphenyl)-2 methyl
benzamide having a molecular weight of 448.94. It is a class IV molecule (Low solubility and low permeability) as per Biopharmaceutics Classification system and its chemical structure is shown below:

Tolvaptan Tolvaptan is marketed by Otsuka Pharmaceutical Company as immediate release uncoated tablets for oral administration under the brand name Samsca® in 15 mg and 30 mg strengths in US and 7.5, 15 and 30 mg in Japan. Inactive ingredients in the Samsca® tablet consists of com starch, hydroxypropyl cellulose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate and microcrystalline cellulose and FD&C Blue No. 2 Aluminum Lake as colorant.

Tolvaptan is used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). It is also approved for Volume Overload and Autosomal Dominant Polycystic Kidney Disease (ADPKD) in some countries.
Tolvaptan is practically insoluble in water. Solubility is a significant physicochemical factor affecting absorption of drug and its therapeutic effectiveness. Therefore, formulation development of drugs having poor aqueous solubility is a challenge. The low dissolution rate and low solubility of drug substances in water frequently leads to inadequate bioavailability.
U.S. Patent No. 5,258,510 assigned to Otsuka Pharma Co Ltd discloses Tolvaptan as a product.
JP Patent No. 4210355 assigned to Otsuka Pharma discloses a solid
pharmaceutical composition containing Tolvaptan and
hydroxypropylcellulose (HPC) wherein an amorphous composite is formed.
U.S. Patent Publication No. 20100323006 assigned to Otsuka Pharma discloses the effect of various disintegrants on the composition prepared using amorphous composite of Tolvaptan and HPC.
U.S. Patent No. 9,345,712 assigned to Hetero discloses a solid dispersion composition of Tolvaptan and povidone, wherein the ratio of Tolvaptan to povidone is 1:0.1 to 1:0.5.
U.S. Patent No. 9,408,915 assigned to Jiangsu Hengriu Medicine Pvt. Ltd. discloses a pharmaceutical amorphous solid dispersion of Tolvaptan and cross-linked polyvinylpyrrolidone as a carrier.

Above mentioned prior arts disclose solid dispersions of Tolvaptan using hydroxypropyl cellulose (HPC) and heterocyclic amide-group containing polymeric compound like PVP and Crospovidone as carriers.
Still, there exists a need to develop alternative compositions of Tolvaptan using simplified process with improved solubility, stability and dissolution. Accordingly, inventors of the present invention have preparaed a simple, reproducible and cost-effective process of pharmaceutical compositions of Tolvaptan. Further, the pharmaceutical compositions prepared according to the proposed manufacturing process of the present invention possess desirable formulation attributes comparable to the innovator's marketed product.
SUMMARY OF THE INVENTION
One embodiment of the present invention relates to pharmaceutical compositions comprising Tolvaptan and/or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with pharmaceutically acceptable excipients.
Another embodiment of the present invention relates to pharmaceutical compositions comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipient is a carrier.
Another embodiment of the present invention relates to pharmaceutical compositions comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, wherein pharmaceutically acceptable excipient is a carrier selected from the group consisting of hydroxypropyl methylcellulose, maltodextrin, Polyacrylates and polymethacrylates, Polyethylene glycol (PEG), Mannitol, Lactose monohydrate, Dextrose, Sucrose, Galactose,

Sorbitol, Maltose, Xylitol, Pectin, Galactomannan, Cyclodextrins, Pentaerythritol, Pentaerythrityl tetra acetate, Urea, Urethane, Poloxamers, texaphor, Deoxycholic acid, Tweens and Spans and mixtures thereof.
Another embodiment of the present invention relates to a pharmaceutical composition comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, wherein the composition is free of Hydroxypropyl cellulose (HPC) and/or heterocyclic amide-group containing polymeric compound.
Yet another embodiment of the present invention relates to a pharmaceutical composition comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, wherein the composition is free of HPC and/or heterocyclic amide-group containing polymeric compound and comprises of pharmaceutically acceptable excipients selected from binder, diluent, disintegrant, lubricant, surfactants, glidants.
Another embodiment of the present invention relates to pharmaceutical compositions comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, wherein pharmaceutically acceptable excipient is a carrier selected from the group consisting of hydroxypropyl methylcellulose, hypromellose phthalate, maltodextrin, Polyacrylates, polymethacrylates, Polyethylene glycol (PEG), Mannitol and Lactose monohydrate.
Another embodiment of the present invention relates to pharmaceutical compositions comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts with one or more carrier wherein the solid

dispersion can be prepared by either co-precipitation, co-evaporation, solvent evaporation such as vacuum drying, hot plate drying, spray drying, freeze drying, spin drying and super critical fluid drying etc.
Another embodiment of the present invention relates to pharmaceutical compositions comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, wherein the ratio of Tolvaptan to carrier is 1:0.2 to 1: 5.
Another embodiment of the present invention relates to a pharmaceutical composition comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, wherein the composition comprises at least one or more pharmaceutically acceptable excipients.
Another embodiment of the present invention relates to a pharmaceutical composition comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, wherein the particle size of Tolvaptan solid dispersion or premix is less than 300um.
In an another embodiment of the present invention the pharmaceutical composition comprises solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts with one or more carrier, wherein the preparation of solid dispersion comprises
a) dissolving a solution of tolvaptan and carrier in a solvent selected from the group consisting of water, an alcohol, an ester, a polar aprotic solvent, and mixtures thereof;
b) optionally, filtering the solvent solution to remove insoluble matter; and

c) substantially removing the solvent from the solution to produce the solid dispersion of Tolvaptan with the carrier.
In yet another embodiment of the present invention the pharmaceutical composition comprises solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, wherein the process of preparing solid dispersion also includes the removal of the solvent in step(c) as mentioned above using distillation or complete evaporation of the solvent, spray drying, vacuum drying, lyophihzation or freeze drying, agitated thin-film drying, or a combination thereof.
In another embodiment of the present invention the pharmaceutical composition comprises of a solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, wherein the solid dispersion is free of residual solvent.
Another embodiment of the present invention relates to a pharmaceutical composition comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts thereof with one or more carrier, wherein the composition is prepared by any of the process selected from dry granulation, wet granulation, spray granulation, and direct compression tableting processes.
Another embodiment of the present invention relates to a pharmaceutical composition comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, wherein the composition is an immediate release tablet and/or orally disintegrating tablet.

Another embodiment of the present invention relates to a pharmaceutical composition comprising amorphous and/or crystalline Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with pharmaceutically acceptable excipients.
In another embodiment of the present invention the pharmaceutical composition comprises solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof, with one or more carrier wherein Tolvaptan is present in an amount ranging from about 2 mg to about 150 mg.
Another embodiment of the present invention relates to the process for preparation of a pharmaceutical composition comprising solid dispersion or premix of Tolvaptan free of HPC and/or heterocyclic amide-group containing polymeric compound, wherein the process comprises:
a) blending a mixture of Tolvaptan solid dispersion or premix with one or more carrier and optionally other pharmaceutically acceptable excipients.
b) granulating the blend of step (a) with a solvent optionally containing binder;
c) drying the wet granules;
d) milling and sizing the dried granules, followed by adding at least one lubricant/glidant and optionally other pharmaceutically acceptable excipients to the dried milled granules; and
e) compressing the lubricated granules into tablets.
Another embodiment of the present invention relates to a pharmaceutical composition comprising amorphous and/or crystalline Tolvaptan free of HPC, wherein the process comprises: a) blending a mixture of amorphous Tolvaptan with a pharmaceutical
acceptable excipient and optionally other pharmaceutically acceptable
excipients.

b) granulating the blend of step (a) with a solvent optionally containing binder;
c) drying the wet granules;
d) milling and sizing the dried granules, followed by adding at least one lubricant/glidant and optionally other pharmaceutically acceptable excipients to the dried milled granules; and
e) compressing the lubricated granules into tablets.
In further embodiment, the present invention includes method of using the pharmaceutical composition comprising solid dispersion or granule or premix of Tolvaptan in the treatment of clinically significant hypervolemic and euvolemic hyponatremia, including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH).
DETAILED DESCRIPTION OF THE INVENTION
The present invention can be more readily understood by reading the following detailed description of the invention and study of the included examples. As used herein, the term "composition", as in pharmaceutical composition, is intended to encompass a drug product comprising Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof, and the other inert ingredient(s) (pharmaceutically acceptable excipients). Such pharmaceutical compositions are synonymous with "formulation" and "dosage form". Pharmaceutical compositions of the invention include, but are not limited to, granules, tablets (single layered tablets, multilayered tablets, mini tablets, bioadhesive tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified release tablets, orally disintegrating tablets, pulsatile release tablets, timed release tablets, delayed release, controlled release, extended release and sustained release tablets), granules, capsules (hard and soft or liquid filled soft gelatin capsules), pills, troches, sachets, powders, microcapsules, minitablets, tablets in capsules and

microspheres, matrix compositions and the like. Preferably, the pharmaceutical composition refers to tablets and capsules. More preferably, the pharmaceutical composition refers to immediate release tablets.
Unless otherwise stated the weight percentages expressed herein are based on the final weight of the composition or formulation.
The term "excipient" means a pharmacologically inactive component such as a diluent, lubricant, surfactant, carrier, or the like as known in the art. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient. Co-processed excipients are also covered under the scope of present invention. Further, excipient may be in the form of powders or in the form of dispersion. Combination of excipients performing the same function may also be used to achieve desired formulation characteristics.
The term "w/w" as used herein refers the total weight of the pharmaceutical composition.
The term "solid dispersion" and "premix" refers to the dispersion of one or more active agents in a polymer matrix at solid state prepared by a variety of methods, including spray drying, the melting (fusion), solvent evaporation, or the melting-solvent method and other methods known in the art.
By the phrase "carrier / polymer" is meant a component present in the solid dispersion together with Tolvaptan and possibly one or more other drugs.
Pharmaceutical compositions of the invention include, but are not limited to, "granules" or "premixes" or "pellets" or "spheres" or "solid dispersion" or "powder" which could be administered in the form of an oral solution or suspension or can be compressed into tablets. An oral solution

or suspension has the additional advantage of being easier to swallow and hence a better method of administration for those patients who have problems swallowing tablets. Granules with the desired bulk density, tap density and size range characteristics can be formed by using a fluid bed process.
As used herein, the term "about" means ± approximately 20% of the indicated value, such that "about 10 percent" indicates approximately 08 to 12 percent.
The term "heterocyclic amide-group containing polymeric compound" include, but are not limited to, polyvinylpyrrolidone (PVP), cross-linked polyvinylpyrrolidone, and copolymers containing vinylpyrrolidone monomer units.
The present invention relates to pharmaceutical compositions comprising Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof. Preferably, Tolvaptan in the present invention is used in an amount of about 1-80% by weight, more preferably, 1-40%.
The present invention relates to pharmaceutical compositions comprising amorphous and/or crystalline Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof. Preferably, amorphous and/or crystalline Tolvaptan in the present invention is used in an amount of about 1-80% by weight, more preferably, 1-40%.
One embodiment of the present invention relates to pharmaceutical compositions comprising Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with pharmaceutically acceptable excipients.
Another embodiment of the present invention relates to pharmaceutical compositions comprising solid dispersion or granule or premix of Tolvaptan or its

pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with pharmaceutically acceptable excipients, wherein pharmaceutically acceptable excipient is a carrier.
Another embodiment of the present invention relates to pharmaceutical compositions comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, selected from the group consisting of hydroxypropyl methylcellulose, maltodextrin, Polyacrylates and polymethacrylates, Polyethylene glycol (PEG), Mannitol, Lactose monohydrate, Dextrose, Sucrose, Galactose, Sorbitol, Maltose, Xylitol, Pectin, Galactomannan, Cyclodextrins, Pentaerythritol, Pentaerythrityl tetra acetate, Urea, Urethane, Poloxamers, texaphor, Deoxycholic acid, Tweens and Spans and mixtures thereof. Carrier in the present invention is used in an amount of about 1-80%
Another embodiment of the present invention relates to a pharmaceutical composition comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, wherein the composition is free of Hydroxypropyl cellulose (HPC) and/or heterocyclic amide-group containing polymeric compound.
Yet another embodiment of the present invention relates to a pharmaceutical composition comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, wherein the composition is free of HPC and/or heterocyclic amide-group containing polymeric compound and comprises of pharmaceutically acceptable excipients selected from binder, diluent, disintegrant, lubricant, surfactants, glidants wetting agent, solubilizer, stabilizer, sweetener, flavoring agent and coloring agent.

Another embodiment of the present invention relates to pharmaceutical compositions comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, wherein pharmaceutically acceptable excipient is a carrier selected from the group consisting of hydroxypropyl methylcellulose, hypromellose phthalate, maltodextrin, Polyacrylates, polymethacrylates, Polyethylene glycol (PEG), Mannitol and Lactose monohydrate.
Another embodiment of the present invention relates to pharmaceutical compositions comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts with one or more carrier wherein the solid dispersion can be prepared by either co-precipitation, co-evaporation, solvent evaporation such as vacuum drying, hot plate drying, spray drying, freeze drying, spin drying and super critical fluid drying etc.
Another embodiment of the present invention relates to pharmaceutical compositions comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, wherein the ratio of Tolvaptan to carrier is 1:0.2 to 1: 5.
Another embodiment of the present invention relates to a pharmaceutical composition comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, wherein the composition comprises at least one or more pharmaceutically acceptable excipients.
Another embodiment of the present invention relates to a pharmaceutical composition comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or

mixtures thereof with one or more carrier, wherein the particle size of Tolvaptan solid dispersion or premix is less than 300um.
In an another embodiment of the present invention the pharmaceutical composition comprises solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts with one or more carrier, wherein the preparation of solid dispersion comprises
a) dissolving a solution of tolvaptan and carrier in a solvent selected from the group consisting of water, an alcohol, an ester, a polar aprotic solvent, and mixtures thereof;
b) optionally, filtering the solvent solution to remove insoluble matter; and
c) substantially removing the solvent from the solution to produce the solid dispersion of Tolvaptan with the carrier.
In yet another embodiment of the present invention the pharmaceutical composition comprises solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, wherein the process of preparing solid dispersion also includes the removal of the solvent in step-(c) mentioned above using distillation or complete evaporation of the solvent, spray drying, vacuum drying, lyophilization or freeze drying, agitated thin-film drying, or a combination thereof.
In another embodiment of the present invention the pharmaceutical composition comprises of a solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, wherein the solid dispersion is free of residual solvent.
Another embodiment of the present invention relates to a pharmaceutical composition comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts thereof with one or more carrier, wherein the

composition is prepared by any of the process selected from dry granulation, wet granulation, spray granulation, and direct compression tableting processes.
Another embodiment of the present invention relates to a pharmaceutical composition comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, wherein the composition is an immediate release tablet and/or orally disintegrating tablet.
Another embodiment of the present invention relates to a pharmaceutical composition comprising amorphous and/or crystalline Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with pharmaceutically acceptable excipients.
In another embodiment of the present invention the pharmaceutical composition comprises solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof, with one or more carrier wherein Tolvaptan is present in an amount ranging from about 1 mg to about 150 mg.
Another embodiment of the present invention relates to the process for preparation of a pharmaceutical composition comprising solid dispersion or premix of Tolvaptan free of HPC and/or heterocyclic amide-group containing polymeric compound, wherein the process comprises:
a) blending a mixture of an Tolvaptan solid dispersion or premix with one or more carrier and optionally other pharmaceutically acceptable excipients.
b) granulating the blend of step (a) with a solvent optionally containing binder;
c) drying the wet granules;

d) milling and sizing the dried granules, followed by adding at least one lubricant/glidant and optionally other pharmaceutically acceptable excipients to the dried milled granules; and
e) compressing the lubricated granules into tablets.
Another embodiment of the present invention relates to a pharmaceutical composition comprising amorphous and/or crystalline Tolvaptan free of HPC, wherein the process comprises:
a) blending a mixture of amorphous Tolvaptan with a pharmaceutical acceptable excipient and optionally other pharmaceutically acceptable excipients.
b) granulating the blend of step (a) with a solvent optionally containing binder;
c) drying the wet granules;
d) milling and sizing the dried granules, followed by adding at least one lubricant/glidant and optionally other pharmaceutically acceptable excipients to the dried milled granules; and
e) compressing the lubricated granules into tablets.
Another embodiment of the present invention encompasses a pharmaceutical composition comprising amorphous and/ or crystalline Tolvaptan and a pharmaceutically acceptable excipient selected from diluent, binder, disintegrant, surfactant, lubricant, wetting agent, glidant, solubilizer, stabilizer, sweetener, flavoring agent and coloring agent.
In another embodiment of the invention, the pharmaceutical composition comprising an amorphous and/ or crystalline Tolvaptan is prepared by using wet or dry granulation, top spray granulation, hot melt extrusion and spray drying process. Any pharmaceutically acceptable granulating agent can be used for wet granulation. Suitable granulating agents include water, esters such as ethyl acetate; ketones such as acetone; alcohols such as methanol, ethanol, isopropanol,

butanol; dichloromethane and combinations thereof. Preferably, the granulating agent used during wet granulation is water.
In another embodiment of the invention, wet granulation can be performed using Rapid mixer granulator, Fluid bed granulator, Planetary mixer and the like.
In further embodiment, the present invention includes method of using the pharmaceutical composition comprising solid dispersion or premix of Tolvaptan in the treatment of clinically significant hypervolemic and euvolemic hyponatremia, including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH).
Various pharmaceutically acceptable excipients i.e., carriers used for preparing Solid dispersion include but are not limited to Sugars like Dextrose, Sucrose, Galactose, Sorbitol, Maltose, Xylitol, Mannitol, Lactose; Acids include Citric acid, Succinic Acid; Polymeric materials include PEG(polyethylene glycol); Celluloses include HPMC (hydroxypropylmethylcellulose), HEC (hydroxyethyl cellulose), Pectin, Galactomannan, CDs (various grades of cyclodextrins); Insoluble polymers: include HPMC[hydroxypropylmethylcellulose], and Eudragits; Surfactants include Polyoxyethylene stearate, Renex, Poloxamers, texafor, Deoxycholic acid, inulin, inutec SP1, compritol 888 ATO, gelucire 44/14 and poloxamer-407, various grades of Tweens and Spans; other carriers include Pentaerythritol, Pentaerythrityl tetra acetate, Urea, Urethane.
Solvents suitable for processing the pharmaceutical compositions comprises of one or more of solvents such as dichloromethane, ethanol, methanol, isopropyl alcohol, acetone, benzene, carbon disulphide, carbon tetrachloride, 1,2 dichloroethane, N,N-dimethylformamide, 1,4-dioxane, ethyl acetate, ethyl ether, ethylene glycol, 2-ethoxyethanol (acetate), formaldehyde, methyl n-butyl ketone, methyl ethyl ketone, 2-methoxyethanol (acetate), perchloroethylene, toluene,

1,1,1-trichloroethane, trichloroethylene and mixtures thereof; and aqueous solvents such as water.
Diluents or fillers are substances which usually provide bulk to the composition. Various useful fillers or diluents include, but are not limited to calcium phosphate (anhydrous or dihydrate), dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, calcium sulfate, dextrates, dextrin, dextrose, fructose, kaolin, anhydrous lactose, lactose monohydrate, maltose, sugar alcohol (such as mannitol, sorbitol, xylitol, lactitol, maltitol, erythritol, isomalt etc.), sucrose, starch, pregelatinized starch, cellulose derivatives (microcrystalline cellulose, silicified microcrystalline cellulose etc.) or talc. Preferably, filler is used in an amount of about 5 - 90 % by weight. More preferably, filler is used in an amount of at least 20% by weight.
Binders impart cohesiveness to formulation. Various useful binders include, but are not limited to acacia, alginic acid, sodium alginate, carbomer, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, glucose, guar gum, hydroxypropylmethyl cellulose, maltose, methylcellulose, starch, pregelatinized starch, modified starch, polyvinyl alcohol or polyethylene oxide. Binder is optionally used in amounts of about 0-20 % by weight.
Various useful disintegrants include, but are not limited to, alginic acid, croscarmellose sodium, carmellose calcium, potassium polacrilin, sodium starch glycolate, low substituted hydroxypropyl cellulose or starch. Preferably, disintegrant is optionally used in amounts of about 0-10 % by weight.
Lubricants are added to a pharmaceutical composition for ease in processing, to prevent adhesion to the equipment during processing. Lubricants used in the composition include lubricants commonly used in solid pharmaceutical compositions. Lubricants used in the composition include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, glyceryl behenate,

polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, vegetable oil, sodium lauryl sulfate, silicon dioxide, carnauba wax, sucrose stearate or zinc stearate. Preferably, lubricant is present in an amount of about 0.1- 5% by weight.
Glidants improve flowability and accuracy of dosing. Glidants used in the composition include, but are not limited to, colloidal silicon dioxide, magnesium trisihcate, starch, talc, or tribasic calcium phosphate. Preferably, the glidants are used in amounts of about 0.1-2% by weight.
Sweeteners that can be used include sucrose, sucralose, aspartame, stevia extract, glycyrrhiza, saccharine, saccharine sodium, acesulfame, sucralose and dipotassium glycyrrhizinate etc.
Useful flavoring agents include pharmaceutically acceptable natural oils, natural flavors, and artificial flavors. Representative flavors include, without limitation thereto, menthol, peppermint, wintergreen, orange, cherry, and other fruits, vanilla, almond and other nuts, etc. Mixtures of two or more flavoring agents frequently are useful.
Suitable coloring agents include, without limitation, one or more natural and/or artificial colorants such as FD&C coloring agents, natural juice concentrates, pigments such as titanium oxide, silicon dioxide, iron oxides, zinc oxide, and the like. There is no limitation on color or flavor that is useful in the present invention, and these characteristics will likely be chosen based on the age of the patient consuming the solid dosage form.
Suitable solvents include aqueous or organic solvents. Preferable solvents include, but are not limited to, water, esters such as ethyl acetate; ketones such as acetone; alcohols such as methanol, ethanol, isopropanol, butanol; dichloromethane, chloroform, dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), ether, diethyl ether and combinations thereof.

Surfactants or surface-active agents improve wettability of the dosage form and/or enhance its dissolution. Surfactants contemplated in the present invention include but are not limited to anionic surfactants, amphoteric surfactants, non-ionic surfactants and macromolecular surfactants. Suitable examples of anionic surfactants include but are not limited to sodium lauryl sulphate, sodium cetyl stearyl sulphate or sodium dioctyl sulphosuccinate etc. Suitable example of an amphoteric surfactant include but is not limited to lecithin. Suitable examples of non-ionic surfactants include but is not limited to cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, cholesterol, sorbitan fatty acid esters such as sorbitan mono-oleate, polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polysorbate 20, polyoxyethylene fatty acid glycerides such as macrogol 1000 glycerol monostearate, polyoxyethylene fatty acid esters such as polyoxyl 40 stearate, polyoxyethylene fatty alcohol ethers such as polyoxyl 10 oleyl ether, glycerol fatty acid esters such as glycerol monostearate, commercially available SEPITRAP® 80 or SEPITRAP® 4000 etc. The surfactant may constitute from about 1% w/w to about 5% w/w of the total composition.
In another embodiment of the invention, the pharmaceutical compositions are formulated into solid pharmaceutical dosage forms. Solid pharmaceutical dosage forms include, but are not limited to, tablets, capsules, powders, granules and sachets. Preferably, the solid pharmaceutical dosage form is a tablet or capsule. More preferably, the solid pharmaceutical dosage form is a tablet or orally disintegrating tablet.
In yet another embodiment of the invention, the pharmaceutical compositions comprise about 1 mg to about 90 mg of Tolvaptan. Preferably, the pharmaceutical compositions comprise about 1 mg to about 60 mg of Tolvaptan. More preferably, the pharmaceutical compositions comprise about 1 mg to about 30 mg of Tolvaptan.

In further embodiment, the present invention includes method of using the pharmaceutical composition comprising solid dispersion or granule or premix of Tolvaptan in the treatment of clinically significant hypervolemic and euvolemic hyponatremia, including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH).
In an another embodiment of the present invention the pharmaceutical composition comprises of solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, wherein the process of preparation of solid dispersion comprises a) preparing a solution of tolvaptan and the carrier in a solvent selected from the group consisting of water, an alcohol, an ester, a polar aprotic solvent, and mixtures thereof; b) optionally, filtering the solvent solution to remove insoluble matter; and c) substantially removing the solvent from the solution to produce the solid dispersion of Tolvaptan with the pharmaceutically acceptable excipient.
In an another embodiment of the present invention the pharmaceutical composition comprises of solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts with one or more carrier, wherein the solvent used in the solid dispersion process is removed using distillation or complete evaporation of the solvent, spray drying, vacuum drying, lyophilization or freeze drying, agitated thin-film drying, or a combination thereof. The process for the invention besides being cost effective, also makes it possible to prepare a pharmaceutical composition of Tolvaptan, wherein the composition has desirable formulation technical attributes.
The solid dispersion of tolvaptan with a pharmaceutically acceptable carrier obtained by the processes disclosed herein may be characterized by one or more of their powder X-ray diffraction (XRD) pattern, infrared absorption (IR) spectrum, and SEM images of the morphological analysis.

In another embodiment the present invention includes tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, form prepared by the above process can be subjected to in vitro dissolution evaluation according to Test 711 "Dissolution" in the United States Pharmacopoeia 37, United States Pharmacopoeial Convention, Inc., Rockville, Md., 2014 ("USP") to determine the rate at which the active substance is released from the dosage form, and the content of the active substance can be determined in solution by high performance liquid chromatography. When comparing the test and reference products (of US and Japan), dissolution profiles should be compared using a similarity factor (f2). The similarity factor is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) of dissolution between the two curves.
£2 = 50 • log {[1 + (l/n)St=ln (Rt - Tt)2]-0.5 • 100} Two dissolution profiles are considered similar when the f2 value is equal to or greater than 50.
In another embodiment, dissolution of the pharmaceutical compositions of the present invention were done in 900 ml of 0.22% Sodium Lauryl Sulfate (SLS) in Water (Office of Generic Drugs dissolution database) using a USP II apparatus (paddle) at a temperature of 37±0.5°C and a rotation speed of 50 revolutions per minute.
It is desirable that the pharmaceutical compositions prepared according the present invention are expected to have formulation attributes, like dissolution and stability comparable to the innovator's marketed product.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to

the following examples describing in detail method for the preparation of Tolvaptan pharmaceutical composition. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. Following examples are set out to illustrate the invention and do not limit the scope of the present invention. Following examples are set out to illustrate the invention and do not limit the scope of the present invention.
EXAMPLES
The following examples are intended to further illustrate certain preferred
embodiments of the invention and are not limiting in nature.
Table 1: represents the pharmaceutical composition using different carriers

Ingredient Example 1 Example 2
Qty/tab(mg) Qty/tab(mg)
Solid dispersion
Tolvaptan 30.0 30.0
PEG6000 30.0 -
HPMC5cps - 30.0
Ethanol/Dichloromethane q.s. q.s.
Extrgranular
Avicel PH 101 60.0 70.0
Lactose monohydrate (Pharamtose200M) 38.0 38.0
Crosscarmellose sodium 15.0 15.0
Pregelatinised starch - 15.0
HPMC5cps 5.0 -
Magnesium stearate 2.0 2.0
Average weight (mg) 180.0 200.0
Manufacturing process:

a) Dissolve Tolvaptan and HPMC/PEG in a solvent mixture of Ethanol and dichloromethane in the ratio of 1:4 or IPA: Methylene chloride in the ratio of 3:7.
b) optionally, filtering the solvent solution to remove insoluble matter; and allow the solvent to evaporate to produce the solid dispersion of Tolvaptan with HPMC/PEG.
c) remove the powder and sift it through #40 mesh screen, mix the premix/solid dispersion of step (c) with extragranular ingredients sifted through sieve of mesh size #40 in a suitable blender.
d) lubricate the blend of step (d) with magnesium stearate.
e) optionally, compress the lubricated blend of step (e) into tablets using 8mm round punches.
The tablets in the above example may contain flavoring/sweetening agent and
optionally a film coating.
Preferred method of manufacture is direct compression/ dry granulation/ wet
granulation.
Table 2: represents the physicochemical properties of the Tablet blend and compressed tablets

Blend properties
Example 1 Example 2
Bulk Density (g/ml) 0.45 0.42
Tapped Density (g/ml) 0.58 0.55
Physical parameters of tablets
Hardness (Kp) 6.0-9.0 3.0-7.0
Tablet Thickness (mm) 3.5±0.2 3.6±0.2
Friability (%w/w) 0.2 0.3
Disintegration Time (min) 3.5-4.5 3-4.5

We Claim:

1.A pharmaceutical composition comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier, wherein the composition is free of Hydroxypropyl cellulose (HPC) and/or heterocyclic amide-group containing polymeric compound.
2. A pharmaceutical composition comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with a pharmaceutically acceptable excipient, wherein pharmaceutically acceptable excipient is a carrier and the ratio of Tolvaptan to carrier is 1:0.2 to 1: 5.
3. The pharmaceutical compositions according to claim 2, wherein the carrier is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), maltodextrin, Polyacrylates and polymethacrylates, Polyethylene glycol (PEG), Mannitol, Lactose monohydrate, Dextrose, Sucrose, Galactose, Sorbitol, Maltose, Xylitol, Pectin, Galactomannan, Cyclodextrins, Pentaerythritol, Pentaerythrityl tetra acetate, Urea, Urethane, Poloxamers, texaphor, Deoxycholic acid, Tweens and Spans and mixtures thereof.
4. The pharmaceutical composition according to claim 3, wherein the composition is free of HPC and/or heterocyclic amide-group containing polymeric compound and comprises of pharmaceutically acceptable excipients selected from binder, diluent, disintegrant, lubricant, surfactants, glidants.
5. A pharmaceutical composition comprising solid dispersion or granule or premix of Tolvaptan or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof with one or more carrier,

wherein the particle size of Tolvaptan solid dispersion or premix is less than 300um.
6. The process for preparation of solid dispersion or premix according to claim 1
comprises of:
a) dissolving a solution of Tolvaptan and carrier in a solvent selected from the group consisting of water, an alcohol, an ester, a polar aprotic solvent, and mixtures thereof;
b) optionally, filtering the solvent solution to remove insoluble matter; and
c) substantially removing the solvent from the solution to produce the solid dispersion of Tolvaptan with the carrier.

7. The pharmaceutical composition according to claim 6, wherein the solid dispersion is free of residual solvent.
8. The pharmaceutical composition according to claim 1, wherein the composition is prepared by any of the process selected from dry granulation, wet granulation, spray granulation, and direct compression tableting processes.
9. A process for preparing a pharmaceutical composition comprising solid dispersion or premix of Tolvaptan free of HPC and/or heterocyclic amide-group containing polymeric compound, wherein the process comprises:

a) blending a mixture of a Tolvaptan solid dispersion or premix with one or more carrier and optionally other pharmaceutically acceptable excipients.
b) granulating the blend of step (a) with a solvent optionally containing binder;
c) drying the wet granules;
d) milling and sizing the dried granules, followed by adding at least one lubricant/glidant and optionally other pharmaceutically acceptable excipients to the dried milled granules; and

e) compressing the lubricated granules into tablets.
10. A process for preparing a pharmaceutical composition comprising amorphous and/or crystalline Tolvaptan free of HPC, wherein the process comprises:
a) blending a mixture of amorphous Tolvaptan with a pharmaceutical acceptable excipient and optionally other pharmaceutically acceptable excipients.
b) granulating the blend of step (a) with a solvent optionally containing binder;
c) drying the wet granules;
d) milling and sizing the dried granules, followed by adding at least one lubricant/glidant and optionally other pharmaceutically acceptable excipients to the dried milled granules; and
e) compressing the lubricated granules into tablets.