FIELD OF THE INVENTION

The invention relates to pharmaceutical compositions comprising tolvaptan or a pharmaceutically acceptable salt thereof.

Particularly, the invention relates to solid dispersion compositions of tolvaptan and process for preparing the same.

BACKGROUND

Tolvaptan is chemically described as (±)-4'-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-l-benzazepin-l-yl) carbonyl]-otolu-m-toluidide. Its empirical formula is C26H25C1N2O3, with structural formula as follows:

In the United States, tolvaptan is available as oral tablets containing 15mg or 30mg of tolvaptan, with trade name SAMSCA® by Otsuka America Pharmaceutical.

U.S. Patent No. 5,258,510 discloses tolvaptan.

U.S. Patent Application Publication No. 2010/0323006 A1 discloses process for the preparation of tolvaptan compositions by a method, comprising: step 1 of producing an amorphous composite from tolvaptan and hydroxypropyl cellulose; step 2 of mixing the amorphous composite obtained in step 1 with at least one member selected from the group consisting of low substituted hydroxypropylcellulose, carmellose, sodium carboxy methyl starch, and crospovidone; and step 3 of processing the mixture obtained in step 2 into a solid preparation.

Still, there is a need to develop alternative compositions of tolvaptan using simplified process. Accordingly, inventors of the present invention have developed novel compositions of tolvaptan and process for preparing the same.

SUMMARY

The present invention relates to solid oral compositions comprising solid dispersion comprising tolvaptan, a polymer and one or more pharmaceutically acceptable excipients.

One embodiment of this invention relates to pharmaceutical composition by a solid dispersion process comprising (a) tolvaptan or a pharmaceutically acceptable salt thereof; and (b) a polymer selected from a graft copolymer comprised of polyethylene glycol, polyvinylcaprolactam and polyvinylacetate; povidone; and combinations thereof.

Another embodiment of this invention relates to solid dispersion composition comprising tolvaptan or a pharmaceutically acceptable salt thereof; a polymer; and polacrilin potassium as disintegrant.

Another embodiment of this invention relates to solid pharmaceutical composition comprising tolvaptan or a pharmaceutically acceptable salt thereof; a polymer, a disintegrant, a solubilizing agent/ surfactant, and one or more pharmaceutically acceptable excipients; wherein said composition is prepared by hot melt extrusion process.

Another embodiment of this invention relates to pharmaceutical compositions prepared by fluid bed granulation (top spray granulation) comprising tolvaptan, povidone and one or more pharmaceutically acceptable excipients.

In yet another embodiment of this invention provides process for the preparation of tolvaptan composition by fluid bed granulation comprises the steps of: (a) sifting one or more excipients followed by loading into fluid bed processor, (b) dissolving tolvaptan and at least one polymer in a solvent or mixture of solvents, (c) granulating the dry mix of step (a) by spraying the solution of step (b) onto it, (d) blending the granules of step (c) with extragranular excipients if any, followed by lubrication, and finally (e) compressing the lubricated materials of step (d) into tablets or filling into capsules.

Also included in the present invention is use of tolvaptan composition for treating hyponatremia.

DETAILED DESCRIPTION

The present invention relates to pharmaceutical compositions of tolvaptan. More particularly, the present invention relates to solid dispersion compositions of tolvaptan and process for their preparation.

The term "tolvaptan" as used herein according to the present invention includes tolvaptan in the form of free base, a pharmaceutically acceptable salt thereof, amorphous tolvaptan, crystalline tolvaptan, any isomer, derivative, hydrate, solvate or prodrug or a combination thereof.

The term "composition" or "solid oral composition" or "dosage form" as used herein synonymously include solid dosage forms such as tablets, capsules, powder, particles, granules, pellets, mini-tablets and the like meant for oral administration.

A "composition" comprises an active pharmaceutical ingredient and at least one pharmaceutically acceptable excipient.

The term "active pharmaceutical ingredient" herein refers to tolvaptan or a pharmaceutically acceptable salt thereof.

The term "pharmaceutically acceptable excipient" includes a pharmaceutically acceptable material such as, fillers, diluents, carriers and the like, suitable for administering an active pharmaceutical ingredient. Each excipient should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

Generally the pharmaceutical compositions of the present invention prepared in unit dosage forms, meant for immediate release.

As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus for example, a reference to "a method" or "a process" includes one or more methods, one or more processes and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

The present invention relates to solid oral compositions comprising tolvaptan with one or more pharmaceutically acceptable excipients and process for their preparation.

According to the present invention pharmaceutically acceptable excipients selected from polymers, diluents, binders, disintegrants, solubilizing agents/ surfactants, glidants, lubricants and combinations thereof.

Polymers: Various useful polymers include but are not limited to a graft copolymer comprised of polyethylene glycol, polyvinylcaprolactam and polyvinylacetate (Soluplus®), copovidone, povidone, hydroxypropyl methylcellulose and poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1:2:1 (Eudragit E PO) and the like, and combinations thereof.

Diluents: Various useful diluents include but are not limited to lactose, microcrystalline cellulose, starch, corn starch, pregelatinized starch, maize starch, potato starch, powdered celluloses, sorbitol, xylitol, dibasic calcium phosphate, calcium phosphate, calcium carbonate, magnesium carbonate and the like, and combinations thereof.

Binders: Various useful binders include but are not limited to polyvinyl pyrrolidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch, powdered acacia, gelatin, guar gum, carbomers and the like, and combinations thereof.

Disintegrants: Various useful disintegrants include but are not limited to polacrilin potassium, croscarmellose sodium, sodium starch glycolate, crospovidone, pregelatinized starch, and the like, and combinations thereof.

Solubilizing agents/ Surfactants: Various useful solubilizing agents/ surfactants include but are not limited to sorbitan mono laurate, sodium lauryl sulphate, polyoxyethylene-polyoxypropylene block copolymers (also known as poloxamers), polyethylene glycols, sodium stearyl sulfate, sodium oleyl sulfate, sodium cetyl sulfate, sodium dodecylbenzene sulfonate, dialkyl sodium sulfosuccinates, polysorbates and the like, and combinations thereof.

Glidants: One or more glidants, which improve the flow of a powder blend can be used. Useful glidants include but are not limited to, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, and other forms of silicon dioxide, such as aggregated silicates and hydrated silica the like, and combinations thereof.

Lubricants: Various useful lubricants include but are not limited to magnesium stearate, stearic acid, talc, fumaric acid, palmitic acid, sodium stearyl fumarate, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols and the like, and combinations thereof.

In one aspect, the present invention relates to pharmaceutical composition by a solid dispersion process comprising (a) tolvaptan or a pharmaceutically acceptable salt thereof; and (b) a polymer selected from a graft copolymer comprised of polyethylene glycol, polyvinylcaprolactam and polyvinylacetate; povidone; and combinations thereof.

In another aspect, the present invention relates to solid dispersion composition comprising tolvaptan or a pharmaceutically acceptable salt thereof; a polymer; and polacrilin potassium as disintegrant.

The pharmaceutical compositions of tolvaptan may be processed by a solid dispersion process such as hot melt extrusion, fluid bed granulation, spray drying, melt agglomeration, co-precipitation, freeze drying, solvent evaporation, nitrogen stream, amorphous precipitation in crystalline matrix, supercritical fluid, eutectics or solid solution process.

In one aspect, this invention relates to pharmaceutical composition of tolvaptan prepared by hot melt extrusion process. In another aspect, hot melt extrusion process comprises the steps of: (a) sifting and blending tolvaptan, a polymer and one or more excipients with a surfactant, (b) passing the materials of step (a) through hot melt extruder to form extrudes followed by milling, (c) blending the milled extrudes of step (b) with extra-granular excipients, followed by lubrication, and finally (d) compressing the lubricated materials of step (c) into tablets or filling into capsules.

Extruders suitable for processing the pharmaceutical compositions of the present invention include twin screw extruder, single screw extruder or else intermeshing screw extruders, preferably twin screw extruder (Pharma HME 24) from Thermo Fisher Scientific.

Another aspect of this invention relates to solid pharmaceutical composition comprising tolvaptan or a pharmaceutically acceptable salt thereof; a polymer, a disintegrant, a solubilizing agent/ surfactant, and one or more pharmaceutically acceptable excipients; wherein said composition is prepared by hot melt extrusion process.

In another aspect, this invention also provides process for preparation of tolvaptan composition by fluid bed granulation comprises the steps of: (a) sifting one or more excipients followed by loading into fluid bed processor, (b) dissolving tolvaptan and at least one polymer in a solvent or mixture of solvents, (c) granulating the dry mix of step (a) by spraying the solution of step (b) onto it, (d) blending the granules of step (c) with extragranular excipients if any, followed by lubrication, and finally (e) compressing the lubricated materials of step (d) into tablets or filling into capsules.

In further aspect of the present invention, solvents suitable for processing the pharmaceutical compositions include one or more of organic solvents such as dichloromethane, ethanol, methanol, acetaldehyde, acetone, benzene, carbon disulphide, carbon tetrachloride, 1,2 dichloroethane, N,N-dimethylformamide, 1,4-dioxane, epichlorhydrin, ethyl acetate, ethyl ether, ethylene glycol, 2-ethoxyethanol (acetate), formaldehyde, isopropanol, methyl n-butyl ketone, methyl ethyl ketone, 2-methoxyethanol (acetate), perchloroethylene, toluene, 1,1,1-trichloroethane, trichloroethylene; and the like, and combinations thereof; and aqueous solvents such as water.

In yet another aspect, this invention relates to pharmaceutical compositions prepared by fluid bed granulation (top spray granulation) comprising tolvaptan, povidone and one or more pharmaceutically acceptable excipients.

Also included in the present invention is use of tolvaptan composition for treating hyponatremia.

EXAMPLES

The following examples further describe and demonstrate particular embodiments within the scope of the present invention. The examples are given solely for illustration and are not to be construed as limitations as many variations are possible without departing from spirit and scope of the invention.

Example 1:

Table 1: Tablet compositions of Tolvaptan prepared by hot melt extrusion process:

Soluplus' - a grart copolymer comprised ot polyethylene glycol, polyvinylcaprolactam and polyvinylacetate.

Preparation method:

1. Tolvaptan, soluplus were blended with sorbitan mono laurate in a high shear mixer,

2. blend of step 1, was fed into a extruder, and the resulted extrudes were milled,

3. milled extrudes of step 2, were blended with lactose monohydrate, croscarmellose sodium and FD&C blue,

4. blend of step 3, was lubricated with magnesium stearate, and finally compressed into tablets.
Example 2:

Table 2: Tablet compositions of Tolvaptan prepared by hot melt extrusion process:

Preparation method

1. Tolvaptan, copovidone were blended with sorbitan mono laurate in a high shear mixer,

2. blend of step 1, was fed into a extruder, and the resulted extrudes were milled,

3. milled extrudes of step 2, were blended with lactose monohydrate, croscarmellose sodium and FD&C blue,

4. blend of step 3, was lubricated with magnesium stearate, and finally compressed into tablets or filled into capsules.

Example 3:

Table 3: Tablet compositions of Tolvaptan prepared by fluid bed top spray granulation method:

Soluplus"- a graft copolymer comprised of polyethylene glycol, polyvinylcaprolactam and polyvinylacetate.

Preparation method

1. Lactose monohydrate, microcrystalline cellulose, corn starch and polacrilin potassium were mixed in a fluid bed granulator,

2. tolvaptan and soluplus were dissolved in a mixture of dichloro methane and ethanol under continuous stirring to get a clear solution,

3. dry mix of step 1, was granulated by spraying the solution of step 2 onto it,

4. granules of step 3, were blended with extragranular polacrilin potassium and FD&C blue,

5. blend of step 4, was lubricated with magnesium stearate, and finally

6. lubricated blend of step 5, was compressed into tablets or filled into capsules.

Example 4:

Table 4: Tablet compositions of Tolvaptan prepared by top spray granulation method:


Preparation method

1. Lactose monohydrate, microcrystalline cellulose, corn starch and croscarmellose sodium
were mixed in a fluid bed granulator,

2. tolvaptan and povidone were dissolved in a mixture of dichloro methane and ethanol
under continuous stirring to get a clear solution,

3. dry mix of step 1, was granulated by spraying the solution of step 2 onto it,

4. granules of step 3, were blended with extragranular croscarmellose sodium and FD&C
blue,

5. blend of step 4, was lubricated with magnesium stearate, and finally

6. lubricated blend of step 5, was compressed into tablets or filled into capsules.
Comparative example 5:

Table 5: Tablet compositions of Tolvaptan prepared by wet granulation method:

Preparation method

1. Tolvaptan, lactose monohydrate, microcrystalline cellulose, corn starch, croscarmellose
sodium and FD&C blue were sifted,

2. binder solution was prepared using povidone and purified water,

3. sifted materials of step 1, were loaded into rapid mixer granulator and granulated using
binder solution of step 2.

4. the wet mass of step 3 was dried and milled to get the desired granules,

5. granules of step 4 were lubricated with magnesium stearate,

6. lubricated granules of step 5 were compressed into tablets using suitable punches.
Comparative study on dissolution time:

Dissolution test was performed for tablets prepared as per the Example 4 and Comparative example 5, using USP apparatus II, 100 rpm, in 900 ml of purified water with 1% sodium lauryl sulphate.

Table 6:

Based on the results presented in Table 6, tolvaptan compositions prepared by fluid bed top spray granulation (Example-4) showed improved dissolution properties as compared to compositions prepared by conventional wet granulation (Comparative example 5).

WE CLAIM:

1. A pharmaceutical composition by a solid dispersion process comprising (a) tolvaptan or a pharmaceutically acceptable salt thereof; and (b) a polymer selected from a graft copolymer comprised of polyethylene glycol, polyvinylcaprolactam and polyvinylacetate; povidone; and combinations thereof.

2. The composition of claim 1, wherein the composition is prepared by hot melt extrusion, top spray granulation, spray drying, coprecipitation or solvent evaporation process.

3. The composition according to claim 1, is in the form of a tablet or granules or a capsule.

4. A solid pharmaceutical composition comprising: (a) tolvaptan or a pharmaceutically acceptable salt thereof; (b) a polymer, (c) a disintegrant, (d) a solubilizing agent/ surfactant, and (e) one or more pharmaceutically acceptable excipients; wherein said composition is prepared by hot melt extrusion process.

5. The composition according to claim 4, wherein said polymer selected from a graft copolymer comprised of polyethylene glycol, polyvinylcaprolactam and polyvinylacetate; povidone; and combinations thereof; and solubilizing agent is sorbitan monolaurate.

6. A process for preparation of tolvaptan composition by top spray granulation comprises the steps of: (a) sifting one or more excipients followed by loading into fluid bed processor, (b) dissolving tolvaptan and at least one polymer in a solvent or mixture of solvents, (c) granulating the dry mix of step (a) by spraying the solution of step (b) onto it, (d) blending the granules of step (c) with extragranular excipients if any, followed by lubrication, and finally (e) compressing the lubricated materials of step (d) into tablets or filling into capsules.

7. The composition according to claim 6, wherein said polymer selected from povidone; a graft copolymer comprised of polyethylene glycol, polyvinylcaprolactam and polyvinylacetate; and combinations thereof.

8. The composition of any of the preceding claims, wherein the ratio of tolvaptan to polymer is in the range of from 1:0.1 to 1:4.

9. A solid dispersion composition comprising (a) tolvaptan or a pharmaceutically acceptable salt thereof; (b) a polymer; and (c) polacrilin potassium as disintegrant.

10. The method of treating hyponatremia in a patient in need thereof, comprising administering to the patient the composition of any one of claims 1-9.