A solid dispersion of enzalutamide

Abstract

The present invention relates to a solid dispersion comprising enzalutamide or its pharmaceutically acceptable salts, hydroxypropyl methylcellulose phthalate (HPMCP), soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), surfactant, and optionally at least one pharmaceutically acceptable excipient. The present invention also relates to a pharmaceutical composition comprising the solid dispersion of enzalutamide and its use for treating prostate cancer. The present invention further relates to a process for preparation of the solid dispersion of enzalutamide and the pharmaceutical composition comprising the solid dispersion of enzalutamide.

Description

[0001] A SOLID DISPERSION OF ENZALUTAMIDE

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a solid dispersion comprising enzalutamide or its pharmaceutically acceptable salts, hydroxypropyl methylcellulose phthalate (HPMCP), soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), surfactant, and optionally at least one pharmaceutically acceptable excipient. The present invention also relates to a pharmaceutical composition comprising the solid dispersion of enzalutamide and its use for treating prostate cancer. The present invention further relates to a process for preparation of the solid dispersion of enzalutamide and the pharmaceutical composition comprising the solid dispersion of enzalutamide.

[0004] BACKGROUND OF THE INVENTION

[0005] Enzalutamide is chemically known as 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]- 5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide (I).

[0006] WO 2006124118 A1 discloses enzalutamide and its salts for the treatment of prostate cancer.

[0007] Enzalutamide is marketed under brand name Xtandi® by Astellas Pharma since 2013 in Europe. Initially, 40 mg Xtandi® soft gelatin capsule was approved (four 40 mg soft capsules, as single oral daily dose i.e. 160 mg daily) in 2013. In 2017, 40 mg and 80 mg Xtandi® tablet was approved. The new tablet formulation is smaller size dosage form compared to capsule that helps patients having difficulty in swallowing.

[0008] According to European Public Assessment Report (EPAR), enzalutamide is a crystalline solid, practically insoluble in aqueous media between pH 1 -11 but highly permeable (BCS class II) and thus, dissolution of the enzalutamide is rate-limiting for bioavailability. Moreover, due to low solubility of crystalline form of enzalutamide, converting crystalline active ingredient to amorphous solid state is well known technique to improve the solubility as it offers improved apparent solubility and dissolution rate due to the lower energy barrier required to dissolve active ingredient. Specifically, in the polymeric solid dispersion, drug is incorporated as molecular dispersion in a polymeric matrix. The polymers act as stabilizers by decreasing molecular mobility, and hence inhibit nucleation and crystal growth, while molecular drug-polymer interactions may further inhibit recrystallization.

[0009] US 11839689 B2 discloses pharmaceutical composition comprising a solid dispersion consisting essentially of amorphous enzalutamide and hydroxypropyl methylcellulose acetate succinate (HPMCAS). Specifically, US ‘689 discloses that solid dispersion of enzalutamide and HPMCAS shows higher solubility as compared to solid dispersion of enzalutamide with other polymers.

[0010] WO 2021064123 A1 discloses tablet composition comprising a granulate consisting of a co-precipitate on a substrate, wherein the co-precipitate comprises enzalutamide in amorphous form and a cellulosic concentration enhancing polymer. Specifically, WO ‘123 discloses co-precipitate comprises enzalutamide in amorphous form and HPMCAS or HPMCP (hydroxypropylmethylcellulose phthalate).

[0011] WO 2021240206 A1 discloses pharmaceutical composition comprising enzalutamide, characterized in that it comprises enzalutamide and at least one anionic polymer (copolymer of methacrylic acid and ethyl acrylate i.e. Eudragit®) and / or at least one non-ionic polymer (co-polymer of vinyl pyrrolidone and vinyl acetate i.e. Kollidon VA64). Atishkumar et. al. (International Journal of Health Sciences, 6(S4), 12074-12087) discloses enzalutamide ternary solid dispersion using soluplus® and poloxamer prepared by spray drying technique to increase the dissolution.

[0012] WO 2018199282 A1 discloses pharmaceutical composition containing enzalutamide and polyvinyl alcohol solid dispersion, wherein the compositions with polyvinyl alcohol show a pH independent release.

[0013] CN 105030685 B discloses spray drying process for preparation of solid dispersion using ethanolic solution of povidone K30 and enzalutamide, then the solid dispersion was mixed with other excipients and compressed to tablet.

[0014] Rongmin et. al. (Jinri Yaoxue, Volume: 31 , Issue: 4, Pages: 290-294) discloses preparation of enzalutamide ternary solid dispersion by hot melt extrusion. It further discloses that ternary solid dispersion of enzalutamide, Hypromellose acetate succinate (HPMCAS-H) with soluplus®, p-Cyclodextrin (p-CD) or croscarmellose sodium (CCMC- Na) prepared by hot melt extrusion improves the solubility and physical stability of enzalutamide solid dispersion.

[0015] In general, for such polymer based solid dispersion, it is believed when solid dispersion system comes into contact with gastrointestinal media, dissolution will occur to a supersaturated state, which is more or less stabilized by the polymer. This has been shown to significantly enhance the bioavailability of poorly water-soluble BCS Class II active ingredients. However, few challenges also associated with that solid dispersion such as a) high inter-individual variability of drug performance and b) instability of the solid state which results in a tendency for recrystallisation or precipitation of the active ingredient during the storage. This may lead to decrease in dissolution profile and thus bioavailability of the active ingredient. Therefore, there still exists need to provide a solid dispersion of enzalutamide using specific excipient(s) that able to form stable solid dispersion, prevent recrystallisation or precipitation of the drug, and aid to increase the solubility of the drug to provide desired dissolution rate and thus provide desired bioavailability.

[0016] The inventors of the present invention surprisingly found that solid dispersion comprising enzalutamide or its pharmaceutically acceptable salts, hydroxypropyl methylcellulose phthalate (HPMCP), soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), surfactant and optionally at least one pharmaceutically acceptable excipient, and composition comprising the said solid dispersion exhibit desired dissolution profiles i.e. similar to the reference product Xtandi® tablet.

[0017] OBJECT OF THE INVENTION

[0018] A main object of the present invention is to provide a solid dispersion comprising enzalutamide or its pharmaceutically acceptable salts, hydroxypropyl methylcellulose phthalate (HPMCP), soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), surfactant and optionally at least one pharmaceutically acceptable excipient, which exhibits dissolution profiles similar to the reference product Xtandi® tablet.

[0019] Yet another object of the present invention is to provide a pharmaceutical composition comprising the said solid dispersion, which exhibits dissolution profiles similar to the reference product Xtandi® tablet.

[0020] Yet another object of the invention is to provide a commercially scalable and robust process for preparation of the said solid dispersion and the said pharmaceutical composition.

[0021] Yet another object of the present invention is to provide pharmaceutical composition comprising the said solid dispersion, which overcomes the problems of the prior art. SUMMARY OF THE INVENTION

[0022] In one aspect, the present invention provides a solid dispersion comprising: a. enzalutamide or its pharmaceutically acceptable salts, b. hydroxypropyl methylcellulose phthalate (HPMCP), c. soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), d. surfactant, and e. optionally at least one pharmaceutically acceptable excipient.

[0023] In one aspect, the present invention provides a solid dispersion comprising: a. enzalutamide or its pharmaceutically acceptable salts, b. hydroxypropyl methylcellulose phthalate (HPMCP), c. soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), d. surfactant, and e. at least one pharmaceutically acceptable excipient.

[0024] In another aspect, the present invention provides a solid dispersion comprising: a. 10 to 30 wt.% of enzalutamide or its pharmaceutically acceptable salts, b. 50 to 80 wt.% of hydroxypropyl methylcellulose phthalate (HPMCP), c. 5 to 20 wt.% of soluplus® (polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol), d. 0.2 to 5 wt.% of surfactant, and e. optionally at least one pharmaceutically acceptable excipient, wherein the weight percent is based on the total weight of the solid dispersion.

[0025] In another aspect, the present invention provides a solid dispersion comprising: a. 10 to 30 wt.% of enzalutamide or its pharmaceutically acceptable salts, b. 50 to 80 wt.% of hydroxypropyl methylcellulose phthalate (HPMCP), c. 5 to 20 wt.% of soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), d. 0.2 to 5 wt.% of surfactant selected from sodium lauryl sulphate and polysorbate 80, and e. optionally at least one pharmaceutically acceptable excipient, wherein the weight percent is based on the total weight of the solid dispersion.

[0026] In another aspect, the present invention provides a solid dispersion comprising: a. 10 to 20 wt.% of enzalutamide or its pharmaceutically acceptable salts, b. 50 to 70 wt.% of hydroxypropyl methylcellulose phthalate (HPMCP), c. 5 to 15 wt.% of soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), d. 0.5 to 1 wt.% of sodium lauryl sulphate, and e. optionally at least one pharmaceutically acceptable excipient, wherein the weight percent is based on the total weight of the solid dispersion.

[0027] In another aspect, the present invention provides a process for preparation of the solid dispersion of enzalutamide comprises: a. mixing enzalutamide or its pharmaceutically acceptable salts, hydroxypropyl methylcellulose phthalate (HPMCP), soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), surfactant, suitable solvent and optionally a pharmaceutically acceptable excipient to obtain suspension / solution; and b. spray drying the suspension / solution of step a) to obtain powder mixture.

[0028] In another aspect, the present invention provides a process for preparation of the solid dispersion of enzalutamide comprises: a. mixing enzalutamide or its pharmaceutically acceptable salts, hydroxypropyl methylcellulose phthalate (HPMCP), soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), surfactant, suitable solvent and optionally a pharmaceutically acceptable excipient to obtain suspension / solution; and b. granulating at least one pharmaceutically acceptable excipient using suspension / solution of step a) to obtain granules. In another aspect, the present invention provides a pharmaceutical composition comprising the solid dispersion of enzalutamide, and at least one pharmaceutically acceptable excipient.

[0029] In another aspect, the present invention provides a pharmaceutical composition comprising: a. about 80 to 97 wt.% of the solid dispersion of enzalutamide, and b. at least one pharmaceutically acceptable excipient, wherein the weight percent is based on the total weight of the composition.

[0030] In another embodiment, the present invention provides tablet comprising: a. about 80 to 97 wt.% of the solid dispersion of enzalutamide, and b. at least one pharmaceutically acceptable excipient, wherein the weight percent is based on the total weight of the composition.

[0031] In another embodiment, the present invention provides tablet comprising: a. about 80 to 97 wt.% of the solid dispersion of enzalutamide comprising: i) enzalutamide or its pharmaceutically acceptable salts, ii) hydroxypropyl methylcellulose phthalate (HPMCP), iii) soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), iv) surfactant, and v) optionally at least one pharmaceutically acceptable excipient; and b. at least one pharmaceutically acceptable excipient, wherein the weight percent is based on the total weight of the composition.

[0032] In another embodiment, the present invention provides tablet comprising: a. about 80 to 97 wt.% of the solid dispersion of enzalutamide comprising: i) enzalutamide or its pharmaceutically acceptable salts, ii) hydroxypropyl methylcellulose phthalate (HPMCP), iii) soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), iv) surfactant, and v) at least one pharmaceutically acceptable excipient; and b. at least one pharmaceutically acceptable excipient, wherein the weight percent is based on the total weight of the composition.

[0033] In another aspect, the present invention provides a process for preparation of a pharmaceutical composition comprising the solid dispersion of enzalutamide and at least one pharmaceutically acceptable excipient.

[0034] In another aspect, enzalutamide is substantially in an amorphous form in the solid dispersion or the pharmaceutical composition of the present invention.

[0035] In another aspect, the present invention discloses the use of such solid dispersion or pharmaceutical composition as medicament in the treatment of prostate cancer.

[0036] In another aspect, the present invention discloses the use of such pharmaceutical composition as medicament in the treatment of prostate cancer.

[0037] The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

[0038] DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0039] The present invention will now be more specifically illustrated as hereunder.

[0040] Definitions:

[0041] The term “%”, “wt.%” or “%w / w” used in this specification means the percentage by the total weight of the solid dispersion or composition unless otherwise stipulated.

[0042] The term "about" can indicate a difference of 10 percent of the value specified. Numerical ranges as used herein are meant to include every number and subset of numbers enclosed within that range, whether particularly disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range.

[0043] The term “composition” or “pharmaceutical composition” as used in the present invention means solid pharmaceutical composition includes, without limitation, tablets, caplets, pellets, granules, capsules and beads.

[0044] The term "solid dispersion" refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components. The term "solid dispersion" as used herein, refers to stable solid dispersions comprising amorphous drug substance and a pharmaceutically acceptable excipient. Further, the term "solid dispersion" or “solid dispersion of enzalutamide”, can be used interchangeably, as used herein refers to stable solid dispersions comprising amorphous enzalutamide and pharmaceutically acceptable excipients like HPMCP, soluplus®, surfactant or mixture thereof. Herein "amorphous enzalutamide” means the solid dispersion contains enzalutamide in a substantially amorphous solid-state form i.e. at least about 80% of the enzalutamide in the solid dispersion is in an amorphous form. More preferably, at least about 90% and most preferably at least about 95% of enzalutamide in the solid dispersion is in amorphous form. The said solid dispersion can be in the form of powder, granules, or pellets.

[0045] The term “Enzalutamide” as used in the present invention includes, but is not limited to, Enzalutamide per se or its pharmaceutically acceptable salts, and its various crystalline and amorphous forms. Preferably, the solid dispersion or composition of the present invention comprises substantially amorphous enzalutamide or its pharmaceutically acceptable salts, more preferably, substantially amorphous enzalutamide base.

[0046] It is known that enzalutamide is practically insoluble in aqueous media and hence dissolution of the enzalutamide is rate-limiting for bioavailability. The inventors of the present invention have surprisingly found when the solid dispersion of enzalutamide was prepared by using HPMCP, soluplus® and surfactant, the said solid dispersion or composition comprising the said dispersion exhibits desired dissolution profile i.e. similar to the reference product Xtandi® tablet.

[0047] In one embodiment, the present invention provides a solid dispersion comprising: a. enzalutamide or its pharmaceutically acceptable salts, b. hydroxypropyl methylcellulose phthalate (HPMCP), c. soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), d. surfactant, and e. optionally at least one pharmaceutically acceptable excipient.

[0048] In one embodiment, the present invention provides a solid dispersion comprising: a. enzalutamide or its pharmaceutically acceptable salts, b. hydroxypropyl methylcellulose phthalate (HPMCP), c. soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), d. surfactant, and e. at least one pharmaceutically acceptable excipient.

[0049] The solid dispersion of the present invention comprises 10 to 30 wt.% of enzalutamide or its pharmaceutically acceptable salts, preferably 10 to 20 wt.% of enzalutamide or its pharmaceutically acceptable salts based on the total weight of the solid dispersion.

[0050] The solid dispersion of the present invention comprises 50 to 80 wt.% of hydroxypropyl methylcellulose phthalate (HPMCP), preferably 50 to 70 wt.% of HPMCP based on the total weight of the solid dispersion. HPMCP prevents the precipitation or crystallization of enzalutamide.

[0051] The solid dispersion of the present invention comprises 5 to 20 wt.% of soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), preferably 5 to 15 wt.% of soluplus® based on the total weight of the solid dispersion. Soluplus® is a solubilizer and crystallization inhibitor which prevents the precipitation or crystallization of enzalutamide and aids in the solubilization of enzalutamide.

[0052] In one of the embodiments, different crystallization inhibitors such as cellulosic polymer like hydroxypropyl cellulose, hydroxypropyl methylcellulose or their derivative may be used along with or without Soluplus®.

[0053] The solid dispersion of the present invention comprises surfactant which includes, but are not limited to, sulfonated hydrocarbons and their salts such as dioctyl sodium sulfocuccinate or sodium laurylsulfate; poloxamer (synthetic block copolymers of hydrophilic poly(oxyethylene) and hydrophobic poly(oxypropylene)); and polyoxyethylene sorbitan fatty acid esters such as polysorbate 80 and polysorbate 20. The solid dispersion of the present invention preferably comprises sodium laurylsulfate, polysorbate-80 or mixture thereof. The amount of the surfactant in the solid dispersion is 0.2 to 5 wt.%, preferably 0.5 to 1 wt.% based on the total weight of the solid dispersion.

[0054] The solid dispersion can also contain a suitable pharmaceutically acceptable excipient such as diluent and disintegrant.

[0055] In another embodiment, the present invention provides a solid dispersion comprising: a. 10 to 30 wt.% of enzalutamide or its pharmaceutically acceptable salts, b. 50 to 80 wt.% of hydroxypropyl methylcellulose phthalate (HPMCP), c. 5 to 20 wt.% of soluplus® (polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol), d. 0.2 to 5 wt.% of surfactant, and e. optionally at least one pharmaceutically acceptable excipient, wherein the weight percent is based on the total weight of the solid dispersion.

[0056] In another embodiment, the present invention provides a solid dispersion comprising: a. 10 to 30 wt.% of enzalutamide or its pharmaceutically acceptable salts, b. 50 to 80 wt.% of hydroxypropyl methylcellulose phthalate (HPMCP), c. 5 to 20 wt.% of soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), d. 0.2 to 5 wt.% of surfactant selected from sodium lauryl sulphate and polysorbate 80, and e. optionally at least one pharmaceutically acceptable excipient, wherein the weight percent is based on the total weight of the solid dispersion.

[0057] In another embodiment, the present invention provides a solid dispersion comprising: a. 10 to 20 wt.% of enzalutamide or its pharmaceutically acceptable salts, b. 50 to 70 wt.% of hydroxypropyl methylcellulose phthalate (HPMCP), c. 5 to 15 wt.% of soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), d. 0.5 to 1 wt.% of sodium lauryl sulphate, and e. optionally at least one pharmaceutically acceptable excipient, wherein the weight percent is based on the total weight of the solid dispersion.

[0058] In another embodiment, the present invention provides a pharmaceutical composition comprising the solid dispersion of enzalutamide, and at least one pharmaceutically acceptable excipient.

[0059] In another embodiment, the present invention provides a pharmaceutical composition comprising: a. about 80 to 97 wt.% of the solid dispersion of enzalutamide, and b. at least one pharmaceutically acceptable excipient, wherein the weight percent is based on the total weight of the composition.

[0060] In another embodiment, the pharmaceutical composition is a solid pharmaceutical composition such as tablet, caplet, pellet, granule, capsule and bead.

[0061] In another embodiment, the present invention provides tablet comprising: a. about 80 to 97 wt.% of the solid dispersion of enzalutamide, and b. at least one pharmaceutically acceptable excipient, wherein the weight percent is based on the total weight of the composition.

[0062] In another embodiment, the present invention provides tablet comprising: a. about 80 to 97 wt.% of the solid dispersion of enzalutamide comprising: i) enzalutamide or its pharmaceutically acceptable salts, ii) hydroxypropyl methylcellulose phthalate (HPMCP), iii) soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), iv) surfactant, and v) optionally at least one pharmaceutically acceptable excipient; and b. at least one pharmaceutically acceptable excipient, wherein the weight percent is based on the total weight of the composition.

[0063] In another embodiment, the present invention provides tablet comprising: a. about 80 to 97 wt.% of the solid dispersion of enzalutamide comprising: i) enzalutamide or its pharmaceutically acceptable salts, ii) hydroxypropyl methylcellulose phthalate (HPMCP), iii) soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), iv) surfactant, and v) at least one pharmaceutically acceptable excipient; and b. at least one pharmaceutically acceptable excipient, wherein the weight percent is based on the total weight of the composition.

[0064] The pharmaceutically acceptable excipient in accordance with the present invention are well known and are those excipients which are conventionally used by the person skilled in the art for the preparation of the solid dispersion and the pharmaceutical composition. The pharmaceutically acceptable excipient includes, but is not limited to, diluent, binder, disintegrant, lubricant, glidant and coating material such as plasticizer, film forming polymer, opacifier and pigment. Diluent includes, but are not limited to, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, silicified microcrystalline cellulose, starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide or mixtures thereof. The amount of diluent is from about 5 wt.% to about 50 wt.%, preferably from about 5 wt.% to about 15 wt.% based on the total weight of the composition.

[0065] Binder includes, but are not limited to, povidone, copovidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, xanthan gum, sorbitol, sucrose, gum arabic, pullulan, gelatin, sodium alginate, com syrup, carbomers or mixtures thereof. The solid dispersion or composition comprising solid dispersion may comprise binder. Binder may be used in amount of about 0.1 wt.% to about 5 wt.% based of the total weight of the composition.

[0066] Disintegrant includes, but is not limited to, sodium starch glycolate, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, pregelatinized starch, and sodium alginate or mixtures thereof. The amount of the disintegrant is preferably from about 5 wt.% to about 20 wt.%, more preferably from about 5 wt.% to about 10 wt.% based on the total weight of the composition.

[0067] Suitable lubricants and / or glidants includes, but is not limited to, magnesium stearate, hydrogenated vegetable oil, glyceryl behenate, glyceryl monostearate, stearic acid, sodium stearyl fumarate, sodium starch fumarate, calcium stearate, zinc stearate, aluminum silicate, talc, colloidal silicon dioxide, sucrose esters of fatty acid, waxes, silica gel, or mixtures thereof. The preferred glidant is colloidal silicon dioxide and the preferred lubricant is magnesium stearate. The present invention comprises a lubricant and / or glidant in an amount of from about 0.1 wt.% to about 10 wt.%, preferably, about 0.1 wt.% to about 2 wt.% based on the total weight of the composition. The pharmaceutical composition of the present invention may further be coated with a film-forming polymer and one or more pharmaceutically acceptable excipients, using techniques well known in the art e.g., spray coating in a conventional coating pan, or a fluidized bed processor, or dip coating. Alternatively, coating can also be performed using a hot melt technique.

[0068] The film coating may contain one or more film-forming polymers, and optionally one or more pharmaceutically acceptable excipients. A suitable film-forming polymer is selected from the group comprising hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate trimellitate, methacrylic acid copolymers e.g., Eudragit®, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, or mixtures thereof. A preferred film- forming polymer is hydroxypropyl methyl cellulose, polyethylene glycol, or mixtures thereof. Other suitable film-forming polymers which are known in art may also be used. The film coating may also contain opacifiers like titanium dioxide, plasticizer like polyethylene glycol, flow aids like talc and pigment like iron oxide yellow or red iron oxide.

[0069] The process to obtain solid dispersion of the present invention includes various techniques or methods including, but are not limited to, solvent evaporation method, fusion method, kneading method, melting method, spray drying method, granulation, cogrinding method, lyophilization technique, hot melt extrusion, melt agglomeration, supercritical fluid (SCF) technology and the like. Preferably, the process for the preparation of the solid dispersion of the present invention is spray drying or granulation.

[0070] In one embodiment, the solid dispersion of the present invention is prepared by spray drying technology which includes dissolving enzalutamide in a suitable solvent with additional excipient, and spray drying the enzalutamide solution or suspension at 160 °C ± 20 °C, preferably 160 °C ± 10 °C, to obtain spray dried powder. In one embodiment, the solid dispersion of the present invention is prepared by wet granulation which includes dissolving enzalutamide in a suitable solvent with or without additional excipient and granulating pharmaceutically acceptable excipients with enzalutamide solution or suspension using suitable technology like rapid mixer granulation or fluid bed granulation. The granules can be dried at temperature of 50 °C ± 10 °C.

[0071] In another embodiment, the present invention provides a process for preparation of the solid dispersion of enzalutamide comprises: a. mixing enzalutamide or its pharmaceutically acceptable salts, hydroxypropyl methylcellulose phthalate (HPMCP), soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), surfactant, suitable solvent and optionally a pharmaceutically acceptable excipient to obtain solution / suspension; and b. spray drying the solution / suspension of step a) to obtain powder mixture.

[0072] In another embodiment, the present invention provides a process for preparation of the solid dispersion of enzalutamide comprises: a. mixing enzalutamide or its pharmaceutically acceptable salts, hydroxypropyl methylcellulose phthalate (HPMCP), soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), surfactant, suitable solvent and optionally a pharmaceutically acceptable excipient to obtain solution / suspension; and b. granulating at least one pharmaceutically acceptable excipient using solution / suspension of step a) to obtain granules.

[0073] Suitable solvents in the present invention, but not limited to, can be selected from ethanol, methanol, isopropanol, acetone, N,N-dimethylformamide, N-methyl-2-pyrrolidone, acetonitrile, water or a mixture thereof. The solvent can be used for preparing solid dispersion or for preparing the coating solution or suspension.

[0074] In another embodiment, the pharmaceutical composition can be prepared by using the granules or the spray dried powder containing solid dispersion of enzalutamide. For example, tablets comprising enzalutamide solid dispersion and a pharmaceutically acceptable excipient can be prepared by using known technology in the field of pharmaceuticals such as direct compression, wet-granulation and roller-compaction.

[0075] Moreover, the pharmaceutical composition of the present invention is very suitable for production on commercial scale making use of equipment and techniques commonly used in industry.

[0076] The following examples are intended to illustrate the scope of the present invention but not to limit it thereto.

[0077] Examples:

[0078] Example-1 : Solid dispersion containing HPMCP, Surfactant and Soluplus®

[0079] Table-1 (S)

[0080] * Opadry 03F220132 Yellow contains hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, talc and iron oxide yellow

[0081] Process for the preparation Example 1(a) and (c): i) a granulating suspension containing enzalutamide, hydroxypropyl methylcellulose phthalate (HPMCP), soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), SLS / polysorbate 80, acetone and purified water was prepared, ii) microcrystalline cellulose and croscarmellose sodium (50 mg) were granulated by using the granulating suspension of step i) and the obtained granules were dried, iii) the dried granules of step ii) were mixed with silicified microcrystalline cellulose and compacted using roller compaction, iv) the obtained compact was milled to obtain granules, v) the granules of step iv) was mixed with croscarmellose sodium (10 mg), colloidal silicon dioxide and magnesium stearate, and vi) the mixture of step v) was compressed to tablet and that was coated with Opadry Yellow. Process for the preparation Example 1(b): i) a granulating suspension containing enzalutamide, hydroxypropyl methylcellulose phthalate (HPMCP), soluplus® (polyvinyl caprolactampolyvinyl acetate-polyethylene glycol), SLS, acetone and purified water was prepared, ii) the granulating suspension of step i) was spray dried using spray drier (Buchi Mini Spray Dryer) to obtain powder mixture, iii) the powder mixture obtained in step ii) was mixed with silicified microcrystalline cellulose, microcrystalline cellulose and croscarmellose sodium (50 mg), iv) compacting the mixture step iii) using roller compactor, v) the obtained compact of step iv) was milled to obtain granules, vi) the granules of step v) was mixed with croscarmellose sodium (10 mg), colloidal silicon dioxide and magnesium stearate, and vii) the mixture of step vi) was compressed to tablet and that was coated with Opadry Yellow.

[0082] Example-2: Solid dispersion containing HPMCP without Surfactant / Soluplus®

[0083] Table-2 * Opadry® 03F220132 Yellow contains hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, talc and iron oxide yellow

[0084] Process for the preparation: The tablets of example 2(a) and 2(b) were prepared using same process as given in example 1 (a) without using Soluplus® for 2(a) and without using surfactant for 2(b).

[0085] Example-3: Dissolution data of Example 1 and Example 2 measured at pH 6.8, using Sodium Phosphate Buffer + 0.2% SLS(w / v), 50 rpm with USP apparatus II at 37 °C ± 0.5 °C Table-3

[0086]

[0087] Dissolution of example-1 , example-2 and reference product Xtandi® tablets were performed using standard USP apparatus II, at pH 6.8, using sodium phosphate buffer + 0.2% SLS(w / v), 50 rpm at 37 °C ± 0.5 °C. The drug release was determined by using an HPLC method.

[0088] From the above dissolution data, it is evident that dissolution of example-1 (with HPMCP, Soluplus® and surfactant) is better than example-2 (without Soluplus® or surfactant). Further, tablets of example-1 (a to c) exhibit a similar dissolution profile as that of reference product Xtandi® tablet.

Claims

Claims1 . A solid dispersion comprising: a. enzalutamide or its pharmaceutically acceptable salts, b. hydroxypropyl methylcellulose phthalate (HPMCP), c. soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), d. surfactant, and e. optionally at least one pharmaceutically acceptable excipient.

2. The solid dispersion as claimed in claim 1 , wherein enzalutamide is substantially in an amorphous form.

3. The solid dispersion as claimed in claim 1 , wherein the amount of enzalutamide, soluplus® and surfactant is 10 to 30 wt.%, 5 to 20 wt.% and 0.2 to 5 wt.% respectively.

4. The solid dispersion as claimed in claim 1 , wherein the surfactant is selected from sulfonated hydrocarbons and their salts, poloxamer, and polyoxyethylene sorbitan fatty acid esters.

5. The solid dispersion as claimed in claim 4, wherein the surfactant is selected from sodium lauryl sulphate and polysorbate 80.

6. The solid dispersion as claimed in claim 1 , wherein the pharmaceutically acceptable excipient is diluent, disintegrant or mixture thereof.

7. A process for the preparation of the solid dispersion as claimed in any preceding claim comprises: a. mixing enzalutamide or its pharmaceutically acceptable salts, hydroxypropyl methylcellulose phthalate (HPMCP), soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), surfactant, suitable solvent and optionally a pharmaceutically acceptable excipient to obtain solution / suspension; andb. spray drying the solution / suspension of step a) to obtain powder mixture or granulating at least one pharmaceutically acceptable excipient using solution / suspension of step a) to obtain granules.

8. A pharmaceutical composition comprising the solid dispersion as claimed in claim 1.

9. The pharmaceutical composition as claimed in claim 8, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

10. The pharmaceutical composition as claimed in claim 8 comprises: a. about 80 to 97 wt.% of the solid dispersion of enzalutamide, and b. at least one pharmaceutically acceptable excipient, wherein the weight percent is based on the total weight of the composition.11 . Use of the pharmaceutical composition as claimed in claim 8-10 as medicament in the treatment of prostate cancer.

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