DESC:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:

“PHARMACEUTICAL COMPOSITION”

2. APPLICANT:

(a) NAME: CIPLA LIMITED

(b)NATIONALITY: Indian Company incorporated under the
Companies Act, 1956

(c) ADDRESS: Cipla House, Peninsula Business Park,
Ganpatrao Kadam Marg, Lower Parel,
Mumbai – 400013, Maharashtra. India.

3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be formed.

FIELD OF INVENTION:
The present invention relates to pharmaceutical compositions comprising a tyrosine kinase inhibitor, a process for preparing such pharmaceutical compositions and use of the said pharmaceutical compositions for the treatment of cancer more specifically melanoma.

BACKGROUND AND PRIOR ART:
Melanoma is an aggressive type of skin cancer that carries significant morbidity and mortality. It was estimated that more than 68,000 Americans were diagnosed with melanoma in 2010. This number was up from the 54,200 new cases of melanoma expected in 2003.

Primary melanoma is a malignant neoplasm of neural crest–derived melanocytes, specialized pigmented cells predominately found in the basal layer of the epidermis. The normal function of melanocytes is to produce and transfer a dark pigment called melanin to mitotically active keratinocytes, which are also found in the epidermis. The transferred melanin is concentrated in the perinuclear space of keratinocytes and protects the nucleus from UV radiation damage.

The transformation of melanocytes to tumor cells occurs in both genetically normal and predisposed patients. Although melanoma pathogenesis is complex and not completely understood, it likely involves interactions between environmental factors, accumulation of sequential genetic alterations, activation of oncogenes, inactivation of tumor suppressor genes, and impaired DNA repair.

Melanoma treatment would be directed towards surgery and would be considered as a line of treatment at any stage of melanoma. Other therapies considered would be the biologic therapy, targeted therapy, chemotherapy, radiation and the like. This array of therapies would be invasive and especially surgery would be beneficial in cases where the melanoma is limited and where complete resection is possible.

If the melanoma is undetected in the early stages it may spread throughout the body and progress to the stage IV or metastatic melanoma. Many drugs are available either alone or in combination for oral therapy or parenteral therapy in the present era for treating or controlling metastatic melanoma. One amongst such drugs is Vemurafenib.

Vemurafenib is indicated for the treatment of patients with unresectable or metastatic melanoma. Vemurafenib is structurally represented as:

WO2013087546 discloses a composition comprising solid dispersion comprising a polymer, PVP or copovidone, vemurafenib and, optionally, a surfactant and/or hydroxypropyl methylcellulose-acetate succinate.

WO2010114928 discloses a solid dispersion comprising vemurafenib molecularly dispersed within a polymer matrix formed by an ionic polymer in its solid state.

WO2011057974 discloses a method of manufacturing a solid dispersion of the amorphous form of vemurafenib and HPMCAS (Hydroxypropylmethylcellulose Acetate Succinate) for the treatment of malignant melanoma.

The recommended dose of vemurafenib is 960 mg twice daily. Tablets comprising 240 mg vemurafenib are sold under the trade name Zelboraf®. Thus, the required dosage is comprised in four Zelboraf® tablets that have to be administered orally twice a day.

This situation is unsatisfactory and inconvenient to the patients especially cancer patients since their medications usually consist of multiple drug regimen demanding the administration of large numbers of tablets or capsules often along with intravenous therapy.
Further, these cancer patients often suffer from nausea and lesions of the oral mucosa. Therefore the oral administration of vemurafenib may be hampered by factors such as emesis and ingestion and would ultimately lead to decreased bioavailability of vemurafenib.
Although the above prior art addresses the issues of bioavailability and drug regimens none of them disclose a composition which facilitates better patient compliance as well as technical and economic advantage.

Nevertheless there is an imperative requirement to develop a robust composition of vemurafenib ensuring patient compliance, ease of administration and an acceptable dosing regimen and bioavailability.

OBJECT OF THE INVENTION:
The object of the present invention is to provide a pharmaceutical composition comprising vemurafenib and one or more pharmaceutically acceptable excipients.

Another object of the present invention is to provide a pharmaceutical composition comprising vemurafenib which ensure patient compliance.

Still another object of the present invention is to provide a pharmaceutical composition comprising vemurafenib having improved surface area and solubility.

Yet another object of the present invention is to provide a pharmaceutical composition comprising vemurafenib having a reduced dose.

Another object of the present invention is to provide a pharmaceutical composition comprising vemurafenib for once or twice a day administration.

Yet another object of the present invention is to provide a process for preparing a pharmaceutical composition comprising vemurafenib and one or more pharmaceutically acceptable excipients.

Still another object of the present invention is to provide a method of treating melanoma by administering a pharmaceutical composition comprising vemurafenib.

Another object of the present invention is to provide the use of pharmaceutical composition comprising vemurafenib for the treatment of melanoma.
SUMMARY OF THE INVENTION:
According to an aspect of the present invention, there is provided a pharmaceutical composition comprising vemurafenib and one or more pharmaceutically acceptable excipients.

According to another aspect of the invention, there is provided a process for preparing a pharmaceutical composition comprising vemurafenib with at least one or more pharmaceutically acceptable excipients.

According to yet another aspect of the present invention there is provided a method of treating unresectable or metastatic melanoma by administering a therapeutically effective amount of a pharmaceutical composition comprising vemurafenib and one or more pharmaceutically acceptable excipients to a patient in need thereof.

According to still another aspect of the invention there is provided a use of the pharmaceutical composition comprising vemurafenib and one or more pharmaceutically acceptable excipients for treating unresectable or metastatic melanoma.

DETAILED DESCRIPTION OF THE INVENTION:
Vemurafenib is commercially available as a conventional film coated tablet formulation for the treatment of unresectable or metastatic melanoma with BRAFV600E mutation. The required dosage is comprised in four vemurafenib tablets that have to be administered orally twice a day. Further, cancer patients are usually on a multiple drug regimen demanding the administration of large numbers of tablets or capsules often along with intravenous therapy.
Patient compliance in such a regimen can be addressed by decreasing the number of tablets or capsules administered as well as the type of dosage forms that are administered, with due consideration to the bioavailability of the administered drug . The bioavailability of the drug cannot be compromised to meet patient compliance.

The above criteria could be met by formulating a composition with a reduced or low dose such that it exhibits similar or increased bioavailability. Hence, vemurafenib as an active pharmaceutical agent used for treating melanoma, would be, preferred in a low dose oral composition provided in such dosage forms which exhibit desired therapeutic effect and at the same time would ensure patient compliance. A low dose orally dispersible composition of vemurafenib when designed was considered as the best approach, as these compositions could be dispersed in water and then easily administered to the patient and thus be advantageous for use in elder and noncompliant cancer patients.

The present invention provides a pharmaceutical composition comprising vemurafenib which would ensure patient compliance due to simplification of therapy, ease of administration, an acceptable dosing regimen and bioavailability.

The term “vemurafenib” is used in broad sense to include not only “vemurafenib” per se but also its pharmaceutically acceptable derivatives thereof. Suitable derivatives include pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable anhydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable isomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable tautomers, pharmaceutically acceptable complexes etc.

The term “low dose” as used herein refers to a therapeutically effective dose of vemurafenib, which dose is less than the usual or the conventional dose required to produce equal or higher therapeutic effect.

The term "pharmaceutical composition" includes tablets, coated tablet, powder, powder for reconstitution, pellets, beads, mini-tablets, multilayer tablet, bilayered tablet, tablet-in-tablet, pills, micro-pellets, small tablet units, MUPS (multiple unit pellet system), disintegrating tablets, dispersible tablets, granules, microspheres, multiparticulates, capsule (filled with powder, powder for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, orally disintegrating MUPS, disintegrating tablets, dispersible tablets, granules, sprinkles, microspheres and multiparticulates), sachets (filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, modified release tablets or capsules, effervescent granules, granules, sprinkles, microspheres and multiparticulates), or sprinkles which may also be envisaged under the ambit of the invention.
However, other dosage forms such as oral liquid dosage forms (liquids, liquid dispersions, suspensions, solutions, emulsions, syrups, elixirs) may also be envisaged under the ambit of the invention.

Preferably, the pharmaceutical composition is in an oral dosage form, preferably the oral dosage form is a single unit dosage form, preferably the composition is a solid oral dosage form and preferably the single unit dosage form is for adapted once or twice a day administration.

Preferably, the pharmaceutical composition of the present invention comprising vemurafenib is in form of an oral tablet.

Suitably, the pharmaceutical composition comprising vemurafenib, according to the present invention is presented in a tablet dosage form, more preferably as dispersible, disintegrating or coated tablets.

According to one aspect of the present invention, there is provided a pharmaceutical compositions comprising vemurafenib with one or more pharmaceutically acceptable excipients wherein the composition comprises less than 1920 mg of vemurafenib or wherein the composition is formulated to provide a total daily dose of less than 1920 mg of vemurafenib.

The pharmaceutical composition, according to the present invention may be administered at least once or twice a day. Preferably the pharmaceutical compositions are administered once or twice a day in a dose which is less than the conventionally administered dose, which is from about 100 mg to about 1500 mg of vemurafenib, preferably from about 150 mg to about 1000 mg, preferably from about 200 mg to about 900 mg, most preferably from about 300 mg to about 800 mg of vemurafenib.

Suitably, the pharmaceutical composition comprising vemurafenib, according to the present invention is presented in a tablet dosage form, more preferably as dispersible, disintegrating or coated tablets.
The inventors of the present invention have also further observed that the solubility properties of vemurafenib improved by nanosizing thus leading to better bioavailability of the drug as well as reducing the dose of the drug.

Nanonization of hydrophobic or poorly water-soluble drugs generally involves the production of drug nanocrystals through either chemical precipitation (bottom-up technology) or disintegration (top-down technology). Different methods may be utilized to reduce the particle size of the hydrophobic or poorly water soluble drugs. [Huabing Chen et al., discusses the various methods to develop nanoformulations in “Nanonization strategies for poorly water-soluble drugs,” Drug Discovery Today, Apr 2011;16(7-8):354-60.

The present invention thus provides a pharmaceutical composition comprising vemurafenib wherein the vemurafenib is in the form of particles, wherein substantially all the particles are nanosized.

The term “nanosize” as used herein refers to vemurafenib particles having an average particle size of less than 2000 nm, preferably less than 1000 nm.

Mostly all particles have a particle size of less than 2000 nm, preferably less than 1000 nm. The particle size of vemurafenib varies with D90 not less than 700 nm, preferably less than 300 nm.

The term “particles” as used herein refers to individual particle of vemurafenib, or particles of vemurafenib granules and/or mixtures thereof.

The nanosize particles of the present invention can be obtained by any of the process such as but not limited to milling, precipitation, homogenization, high pressure homogenization, spray-freeze drying, supercritical fluid technology, double emulsion/solvent evaporation, PRINT (Particle replication in non-wetting templates), thermal condensation, ultrasonication, spray drying or the like. Such nanoparticles obtained by any of these processes may further be formulated into desired dosage forms.

The nanoparticles of the present invention may be prepared by
(1) homogenizing vemurafenib and at least one excipient to produce a homogenized dispersion; and
(2) milling the said homogenized dispersion to produce a slurry comprising vemurafenib a having an average particle size of less than 2000 nm
(3) processing the slurry to obtain the desired dosage form.

Suitable excipients may be used for formulating the dosage form according to the present invention such as, but not limited to, disintegrants, diluents, plasticizers, binders, glidants, lubricants, sweeteners, flavoring agents, anti-caking agents, anti-microbial agents, antifoaming agents, emulsifiers, surfactants, buffering agents and coloring agents and the like or mixtures thereof.

Suitable carriers, diluents or fillers for use, in the pharmaceutical compositions of the present invention may comprise one or more, but not limited to lactose (for example, spray-dried lactose, a-lactose, ß-lactose) lactose available under the trade mark Tablettose, various grades of lactose available under the trade mark Pharmatose or other commercially available forms of lactose, lactitol, saccharose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin, croscarmellose sodium, microcrystalline cellulose (for example, microcrystalline cellulose available under the trade mark Avicel), silicified microcrystalline cellulose, hydroxypropylcellulose, L-hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC) or hypromellose, hydroxypropyl methylcellulose acetate succinate (HPMCAS) or hypromelloseacetate succinate, methylcellulose polymers (such as, for example, Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethyl hydroxyethyl cellulose and other cellulose derivatives, starches or modified starches (including potato starch, corn starch, maize starch and rice starch), pregelatinized starch calcium carbonate, calcium sulfate, sugar, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like or mixtures thereof.

The amount of carriers, diluents or fillers in the pharmaceutical compositions range from about 15 % to about 60 %, of the total weight of the composition.

Suitable disintegrants or super disintegrants include, but are not limited to, agar-agar, calcium carbonate, crystalline cellulose, crospovidone, povidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, alginic acid, alginates such as sodium alginate other algins, other celluloses, gums, ion-exchange resins, magnesium aluminum silicate, sodium dodecyl sulfate, sodium carboxymethyl cellulose, croscarmellose sodium, cross-linked PVP, carboxymethyl cellulose calcium, crosslinked sodium carboxymethyl cellulose, docusate sodium, guar gum, low-substituted HPC, polacrilin potassium, poloxamer, povidone, sodium glycine carbonate and sodium lauryl sulfate and the like or combinations thereof.

The amount of disintegrant in the pharmaceutical compositions range from about 1% to about 30%, of the total weight of the composition.

Suitable binders may also be present in the pharmaceutical compositions of the present invention, which may comprise one or more, but not limited to polyvinyl pyrrolidone (also known as povidone), polyethylene glycol(s), acacia, alginic acid, agar, calcium carragenan, cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, dextrin, gelatin, gum arabic, guar gum, tragacanth, sodium alginate and the like or mixtures thereof.

The amount of binder in the pharmaceutical compositions range from about 5% w/w to about 20 % w/w, of the total weight of the composition.

Glidants, anti-adherents and lubricants may also be incorporated in the pharmaceutical compositions of the present invention, which may comprise one or more, but not limited to stearic acid and pharmaceutically acceptable salts or esters thereof (for example, magnesium stearate, calcium stearate, zinc stearate, sodium stearylfumarate or other metallic stearate), talc, croscarmellose sodium, waxes (for example, microcrystalline waxes) and glycerides, mineral oil, light mineral oil, PEG, silica acid or a derivative or salt thereof (for example, silicates, silicon dioxide, colloidal silicon dioxide and polymers thereof, crospovidone, magnesium aluminosilicate and/ or magnesium aluminometasilicate), microcrystalline cellulose (for example, microcrystalline cellulose available under the trade mark Avicel), silicified microcrystalline cellulose, sucrose ester of fatty acids, hydrogenated vegetable oils (for example, hydrogenated castor oil, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), glycerin, sorbitol, mannitol, other glycols, sodium lauryl sulfate, talc, long chain fatty acids and their salts, ethyl oleate, ethyl laurate, agar, syloid silica gel (a coagulated aerosol of synthetic silica (Evonik Degussa Co., Plano, Tex. USA), a pyrogenic silicon dioxide (CAB-O-SIL, Cabot Co., Boston, Mass. USA) and the like or combinations thereof.

The amount of glidants, anti-adherents and lubricants in the pharmaceutical compositions range from about 0.1 % w/w to about 5% w/w, of the total weight of the composition.

Suitable solvents may also be incorporated in the pharmaceutical compositions of the present invention, which may comprise one or more, but not limited to acetone, methanol, ethanol, dimethylacetamide, dimethylformamide, dimethyl sulfoxide (DMSO), N-methyl pyrrolidone and the like or combinations thereof.

Suitable anti-caking additives include, but are not limited to, calcium silicate, magnesium silicate, silicon dioxide, colloidal silicon dioxide, talc and the like or combinations thereof.
Suitable anti-microbial agents or preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, butyl paraben, cetylpyridinium chloride, cresol, chlorobutanol, dehydroacetic acid, ethylparaben, methylparaben, phenol, phenylethyl alcohol, phenoxyethanol, phenylmercuric acetate, phenylmercuric nitrate, potassium sorbate, propylparaben, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid,citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, thimersol, thymo, and the like or combinations thereof.

Suitable sweetening agent or taste-masking agents include, but are not limited to, essential oils, water soluble extracts, sugar (natural or synthetic), monosaccharides, oligosaccharides, aldose, ketose, dextrose, maltose, lactose, glucose, fructose, sucrose, mannitol xylitol, D-sorbitol, erythritol, pentitol, hexitol, malitol, acesulfame potassium, talin, glycyrrhizin, sucralose, aspartame, saccharin, sodium saccharin, acesulfame, thaumatin, dihydrochalcone, alitame, miraculin, monellin, stevsidesodium cyclamate, eugenylformate aldehyde flavorings and the like or combinations thereof.

Suitable flavors include, but are not limited to, essential oils including distillations, solvent extractions, or cold expressions of chopped flowers, leaves, peel or pulped whole fruit containing mixtures of alcohols, esters, aldehydes and lactones; essences including either diluted solutions of essential oils, or mixtures of synthetic chemicals blended to match the natural flavor of the fruit (e.g., strawberry, raspberry and black currant); artificial and natural flavors of brews and liquors, e.g., cognac, whisky, rum, gin, sherry, port, and wine; tobacco, coffee, tea, cocoa, and mint; fruit juices including expelled juice from washed, scrubbed fruits such as lemon, orange, and lime; spear mint, pepper mint, wintergreen, cinnamon, cacoe/cocoa, vanilla, liquorice, menthol, eucalyptus, aniseeds nuts (e.g., peanuts, coconuts, hazelnuts, chestnuts, walnuts, colanuts), almonds, raisins; and powder, flour, or vegetable material parts including tobacco plant parts, e.g., genus Nicotiana, in amounts not contributing significantly to the level of nicotine, ginger and the like and/or combinations thereof.

Suitable antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylatedhydroxyanisole, edetic acid, and edetate salts, and the like or combinations thereof.

Suitable texture enhancers include, but are not limited to, pectin, polyethylene oxide, and carrageenan, and the like or combinations thereof.

Surface stabilizers, according to the present invention, are surfactants that are capable of stabilizing the increased surfaced charge drug. Suitable amphoteric, non-ionic, cationic or anionic surfactants may be included in the pharmaceutical compositions of the present invention.

According to the present invention, surfactants may comprise of one or more, but not limited to Polysorbates, Sodium dodecyl sulfate (sodium lauryl sulfate), Lauryl dimethyl amine oxide, Docusate sodium, Cetyltrimethyl ammonium bromide (CTAB)
Polyethoxylated alcohols, Polyoxyethylenesorbitan, Octoxynol, N, N–dimethyldodecylamine–N–oxide, Hexadecyltrimethylammonium bromide, Polyoxyl 10 lauryl ether, Brij, Bile salts (sodium deoxycholate, sodium cholate), Polyoxyl castor oil, Nonylphenolethoxylate Cyclodextrins, Lecithin, Methylbenzethonium chloride. Carboxylates, Sulphonates, Petroleum sulphonates, alkylbenzenesulphonates, Naphthalenesulphonates, Olefin sulphonates, Alkyl sulphates, Sulphates, Sulphated natural oils & fats, Sulphated esters, Sulphatedalkanolamides, Alkylphenols, ethoxylated & sulphated, Ethoxylated aliphatic alcohol, polyoxyethylene surfactants, carboxylic esters Polyethylene glycol esters, Anhydrosorbitol ester & its ethoxylated derivatives, Glycol esters of fatty acids, Carboxylic amides, Monoalkanolamine condensates, Polyoxyethylene fatty acid amides, Quaternary ammonium salts, Amines with amide linkages, Polyoxyethylene alkyl & alicyclic amines, N,N,N,N tetrakis substituted ethylenediamines 2- alkyl 1- hydroxyethyl 2-imidazolines, N -coco 3-aminopropionic acid/ sodium salt, N-tallow 3 -iminodipropionate disodium salt, N-carboxymethyl n dimethyl n-9 octadecenyl ammonium hydroxide, n-cocoamidethyl n-hydroxyethylglycine sodium salt and the like or mixtures thereof.

The amount of the one or more surfactants in the pharmaceutical compositions range from about 2 % w/w to about 10 % w/w, of the total weight of the composition.

Viscosity modifying agents are excipients that are capable of stabilizing the formulation by increasing the viscosity of the formulation and thus preventing physical interaction of nanoparticles under the operating conditions employed.

According to the present invention, viscosity modifying agents may comprise one or more, but not limited to derivatives of sugars, such as lactose, sucrose, saccharose, hydrolyzed starch (maltodextrin) and the like or mixtures thereof.

The amount of viscosity modifying agents in the one or more pharmaceutical compositions range from about 4 % w/w to about 20 % w/w, of the total weight of the composition.

Polymers or polymers blends, according to the present invention, may comprise one or more hydrophilic polymers, but not limited to cellulose derivates like hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, methylcellulose polymers hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene and carboxymethylhydroxyethylcellulose; acrylics like acrylic acid, acrylamide, and maleic anhydride polymers, acacia, gum tragacanth, locust bean gum, guar gum, or karaya gum, agar, pectin, carrageenan, gelatin, casein, zein and alginates, carboxypolymethylene, bentonite, magnesium aluminum silicate, polysaccharides, modified starch derivatives, copolymers and the like or mixtures thereof.

The amount of the one or more polymers or polymers blends in the pharmaceutical compositions range from about 2 % w/w to about 15 % w/w of the total weight of the composition.

Suitable channeling agents for use in pharmaceutical compositions of the present invention, may comprise one or more, but are not limited to sodium chloride, sugars, polyols and the like or mixtures thereof.

The amount of channeling agents in the pharmaceutical compositions range from about 0.5% to about 10% w/w of the total weight of the composition.

The pharmaceutical compositions, according to the present invention, may also optionally be coated, but not limited to seal coating, enteric coating, film coating or a combination thereof.

According to the present invention, the pharmaceutical compositions may be film coated, seal coated or enteric coated with, but not limited to, colour mix systems (such as Opadrycolour mix systems), Aqueous Acrylic Enteric Coating System (such as Acryl-EZE®) and Kollicoat® Protect.

Preferably, the pharmaceutical composition, according to the present invention, may be enteric coated.

The amount of enteric coating system in the pharmaceutical compositions range from about 2 % w/w to about 15 % w/w, of the total weight of the composition.

According to the present invention, the seal coat comprises film forming polymeric materials, such as but not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, methylcellulose, carboxymethylcellulose, hypromellose, acacia, gelatin and the like to increase adherence and coherence of the seal coat.

The amount of seal coating system in the pharmaceutical compositions range from about 1 % w/w to about 4 % w/w of the total weight of the composition.

According to the present invention, pharmaceutically acceptable opacifier for use in the pharmaceutical compositions of the present invention may comprise one or more, but is not limited to titanium dioxide.

Preferably, the pharmaceutical composition comprises vemurafenib in combination with pharmaceutical excipients comprising carriers, diluents or fillers; disintegrants; binders; glidants, lubricants or anti-adherents.

Preferably, the pharmaceutical composition comprises vemurafenib in combination with lactose, croscarmellose sodium, hydroxyl propyl cellulose, purified water, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate.

Alternatively, the pharmaceutical composition comprises vemurafenib in combination with sodium lauryl sulphate, hypromellose, docusate sodium, lactose monohydrate, purified water, crospovidone, sodium chloride, silicified microcrystalline cellulose, magnesium stearate and an Aqueous Acrylic Enteric Coating System. Optionally, the pharmaceutical composition further comprises hypromellose acetate succinate.

The present invention also provides a method of treating unresectable or metastatic melanoma by administering a pharmaceutical compositions comprising vemurafenib.
The present invention also provides the use of the pharmaceutical compositions comprising vemurafenib for treating unresectable or metastatic melanoma.

The pharmaceutical compositions of the present invention may further comprise at least one additional active ingredient such as, but not limited to, MEK inhibitor, ERK inhibitor, phosphoinositide 3-kinase inhibitor, topoisomerase inhibitor, PDK inhibitor, OXPHOS inhibitors, mitochondrial inhibitors, c-KIT inhibitors, EGFR inhibitor, anti-CTLA4 antibody, DLL4 antagonist, anti-HMW-MAA antibody, peginterferon alfa-2a, dihydroorotate dehydrogenase inhibitor, AKT inhibitor compounds, proteins, synthetic proteins, antibodies, MDM2 inhibitors, cardiac glycosides, histone deacetylase inhibitor, tyrosine kinase inhibitor, inhibitor of CDK4, PI3K beta inhibitor, MAPK pathway inhibitor, interleukin-2, c-Met antagonists, Hsp90 inhibitors, Wnt pathway inhibitors, pyruvate dehydrogenase kinase inhibitors, ERK pathway inhibitors, anti-ErbB3 antibody, MDM2 inhibitor and the like or combinations thereof.

Preferably, the pharmaceutical compositions of the present invention, may comprise at least one additional active ingredient such as, but not limited to, cetuximab, erlotinib, tremelimumab, lenvatinib, sorafenib, dideoxyinosine, tigecycline, bafetinib, stavudine, crizotinib, tivantinib, onartuzumab, selumetinib, irinotecan, ipilimumab, masitinib, cobimetinib and the like or combinations thereof.

The following examples are for the purpose of illustration of the invention only and is not intended in any way to limit the scope of the present invention.
Example 1:
Sr. No. Ingredients Quantity (mg/tab)
Dry Mix
1. Vemurafenib 960.0
2. Lactose 377.0
3. Croscarmellose sodium 50.0
Binder Solution
4. Hydroxy propyl cellulose 25.0
5. Purified Water q.s.
Blending & Lubrication
6. Croscarmellose Sodium 50.0
7. Microcrystalline Cellulose 510.0
8. Colloidal Silicon Dioxide 12.0
9. Magnesium Stearate 16.0
Total Weight 2000.0

Process:
1) Vemurafenib, lactose and croscarmellose sodium were added and mixed.
2) The mixture obtained in step (1) was granulated with the binder solution obtained by dissolving hydroxy propyl cellulose in water.
3) The granules obtained in step (2) were dried, blended and lubricated using microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.
4) The lubricated granules obtained in step (3) were compressed to form dispersible tablets.

Example 2:
Sr. No. Ingredients Quantity (mg/tab)
Dry Mix
1. Vemurafenib 240.0
2. Lactose 94.25
3. Croscarmellose sodium 12.5
Binder Solution
4. Hydroxy propyl cellulose 6.25
5. Purified Water q.s.
Blending & Lubrication
6. Croscarmellose Sodium 12.5
7. Microcrystalline Cellulose 127.5
8. Colloidal Silicon Dioxide 3.0
9. Magnesium Stearate 4.0
Total Weight 500.0

Process:
1) Vemurafenib, lactose and croscarmellose sodium were added and mixed.
2) The mixture obtained in step (1) was granulated with the binder solution by dissolving hydroxy propyl cellulose in water.
3) The granules obtained in step (2) were dried, blended and lubricated using microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.
4) The lubricated granules obtained in step (3) were compressed to form dispersible tablets.

Example 3:
Sr. No. Ingredients Quantity (mg/tab)
Drug - Binder Slurry
1. Vemurafenib 120.0 -720.0
2. Sodium Lauryl Sulphate 6.9-41.4
3. Hypromellose 25.0-150.0
4. Docusate Sodium 2.5-15.0
5. Lactose Monohydrate 25.0-150.0
6. Purified water q.s
Dry Mix
7. Lactose Monohydrate 62.5-375.0
8. Crospovidone 25.0 -150.0
Blending & Lubrication
9. Sodium Chloride 15.0-90.0
10. Crospovidone 10.0-60.0
11. Silicified Microcrystalline Cellulose 59.2-243.2
12. Magnesium Stearate 0.9-5.4
Core Weight 352.0-2000.0
13. Aqueous Acrylic Enteric Coating System 14.0-80.0
14. Purified Water q.s.
Coated Tablet Weight 366.0-2080.0

Process:
A) Drug-Binder Slurry Preparation:
1) Docusate sodium, Hypromellose, Lactose and Sodium Lauryl Sulphate were dissolved in water.
2) Vemurafenib was dispersed in the solution obtained in step (1) and then milled to form a slurry.
B) Granulation:
3) The slurry obtained in step (2) was sprayed onto lactose and crospovidone and granulated.
C) Blending & Lubrication:
4) The granules obtained in step (3) were dried and blended with crospovidone, silicified microcrystalline cellulose, sodium chloride and lubricated with magnesium stearate.
D) Compression& Coating:
5) The lubricated granules obtained in step (4) were compressed to form tablets and were coated.

Example 4:
Sr. No. Ingredients Quantity (mg/tab)
Drug - Binder Slurry
1. Vemurafenib 120.0
2. Sodium Lauryl Sulphate 6.9
3. Hypromellose 25.0
4. Docusate Sodium 2.5
5. Lactose Monohydrate 25.0
6. Purified water q.s
Dry Mix
7. Lactose Monohydrate 62.5
8. Crospovidone 25.0
Blending & Lubrication
9. Sodium Chloride 15.0
10. Crospovidone 10.0
11. Silicified Microcrystalline Cellulose 59.2
12. Magnesium Stearate 0.9
Core Weight 352.0
Coating
13. Aqueous Acrylic Enteric Coating System 14.0
14. Purified Water q.s.
Coated Tablet Weight 366.0

Process:
A) Drug Slurry Preparation:
1) Docusate sodium, Hypromellose, Lactose and Sodium Lauryl Sulphate were dissolved in water.
2) Vemurafenib was dispersed in the solution obtained in step (1) and then milled to form a slurry.
B) Granulation:
3) The slurry obtained in step (2) was sprayed onto lactose and crospovidone and granulated.
C) Blending & Lubrication:
4) The granules obtained in step (3) were dried, blended with crospovidone, silicified microcrystalline cellulose, sodium chloride and lubricated with magnesium stearate
D) Compression & Coating:
5) The lubricated granules obtained in step (4) were compressed to form tablets and were coated.

Example 5:
Sr. No. Ingredients Quantity (mg/tab)
Drug - Binder Slurry
1. Vemurafenib 120.0
2. Sodium Lauryl Sulphate 6.9
3. Hypromellose 25.0
4. Docusate Sodium 2.5
5. Lactose Monohydrate 25.0
6. Purified water q.s
Dry Mix
7. Lactose Monohydrate 62.5
8. Hypromellose Acetate Succinate 120.0
9. Crospovidone 25.0
Blending & Lubrication
10. Sodium Chloride 15.0
11. Crospovidone 10.0
12. Silicified Microcrystalline Cellulose 59.2
13. Magnesium Stearate 0.9
Tablet Weight 472.0

Process:
A) Drug - Binder Slurry Preparation:
1) Docusate sodium, Hypromellose, Lactose and Sodium Lauryl Sulphate were dissolved in water.
2) Vemurafenib was dispersed in the solution obtained in step (1) and then milled to form a slurry.
B) Granulation:
3) The slurry obtained in step (2) was sprayed onto lactose, hypromellose acetate succinate and crospovidone and granulated.

C) Blending & Lubrication:
4) The granules obtained in step (3) were dried, blended with crospovidone, silicified microcrystalline cellulose, sodium chloride and lubricated with magnesium stearate.
D) Compression:
5) The lubricated granules obtained in step (4) were compressed to form dispersible tablets.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.
It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

It must be noted that, 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. ,CLAIMS:WE CLAIM:

1. A pharmaceutical composition comprising vemurafenib and one or more pharmaceutically acceptable excipients.
2. The pharmaceutical composition according to claim 1 comprising vemurafenib in the form of a pharmaceutically acceptable derivative thereof.
3. The pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable derivative is a salt, solvate, complex, hydrate, ester, tautomer, anhydrate, enantiomer, polymorph, derivative or prodrug.
4. The pharmaceutical composition according to any preceding claim, wherein the composition comprises less than 1920 mg of vemurafenib.
5. The pharmaceutical composition according to any preceding claim, wherein the composition is formulated to provide a total daily dose of less than 1920 mg of vemurafenib.
6. The pharmaceutical composition according to any preceding claim, adapted for once or twice a day administration.
7. The pharmaceutical composition according to any preceding claim, wherein the composition is in an oral dosage form.
8. The pharmaceutical composition according to claim 7, wherein the oral dosage form is adapted for once or twice a day administration.
9. The pharmaceutical composition according to any one of claims 7 and 8, wherein the composition is a solid oral dosage form.
10. The pharmaceutical composition according to claim 9, wherein the solid oral dosage form is a tablet, coated tablet, powder, powder for reconstitution, pellets, beads, mini-tablet, multilayer tablet, bilayered tablet, tablet-in-tablet, pill, micro-pellet, small tablet unit, MUPS (multiple unit pellet system), disintegrating tablet, dispersible tablet, granules, microspheres, multiparticulates, capsule (filled with powder, powder for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, orally disintegrating MUPS, disintegrating tablets, dispersible tablets, granules, sprinkles, microspheres and multiparticulates), sachet (filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, modified release tablets or capsules, effervescent granules, granules, sprinkles microspheres and multiparticulates) or sprinkles.
11. The pharmaceutical composition according to any one of claims 7 to and 8, wherein the composition is a liquid oral dosage form.
12. The pharmaceutical composition according to claim 11, wherein the liquid oral dosage form is an emulsion, solution, suspension, syrup or elixir.
13. The pharmaceutical composition according to any preceding claim, wherein the vemurafenib particles are nano-sized.
14. The pharmaceutical composition according to any preceding claim, wherein the vemurafenib particles have an average particle size of less than 2000 nanometers.
15. The pharmaceutical composition according to any preceding claim, wherein the vemurafenib particles have an average particle size of less than 1000 nanometers.
16. The pharmaceutical composition according to any preceding claim, wherein the one or more pharmaceutically acceptable excipients is selected from disintegrants; carriers, diluents; fillers, plasticizers, binders, glidants, anti-adherents, lubricants, solvents, sweetening agents, taste-masking agents, flavoring agents, anti-caking agents, anti-microbial agents, preservatives, antifoaming agents, emulsifiers, surfactants, antioxidants, viscosity modifying agents, texture enhancers, surface stabilizers, buffering agents, coloring agents, channeling agents, or any combination thereof.
17. The pharmaceutical composition according to claim 16, wherein the composition comprises one or more surfactants, wherein the amount of surfactants range from about 2 % w/w to about 10 % w/w of the total weight of the composition.
18. The pharmaceutical composition according to claim 16, wherein the composition comprises one or more viscosity modifying agents, wherein the amount of viscosity modifying agents range from about 4 % w/w to about 20 % w/w of the total weight of the composition.
19. The pharmaceutical composition according to claim 16, wherein the composition comprises one or more polymers, wherein the amount of polymers range from about 2 % w/w to about 15 % w/w of the total weight of the composition.
20. A method of treating unresectable or metastatic melanoma by administering a therapeutically effective amount of a composition according to any preceding claim to a patient in need thereof.
21. A method of treatment according to claim 20, wherein the method comprises administering a total daily dose of the vemurafenib of less than 1920 mg.
22. The pharmaceutical composition according to claim 1 to 19 for use in the treatment of unresectable or metastatic melanoma.
23. The pharmaceutical composition for use according to claim 22, wherein the use comprises administering a total daily dose of the vemurafenib of less than 1920 mg.
24. Use of a pharmaceutical composition according to any one of claims 1 to 19 in the manufacture of a medicament for the treatment of unresectable or metastatic melanoma.
25. Use of a pharmaceutical composition according to claim 24, wherein the use comprises administering a total daily dose of the vemurafenib of less than 1920 mg
26. A pharmaceutical composition as substantially described herein with reference to the examples.
27. A process for preparing a pharmaceutical composition as substantially described herein with reference to the examples.

Dated this 12th day of February, 2015

Dr. Gopakumar G. Nair
(Regn.No.: IN/PA 509)
Agent for the Applicant
Gopakumar Nair Associates