WO2015145157A1 - Pharmaceutical composition comprising pazopanib - Google Patents

Pharmaceutical composition comprising pazopanib Download PDF

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Publication number
WO2015145157A1
WO2015145157A1 PCT/GB2015/050902 GB2015050902W WO2015145157A1 WO 2015145157 A1 WO2015145157 A1 WO 2015145157A1 GB 2015050902 W GB2015050902 W GB 2015050902W WO 2015145157 A1 WO2015145157 A1 WO 2015145157A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
pazopanib
composition according
inhibitor
agents
Prior art date
Application number
PCT/GB2015/050902
Other languages
French (fr)
Inventor
Geena Malhotra
Preeti Raut
Original Assignee
Cipla Limited
Turner, Craig
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cipla Limited, Turner, Craig filed Critical Cipla Limited
Publication of WO2015145157A1 publication Critical patent/WO2015145157A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a pharmaceutical composition comprising a tyrosine kinase inhibitor, and more particularly, to a pharmaceutical composition comprising pazopanib, a process for preparing the pharmaceutical composition and its use in the treatment of cancer such as renal cell carcinoma and soft tissue sarcoma.
  • Renal cell carcinoma formerly known as hypernephroma
  • hypernephroma is a kidney cancer that originates in the lining of the proximal convoluted tubule, one type of very small tubes in the kidney that transports waste molecules from the blood to the urine. It is the most common type of kidney cancer in adults, responsible for approximately 90% to 95% of cases. It has been described as one of the deadliest of cancers affecting the genitourinary tract. Initial treatment is, most commonly either partial or complete removal of the affected kidney(s) and remains the mainstay of curative treatment. Where the cancer has not metastasized (spread to other organs) or burrowed deeper into the tissues of the kidney the 5 -year survival rate is 60% to 70%, but this is lowered considerably when the cancer has spread.
  • Renal cell carcinoma represents 2% to 3% of all cancers with an age-standardized rate incidence of 5.8 and mortality of 1.4 per 100,000, respectively, in more developed areas. The highest incidence all over the world is in the Czech Republic, where in 2010 the incidence rate was 14.62 and mortality 5.17 (age-standardized rate/world per 100,000). Renal cell carcinoma is the commonest solid lesion in the kidney and accounts for approximately 90% of all kidney malignancies. It includes different types, with specific histopathological and genetic characteristics. There is a 1.5 :1.0 predominance of men over women, with the peak incidence occurring between the ages of 60 and 70.
  • a sarcoma is a type of cancer that develops from certain tissues, like bone or muscle.
  • sarcoma There are two main types of sarcoma: bone sarcomas and soft tissue sarcomas.
  • Soft tissue sarcomas can develop from soft tissues like fat, muscle, nerves, fibrous tissues, blood vessels, or deep skin tissues. They can be found in any part of the body. Most of them develop in the arms or legs. They can also be found in the trunk, head and neck area, internal organs, and the area in back of the abdominal cavity (known as the retroperitoneum). Sarcomas are not common tumors, and most cancers are the type of tumors called carcinomas.
  • Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor that blocks tumour growth and inhibits angiogenesis. It has been approved for renal cell carcinoma and soft tissue sarcoma. It is an angiogenesis inhibitor which targets vascular endothelial growth factor receptors VEGFR-1, VEGFR-2, VEGFR-3 and platelet-derived growth factor receptors PDGFR- a, PGDFR-3 and c-Kit.
  • Pazopanib has the chemical name 5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl]amino]-2-methylbenzolsulfonamide and is structurally represented as
  • WO2013066616 discloses a composition suitable for reconstitution into an aqueous suspension of pazopanib to target the pediatric and geriatric population.
  • WO2011140343 discloses aformulation suitable for ocular administration, comprising pazopanib along with modified cyclodextrin that lowers the dissociation constant of pazopanib.
  • "The Frequency and Severity of Cardiovascular Toxicity from Targeted Therapy in Advanced Renal Cell Carcinoma Patients", February 2013, published in the US National Library of Medicine National Institutes of Health discloses the frequency and severity of cardiovascular toxicity in advanced renal cell carcinoma patients treated with targeted cancer therapies such as pazopanib and other similar cancer treating agents which are relatively new.
  • Pazopanib is available in a hydrochloride salt form.
  • the recommended dose of pazopanib is 800 mg once daily.
  • Tablets comprising 200 mg pazopanib are sold under the trade name VOTRIENT ® .
  • VOTRIENT ® contains 216.7 mg of pazopanib hydrochloride, equivalent to 200 mg of pazopanib free base.
  • the required dosage is comprised in four VOTRIENT ® tablets that have to be administered orally once a day.
  • pazopanib has pharmacokinetic properties that are affected by the prandial status of a patient receiving the treatment, i.e. it exhibits a "food effect".
  • bioavailability or systemic exposure of pazopanib increases when administered with food.
  • Pazopanib AUC values were approximately 2 times higher when administered with a low fat (5% fat) or with a high fat (50% fat) meal respectively.
  • pazopanib may be hampered by factors such as emesis and ingestion and would ultimately lead to decreased bioavailability of pazopanib.
  • pazopanib may include serious side effects such as cardiotoxicity, bloody or tarry stools, coughing up blood, loss of appetite, dark urine, jaundice (yellowing of the skin or eyes), sudden numbness or weakness, problems with speech or balance, chest pain, or vision and hearing problems.
  • the pharmaceutical composition comprising pazopanib should be stable as well as exhibit optimal dissolution properties. However, these characteristics are often difficult to achieve with high concentrations of pazopanib.
  • the inventors of the present invention have appreciated the above problems associated with prior art compositions comprising pazopanib and methods of treating patients using pazopanib. Attempts to address the prior art problems have led the inventors of the present invention to develop a pharmaceutical composition comprising pazopanib that has better bioavailability, stability and patient compliant.
  • Another object of the present invention is to provide a pharmaceutical composition comprising nanosized pazopanib along with one or more pharmaceutically acceptable excipients.
  • Another object of the present invention is to provide a pharmaceutical composition comprising pazopanib having improved surface area and solubility.
  • Another object of the present invention is to provide a pharmaceutical composition comprising nanosized pazopanib having improved surface area and solubility.
  • Another object of the present invention is to provide a pharmaceutical composition comprising nanosized pazopanib exhibiting minimal food effect.
  • Yet another object of the present invention is to provide a pharmaceutical composition comprising a reduced dose of pazopanib.
  • Yet another object of the present invention is to provide a pharmaceutical composition comprising a reduced dose of nanosized pazopanib.
  • Another object of the present invention is to provide a pharmaceutical composition comprising pazopanib for once a day administration.
  • Another object of the present invention is to provide a pharmaceutical composition comprising nanosized pazopanib for once a day administration.
  • Another object of the present invention is to provide a process for preparing the pharmaceutical composition comprising pazopanib.
  • Another object of the present invention is to provide a process for preparing the pharmaceutical composition comprising nanosized pazopanib.
  • Yet another object of the present invention is to provide a method of treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma which method comprises administering a pharmaceutical composition comprising pazopanib.
  • Yet another object of the present invention is to provide a method of treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma which method comprises administering a pharmaceutical composition comprising nanosized pazopanib.
  • Another object of the present invention is to provide the use of a pharmaceutical composition comprising pazopanib, in the manufacture of a medicament for the treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma.
  • Another object of the present invention is to provide the use of a pharmaceutical composition comprising nanosized pazopanib, in the manufacture of a medicament for the treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma.
  • Another object of the present invention is to provide a pharmaceutical composition comprising pazopanib for use in treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma.
  • Another object of the present invention is to provide a pharmaceutical composition comprising nanosized pazopanib for use in treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma.
  • a pharmaceutical composition comprising pazopanib and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising nanosized pazopanib, wherein preferably the nanoparticles have an average particle size of less than about 2000 nm.
  • a pharmaceutical composition comprising nanosized pazopanib along with one or mor pharmaceutically acceptable excipients.
  • a process for preparing a pharmaceutical composition comprising pazopanib and one or more pharmaceutically acceptable excipients.
  • a process for preparing a pharmaceutical composition comprising nanosized pazopanib along with one or more pharmaceutically acceptable excipients.
  • a method of treating advanced renal cell carcinoma and advanced soft tissue sarcoma comprising administering a therapeutically effective amount of a pharmaceutical composition comprising pazopanib according to the present invention to a patient in need thereof.
  • a method of treating advanced renal cell carcinoma and advanced soft tissue sarcoma comprising administering a therapeutically effective amount of a pharmaceutical composition comprising nanosized pazopanib according to the present invention to a patient in need thereof.
  • a pharmaceutical composition comprising pazopanib according to the present invention in the manufacture of a medicament for the treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma.
  • a pharmaceutical composition comprising nanosized pazopanib according to present invention in the manufacture of a medicament for the advanced renal cell carcinoma and advanced soft tissue sarcoma.
  • a pharmaceutical composition comprising pazopanib according to the present invention for use in treating advanced renal cell carcinoma and advanced soft tissue sarcoma.
  • a pharmaceutical composition comprising nanosized pazopanib according to the present invention for use in treating advanced renal cell carcinoma and advanced soft tissue sarcoma.
  • Pazopanib is commercially available as a conventional film coated tablet formulation for the treatment of advanced renal cell carcinoma and the treatment of advanced soft tissue sarcoma in patients who have undergone chemotherapy previously.
  • the required dosage is comprised in four pazopanib tablets that have to be administered once a day.
  • 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 as well as side effects 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.
  • compositions with a reduced or low dose such that it exhibits similar or increased bioavailability.
  • a lower dose of pazopanib it may be possible to reduce the side effects while retaining its therapeutic and preventive efficacy.
  • pazopanib as an active pharmaceutical agent, used for treating kidney cancer, would be preferred in an oral composition with a low dose and in a dosage form which exhibits desired therapeutic effect and at the same time ensuring patient compliance.
  • the present invention provides a pharmaceutical composition comprising pazopanib which would ensure patient compliance due to simplification of therapy, ease of administration, an acceptable dosing regimen, bioavailability and which nullifies the food effect.
  • pazopanib is used in broad sense to include not only “pazopanib” per se but also its pharmaceutically acceptable derivatives thereof.
  • suitable pharmaceutically acceptable 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.
  • pazopanib is present in the form of pazopanib hydrochloride.
  • the term "low dose” or “reduced dose” as used herein refers to a therapeutically effective dose of pazopanib, which dose is less than the usual or the conventional dose required to produce equal or higher therapeutic effect.
  • the pharmaceutical composition of the invention may be administered at least once a day to a patient in need thereof. More preferably, the pharmaceutical composition of the invention is administered once a day such that the total daily dose administered to a patient in a dose which is less than the conventionally administered daily dose.
  • the composition of the invention comprises less than 800 mg of pazopanib. More preferably, the composition of the invention comprises from about 100 mg to about 800 mg of pazopanib.
  • the composition of the invention comprises from about 125 mg to about 700 mg pazopanib.
  • the pharmaceutical composition of the present invention may comprise from about 175 mg to about 600 mg of pazopanib or from about 225 mg to about 500 mg of pazopanib.
  • the conventional dose of VOTRIENT ® is 800 mg per day.
  • Pazopanib is preferably present in pharmaceutical compositions of the invention in an amount of from about 25% to about 60% by weight of the composition. More preferably, pazopanib is present in the compositions in an amount of from about 30% to about 55% by weight of the composition. Most preferably, the pazopanib is present in an amount of from about 35% to about 50% by weight of the composition.
  • the inventors of the present invention have also found that the solubility properties of pazopanib are improved by nanosizing thus leading to better bioavailability and dose reduction 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.
  • the pharmaceutical composition of the present invention preferably comprises pazopanib in the form of nanoparticles.
  • nanosize refers to pazopanib particles having an average particle size of less than about 2000 nm, preferably less than about 1000 nm.
  • the particles may have an average particle size of less than 700 nm. More preferably, the particles may have an average particle size of less than 500 nm. Most preferably, the particles may have an average particle size ofless than about 250 nm or less than about 150 nm.
  • the pazopanib particles may have a particle size distribution with a D90 less than 700 nm, preferably less than 300 nm, more preferably less than 100 nm.
  • the present invention thus provides a pharmaceutical composition, which preferably comprises pazopanib, wherein the pazopanib is in the nanosize range.
  • particle refers to an individual particle of pazopanib, or particles of pazopanib, or pazopanib granules and/or mixtures thereof.
  • the particles of the present invention may comprise pazopanib and the one or more pharmaceutically acceptable excipients.
  • nanosize particles of the present invention can be obtained by any process known in the art, such as, but not limited to, milling, precipitation, homogenization, high pressure homogenization, spray-freeze drying, supercritical fluid technology, double emulsion/solvent evaporation, Particle replication in non-wetting templates (PRINT), thermal condensation, ultrasonication, spray drying or the like. Nanoparticles obtained by any of these processes may further be formulated into desired dosage forms.
  • the particle size can be measured by any method known in the art.
  • the particle size may be measured using known laser diffraction methods.
  • the pharmaceutical composition comprising pazopanib according to the present invention may be administered orally through unit dosage forms including tablets, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, multiple unit pellet systems (MUPS), disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), powders for reconstitution and sprinkles, however, other dosage forms such as controlled release formulations, lyophilized formulations, modified release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, dual release formulations and the like.
  • MUPS unit pellet systems
  • Liquid dosage form liquids, suspensions, solutions, dispersions, ointments, creams, emulsions, microemulsions, sprays, spot-on), injection preparations etc.
  • the unit dosage forms comprise nanosized pazopanib.
  • the pharmaceutical composition comprising pazopanib according to the present invention may be administered in a solid oral dosage form such as tablets, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates) and sprinkles.
  • the solid oral dosage forms comprise nanosized pazopanib.
  • the pharmaceutical composition comprising pazopanib, according to the present invention is presented in a tablet dosage form.
  • the tablet dosage forms comprise nanosized pazopanib.
  • the methods and uses of the invention preferably comprise administering a total daily dose of less than 800 mg of pazopanib, preferably from about 100 mg pazopanib to about 800 mg pazopanib to a patient in need thereof.
  • Pazopanib may be administered with a total daily dose of from about 125 mg to about 700 mg, preferably from about 175 mg to about 600 mg or more preferably from about 225 mg to about 500 mg.
  • compositions of the invention may be administered at least once a day to a patient in need thereof.
  • Suitable excipients may be used for formulating the dosage form according to the present invention such as, but not limited to, surface stabilizers, viscosity modifying agents, polymers, disintegrants or super disintegrants, diluents, plasticizers, binders, glidants, lubricants, sweeteners, flavoring agents, anti-caking agents, anti-microbial agents, antifoaming agents, emulsifiers, surfactants, buffering agents, coloring agents, carriers, fillers, anti-adherents, solvents, taste-marking agents, preservatives, antioxidants, viscosity modifying agents, texture enhancers, surface stabilisers, channeling agents, or combinations thereof.
  • Suitable surface stabilizers mean surfactants that are capable of stabilizing the increased surface charge of the nanosized drug.
  • Suitable amphoteric, non-ionic, cationic or anionic surfactants may be included as surface stabilizers in the pharmaceutical composition of 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, Cetyl trimethyl ammonium bromide (CTAB), Polyethoxylated alcohols, Polyoxyethylene sorbitan, Octoxynol, N, N-dimethyldodecylamine-N-oxide, Hexadecyltrimethylammonium bromide, Polyoxyl 10 lauryl ether, Brij, Bile salts (sodium deoxycholate, sodium cholate), Polyoxyl castor oil, Nonylphenol ethoxylate Cyclodextrins, Lecithin, Methylbenzethonium chloride.
  • CTAB Cetyl trimethyl ammonium bromide
  • Polyethoxylated alcohols Polyoxyethylene sorbitan
  • Octoxynol N, N-dimethyldodecy
  • Carboxylates Sulphonates, Petroleum sulphonates, alkylbenzenesulphonates, Naphthalenesulphonates, Olefin sulphonates, Alkyl sulphates, Sulphates, Sulphated natural oils & fats, Sulphated esters, Sulphated alkanolamides, Alkylphenols, ethoxylated & sulphated, Ethoxylated aliphatic alcohol, polyoxyethylene surfactants, carboxylic esters Polyethylene glycol esters, Anhydrosorbitol ester & it's 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, ⁇ , ⁇ , ⁇ , ⁇ tetrakis substituted ethylenediamines 2- al
  • the amount of surface stabilizers in the pharmaceutical composition comprising pazopanib preferably range from about 2 % to about 10 % of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form.
  • Suitable viscosity modifying agents are excipients that are capable of stabilizing the nanoparticles by increasing the viscosity of the composition and thus, preventing physical interaction of nanoparticles under the operating conditions employed.
  • viscosity modifying agents may comprise one or more, but not limited to, derivatives of sugars, such as lactose, lactose monohydrate, saccharose, hydrolyzed starch (maltodextrin) or combinations thereof.
  • the amount of viscosity modifying agents in the pharmaceutical composition comprising pazopanib preferably range from about 4 % to about 20 % of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form.
  • Suitable polymers according to the present invention may comprise one or more hydrophilic polymers, but not limited to, cellulose derivates like hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose (hypromellose), methylcellulose polymers hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene and carboxymethyl hydroxyethylcellulose; 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, or modified starch derivatives and copolymers.
  • hydrophilic polymers but not limited to, cellulose derivates like hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose (hypromellose), methylcellulose polymers hydroxye
  • the amount of polymers in the pharmaceutical composition comprising pazopanib preferably range from about 2 % to about 15 % of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form.
  • Suitable disintegrants or super disintegrants include, but are not limited to, agar-agar, calcium carbonate, microcrystalline 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, polyvinyl pyrollidone, cross-linked PVP, carboxymethyl cellulose calcium, crosslinked sodium carboxymethyl cellulose, docusate sodium, guar gum, low-
  • Suitable glidants, anti-adherents and lubricants according to the present invention include, but are not limited to, stearic acid and pharmaceutically acceptable salts or esters thereof (for example, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate or other metallic stearate), talc, 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 alumino metasilicate), 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
  • the amount of glidants, anti-adherants and lubricants in the pharmaceutical composition comprising pazopanib preferably range from about 0.25 % to about 5 % of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form.
  • Suitable channeling agents according to the present invention include, but are not limited to, sodium chloride, sugars, polyols and the like or mixtures thereof.
  • the amount of channeling agents in the pharmaceutical composition comprising pazopanib preferably range from about 0.5 % to about 10% of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form.
  • Suitable binders may also 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 carboxymethyl cellulose, dextrin, gelatin, gum arabic, guar gum, tragacanth, sodium alginate, or mixtures thereof or any other suitable binder.
  • polyvinyl pyrrolidone also known as povidone
  • polyethylene glycol(s) polyethylene glycol(s)
  • acacia alginic acid
  • agar calcium carragenan
  • cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium
  • the amount of binder in the pharmaceutical compositions preferably range from about 5 % w/w to about 20 % w/w, of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form.
  • Suitable carriers, diluents or fillers for use, in the pharmaceutical composition of the present invention may comprise one or more, but not limited to lactose (for example, spray-dried lactose, a-lactose, ⁇ -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), hydroxypropylcellulose, L-hydroxyprop
  • the amount of carriers, diluents or fillers in the pharmaceutical compositions preferably range from about 15 % w/w to about 60 % w/w of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form.
  • Suitable anti-caking additives that may also be incorporated in the low dose pharmaceutical composition include, but are not limited to, calcium silicate, magnesium silicate, silicon dioxide, colloidal silicon dioxide, talc, or combinations thereof.
  • Suitable anti-microbial agents or preservatives that may also be incorporated in the low dose pharmaceutical composition 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, or combinations thereof.
  • Suitable sweetening agent or taste-masking agents that may also be incorporated in the low dose pharmaceutical composition 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, stevside sodium cyclamate, eugenylformate aldehyde flavorings or combinations thereof.
  • Suitable flavors that may also be incorporated in the low dose pharmaceutical composition 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, cacao/cocoa, vanilla, liquorice, menthol, eucalyptus, aniseeds nuts (e.g., peanuts, coconuts, hazelnuts, chestnuts, walnuts, colanut
  • Suitable antioxidants that may also be incorporated in the low dose pharmaceutical composition include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate salts, or combinations thereof.
  • Suitable texture enhancers that may also be incorporated in the low dose pharmaceutical composition include, but are not limited to, pectin, polyethylene oxide, and carrageenan, or combinations thereof.
  • a process for preparing a pharmaceutical composition as described herein comprises admixing one or more pharmaceutically acceptable excipients with pazopanib, wherein the pazopanib is preferably in a nanosized form.
  • the process may comprise homogenizing pazopanib and at least one excipient to produce a homogenized dispersion of the pazopanib in the excipient.
  • the process further comprises processing the homogenized dispersion to produce pazopanib particles.
  • the processing may comprise milling the homogenized dispersion to produce a slurry of pazopanib particles.
  • the pazopanib particles may be dried and blended.
  • the dispersion comprises pazopanib, at least one surfactant, at least one polymer and at least one carrier, diluent or filler and purified water.
  • the pazopanib particles may be adsorbed by spraying the slurry onto a combination of at least one channeling agent, at least one anti-adherent and at least one disintegrant or super-disintegrant in a fluidized bed granulator.
  • the pazopanib particles may be compressed into unit dosage forms.
  • the pazopanib particles are lubricated before being compressed into unit dosage forms.
  • the unit dosage forms may be coated.
  • the pazopanib particles may have an average particle size of less than about 2000 nm.
  • the pharmaceutical composition of the present invention may be prepared by a process which comprises: (a) preparing a dispersion of pazopanib with docusate sodium, hydroxyl propyl methylcellulose or hypromellose, sodium lauryl sulphate and lactose in purified water; (b) homogenizing the dispersion of step (a) and then nanomilling the homogenized dispersion; (c) adsorbing the nanomilled drug by spraying the nanomilled slurry on sodium chloride, magnesium stearate, silicified microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator; (d) drying and blending the granules obtained in step (c).
  • the granules may be lubricated and finally compressed into tablets.
  • the tablets may further be film coated to form film coated tablets.
  • the pharmaceutical composition may also optionally be coated.
  • coatings comprise, but are not limited to, seal coating, enteric coating, film coating or a combination thereof.
  • the pharmaceutical composition may be film coated, seal coated or enteric coated with, but not limited to, colour mix systems (such as Opadry colour mix systems), Aqueous Acrylic Enteric System (such as Acryl-EZE ® ) and Kollicoat ® Protect.
  • colour mix systems such as Opadry colour mix systems
  • Aqueous Acrylic Enteric System such as Acryl-EZE ®
  • Kollicoat ® Protect Kollicoat ® Protect.
  • the pharmaceutical composition may be film coated.
  • the amount of film coating system in the pharmaceutical compositions preferably range from about 2 % w/w to about 6 % w/w, of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form.
  • Suitable seal coating agents that may be incorporated in the pharmaceutical composition are film forming polymeric materials, such as but not limited to, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, methylcellulose, carboxymethyl cellulose, hypromellose, acacia or gelatin to increase adherence and coherence of the seal coat.
  • the amount of seal coating system in the pharmaceutical compositions preferably range from about 1 % w/w to about 3 % w/w, of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form.
  • pharmaceutically acceptable opacifier may be used in the pharmaceutical composition of the present invention, which comprises titanium dioxide.
  • the amount of opacificer in the pharmaceutical composition comprising pazopanib preferably range from about 1 % to about 4 % of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form.
  • the pharmaceutical composition of the invention comprises one or more surfactants, binders, disintegrants, lubricants, and optionally one or more channeling agents.
  • the pharmaceutical composition of the invention comprises pazopanib nanoparticles in an amount of from 25% to 60% w/w, one or more surfactants present in an amount of from about 2% to about 10 % w/w, one or more binders in an amount of from about 5% to about 20% w/w, one or more disintegrants present in an amount of from about 5% to about 30% w/w, and optionally one or more channeling agents present in an amount of from about 0.5% to about 10% w/w.
  • the pharmaceutical composition of the present invention may further comprise at least one additional active ingredient such as, but not limited to, MEK inhibitor, topoisomerase inhibitor, EGFR inhibitor, anti-CTLA4 antibody, DLL4 antagonist, anti-HMW-MAA antibody, peginterferon alfa-2a, dihydroorotate dehydrogenase inhibitor, AKT inhibitor compounds, 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 or combinations thereof.
  • additional active ingredient such as, but not limited to, MEK inhibitor, topoisomerase inhibitor, EGFR inhibitor, anti-CTLA4 antibody, DLL4 antagonist, anti-HMW-MAA antibody, peginterferon alfa-2a, dihydrooro
  • the pharmaceutical composition of the present invention may further comprise at least one additional active ingredient such as, but not limited to, cisplatin, gemcitabine, temsirolimus, paclitaxel, topotecan, lapatinib, nivolumab, crizotimib, and ifosfomide and the like and combinations thereof.
  • additional active ingredient such as, but not limited to, cisplatin, gemcitabine, temsirolimus, paclitaxel, topotecan, lapatinib, nivolumab, crizotimib, and ifosfomide and the like and combinations thereof.
  • the present invention further provides a method of treating advanced renal cell carcinoma and advance soft tissue sarcoma, the method comprising: administering a therapeutically effective amount of a pharmaceutical composition comprising pazopanib to a patient in need thereof, wherein the pazopanib is preferably in a nanosized form.
  • the present invention also provides the use of a pharmaceutical composition comprising pazopanib according to the present invention in the manufacture of a medicament for the treatment of advanced renal cell carcinoma and advance soft tissue sarcoma, wherein the pazopanib is preferably in a nanosized form.
  • the present invention also provides a pharmaceutical composition comprising pazopanib according to the present invention for use in treatment of advanced renal cell carcinoma and advance soft tissue sarcoma, wherein the pazopanib is preferably in a nanosized form.
  • step (2) Pazopanib was dispersed in the solution obtained in step (1) and then milled to form a slurry.
  • step (2) The drug slurry obtained in step (2) was sprayed on lactose and crospovidone to obtain granules.
  • step (3) The dried granules obtained in step (3) were blended with crospovidone, silicified microcrystalline cellulose and sodium chloride.
  • step (4) The blended granules obtained in step (4) were lubricated with magnesium stearate.
  • step (5) The lubricated granules obtained in step (5) were compressed into tablets and coated with Opadry grey.
  • step (2) Pazopanib was dispersed in the solution obtained in step (1) and then milled to form a slurry.
  • step (3) The drug slurry obtained in step (2) was sprayed on lactose and crospovidone to obtain granules.
  • step (3) Blending and Lubrication:
  • step (3) The dried granules obtained in step (3) were blended with crospovidone, silicified microcrystalline cellulose and sodium chloride.
  • step (4) The blended granules obtained in step (4) were lubricated with magnesium stearate.
  • step (5) The lubricated granules obtained in step (5) were compressed into tablets and coated with Opadry grey.
  • step (3) Pazopanib was dispersed in the solution obtained in step (2) and then milled to form a slurry.
  • step (3) The drug slurry obtained in step (3) was sprayed on lactose and crospovidone to obtain granules.
  • step (4) The dried granules obtained in step (4) were blended with crospovidone, silicified microcrystalline cellulose and sodium chloride.
  • step (5) The blended granules obtained in step (5) were lubricated with magnesium stearate.
  • step (3) Pazopanib was dispersed in the solution obtained in step (2) and then milled to form a slurry.
  • step (3) The drug slurry obtained in step (3) was sprayed on lactose and crospovidone to obtain granules.
  • step (4) The dried granules obtained in step (4) were blended with crospovidone, silicified microcrystalline cellulose and sodium chloride.
  • step (5) The blended granules obtained in step (5) were lubricated with magnesium stearate.
  • step (6) The lubricated granules obtained in step (6) were compressed into tablets and coated with Opadry grey.
  • step (2) Pazopanib was dispersed in the solution obtained in step (1) and then milled to form a slurry.
  • step (2) The drug slurry obtained in step (2) was sprayed on lactose and crospovidone to obtain granules.
  • step (3) The dried granules obtained in step (3) were blended with crospovidone, silicified microcrystalline cellulose and sodium chloride.
  • step (4) The blended granules obtained in step (4) were lubricated with magnesium stearate.
  • step (2) Pazopanib was dispersed in the solution obtained in step (1) and then milled to form a slurry.
  • step (3) The drug slurry obtained in step (2) was sprayed on lactose and crospovidone to obtain granules.
  • step (3) Blending and Lubrication:
  • step (3) The dried granules obtained in step (3) were blended with crospovidone, silicified microcrystalline cellulose and sodium chloride. 5) The blended granules obtained in step (4) were lubricated with magnesium stearate.
  • step (3) Pazopanib was dispersed in the solution obtained in step (2) and then milled to form a slurry.
  • step (3) The drug slurry obtained in step (3) was sprayed on lactose and crospovidone to obtain granules.
  • step (4) The dried granules obtained in step (4) were blended with crospovidone, silicified microcrystalline cellulose and sodium chloride.
  • step (3) Pazopanib was dispersed in the solution obtained in step (2) and then milled to form a slurry.
  • step (3) The drug slurry obtained in step (3) was sprayed on lactose and crospovidone to obtain granules.
  • step (4) The dried granules obtained in step (4) were blended with crospovidone, silicified microcrystalline cellulose and sodium chloride.
  • step (2) Pazopanib was dispersed in the solution obtained in step (1) and then milled to form a slurry.
  • step (3) The drug slurry obtained in step (2) was sprayed on lactose and crospovidone to obtain granules.
  • step (3) Blending and Lubrication:
  • step (3) The dried granules obtained in step (3) were blended with crospovidone, silicified microcrystalline cellulose and sodium chloride
  • step (5) The lubricated granules obtained in step (5) were compressed to produce dispersible tablets.
  • step (2) The drug slurry obtained in step (2) was sprayed on lactose and crospovidone to obtain granules.
  • step (3) Blending and Lubrication: 4) The dried granules obtained in step (3) were blended with crospovidone, silicified microcrystalline cellulose and sodium chloride
  • step (4) The blended granules obtained in step (4) were lubricated with magnesium stearate.

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Abstract

The present invention relates to a pharmaceutical composition comprising a tyrosine kinase inhibitor and one or more pharmaceutically acceptable excipients, a process for preparing such pharmaceutical composition and its use in the treatment of renal cell carcinoma and soft tissue sarcoma.

Description

PHARMACEUTICAL COMPOSITION COMPRISING PAZOPANIB
FIELD OF INVENTION
The present invention relates to a pharmaceutical composition comprising a tyrosine kinase inhibitor, and more particularly, to a pharmaceutical composition comprising pazopanib, a process for preparing the pharmaceutical composition and its use in the treatment of cancer such as renal cell carcinoma and soft tissue sarcoma.
BACKGROUND AND PRIOR ART
Renal cell carcinoma, formerly known as hypernephroma, is a kidney cancer that originates in the lining of the proximal convoluted tubule, one type of very small tubes in the kidney that transports waste molecules from the blood to the urine. It is the most common type of kidney cancer in adults, responsible for approximately 90% to 95% of cases. It has been described as one of the deadliest of cancers affecting the genitourinary tract. Initial treatment is, most commonly either partial or complete removal of the affected kidney(s) and remains the mainstay of curative treatment. Where the cancer has not metastasized (spread to other organs) or burrowed deeper into the tissues of the kidney the 5 -year survival rate is 60% to 70%, but this is lowered considerably when the cancer has spread.
Renal cell carcinoma (RCC) represents 2% to 3% of all cancers with an age-standardized rate incidence of 5.8 and mortality of 1.4 per 100,000, respectively, in more developed areas. The highest incidence all over the world is in the Czech Republic, where in 2010 the incidence rate was 14.62 and mortality 5.17 (age-standardized rate/world per 100,000). Renal cell carcinoma is the commonest solid lesion in the kidney and accounts for approximately 90% of all kidney malignancies. It includes different types, with specific histopathological and genetic characteristics. There is a 1.5 :1.0 predominance of men over women, with the peak incidence occurring between the ages of 60 and 70. A sarcoma is a type of cancer that develops from certain tissues, like bone or muscle. There are two main types of sarcoma: bone sarcomas and soft tissue sarcomas. Soft tissue sarcomas can develop from soft tissues like fat, muscle, nerves, fibrous tissues, blood vessels, or deep skin tissues. They can be found in any part of the body. Most of them develop in the arms or legs. They can also be found in the trunk, head and neck area, internal organs, and the area in back of the abdominal cavity (known as the retroperitoneum). Sarcomas are not common tumors, and most cancers are the type of tumors called carcinomas.
Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor that blocks tumour growth and inhibits angiogenesis. It has been approved for renal cell carcinoma and soft tissue sarcoma. It is an angiogenesis inhibitor which targets vascular endothelial growth factor receptors VEGFR-1, VEGFR-2, VEGFR-3 and platelet-derived growth factor receptors PDGFR- a, PGDFR-3 and c-Kit.
Pazopanib has the chemical name 5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl]amino]-2-methylbenzolsulfonamide and is structurally represented as
Figure imgf000003_0001
"Pazopanib versus sunitinib in metastatic renal-cell carcinoma", August 2013, published in the New England Journal of Medicine concluded that for the treatment of renal cell carcinoma, pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib and it is also much more favoured over other similar antineoplastic agents.
WO2013066616 discloses a composition suitable for reconstitution into an aqueous suspension of pazopanib to target the pediatric and geriatric population.
WO2011140343 discloses aformulation suitable for ocular administration, comprising pazopanib along with modified cyclodextrin that lowers the dissociation constant of pazopanib. "The Frequency and Severity of Cardiovascular Toxicity from Targeted Therapy in Advanced Renal Cell Carcinoma Patients", February 2013, published in the US National Library of Medicine National Institutes of Health discloses the frequency and severity of cardiovascular toxicity in advanced renal cell carcinoma patients treated with targeted cancer therapies such as pazopanib and other similar cancer treating agents which are relatively new.
Pazopanib is available in a hydrochloride salt form. The recommended dose of pazopanib is 800 mg once daily. Tablets comprising 200 mg pazopanib are sold under the trade name VOTRIENT®. VOTRIENT® contains 216.7 mg of pazopanib hydrochloride, equivalent to 200 mg of pazopanib free base. Thus, the required dosage is comprised in four VOTRIENT® tablets that have to be administered orally once a day.
One of the issues with pazopanib is that its pharmacokinetic properties are affected by the prandial status of a patient receiving the treatment, i.e. it exhibits a "food effect". In particular, the bioavailability or systemic exposure of pazopanib increases when administered with food. Pazopanib AUC values were approximately 2 times higher when administered with a low fat (5% fat) or with a high fat (50% fat) meal respectively.
This situation is unsatisfactory and inconvenient to 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 pazopanib may be hampered by factors such as emesis and ingestion and would ultimately lead to decreased bioavailability of pazopanib.
Side effects caused by the different drugs taken by the patients during the cancer treatment should also be taken into consideration in addition to the food effect and therefore, different approaches are being considered to decrease the side effects of such drugs. The administration of pazopanib may include serious side effects such as cardiotoxicity, bloody or tarry stools, coughing up blood, loss of appetite, dark urine, jaundice (yellowing of the skin or eyes), sudden numbness or weakness, problems with speech or balance, chest pain, or vision and hearing problems.
Hence, it would be desirable to reduce the dosing regimen as well as nullify the food effect of pazopanib. Further, the pharmaceutical composition comprising pazopanib should be stable as well as exhibit optimal dissolution properties. However, these characteristics are often difficult to achieve with high concentrations of pazopanib.
The above mentioned drawbacks such as dosage, reduction of side effects and ease of administration of pazopanib thereby facilitating patient compliance, have not been previously considered. Thus, the currently commercialized dosage form and the recommended dose still do not address these drawbacks associated with the pazopanib therapy.
The inventors of the present invention have appreciated the above problems associated with prior art compositions comprising pazopanib and methods of treating patients using pazopanib. Attempts to address the prior art problems have led the inventors of the present invention to develop a pharmaceutical composition comprising pazopanib that has better bioavailability, stability and patient compliant.
OBJECT OF THE INVENTION
An object of the present invention is to provide a pharmaceutical composition comprising pazopanib and one or more pharmaceutically acceptable excipients. Another object of the present invention is to provide a pharmaceutical composition comprising nanosized pazopanib.
Another object of the present invention is to provide a pharmaceutical composition comprising nanosized pazopanib along with one or more pharmaceutically acceptable excipients.
Another object of the present invention is to provide a pharmaceutical composition comprising pazopanib having improved surface area and solubility.
Another object of the present invention is to provide a pharmaceutical composition comprising nanosized pazopanib having improved surface area and solubility.
Yet another object of the present invention is to provide a pharmaceutical composition comprising pazopanib exhibiting increased bioavailability. Yet another object of the present invention is to provide a pharmaceutical composition comprising nanosized pazopanib exhibiting increased bioavailability. Another object of the present invention is to provide a pharmaceutical composition comprising pazopanib exhibiting minimal food effect.
Another object of the present invention is to provide a pharmaceutical composition comprising nanosized pazopanib exhibiting minimal food effect.
Yet another object of the present invention is to provide a pharmaceutical composition comprising a reduced dose of pazopanib.
Yet another object of the present invention is to provide a pharmaceutical composition comprising a reduced dose of nanosized pazopanib.
Another object of the present invention is to provide a pharmaceutical composition comprising pazopanib for once a day administration.
Another object of the present invention is to provide a pharmaceutical composition comprising nanosized pazopanib for once a day administration.
Another object of the present invention is to provide a process for preparing the pharmaceutical composition comprising pazopanib.
Another object of the present invention is to provide a process for preparing the pharmaceutical composition comprising nanosized pazopanib.
Yet another object of the present invention is to provide a method of treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma which method comprises administering a pharmaceutical composition comprising pazopanib.
Yet another object of the present invention is to provide a method of treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma which method comprises administering a pharmaceutical composition comprising nanosized pazopanib.
Another object of the present invention is to provide the use of a pharmaceutical composition comprising pazopanib, in the manufacture of a medicament for the treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma. Another object of the present invention is to provide the use of a pharmaceutical composition comprising nanosized pazopanib, in the manufacture of a medicament for the treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma.
Another object of the present invention is to provide a pharmaceutical composition comprising pazopanib for use in treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma.
Another object of the present invention is to provide a pharmaceutical composition comprising nanosized pazopanib for use in treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma. SUMMARY OF THE INVENTION
According to an aspect of the present invention, there is provided a pharmaceutical composition comprising pazopanib and one or more pharmaceutically acceptable excipients.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising nanosized pazopanib, wherein preferably the nanoparticles have an average particle size of less than about 2000 nm.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising nanosized pazopanib along with one or mor pharmaceutically acceptable excipients.
According to another aspect of the invention, there is provided a process for preparing a pharmaceutical composition comprising pazopanib and one or more pharmaceutically acceptable excipients.
According to another aspect of the present invention there is provided a process for preparing a pharmaceutical composition comprising nanosized pazopanib along with one or more pharmaceutically acceptable excipients. According to another aspect of the present invention there is provided a method of treating advanced renal cell carcinoma and advanced soft tissue sarcoma, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising pazopanib according to the present invention to a patient in need thereof.
According to another aspect of the present invention there is provided a method of treating advanced renal cell carcinoma and advanced soft tissue sarcoma, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising nanosized pazopanib according to the present invention to a patient in need thereof.
According to another aspect of the present invention there is provided the use of a pharmaceutical composition comprising pazopanib according to the present invention in the manufacture of a medicament for the treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma.
According to another aspect of the present invention there is provided the use of a pharmaceutical composition comprising nanosized pazopanib according to present invention in the manufacture of a medicament for the advanced renal cell carcinoma and advanced soft tissue sarcoma. According to another aspect of the present invention there is provided a pharmaceutical composition comprising pazopanib according to the present invention for use in treating advanced renal cell carcinoma and advanced soft tissue sarcoma.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising nanosized pazopanib according to the present invention for use in treating advanced renal cell carcinoma and advanced soft tissue sarcoma.
DETAILED DESCRIPTION OF THE INVENTION
Pazopanib is commercially available as a conventional film coated tablet formulation for the treatment of advanced renal cell carcinoma and the treatment of advanced soft tissue sarcoma in patients who have undergone chemotherapy previously. The required dosage is comprised in four pazopanib tablets that have to be administered once 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 as well as side effects 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 inventors have found that the above criteria could be met by formulating a composition with a reduced or low dose such that it exhibits similar or increased bioavailability. Also, with a lower dose of pazopanib, it may be possible to reduce the side effects while retaining its therapeutic and preventive efficacy.
Hence, pazopanib as an active pharmaceutical agent, used for treating kidney cancer, would be preferred in an oral composition with a low dose and in a dosage form which exhibits desired therapeutic effect and at the same time ensuring patient compliance.
The present invention provides a pharmaceutical composition comprising pazopanib which would ensure patient compliance due to simplification of therapy, ease of administration, an acceptable dosing regimen, bioavailability and which nullifies the food effect.
The term "pazopanib" is used in broad sense to include not only "pazopanib" per se but also its pharmaceutically acceptable derivatives thereof. Suitable pharmaceutically acceptable 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. Preferably, pazopanib is present in the form of pazopanib hydrochloride. The term "low dose" or "reduced dose" as used herein refers to a therapeutically effective dose of pazopanib, which dose is less than the usual or the conventional dose required to produce equal or higher therapeutic effect. Preferably, the pharmaceutical composition of the invention, according to the present invention may be administered at least once a day to a patient in need thereof. More preferably, the pharmaceutical composition of the invention is administered once a day such that the total daily dose administered to a patient in a dose which is less than the conventionally administered daily dose. Preferably, the composition of the invention comprises less than 800 mg of pazopanib. More preferably, the composition of the invention comprises from about 100 mg to about 800 mg of pazopanib. Most preferably, the composition of the invention comprises from about 125 mg to about 700 mg pazopanib. The pharmaceutical composition of the present invention may comprise from about 175 mg to about 600 mg of pazopanib or from about 225 mg to about 500 mg of pazopanib. The conventional dose of VOTRIENT®, the current trade name for pazopanib, is 800 mg per day.
Pazopanib is preferably present in pharmaceutical compositions of the invention in an amount of from about 25% to about 60% by weight of the composition. More preferably, pazopanib is present in the compositions in an amount of from about 30% to about 55% by weight of the composition. Most preferably, the pazopanib is present in an amount of from about 35% to about 50% by weight of the composition.
The inventors of the present invention have also found that the solubility properties of pazopanib are improved by nanosizing thus leading to better bioavailability and dose reduction 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, Volume 00, Number 00, March 2010]. Thus, the pharmaceutical composition of the present invention preferably comprises pazopanib in the form of nanoparticles.
The term "nanosize" as used herein refers to pazopanib particles having an average particle size of less than about 2000 nm, preferably less than about 1000 nm. Preferably, the particles may have an average particle size of less than 700 nm. More preferably, the particles may have an average particle size of less than 500 nm. Most preferably, the particles may have an average particle size ofless than about 250 nm or less than about 150 nm.
The pazopanib particles may have a particle size distribution with a D90 less than 700 nm, preferably less than 300 nm, more preferably less than 100 nm.
The present invention thus provides a pharmaceutical composition, which preferably comprises pazopanib, wherein the pazopanib is in the nanosize range.
The term "particle" as used herein refers to an individual particle of pazopanib, or particles of pazopanib, or pazopanib granules and/or mixtures thereof. The particles of the present invention may comprise pazopanib and the one or more pharmaceutically acceptable excipients.
The nanosize particles of the present invention can be obtained by any process known in the art, such as, but not limited to, milling, precipitation, homogenization, high pressure homogenization, spray-freeze drying, supercritical fluid technology, double emulsion/solvent evaporation, Particle replication in non-wetting templates (PRINT), thermal condensation, ultrasonication, spray drying or the like. Nanoparticles obtained by any of these processes may further be formulated into desired dosage forms.
The particle size can be measured by any method known in the art. For instance, the particle size may be measured using known laser diffraction methods.
The pharmaceutical composition comprising pazopanib according to the present invention may be administered orally through unit dosage forms including tablets, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, multiple unit pellet systems (MUPS), disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), powders for reconstitution and sprinkles, however, other dosage forms such as controlled release formulations, lyophilized formulations, modified release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, dual release formulations and the like. Liquid dosage form (liquids, suspensions, solutions, dispersions, ointments, creams, emulsions, microemulsions, sprays, spot-on), injection preparations etc. may also be envisaged under the ambit of the invention. Preferably, the unit dosage forms comprise nanosized pazopanib.
Preferably, the pharmaceutical composition comprising pazopanib according to the present invention may be administered in a solid oral dosage form such as tablets, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates) and sprinkles. Preferably, the solid oral dosage forms comprise nanosized pazopanib.
Suitably, the pharmaceutical composition comprising pazopanib, according to the present invention is presented in a tablet dosage form. Preferably, the tablet dosage forms comprise nanosized pazopanib.
The methods and uses of the invention preferably comprise administering a total daily dose of less than 800 mg of pazopanib, preferably from about 100 mg pazopanib to about 800 mg pazopanib to a patient in need thereof. Pazopanib may be administered with a total daily dose of from about 125 mg to about 700 mg, preferably from about 175 mg to about 600 mg or more preferably from about 225 mg to about 500 mg.
The pharmaceutical compositions of the invention may be administered at least once a day to a patient in need thereof.
Suitable excipients may be used for formulating the dosage form according to the present invention such as, but not limited to, surface stabilizers, viscosity modifying agents, polymers, disintegrants or super disintegrants, diluents, plasticizers, binders, glidants, lubricants, sweeteners, flavoring agents, anti-caking agents, anti-microbial agents, antifoaming agents, emulsifiers, surfactants, buffering agents, coloring agents, carriers, fillers, anti-adherents, solvents, taste-marking agents, preservatives, antioxidants, viscosity modifying agents, texture enhancers, surface stabilisers, channeling agents, or combinations thereof. Suitable surface stabilizers, according to the present invention mean surfactants that are capable of stabilizing the increased surface charge of the nanosized drug. Suitable amphoteric, non-ionic, cationic or anionic surfactants may be included as surface stabilizers in the pharmaceutical composition 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, Cetyl trimethyl ammonium bromide (CTAB), Polyethoxylated alcohols, Polyoxyethylene sorbitan, Octoxynol, N, N-dimethyldodecylamine-N-oxide, Hexadecyltrimethylammonium bromide, Polyoxyl 10 lauryl ether, Brij, Bile salts (sodium deoxycholate, sodium cholate), Polyoxyl castor oil, Nonylphenol ethoxylate Cyclodextrins, Lecithin, Methylbenzethonium chloride. Carboxylates, Sulphonates, Petroleum sulphonates, alkylbenzenesulphonates, Naphthalenesulphonates, Olefin sulphonates, Alkyl sulphates, Sulphates, Sulphated natural oils & fats, Sulphated esters, Sulphated alkanolamides, Alkylphenols, ethoxylated & sulphated, Ethoxylated aliphatic alcohol, polyoxyethylene surfactants, carboxylic esters Polyethylene glycol esters, Anhydrosorbitol ester & it's 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, Ν,Ν,Ν,Ν tetrakis substituted ethylenediamines 2- alkyl 1- hydroxy ethyl 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, Phosal 53 MCT, Polyoxyethylene (20) sorbitan trioleate (Tween 85), Oleoyl macrogolglycerides (Labrafil M1944CS), Linoleoyl macrogolglycerides (Labrafil M2125CS), PG monolaurate (Lauroglycol 90), D-alpha-tocopheryl PEG 1000 succinate (Vitamin E TPGS), Polyoxyl 35 castor oil (Cremophor EL, Cremophor ELP), Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40, Cremophor RH 60), Lauroyl macrogolglycerides (Gelucire 44/14, Gelucire 50/13), Lauroyl macrogol-32 glycerides, Lauroyl polyoxyl-32 glycerides, Lauroyl polyoxylglycerides, Caprylocaproyl macrogol glycerides (Labrasol), Polyoxyethylene (20) sorbitan monooleate, (Polysorbate 80/ Tween 80), Polyoxyethylene (20) sorbitan monolaurate (Polysorbate 20/ Tween 20), polyglycerol (polyglyceryl oleate: Plural™ Oleique CC497) propylene glycol (propylene glycol monocaprylate: Capryol™ 90, propylene glycol monolaurate: Lauroglycol 90), polyoxyethylene glycols (PEG-8 stearate: Mirj 45, PEG- 40 stearate: Mirj® 52, PEG-15 hydroxystearate: Solutol® HS15), sorbitan or monoanhydrosorbitol (sorbitan monooleate: Span® 80, sucrose (sucrose monopalmitate: Surfhope® D-1616), Lutrol E 300, Transcutol HP, Transcutol P, Soyabean oil, Labrafac PG, Milyol 840, Pluronic L44, Pluronic L64, Polaxamer 188, and the like or combinations thereof.
The amount of surface stabilizers in the pharmaceutical composition comprising pazopanib preferably range from about 2 % to about 10 % of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form.
Suitable viscosity modifying agents are excipients that are capable of stabilizing the nanoparticles by increasing the viscosity of the composition 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, lactose monohydrate, saccharose, hydrolyzed starch (maltodextrin) or combinations thereof. The amount of viscosity modifying agents in the pharmaceutical composition comprising pazopanib preferably range from about 4 % to about 20 % of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form.
Suitable polymers according to the present invention, may comprise one or more hydrophilic polymers, but not limited to, cellulose derivates like hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose (hypromellose), methylcellulose polymers hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene and carboxymethyl hydroxyethylcellulose; 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, or modified starch derivatives and copolymers.
The amount of polymers in the pharmaceutical composition comprising pazopanib preferably range from about 2 % to about 15 % of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form. Suitable disintegrants or super disintegrants include, but are not limited to, agar-agar, calcium carbonate, microcrystalline 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, polyvinyl pyrollidone, 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 or mixtures thereof. The amount of disintegrants in the pharmaceutical compositions preferably range from about 5 % w/w to about 30 % w/w, of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form.
Suitable glidants, anti-adherents and lubricants according to the present invention include, but are not limited to, stearic acid and pharmaceutically acceptable salts or esters thereof (for example, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate or other metallic stearate), talc, 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 alumino metasilicate), 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., Piano, Tex. USA), a pyrogenic silicon dioxide (CAB-O-SIL, Cabot Co., Boston, Mass. USA), or combinations thereof.
The amount of glidants, anti-adherants and lubricants in the pharmaceutical composition comprising pazopanib preferably range from about 0.25 % to about 5 % of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form. Suitable channeling agents according to the present invention, include, but are not limited to, sodium chloride, sugars, polyols and the like or mixtures thereof.
The amount of channeling agents in the pharmaceutical composition comprising pazopanib preferably range from about 0.5 % to about 10% of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form.
Suitable binders may also 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 carboxymethyl cellulose, dextrin, gelatin, gum arabic, guar gum, tragacanth, sodium alginate, or mixtures thereof or any other suitable binder.
The amount of binder in the pharmaceutical compositions preferably range from about 5 % w/w to about 20 % w/w, of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form. Suitable carriers, diluents or fillers for use, in the pharmaceutical composition of the present invention may comprise one or more, but not limited to lactose (for example, spray-dried lactose, a-lactose, β-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), hydroxypropylcellulose, L-hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC), methylcellulose polymers (such as, for example, Methocel A, Methocel A4C, Methocel Al 5C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, starches or modified starches (including potato starch, corn starch, maize starch and rice starch) or mixtures thereof.
The amount of carriers, diluents or fillers in the pharmaceutical compositions preferably range from about 15 % w/w to about 60 % w/w of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form. Suitable anti-caking additives that may also be incorporated in the low dose pharmaceutical composition include, but are not limited to, calcium silicate, magnesium silicate, silicon dioxide, colloidal silicon dioxide, talc, or combinations thereof.
Suitable anti-microbial agents or preservatives that may also be incorporated in the low dose pharmaceutical composition 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, or combinations thereof.
Suitable sweetening agent or taste-masking agents that may also be incorporated in the low dose pharmaceutical composition 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, stevside sodium cyclamate, eugenylformate aldehyde flavorings or combinations thereof.
Suitable flavors that may also be incorporated in the low dose pharmaceutical composition 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, cacao/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 and ginger or combinations thereof. Suitable antioxidants that may also be incorporated in the low dose pharmaceutical composition include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate salts, or combinations thereof. Suitable texture enhancers that may also be incorporated in the low dose pharmaceutical composition include, but are not limited to, pectin, polyethylene oxide, and carrageenan, or combinations thereof.
There is also provided a process for preparing a pharmaceutical composition as described herein which process comprises admixing one or more pharmaceutically acceptable excipients with pazopanib, wherein the pazopanib is preferably in a nanosized form.
The process may comprise homogenizing pazopanib and at least one excipient to produce a homogenized dispersion of the pazopanib in the excipient. Optionally, the process further comprises processing the homogenized dispersion to produce pazopanib particles. The processing may comprise milling the homogenized dispersion to produce a slurry of pazopanib particles. The pazopanib particles may be dried and blended.
Preferably, the dispersion comprises pazopanib, at least one surfactant, at least one polymer and at least one carrier, diluent or filler and purified water.
The pazopanib particles may be adsorbed by spraying the slurry onto a combination of at least one channeling agent, at least one anti-adherent and at least one disintegrant or super-disintegrant in a fluidized bed granulator.
The pazopanib particles may be compressed into unit dosage forms. Preferably, the pazopanib particles are lubricated before being compressed into unit dosage forms. The unit dosage forms may be coated.
The pazopanib particles may have an average particle size of less than about 2000 nm. The pharmaceutical composition of the present invention, may be prepared by a process which comprises: (a) preparing a dispersion of pazopanib with docusate sodium, hydroxyl propyl methylcellulose or hypromellose, sodium lauryl sulphate and lactose in purified water; (b) homogenizing the dispersion of step (a) and then nanomilling the homogenized dispersion; (c) adsorbing the nanomilled drug by spraying the nanomilled slurry on sodium chloride, magnesium stearate, silicified microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator; (d) drying and blending the granules obtained in step (c). The granules may be lubricated and finally compressed into tablets. The tablets may further be film coated to form film coated tablets.
The pharmaceutical composition, according to the present invention, may also optionally be coated. Examples of coatings comprise, but are not limited to, seal coating, enteric coating, film coating or a combination thereof.
According to an embodiment of the present invention, the pharmaceutical composition may be film coated, seal coated or enteric coated with, but not limited to, colour mix systems (such as Opadry colour mix systems), Aqueous Acrylic Enteric System (such as Acryl-EZE®) and Kollicoat® Protect.
Preferably, the pharmaceutical composition, according to the present invention, may be film coated.
The amount of film coating system in the pharmaceutical compositions preferably range from about 2 % w/w to about 6 % w/w, of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form.
Suitable seal coating agents that may be incorporated in the pharmaceutical composition are film forming polymeric materials, such as but not limited to, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, methylcellulose, carboxymethyl cellulose, hypromellose, acacia or gelatin to increase adherence and coherence of the seal coat.
The amount of seal coating system in the pharmaceutical compositions preferably range from about 1 % w/w to about 3 % w/w, of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form.
Preferably, pharmaceutically acceptable opacifier may be used in the pharmaceutical composition of the present invention, which comprises titanium dioxide. The amount of opacificer in the pharmaceutical composition comprising pazopanib preferably range from about 1 % to about 4 % of the total weight of the composition, wherein the pazopanib is preferably in a nanosized form.
Preferably, the pharmaceutical composition of the invention comprises one or more surfactants, binders, disintegrants, lubricants, and optionally one or more channeling agents.
More preferably, the pharmaceutical composition of the invention comprises pazopanib nanoparticles in an amount of from 25% to 60% w/w, one or more surfactants present in an amount of from about 2% to about 10 % w/w, one or more binders in an amount of from about 5% to about 20% w/w, one or more disintegrants present in an amount of from about 5% to about 30% w/w, and optionally one or more channeling agents present in an amount of from about 0.5% to about 10% w/w.
The pharmaceutical composition of the present invention, may further comprise at least one additional active ingredient such as, but not limited to, MEK inhibitor, topoisomerase inhibitor, EGFR inhibitor, anti-CTLA4 antibody, DLL4 antagonist, anti-HMW-MAA antibody, peginterferon alfa-2a, dihydroorotate dehydrogenase inhibitor, AKT inhibitor compounds, 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 or combinations thereof. Preferably, the pharmaceutical composition of the present invention, may further comprise at least one additional active ingredient such as, but not limited to, cisplatin, gemcitabine, temsirolimus, paclitaxel, topotecan, lapatinib, nivolumab, crizotimib, and ifosfomide and the like and combinations thereof.
The present invention further provides a method of treating advanced renal cell carcinoma and advance soft tissue sarcoma, the method comprising: administering a therapeutically effective amount of a pharmaceutical composition comprising pazopanib to a patient in need thereof, wherein the pazopanib is preferably in a nanosized form. The present invention also provides the use of a pharmaceutical composition comprising pazopanib according to the present invention in the manufacture of a medicament for the treatment of advanced renal cell carcinoma and advance soft tissue sarcoma, wherein the pazopanib is preferably in a nanosized form.
The present invention also provides a pharmaceutical composition comprising pazopanib according to the present invention for use in treatment of advanced renal cell carcinoma and advance soft tissue sarcoma, wherein the pazopanib is preferably in a nanosized form.
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.
Example 1:
Figure imgf000021_0001
13. Opadry Grey 6.0-36.0
14. Purified Water q.s.
Total weight 246.0-1476.0
Process:
A) Drug Slurry Preparation:
1) Docusate sodium, hydroxypropyl methylcellulose, lactose and sodium lauryl sulphate were dissolved in water.
2) Pazopanib was dispersed in the solution obtained in step (1) and then milled to form a slurry.
B) Granulation:
3) The drug slurry obtained in step (2) was sprayed on lactose and crospovidone to obtain granules.
C) Blending and Lubrication:
4) The dried granules obtained in step (3) were blended with crospovidone, silicified microcrystalline cellulose and sodium chloride.
5) The blended granules obtained in step (4) were lubricated with magnesium stearate.
D) Compression and Coating:
6) The lubricated granules obtained in step (5) were compressed into tablets and coated with Opadry grey.
Example 2:
Figure imgf000022_0001
3. Hydroxypropyl methylcellulose 12.5
4. Docusate Sodium 1.25
5. Lactose Monohydrate 12.5
6. Purified water q.s
Dry Mix
7. Lactose Monohydrate 25.0
8. Crospovidone 12.5
Blending and Lubrication
9. Sodium Chloride 7.5
10. Crospovidone 5.0
11. Silicified Microcrystalline Cellulose 49.95
12. Magnesium Stearate 2.0
Total Weight 240.0
Coating
13. Opadry Grey 6.0
14. Purified Water q.s.
Total weight 246.0
Process:
A) Drug Slurry Preparation:
1) Docusate sodium, hydroxypropyl methylcellulose, lactose and sodium lauryl sulphate were dissolved in water.
2) Pazopanib was dispersed in the solution obtained in step (1) and then milled to form a slurry.
B) Granulation:
3) The drug slurry obtained in step (2) was sprayed on lactose and crospovidone to obtain granules. C) Blending and Lubrication:
4) The dried granules obtained in step (3) were blended with crospovidone, silicified microcrystalline cellulose and sodium chloride.
5) The blended granules obtained in step (4) were lubricated with magnesium stearate. D) Compression and Coating:
6) The lubricated granules obtained in step (5) were compressed into tablets and coated with Opadry grey.
Example 3:
Figure imgf000024_0001
Total Weight 264
Coating
14. Opadry Grey 7.0
15. Purified Water q.s.
Total weight 271
Process:
A) Drug Slurry Preparation:
1) Docusate sodium, hydroxypropyl methylcellulose, lactose and sodium lauryl sulphate were dissolved in water.
2) Cremophor ELP was dissolved in the solution obtained in step (1).
3) Pazopanib was dispersed in the solution obtained in step (2) and then milled to form a slurry.
B) Granulation:
4) The drug slurry obtained in step (3) was sprayed on lactose and crospovidone to obtain granules.
C) Blending and Lubrication:
5) The dried granules obtained in step (4) were blended with crospovidone, silicified microcrystalline cellulose and sodium chloride.
6) The blended granules obtained in step (5) were lubricated with magnesium stearate. D) Compression and Coating:
7) The lubricated granules obtained in step (6) were compressed into tablets and coated with Opadry grey. Example 4:
Figure imgf000026_0001
Process:
A) Drug Slurry Preparation: 1) Docusate sodium, hydroxypropyl methylcellulose, lactose and sodium lauryl sulphate were dissolved in water. 2) Labrasol was dissolved in the solution obtained in step (1).
3) Pazopanib was dispersed in the solution obtained in step (2) and then milled to form a slurry.
B) Granulation:
4) The drug slurry obtained in step (3) was sprayed on lactose and crospovidone to obtain granules.
C) Blending and Lubrication:
5) The dried granules obtained in step (4) were blended with crospovidone, silicified microcrystalline cellulose and sodium chloride.
6) The blended granules obtained in step (5) were lubricated with magnesium stearate. D) Compression and Coating:
7) The lubricated granules obtained in step (6) were compressed into tablets and coated with Opadry grey.
Example 5
Figure imgf000027_0001
9. Sodium Chloride 7.5-45.0
10. Crospovidone 5.0-30.0
11. Silicified Microcrystalline Cellulose 49.95-299.7
12. Magnesium Stearate 2.0-12.0
Total Weight 240-1440
Process:
A) Drug Slurry Preparation:
1) Docusate sodium, hydroxypropyl methylcellulose, lactose and sodium lauryl sulphate were dissolved in water.
2) Pazopanib was dispersed in the solution obtained in step (1) and then milled to form a slurry.
B) Granulation:
3) The drug slurry obtained in step (2) was sprayed on lactose and crospovidone to obtain granules.
C) Blending and Lubrication:
4) The dried granules obtained in step (3) were blended with crospovidone, silicified microcrystalline cellulose and sodium chloride.
5) The blended granules obtained in step (4) were lubricated with magnesium stearate.
D) Compression:
6) The lubricated granules obtained in step (5) were compressed into dispersible tablets. Example 6
Figure imgf000028_0001
2. Sodium Lauryl Sulphate 3.45
3. Hydroxypropyl methylcellulose 12.5
4. Docusate Sodium 1.25
5. Lactose Monohydrate 12.5
6. Purified water q.s
Dry Mix
7. Lactose Monohydrate 25.0
8. Crospovidone 12.5
Blending & Lubrication
9. Sodium Chloride 7.5
10. Crospovidone 5.0
11. Silicified Microcrystalline Cellulose 49.95
12. Magnesium Stearate 2.0
Total Weight 240.0
Process:
A) Drug Slurry Preparation:
1) Docusate sodium, hydroxypropyl methylcellulose and sodium lauryl sulphate were dissolved in water.
2) Pazopanib was dispersed in the solution obtained in step (1) and then milled to form a slurry.
B) Granulation:
3) The drug slurry obtained in step (2) was sprayed on lactose and crospovidone to obtain granules. C) Blending and Lubrication:
4) The dried granules obtained in step (3) were blended with crospovidone, silicified microcrystalline cellulose and sodium chloride. 5) The blended granules obtained in step (4) were lubricated with magnesium stearate.
D) Compression:
6) The lubricated granules obtained in step (5) were compressed into dispersible tablets. Example 7
Figure imgf000030_0001
Process:
A) Drug Slurry Preparation:
1) Docusate sodium, hydroxypropyl methylcellulose and sodium lauryl sulphate were dissolved in water. 2) Cremophor ELP was dissolved in the solution obtained in step (1).
3) Pazopanib was dispersed in the solution obtained in step (2) and then milled to form a slurry.
B) Granulation:
4) The drug slurry obtained in step (3) was sprayed on lactose and crospovidone to obtain granules.
C) Blending and Lubrication:
5) The dried granules obtained in step (4) were blended with crospovidone, silicified microcrystalline cellulose and sodium chloride.
6) The blended granules obtained in step (5) were lubricated with magnesium stearate. D) Compression:
7) The lubricated granules obtained in step (6) were compressed into dispersible tablets Example 8
Figure imgf000031_0001
10. Sodium Chloride 7.5
11. Crospovidone 5.0
12. Silicified Microcrystalline Cellulose 49.95
13. Magnesium Stearate 2.0
Total Weight 264
Process:
A) Drug Slurry Preparation:
1) Docusate sodium, hydroxypropyl methylcellulose, and sodium lauryl sulphate were dissolved in water.
2) Labrasol was dissolved in the solution obtained in step (1).
3) Pazopanib was dispersed in the solution obtained in step (2) and then milled to form a slurry.
B) Granulation:
4) The drug slurry obtained in step (3) was sprayed on lactose and crospovidone to obtain granules.
C) Blending and Lubrication:
5) The dried granules obtained in step (4) were blended with crospovidone, silicified microcrystalline cellulose and sodium chloride.
6) The blended granules obtained in step (5) were lubricated with magnesium stearate. D) Compression:
7) The lubricated granules obtained in step (6) were compressed into dispersible tablets. Example 9
Figure imgf000033_0001
Process:
A) Drug Slurry Preparation: 1) Docusate sodium, hydroxypropyl methylcellulose and sodium lauryl sulphate were dissolved in water.
2) Pazopanib was dispersed in the solution obtained in step (1) and then milled to form a slurry.
B) Granulation:
3) The drug slurry obtained in step (2) was sprayed on lactose and crospovidone to obtain granules. C) Blending and Lubrication:
4) The dried granules obtained in step (3) were blended with crospovidone, silicified microcrystalline cellulose and sodium chloride
5) The blended granules obtained in step (4) were lubricated with magnesium stearate. D) Compression:
6) The lubricated granules obtained in step (5) were compressed to produce dispersible tablets.
Example 10
Figure imgf000034_0001
Process:
A) Drug Slurry Preparation:
1) Docusate sodium, hydroxypropyl methylcellulose and sodium lauryl sulphate were dissolved in water. 2) Pazopanib was dispersed in the solution obtained in step (1) and then milled to form a slurry.
B) Granulation:
3) The drug slurry obtained in step (2) was sprayed on lactose and crospovidone to obtain granules.
C) Blending and Lubrication: 4) The dried granules obtained in step (3) were blended with crospovidone, silicified microcrystalline cellulose and sodium chloride
5) The blended granules obtained in step (4) were lubricated with magnesium stearate.
D) Compression:
6) The lubricated granules obtained in step (5) were compressed to produce 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 preferred embodiments and 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

CLAIMS:
1. A pharmaceutical composition comprising pazopanib and one or more pharmaceutically acceptable excipients.
2. The pharmaceutical composition according to claim 1 comprising pazopanib in the form of nanoparticles.
3. The pharmaceutical composition according to claim 2, wherein the nanoparticles have an average particle size of less than about 2000 nanometers.
4. The pharmaceutical composition according to claim 2 or 3, wherein the nanoparticles have an average particle size of less than about 1000 nanometers.
5. The pharmaceutical composition according to any preceding claim comprising pazopanib in the form of a pharmaceutically acceptable derivative thereof.
6. The pharmaceutical composition according to claim 5, wherein the pharmaceutically acceptable derivative is selected from the group comprising of a salt, solvate, complex, hydrate, isomer, ester, tautomer, anhydrate, enantiomer, polymorph or prodrug and a combination thereof.
7. The pharmaceutical composition according to claim 5 or 6, wherein pazopanib is in the form of pazopanib hydrochloride.
8. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutically acceptable excipients comprise disintegrants or super disintegrants, carriers, diluents, fillers, plasticizers, binders, glidants, anti adherants, lubricants, solvents, sweetening agents, taste-masking agents, flavoring agents, anti-caking agents, anti-microbial agents, preservatives, antifoaming agents, emulsifiers, surfactants, buffering agents, coloring agents, viscosity modifying agents, polymers, channeling agents and opacifiers or any combination thereof.
9. The pharmaceutical composition according to claim 8, wherein the composition comprises one or more surfactants optionally in an amount of from about 2% to about 10% of the total weight of the composition.
10. The pharmaceutical composition according to claim 8 or 9, wherein the composition comprises one or more viscosity modifying agents, optionally in an amount of from about 4% to about 20% of the total weight of the composition.
11. The pharmaceutical composition according to claim 8, 9 or 10, wherein the composition comprises at least one polymer, optionally in an amount of from about 2% to about 15%) of the total weight of the composition.
12. The pharmaceutical composition according to any preceding claim, wherein the composition is in an oral dosage form.
13. The pharmaceutical composition according to any preceding claim, wherein the pharmaceutical composition is for once a day administration.
14. The pharmaceutical composition according to claim 12 or 13, wherein the oral dosage form is in the form of a tablet, a coated tablet, powder, powder for reconstitution, pellets, beads, a mini-tablet, a multilayer tablet, a bilayered tablet, a tablet-in-tablet, a pill, a micro-pellet, a small tablet unit, capsules, MUPS (multiple unit pellet system), a disintegrating tablet, a dispersible tablet, granules, microspheres, multi-particulates, a capsule (optionally 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 multi- particulates), a sachet (optionally 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 multi-particulates) or sprinkles.
15. The pharmaceutical composition according to any preceding claim, wherein the pharmaceutical composition comprises less than 800 mg of pazopanib.
16. The pharmaceutical composition according to any preceding claim, further comprising at least one additional active ingredient selected from the group comprising: an MEK inhibitor, a topoisomerase inhibitor, an EGFR inhibitor, an anti- CTLA4 antibody, an DLL4 antagonist, an anti-HMW-MAA antibody, peginterferon alfa-2a, a dihydroorotate dehydrogenase inhibitor, an AKT inhibitor compound, a tyrosine kinase inhibitor, an inhibitor of CDK4, a PI3K beta inhibitor, a MAPK pathway inhibitor, an interleukin-2, a c-Met antagonist, an Hsp90 inhibitor, a Wnt pathway inhibitor, a pyruvatedehydrogenase kinase inhibitor, an ERK pathway inhibitor, an anti-ErbB3 antibody, an MDM2 inhibitor, cisplatin, gemcitabine, temsirolimus, paclitaxel, topotecan, lapatinib, nivolumab, crizotimib, ifosfomide and combinations thereof.
17. A process for preparing a pharmaceutical composition according to any preceding claim which process comprises admixing one or more pharmaceutically acceptable excipients with pazopanib.
18. The pharmaceutical composition according to claim 1 to 16, for use in treating advanced renal cell carcinoma and advanced soft tissue sarcoma.
19. A method of treating advanced renal cell carcinoma and advanced soft tissue sarcoma, wherein the method comprises administering a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1 to 16 to a patient in need thereof.
20. Use of a pharmaceutical composition according to any one of claims 1 to 16, in the manufacture of a medicament for the treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma.
21. A pharmaceutical composition substantially as described herein with reference to the examples.
22. A process for the preparation of a pharmaceutical composition as substantially described herein with reference to the examples.
PCT/GB2015/050902 2014-03-28 2015-03-26 Pharmaceutical composition comprising pazopanib WO2015145157A1 (en)

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