Improved formulations of cabozantinib

Abstract

The present invention relates to pharmaceutical compositions of cabozantinib suitable for oral administration, and more particularly to solid oral compositions comprising cabozantinib fumarate, wherein such compositions comprise a certain amount of microcrystalline cellulose and at least one sugar alcohol The present invention also provides manufacturing processes thereof and use of the said inventive compositions for the prevention, treatment or prophylaxis of disorders in human patients in need thereof.

Description

[0001] IMPROVED FORMULATIONS OF CABOZANTINIB

[0002] CROSS REFERENCE

[0003] The present application claims priority to Indian patent application no. 202411022271, filed on March 22, 2024.

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to pharmaceutical compositions of cabozantinib suitable for oral administration, and more particularly to solid oral compositions comprising cabozantinib fumarate, wherein such compositions comprise a certain amount of microcrystalline cellulose and at least one sugar alcohol. The present invention also provides manufacturing processes thereof and use of the said inventive compositions for the prevention, treatment or prophylaxis of disorders in human patients in need thereof.

[0006] BACKGROUND OF THE INVENTION

[0007] Cabozantinib (S)-malate is chemically described as N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)- N'-(4-fluorophenyl) cyclopropane- 1,1 -dicarboxamide, (2S)-hydroxybutanedioate and is a multiple receptor tyrosine kinase inhibitor. Examples of disorders that may be treated with cabozantinib include but are not limited to renal cell carcinoma (RCC), hepatocellular carcinoma (HCC) and medullary thyroid cancer (MTC).

[0008] Cabozantinib is currently marketed under the brand names CABOMETYX® and COMETRIQ®. CABOMETYX® is available in the form of film-coated oral tablets containing equivalent to 20 mg, 40 mg and 60 mg of cabozantinib; and COMETRIQ® is available in the form of oral capsules containing equivalent to 20 mg and 80 mg of cabozantinib.

[0009] Cabozantinib is characterized as a Biopharmaceutical Classification System (BCS) class II compound, which means that it has low aqueous solubility and high permeability. Cabozantinib is practically insoluble in water and hence, it has been difficult to formulate and deliver oral dosage forms which exhibit good bioavailability.

[0010] Oral administration of poorly soluble active ingredients is often problematic. Cabozantinib is disclosed in WO2019148044A1. WO2022115464A1 and US20230270736A1 disclose pharmaceutical compositions comprising an amorphous solid dispersion of cabozantinib, wherein the compositions exhibit enhanced bioavailability compared to the currently marketed or commercially available formulations.

[0011] Though, the amorphous form of a drug has a higher dissolution rate in body fluids than its crystalline form due to the disordered arrangement of its molecules. However, the instability of the molecules in the amorphous drug is easy to transform into the crystalline state of the drug, which becomes an obstacle to the amorphous preparation of the drug.

[0012] Chinese patent application CN115487157A discloses a tablet formulation comprising cabozantinib malate, a filler, an adhesive, a disintegrating agent, a lubricant, a glidant and a coating agent, wherein the lubricant is sodium stearyl fumarate.

[0013] There still remains a need for stable pharmaceutical compositions of cabozantinib suitable for oral administration, which while providing suitable release and dissolution of the active ingredient, also exhibits properties which enables the manufacture of the dosage form in industrial scale viable and cost-effective.

[0014] An oral dosage form comprising cabozantinib fumarate as the active ingredient is neither available in the market, nor is it reported anywhere.

[0015] SUMMARY OF THE INVENTION

[0016] The present invention provides stable pharmaceutical compositions of cabozantinib, suitable for oral administration, which exhibit improved solubility and bioavailability; and wherein the composition has comparable in-vitro dissolution profile similar to that of commercially available formulation (CABOMETYX®).

[0017] Another object of the present invention is to provide stable, pharmaceutical compositions comprising cabozantinib fumarate as the active ingredient and one or more pharmaceutically acceptable excipients. Another object of the present invention is to provide stable, pharmaceutical compositions comprising a) cabozantinib fumarate, b) microcrystalline cellulose, c) at least one sugar alcohol and d) one or more pharmaceutically acceptable excipients.

[0018] Another object of the present invention is to provide stable, pharmaceutical compositions comprising cabozantinib fumarate as the active ingredient by a manufacturing process which is consistent and therefore feasible for industrial production, while maintaining stability and pharmaceutical equivalence to the reference listed drug.

[0019] Yet another object present invention is to provide a method of treating proliferative disorder comprising administering to a subject in need thereof a therapeutically effective amount of the solid dosage form of any of the aspects and embodiments described herein.

[0020] DETAILED DESCRIPTION OF THE INVENTION

[0021] The present invention relates to stable pharmaceutical compositions of cabozantinib, suitable for oral administration, which exhibit improved solubility and bioavailability; and wherein the composition has comparable in-vitro dissolution profile similar to that of commercially available formulation (CABOMETYX®).

[0022] The term “cabozantinib or a pharmaceutically acceptable salt thereof’ is inclusive of a solvent, tautomer or cocrystal form of cabozantinib or a pharmaceutically acceptable salt thereof.

[0023] The term “solubility” means solubility of cabozantinib or its pharmaceutically acceptable salts in media such as water, buffer, gastrointestinal simulated fluid, gastrointestinal fluid and the like.

[0024] The term “bioavailability” refers to the amount of a drug, i.e. cabozantinib or salt thereof which is absorbed in the body and is able to have an effect. For example, bioavailability may refer to the fraction of drug in systemic circulation following administration to a subject or patient under fed or fasted state.

[0025] The term “in vivo” in general means in the living body of a plant or animal, whereas the term “in vitro” generally means outside the body and in an artificial environment.

[0026] “Bioequivalence” refers to the absence of a significant difference between the bioavailability, i.e., the mean ratio of AUC (over 24 hours) and the mean ratio of Cmax is within 80% to 125% between two pharmaceutical drug products (e.g., a test composition and a reference composition) over the course of a period of time, at the same dose and under the same conditions. The determination of whether or not a test composition is bioequivalent to a reference composition is determined by performing a study, referred to as a bioequivalence or comparative bioavailability study, in a group of subjects under controlled conditions.

[0027] As used herein, the term “stable” is defined as no more than about 5% loss of cabozantinib under typical commercial storage conditions. In certain embodiments, the compositions of the present invention will have no more than about 3% loss of cabozantinib, more preferably, no more than about 2% loss of cabozantinib, under typical commercial storage conditions. The composition retains at least about 95% of the potency of cabozantinib after storing the composition at 40° C. and 75% relative humidity for at least three months. In certain aspects, the term “stable” refers to chemical stability, wherein not more than 2% w / w of total related substances are formed on storage at accelerated conditions of stability at 40° C. and 75% relative humidity or at 25° C. and 60% relative humidity for a period of at least three months or to the extent necessary for use of the composition.

[0028] In one aspect, the present invention provides stable, pharmaceutical compositions comprising cabozantinib fumarate as the active ingredient and one or more pharmaceutically acceptable excipients.

[0029] As used herein “cabozantinib fumarate” refers to the fumarate salt of cabozantinib. In principle, any crystalline form or amorphous form of cabozantinib fumarate may be used for the preparation of the oral dosage forms disclosed herein.

[0030] The pharmaceutical compositions of present invention comprise about 10 mg to about 200 mg of cabozantinib. An embodiment of the present invention comprise cabozantinib in the range of about 20% to about 50% by weight on the basis of the total weight of the composition.

[0031] An “oral dosage form” and an “oral pharmaceutical composition” are used interchangeably herein.

[0032] As further described herein, the present invention provides solid dosage forms comprising cabozantinib fumarate as the active ingredient and one or more pharmaceutically acceptable excipients.

[0033] A “solid dosage form” of the present invention is a pharmaceutically acceptable solid dosage form that is safe for oral administration to humans, where all excipients in the dosage form are pharmaceutically acceptable for use in oral formulations, in other words safe for human ingestion. In frequent embodiments, the solid dosage form is a tablet.

[0034] Solid dosage forms include, but are not limited to, immediate release tablets and capsules, controlled-release (CR) tablets and capsules, fast-dissolve dosage forms, chewable dosage forms, sachets, etc. Preferably, the dosage form of the present invention is in the form of a tablet, including monolayer or bilayer tablets.

[0035] In frequent embodiments of each of the aspects described herein, the solid dosage form of the invention is in the form of a tablet. In some embodiments, the tablet is film coated. In some embodiments, the tablet is a monolayer tablet. In other embodiments, the tablet is a bilayer tablet.

[0036] The term "excipient" means a pharmacologically inactive component such as a diluent, lubricant, surfactant, carrier, or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well, as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient. Co-processed excipients are also covered under the scope of present invention.

[0037] In another embodiment of the present invention there is provided a stable solid oral pharmaceutical composition comprising cabozantinib with one or more pharmaceutically acceptable excipient like diluent, binder, disintegrant, surfactant, wetting agent, lubricant, glidants, surfactants, plasticizers, stabilizing agents, pH adjusting agents, coloring agent, sweetening agents, flavoring agent, antioxidants and combinations thereof.

[0038] In another aspect the present invention provides a stable, pharmaceutical compositions comprising a) cabozantinib fumarate, b) microcrystalline cellulose, c) at least one sugar alcohol and d) one or more pharmaceutically acceptable excipients.

[0039] The present inventors have surprisingly found that the improved pharmaceutical compositions of the present invention involve the use of a lower wt % of microcrystalline cellulose and the use of at least one sugar alcohol in combination with the microcrystalline cellulose, as diluent.

[0040] Unless otherwise recited or required by the context, percent and "%" refer to percent by weight of the composition. In this specification the terms “diluent” and “diluents” are intended to be interpreted in the context of pharmaceutical formulation science. Accordingly, in addition to microcrystalline cellulose, other diluent is selected from among sugar alcohols.

[0041] Suitable sugar alcohols include, but are not limited to ethylene glycol, glycerol , erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, polyglycitol and combinations thereof.

[0042] According to one preferred embodiment, the sugar alcohol is isomalt.

[0043] The pharmaceutical compositions of present invention comprise diluent in the range of about 10% to about 90% by weight of the total weight of the composition, wherein microcrystalline cellulose makes up from 10 to 50 wt % of the total weight of the diluents in the composition and the sugar alcohol makes up from 10 to 70% of the total weight of the diluents in the composition.

[0044] In an embodiment of the present invention, microcrystalline cellulose makes up from 10 to 30 wt % and the sugar alcohol makes up from 20 to 40% by weight of the total weight of the composition.

[0045] In a subclass of any of the above embodiments are compositions comprising 0.5 - 15 % of disintegrant. As used herein, a " disintegrant " refers to one or more pharmaceutically acceptable excipient(s) which is added to the pharmaceutical composition to cause its disintegration to support the release of the active ingredient from the pharmaceutical composition. Examples of disintegrants include croscarmellose sodium, cross-linked polyvinylpyrollidone, sodium starch glycolate or any combination thereof.

[0046] According to one preferred embodiment, the disintegrant comprises croscarmellose sodium.

[0047] In a subclass of any of the above embodiments are compositions comprising 0.5 - 8% of a binder. As used herein, a "binder" refers to one or more pharmaceutically acceptable excipient(s) that imparts enhanced cohesion by binding the active ingredient and the excipients together in a mixture. Examples of binders include polyvinyl pyrrolidone (PVP), polyvinyl acetate, polyvinyl alcohol, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC) and combinations thereof. According to one preferred embodiment, the binder comprises hydroxypropylcellulose (HPC).

[0048] In a subclass of any of the above embodiments are compositions comprising 0.2 - 3% of lubricant / glidants. Examples of lubricants / glidants include colloidal silicon dioxide (Aerosil®), stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like and mixtures thereof. According to one preferred embodiment, the lubricant comprises magnesium stearate.

[0049] In one embodiment of the present invention, there is provided pharmaceutical composition comprising (a) at least 25 %, preferably at least 30 % of cabozantinib fumarate; 10 - 40 % of microcrystalline cellulose; 10 - 40 % of a sugar alcohol; 0.5 - 15 % of a disintegrant; 0.5 - 10 % of a binder; and 0.2 - 5 % of a lubricant.

[0050] In yet another aspect the present invention provides stable, pharmaceutical compositions comprising cabozantinib fumarate as the active ingredient and one or more pharmaceutically acceptable excipients, wherein the composition provides excellent tabletability of the tableting mass, enabling manufacture of the tablets in large industrial scale.

[0051] The pharmaceutical composition of the invention can be, for example, in the form of granules, pellets, capsules or tablets. Such compositions can be prepared, for example, by wet granulation, dry granulation or dry compression. In a preferred embodiment, the pharmaceutical composition of the invention is in the form of a coated or uncoated tablet. According to one preferred embodiment, the tablet is prepared by wet granulation.

[0052] According to one embodiment, the tablet comprises an intragranular part and an extragranular part. According to still another embodiment, the intragranular part comprises cabozantinib fumarate, the diluents, the binder and a portion of the disintegrant, and the extragranular part comprises the lubricant and the rest of the disintegrant.

[0053] In accordance with one embodiment of the invention the process for manufacturing a pharmaceutical composition of the invention is characterized by the steps of (a) mixing the active ingredient (cabozantinib fumarate), diluents, binder and a first portion of the disintegrant; (b) granulating the mixture using water as granulation liquid; (c) drying the wet granules; (d) mixing lubricant and the rest of the disintegrant with the granules; (e) compressing the resulting mass into tablets; and, optionally, coating the tablet with one or further pharmaceutically acceptable filmcoating agent.

[0054] The tablet cores can be optionally provided with a water-soluble film coating, if desired, to facilitate tablet swallowing, to protect from direct contact with the drug substance and to improve aesthetics. Suitable film coating agents can be selected from the group of plasticizers, film-forming agents and colorants. Optionally an anti-tacking agent or opacifier can be used. The plasticizer, such as polyethylene glycol (PEG), the film- forming agent, such as hydroxypropyl methylcellulose (HPMC), and the colorants, such as ferric oxide and titanium dioxide, are combined with filmcoating liquids, preferably water, to result in a homogeneous coating suspension which is brought up, preferably sprayed, on the tablets in a suitable coating device, such as for example a perforated drum coater.

[0055] Suitable film coatings are also commercially available as concentrates that may be diluted with water and optionally a cellulose ether such as HPMC and a plasticiser such as polyethylene glycol prior to application to the composition.

[0056] In accordance with one embodiment of the invention, the pharmaceutical composition of the present invention has comparable in-vitro dissolution profile similar to that of CABOMETYX® tablets.

[0057] In yet another embodiment, the invention provides a solid dosage form, wherein the dosage form: (a) provides a mean fasted AUC in the range of 80% to 125% of the mean fasted AUC for a control immediate release (IR) oral tablet containing an equivalent amount of cabozantinib after administration of a single oral dose to a subject; or (b) provides a mean fasted Cmax in the range of 80% to 125% of the mean fasted Cmax for a control immediate release (IR) oral tablet containing an equivalent amount of cabozantinib after administration of a single oral dose to a subject; or (c) both (a) and (b).

[0058] In another aspect, the invention provides a method of treating proliferative disorder comprising administering to a subject in need thereof a therapeutically effective amount of the solid dosage form of any of the aspects and embodiments described herein.

[0059] As used herein, the term “therapeutically effective amount” means that amount that is expected to elicit the biological or medical response that is being sought by a clinician.

[0060] The proliferative disorder may be cancer. Examples of such proliferative disorders may include, but are not limited to, leukemias such as acute lymphocytic leukemia (or acute lymphoblastic leukemia), acute myeloid leukemia ( or acute myelogenous leukemia), chronic lymphocytic leukemia (or chronic lymphoblastic leukemia), chronic myeloid leukemia (or chronic myelogenous leukemia); age-related macular degeneration and diabetic retinopathy, anal and oral cancers, angiosarcoma, basal cell carcinoma and squamous cell carcinoma, bladder cancer, brain cancer, breast cancer, cancer of the central nervous system, cervical, cervix uteri cancer, choriocarcinoma, colon cancer, gastrointestinal stromal tumor, corpus uteri cancer, esophageal cancer, Ewing’s Sarcoma, eye or ocular cancer, head and neck cancer, hemangioendothelioma, hemangiomas and lymphangiogenesis, Kaposi’s Sarcoma, larynx cancer, liver cancer, lung cancer, lymphoma, mouth / pharynx cancer, multiple myeloma; cardiac hypertrophy, neuroblastoma, neurofibromatosis, ovary cancer, pancreatic cancer, prostate cancer, rectal cancer, renal cancer, rhabdomyosarcoma, skin melanoma, small cell lung cancer, stomach cancer, testis cancer, throat cancer, tuberous sclerosis, and Wilms Tumor.

[0061] In certain embodiments, the proliferative disorder may be renal cell carcinoma (RCC). In certain embodiments, the proliferative disorder may be hepatocellular carcinoma (HCC). In certain embodiments, the proliferative disorder may be differentiated thyroid cancer (DTC). In some embodiments, the proliferative disorder may be medullary thyroid cancer (MTC).

[0062] The present disclosure will be further illustrated and / or demonstrated in the following Examples, which are given for illustration / demonstration purposes only and are not intended to limit the disclosure in any way.

[0063] EXAMPLES

[0064] Example 1: Film-coated tablet composition of cabozantinib fumarate

[0065] Component %w / w

[0066] Cabozantinib fumarate 30.5

[0067] Microcrystalline cellulose 25.0

[0068] Isomalt 29.5

[0069] Croscarmellose Sodium 10.0

[0070] Low substituted hydroxypropyl cellulose 3.0

[0071] Talc 0.5

[0072] Anhydrous silicon dioxide 0.5

[0073] Magnesium stearate 1.0

[0074] Purified water Q.s.

[0075] Procedure:

[0076] 1. Cabozantinib fumarate, microcrystalline cellulose and isomalt were co-sifted. 2. Low substituted hydroxypropyl cellulose and a portion of croscarmellose sodium were cosifted.

[0077] 3. Sifted materials obtained in step 1) and 2) were loaded into blender for mixed.

[0078] 4. The blend mass obtained in step 3) was granulated using water.

[0079] 5. Magnesium stearate, talc, anhydrous colloidal silicon dioxide and the remaining portion of croscarmellose sodium were sifted and mixed.

[0080] 6. Extragranular materials of step 5) were added to the granules obtained in step 5) and mixed, followed by compression and film coating.

[0081] Example 2: Film-coated tablet composition of cabozantinib fumarate

[0082] Component %w / w

[0083] Cabozantinib fumarate 28.5

[0084] Microcrystalline cellulose 27.0

[0085] Mannitol 31.5

[0086] Croscarmellose Sodium 8.0

[0087] Low substituted hydroxypropyl cellulose 3.0

[0088] Talc 0.5

[0089] Anhydrous silicon dioxide 0.5

[0090] Magnesium stearate 1.0

[0091] Purified water Q.s.

[0092] Procedure:

[0093] 1. Cabozantinib fumarate, microcrystalline cellulose and mannitol were co-sifted.

[0094] 2. Low substituted hydroxypropyl cellulose and a portion of croscarmellose sodium were cosifted.

[0095] 3. Sifted materials obtained in step 1) and 2) were loaded into blender for mixed.

[0096] 4. The blend mass obtained in step 3) was granulated using water.

[0097] 5. Magnesium stearate, talc, anhydrous colloidal silicon dioxide and the remaining portion of croscarmellose sodium were sifted and mixed.

[0098] 6. Extragranular materials of step 5) were added to the granules obtained in step 5) and mixed, followed by compression and film coating. Example 3: Film-coated tablet composition of cabozantinib fumarate

[0099] Component %w / w

[0100] Cabozantinib fumarate 31.5

[0101] Microcrystalline cellulose 21.5

[0102] Sorbitol 32.0

[0103] Croscarmellose Sodium 10.0

[0104] Low substituted hydroxypropyl cellulose 3.0

[0105] Talc 0.5

[0106] Anhydrous silicon dioxide 0.5

[0107] Magnesium stearate 1.0

[0108] Purified water Q.s.

[0109] Procedure: 1. Cabozantinib fumarate, microcrystalline cellulose and sorbitol were co-sifted.

[0110] 2. Low substituted hydroxypropyl cellulose and a portion of croscarmellose sodium were cosifted.

[0111] 3. Sifted materials obtained in step 1) and 2) were loaded into blender for mixed.

[0112] 4. The blend mass obtained in step 3) was granulated using water. 5. Magnesium stearate, talc, anhydrous colloidal silicon dioxide and the remaining portion of croscarmellose sodium were sifted and mixed.

[0113] 6. Extragranular materials of step 5) were added to the granules obtained in step 5) and mixed, followed by compression and film coating. Example 4: Film-coated tablet composition of cabozantinib fumarate

[0114] Component %w / w

[0115] Cabozantinib fumarate 30.5

[0116] Microcrystalline cellulose 38.5

[0117] Lactose 19.5

[0118] Croscarmellose Sodium 5.5

[0119] Low substituted hydroxypropyl cellulose 4.0 Talc 0.5

[0120] Anhydrous silicon dioxide 0.5

[0121] Magnesium stearate 1.0

[0122] Purified water Q.s.

[0123] Procedure:

[0124] 1. Cabozantinib fumarate, microcrystalline cellulose and sorbitol were co-sifted.

[0125] 2. Low substituted hydroxypropyl cellulose and a portion of croscarmellose sodium were cosifted.

[0126] 3. Sifted materials obtained in step 1) and 2) were loaded into blender for mixed.

[0127] 4. The blend mass obtained in step 3) was granulated using water.

[0128] 5. Magnesium stearate, talc, anhydrous colloidal silicon dioxide and the remaining portion of croscarmellose sodium were sifted and mixed.

[0129] 6. Extragranular materials of step 5) were added to the granules obtained in step 5) and mixed, followed by compression and film coating.

[0130] Example: 5 Dissolution Studies

[0131] Test tablets prepared as described in Example- 1 were subjected to dissolution testing using USP Apparatus II with paddles spinning at 75 RPM in 900ml of 0.01 N hydrochloric acid as dissolution media and the results are tabulated (Table- 1) below:

[0132] Table -1: Dissolution profile of Example- 1

[0133] The tablets exhibited desirable dissolution performance, with greater than 90% of the drug dissolved at 15 minutes as shown in Table -1 above.

[0134] Example: 6 Stability Studies Test tablets prepared as described in Example- 1 were placed on stability under accelerated conditions at 40°C / 75% RH. The samples were assessed at t=0, 1 month, 2 months, and 3 months for assay / related substances (HPLC) using suitable analytical methods, and the results are tabulated (Table-2) below: Table -2: Stability Study results of Example-1

[0135] N.D.- Not detected; BQL- Below limit of quantification.

[0136] Example?: Comparative in vitro dissolution studies (w.r.t. Test Tablet -2)

[0137] Comparative in vitro dissolution studies were performed for Test Tablets- 1 (prepared as described in Example- 1) and Test Tablets-2 (prepared as described in Example-4). Dissolution was performed in a USP Apparatus II with paddles spinning at 75 RPM in 900ml of 0.01 N hydrochloric acid as dissolution media. Results are provided in Table 3 and FIG. 1. In FIG. 1, diamonds represent the Test Tablets- 1 and squares represent Test Tablets - 2.

[0138] Table -3: Comparative in vitro dissolution data Dissolution profile presented in Table 3 and FIG. 1 demonstrates clearly that the Test Tablet - 1 (with sugar alcohol) shows improved release rate as compared to Test Product-2 (without sugar alcohol). Example 8: Comparative in vitro dissolution studies (w.r.t. Reference Product “CABOMETYX®”)

[0139] Comparative in vitro dissolution studies were performed for Test Tablets- 1 (prepared as described in Example- 1) and Reference Product “CABOMETYX®”. Dissolution was performed in a USP Apparatus II with paddles spinning at 75 RPM in 900ml of 0.01 N hydrochloric acid as dissolution media. Results are provided in Table 4 and FIG. 2. In FIG. 2, diamonds represent the Test Tablets- 1 and squares represent Reference Product.

[0140] Table -4: Comparative in vitro dissolution data

[0141] Dissolution profile presented in Table 4 and FIG. 2 demonstrates clearly that the Test Tablet - 1 shows a release rate similar to that of the Reference Product.

[0142] Example 9: Pharmacokinetic profile studies

[0143] Studies are planned to test the pharmacokinetics and bioavailability of the disclosed compositions. The study is to be an open-label, balanced, randomized, two-treatment, two sequence, two period, two way cross-over, single oral dose bioequivalence study of Cabozantinib film-coated tablets (prepared as described in Example- 1) and the Reference product (CABOMETYX®) in normal, healthy, adult, human subjects under fasting condition.

[0144] The foregoing description is given for clearness of understanding only, and no unnecessary limitations should be understood therefrom. Various modifications and alterations to this disclosure will become apparent to those skilled in the art without departing from the scope and spirit of this disclosure. This disclosure is not intended to be unduly limited by the illustrative embodiments and examples set forth herein, and such examples and embodiments are presented by way of example only.

Claims

We Claim:

1. A pharmaceutical composition, suitable for oral administration, comprising cabozantinib fumarate as the active ingredient and one or more pharmaceutically acceptable excipients.

2. A pharmaceutical composition comprising: a) 20 - 50% per weight of the composition of cabozantinib fumarate, b) 10 - 90% per weight of the composition of diluent, and c) one or more pharmaceutically acceptable excipients.

3. The pharmaceutical composition as claimed in claim 2, wherein the diluent comprises microcrystalline cellulose in combination with at least one sugar alcohol.

4. The pharmaceutical composition as claimed in claim 2, wherein microcrystalline cellulose comprises 10 to 50 wt % of the total weight of the diluents in the composition.

5. The pharmaceutical composition as claimed in claim 2, wherein the sugar alcohol comprises 10 to 70% of the total weight of the diluents in the composition.

6. The pharmaceutical composition as claimed in claim 2, wherein the sugar alcohol is selected from ethylene glycol, glycerol , erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, polyglycitol or cominations thereof.

7. The pharmaceutical composition as claimed in claim 2, wherein the disintegrant is selected from croscarmellose sodium, cross-linked polyvinylpyrollidone, sodium starch glycolate or any combination thereof.

8. The pharmaceutical composition as claimed in claim 2, wherein the binder is selected from polyvinyl pyrrolidone (PVP), polyvinyl acetate, polyvinyl alcohol, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC) and combinations thereof.

9. The pharmaceutical composition as claimed in claim 2, wherein the pharmaceutically acceptable excipient comprises a mixture of disintegrant, binder and lubricant.

10. A process for preparing pharmaceutical composition of cabozantinib fumarate, suitable for oral administration, comprising: a) mixing cabozantinib fumarate, diluents, binder and a first portion of the disintegrant;(b) granulating the mixture using water as granulation liquid;(c) drying the wet granules;(d) mixing lubricant and the rest of the disintegrant with the granules;(e) compressing the resulting mass into tablets; and,(f) optionally, coating the tablet with one or further pharmaceutically acceptable filmcoating agent.

11. A pharmaceutical composition, suitable for oral administration, comprising cabozantinib fumarate, manufactured by the process of claim 10.

12. The pharmaceutical composition according to any of the preceding claims, wherein the composition has an in-vitro dissolution profile similar to that of commercially available cabozantinib malate formulation (CABOMETYX®).A pharmaceutical composition according to any of the preceding claims, wherein the composition provides a dissolution of greater than 90 % of cabozantinib after 15 minutes in 0.01 N hydrochloric acid using paddle apparatus (USP apparatus 2) with paddle speed of 75 rpm at room temperature.

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