DESC:F O R M 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)

“PHARMACEUTICAL COMPOSITION OF CABOZANTINIB AND PROCESS OF PREPARATION THEREOF”

ALEMBIC PHARMACEUTICALS LIMITED
An Indian Company
Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India

The following specification describes the invention and the manner in which it is to be performed:
TECHNICAL FIELD:
The present subject matter relates to a solid oral pharmaceutical composition comprising Cabozantinib or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient. The present subject matter also relates to pharmaceutical compositions comprising a solid dispersion of Cabozantinib or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient. Furthermore, it also relates to methods for manufacturing such compositions, and uses thereof.

BACKGROUND:
Cabozantinib is a small molecule inhibitor of multiple receptor tyrosine kinases, including MET (hepatocyte growth factor receptor), VEGFR2 (vascular endothelial growth factor receptor 2), also known as KDR (kinase insert domain containing receptor), and RET (rearranged during transfection), which are implicated in tumor growth, angiogenesis, and metastatic progression of cancer. It was discovered and developed by Exelixis Inc. It is available as Cabozantinib (S)- maleate and is also known by its chemical name: N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’- (4fluorophenyl) cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate and is reported to have the following chemical structure:

Cabozantinib is approved in the USA as 20mg and 80mg capsule under the brand name Cometriq® and as 20mg, 40mg and 60mg as film coated tablets under the brand name Cabometyx®. Cometriq® is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). Cabometyx® is indicated for the treatment of renal cell carcinoma and hepatocellular carcinoma.
Cabozantinib (S)-malate salt is a white to off-white solid that is practically insoluble in aqueous media.

United States Patent No. US7579473 discloses Cabozantinib and its administration orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.

United States Patent No. US8877776 discloses malate salts of Cabozantinib, including a (L)-malate salt, a (D)-malate salt, a (DL) malate salt, and mixtures thereof; and crystalline (N-1 and N-2) and amorphous forms of the malate salts. It also discloses pharmaceutical compositions comprising at least one malate salts of Cabozantinib; and methods of treating cancer comprising administering at least one malate salt of Cabozantinib. It further discloses pharmaceutical composition comprising Cabozantinib and a pharmaceutically acceptable excipient broadly. The pharmaceutical composition may be in the form of tablet, capsule, liquid suspension, injectable, topical, or transdermal.

United States Patent No. US9724342 discloses tablet formulation with Cabozantinib (S)-malate and excipients as microcrystalline cellulose, lactose anhydrous, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate quantitatively. The process comprises a wet granulation process for formulation of the tablet.

United States Patent No. US9717720 discloses capsule formulation containing crystalline form of Cabozantinib (S)-malate and excipients.

United States Patent No. US10501418 discloses tablet and capsule formulation of crystalline form III of Cabozantinib (S)-malate and excipients, wherein the dosage form may be a solid dispersion.

There is a need in the art for alternative pharmaceutical compositions of Cabozantinib.

In one of the embodiment, the present subject matter relates to a pharmaceutical composition comprising amorphous solid dispersion of Cabozantinib which exhibits improved stability upon storage. Additional embodiment of the present subject matter relates to a pharmaceutical composition comprising amorphous solid dispersion of Cabozantinib wherein the amorphous form is retained in the composition. Additional embodiment of the present subject matter relates to a pharmaceutical composition comprising amorphous solid dispersion of Cabozantinib wherein the amorphous form is retained in the composition and the composition is substantially free of crystalline forms of Cabozantinib.

In an embodiment, the present subject matter relates to a solid oral pharmaceutical composition comprising Cabozantinib or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient. The present subject matter also relates to pharmaceutical compositions comprising a solid dispersion of Cabozantinib or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient. Furthermore, it also relates to methods for manufacturing such compositions, and to their use.

Amorphous Cabozantinib
In an embodiment, the present subject matter relates to a solid oral pharmaceutical composition comprising amorphous solid dispersion of Cabozantinib or a pharmaceutically acceptable salt thereof. The present subject matter also relates to an amorphous solid dispersion of Cabozantinib comprising at least one polymer and / or a stabilizer. The present subject matter also relates to an amorphous solid dispersion of Cabozantinib or a pharmaceutically acceptable salt thereof, at least one polymer and a stabilizer. Furthermore, it also relates to methods for manufacturing such compositions, and to their use.

Amorphous Cabozantinib may be prepared by any known means, including spray-drying, top-spray granulation, hot melt extrusion, and precipitation from solution on addition of a non-solvent.

During the course of development, it was found that contrary to conventional wisdom, crystalline Cabozantinib is more aqueous soluble than amorphous form. It was also found that compositions of amorphous form exhibits less or incomplete dissolution and higher disintegration time than compositions of crystalline form.

It was also observed that a solid dispersion of Cabozantinib and a stabilizer as per the present disclosure provides stable composition with enhanced disintegration and dissolution profile. The stabilizer prevents significant reversion of amorphous Cabozantinib to the crystalline state during storage. Solid dispersion of Cabozantinib prepared without using stabilizer of the present subject matter exhibits lower disintegration and dissolution of the drug in dissolution medium

The present disclosure provides a solid dispersion composition of Cabozantinib or a salt thereof having properties such as improved stability, disintegration time and dissolution.

The present disclosure thus provides, (1) a pharmaceutical composition with improved solubility and absorption of Cabozantinib, (2) a pharmaceutical composition (tablet and the like) with rapid disintegration and dispersibility/dissolution of Cabozantinib, and (3) a process of manufacturing the pharmaceutical composition which has said effects.

SUMMARY OF THE SUBJECT MATTER:
The present subject matter relates to a solid oral pharmaceutical composition comprising Cabozantinib or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient. The present subject matter also relates to pharmaceutical compositions comprising a solid dispersion of Cabozantinib or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient. Furthermore, it also relates to methods for manufacturing such compositions, and to their use.

An aspect of the present subject matter is to provide pharmaceutical compositions comprising a solid dispersion of Cabozantinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carrier.

An aspect of the present subject matter is to provide pharmaceutical compositions comprising a solid dispersion of Cabozantinib or a pharmaceutically acceptable salt thereof and at least one excipient.

An aspect of the present subject matter provides a pharmaceutical composition comprising a solid dispersion of Cabozantinib or a pharmaceutically acceptable salt thereof and at least one polymer.

Another aspect of the present subject matter provides a pharmaceutical composition comprising a solid dispersion of Cabozantinib or a pharmaceutically acceptable salt thereof, at least one polymer and/or at least one stabilizer.

Another aspect of the present subject matter provides a pharmaceutical composition comprising a solid dispersion of Cabozantinib or a pharmaceutically acceptable salt thereof, at least one polymer and / or other excipients prepared by solid dispersion techniques such as spray drying, top spray granulation and hot melt extrusion.

Another aspect of the present subject matter provides a pharmaceutical composition comprising a solid dispersion of Cabozantinib or a pharmaceutically acceptable salt thereof, wherein the composition is a tablet having physical attributes similar to that of Cabometyx®.
In one of the aspect, Cabozantinib is substantially in amorphous form in the solid dispersion and compositions comprising such solid dispersions.

Another aspect of the present subject matter provides a process for preparation of a pharmaceutical composition by spray drying, where the amorphous dispersion is formed by dispersing or dissolving the drug substance, stabilizing polymer and / or other excipients in a suitable solvent to form a feed solution, pumping the feed solution through an atomizer into a drying chamber, and removing the solvent to form the amorphous solid dispersion powder in the drying chamber. The said amorphous powder can be mixed with extra granular excipients and compressed in to tablets.

Another aspect of the present subject matter provides a process for preparation of a pharmaceutical composition by spray drying, where the amorphous dispersion is formed by dispersing or dissolving the drug substance, stabilizing polymer and / or other excipients in a suitable solvent to form a feed solution, pumping the feed solution through an atomizer into a drying chamber, and removing the solvent to form the amorphous solid dispersion powder in the drying chamber. The said amorphous powder is subjected to roller compaction. The roller compacted slugs are granulated and mixed with extra granular excipients and compressed in to tablets.

Another aspect of the present invention provides a process for preparation of a pharmaceutical composition by top-spray granulation, comprising the steps of dissolving drug substance & polymer and / or other excipients in a suitable solvent to form granulation binder solution and spraying the binder solution onto the fluidized substrate comprising at least one pharmaceutical excipient preferably stabilizer to form amorphous dispersion granules. The said amorphous dispersion granules can be mixed with extra granular excipients and compressed in to tablets.

Another aspect of the present subject matter provides a process for preparation of pharmaceutical composition by top-spray granulation, comprising the steps of dissolving drug substance & polymer and / or other excipients in a suitable solvent to form granulation binder solution and spraying the binder solution onto the fluidized substrate comprising at least one pharmaceutical excipient preferably stabilizer to form amorphous dispersion granules. The said amorphous dispersion granules are subjected to roller compaction. The roller compacted slugs are granulated and mixed with extra granular excipients and compressed in to tablets.

Another aspect of the present invention provides a process for preparation of pharmaceutical composition by hot melt extrusion, wherein the dry mix containing pharmaceutical active ingredient, polymer and/or other excipients is processed by applying heat and pressure in a hot melt extruder and the formed extrudes are further milled, lubricated and compressed into tablets.

DETAILED DESCRIPTION OF THE SUBJECT MATTER:
As used herein, "a" or "an" means one or more unless otherwise specified.

The term "Patient" means an animal, preferably a mammal, more preferably human, in need of therapeutic intervention.

The term "Composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

The term “Amorphous” as used herein includes, but is not limited to, the substance substantially lacking a crystalline structure.

The term "stable" and "stability" as used herein refers to both the physical form and the chemical purity of the amorphous Cabozantinib (S)- malate.
The term "stabilizer” as used herein refers to a pharmaceutically acceptable excipient which can be utilized to prepare stabilized compositions of the invention with enhanced dissolution and disintegration and also does not promote substantial reversion of the amorphous drug to the crystalline state during storage.

The term “Dry mix for extrusion” as used herein includes, but is not limited to, a part or component of composition containing mixture of one or more excipients which contains the active ingredient i.e. Cabozantinib (S)- malate.

The term “Extra-granular or Extra-granular portion” as used herein includes, but is not limited to, a part or component of composition mixed or blended with dry mix for extrusion”, “Lubricated”, and which is further subjected to compression to form the tablets.

Accordingly, the present subject matter relates to a solid oral pharmaceutical composition comprising Cabozantinib (S)-malate or a pharmaceutically acceptable salt thereof as an active ingredient, at least one pharmaceutically acceptable excipient, wherein the solid oral pharmaceutical composition is prepared by spray drying, top spray granulation and hot melt extrusion.

The spray drying process according to the subject matter refers to the process where the amorphous dispersion is formed by dispersing or dissolving the drug substance, stabilizing polymer and / or other excipients in a suitable solvent and / or mixture of solvents to form a feed solution, pumping the feed solution through an atomizer into a drying chamber, and removing the solvent to form the amorphous solid dispersion powder in the drying chamber. The said solid dispersion can be mixed/granulated with excipients to form the final formulation.

Top spray granulation according to the subject matter refers to the process where amorphous dispersion is formed by dissolving the drug substance and / or dispersing polymer and / or other excipients in suitable solvent and / mixture of solvents and spraying the resultant solution onto a fluidized bed substrate (or “stabilizer and / or other excipients”). Typically the spraying is performed using an atomizing nozzle. The substrate is maintained in a fluidized state in a fluidized bed while the granulation binder is sprayed onto the substrate particles. In one aspect, a plurality of substrates is used in the process of the invention. Simultaneously, the solvent is evaporated while maintaining the resulting solid dispersion granules in the fluidized state. The fluidization of the substrate is performed in top-spray apparatus known in the art used to fluidize particles and form a fluidized bed. In the method of the invention the solvent is at least partially or completely evaporated to form the amorphous dispersion granules of the invention. The said solid dispersion can be mixed/granulated with extra granular excipients to form the final formulation.

The hot melt extrusion process according to the subject matter refers to the process where the dry mix for extrusion is prepared containing amorphous pharmaceutical active ingredient, stabilizing polymer and / or other excipients which is processed in a hot melt extruder and lubrication is performed and the lubricated blend is further compressed into tablets and coated.

For the purpose of the present subject matter, pharmaceutical composition comprises Cabozantinib (S)-malate in the ‘Amorphous form’ or as a pharmaceutically acceptable salt, or as any mixture thereof.

In one embodiment, Cabozantinib present in the pharmaceutical composition is in the form of Malate salt.

In one embodiment, the amorphous Cabozantinib (S)-malate solid dispersion is prepared, which comprises the steps as:
a) providing a solution of Cabozantinib (S)-malate and at least one polymer and / or at least one pharmaceutically acceptable excipient in an inert solvent or mixture of solvents;
b) removing the solvent from the solution obtained in step a), and
c) isolating the amorphous solid dispersion of Cabozantinib (S)-malate.

In one embodiment, the amorphous Cabozantinib (S)-malate solid dispersion is prepared, which comprises the steps as:
a) providing a solution of Cabozantinib (S)-malate and at least one polymer and / or at least one pharmaceutically acceptable excipient in an inert solvent or mixture of solvents;
b) spraying the resultant solution on to the fluidized bed substrate.
c) simultaneous evaporation or removal of the solvent from the solution obtained in step a), and
d) isolating the amorphous solid dispersion of Cabozantinib (S)-malate.
e) mixing amorphous solid dispersion of Cabozantinib (S)-malate with extragranular excipients and processing the resultant mixture with roller compaction to obtain granules,
f) lubricating the granules obtained in step e) with extragranular material and formulating the mixture to obtain a suitable dosage form.

In one embodiment, the amorphous Cabozantinib (S)-malate solid dispersion is prepared, which comprises the steps as:
a) preparing a solid dry mix of Cabozantinib (S)-malate, polymer and / or pharmaceutically acceptable excipient
b) processing a dry mix obtained in step a) through hot melt extruder
c) collecting extrudates containing amorphous solid dispersion of Cabozantinib (S)- malate.

In further embodiment, solid dispersion retains Cabozantinib in amorphous form as characterized by e.g. Powder X-Ray Diffraction (PXRD) analysis. In further embodiment, PXRD spectra so obtained are substantially devoid of crystalline peaks.

In one embodiment, the amorphous solid dispersions of the present application are stable for at least one month under packed condition. In embodiments, the amorphous solid dispersions of the present application are stable for at least two months under packed condition. In embodiments, the amorphous solid dispersions of the present application are stable for at least six months under packed condition.

Another aspect of the present invention provides a pharmaceutical composition comprising,
(a) Cabozantinib (S)-malate,
(b) one or more pharmaceutically acceptable polymer,
(c) one or more pharmaceutically acceptable surfactant,
(d) one or more pharmaceutically acceptable diluent,
(e) one or more pharmaceutically acceptable disintegrant,
(f) one or more pharmaceutically acceptable lubricant.

Further the present subject matter provides a pharmaceutical composition comprising,
(a) Cabozantinib (S)-malate,
(b) one or more pharmaceutically acceptable polymer,
(c) one or more pharmaceutically acceptable stabilizer,
(d) one or more pharmaceutically acceptable surfactant,
(e) one or more pharmaceutically acceptable diluent,
(f) one or more pharmaceutically acceptable disintegrant,
(g) one or more pharmaceutically acceptable lubricant.

Further the present subject matter provides a pharmaceutical composition comprising,
(a) Cabozantinib (S)-malate,
(b) one or more pharmaceutically acceptable polymer,
(c) one or more pharmaceutically acceptable stabilizer,
(d) one or more pharmaceutically acceptable surfactant,
(e) one or more pharmaceutically acceptable binder,
(f) one or more pharmaceutically acceptable diluent,
(g) one or more pharmaceutically acceptable disintegrant.
(h) one or more pharmaceutically acceptable lubricant.

Further the present subject matter provides a pharmaceutical composition comprising,
(a) amorphous Cabozantinib (S)-malate,
(b) one or more pharmaceutically acceptable polymer and /or stabilizer ,
(c) one or more pharmaceutically acceptable plasticizer,
(d) one or more pharmaceutically acceptable diluent,
(e) one or more pharmaceutically acceptable disintegrant,
(f) one or more pharmaceutically acceptable lubricant.

Further the present subject matter provides a pharmaceutical composition comprising,
(a) amorphous Cabozantinib (S)-malate,
(b) one or more pharmaceutically acceptable polymer and /or stabilizer,
(c) one or more pharmaceutically acceptable surfactant,
(d) one or more pharmaceutically acceptable diluent,
(e) one or more pharmaceutically acceptable disintegrant,
(f) one or more pharmaceutically acceptable lubricant,
wherein a pharmaceutical composition is prepared by hot melt extrusion process.

Further the present subject matter provides a pharmaceutical composition comprising,
(a) amorphous Cabozantinib (S)-malate,
(b) one or more pharmaceutically acceptable polymer,
(c) one or more pharmaceutically acceptable diluent,
(d) one or more pharmaceutically acceptable lubricant.
Further the present subject matter provides a pharmaceutical composition comprising,
(a) amorphous Cabozantinib (S)-malate,
(b) one or more pharmaceutically acceptable polymer,
(c) one or more pharmaceutically acceptable diluent,
(d) one or more pharmaceutically acceptable binder,
(e) one or more pharmaceutically acceptable lubricant,
wherein a pharmaceutical composition is prepared by spray drying process.

Further the present subject matter provides a pharmaceutical composition comprising,
(a) Cabozantinib (S)-malate,
(b) one or more pharmaceutically acceptable polymer,
(c) one or more pharmaceutically acceptable stabilizer,
(d) one or more pharmaceutically acceptable surfactant,
(e) one or more pharmaceutically acceptable binder,
(f) one or more pharmaceutically acceptable diluent,
(g) one or more pharmaceutically acceptable disintegrant.
(h) one or more pharmaceutically acceptable lubricant.
wherein a pharmaceutical composition is prepared by top spray granulation process.

In this specification the terms “polymer” and “polymers” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable polymer according to the present invention can be selected form the group of, but not limited to polyvinyl pyrrolidone, povidone K-30, Soluplus, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinyl acetate, co-povidone, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit EPO or Eudragit-RLPO), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL (HPC-SSL), hydroxypropyl cellulose SL (HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcellulose and the like.

The term “Stabilizer” is intended to be interpreted in the context of pharmaceutical formulation science. Suitable Stabilizer according to the present invention can be selected form the group of, but not limited to magnesium aluminometasilicate (Neusilin®), Attapulgite, hydrated magnesium aluminum Silicate, Bentonite, Calcium Silicate, Colloidal Silicon Dioxide, porous silica, Syloid, Aerosil, Kaolin, Magnesium Aluminum Silicate, Saponite, aluminum hydroxide, Fujisil, Fujicalin, porous calcium silicate, porous ceramics, calcium carbonate and bauxite. Neusilin® is a porous granule of amorphous magnesium aluminometasilicate which retains a tremendous surface area. Neusilin® is involved in solid dosage form not only as an adsorbent but also as a low-toxicity excipient which can increase tablet hardness. Neusilin® also does not promote reversion of the amorphous drug to the crystalline state during storage further it helps to improve disintegration time and dissolution of the dosage form.
The term “diluent” is intended to be interpreted in the context of pharmaceutical formulation science. Suitable diluents according to the present subject matter can be selected form the group of, but not limited to microcrystalline cellulose (MCC), pregelatinized starch, sugar and sugar alcohol such as mannitol, lactose, fructose, isomalt, lactitol, maltitol, sorbitol, erythritol, maltose, polydextrose, sucrose, trehalose and xylitol; calcium carbonate, dicalcium phosphate, calcium sulfate, cellulose acetate, ethylcellulose, inulin, magnesium carbonate, magnesium oxide, maltodextrin, sodium bicarbonate, sodium carbonate and sodium chloride.
The term “binder” is intended to be interpreted in the context of pharmaceutical formulation science. Suitable binder according to the present subject matter can be selected form the group of, but not limited to povidone, copovidone pregelatinized starch, cellulose, methyl cellulose, ethyl cellulose, cellulose derivatives (e.g., Hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC)), and polyethylene glycol, Hydroxypropyl methyl cellulose acetate succinate (HPMC-AS).

The terms “disintegrant” and “disintegrants” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable disintegrants according to the present subject matter can be selected form but not limited to croscarmellose sodium (CCS), sodium starch glycolate (SSG), pregelatinized starch, alginic acid, sodium alginate, carboxymethylcellulose calcium, chitosan, crospovidone, glycine, , guar gum, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, sodium carboxymethylcellulose, and starch.

The terms “surfactant” and “surfactants” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable pharmaceutical surfactant according to the present subject matter can be selected form but not limited to sodium lauryl sulfate (SLS), poloxamers, polysorbate, sodium dodecyl benzene sulfonate, alkali metal or ammonium salts of lauroyl sarcosinate, myristoyl sarcosinate, palmitoyl sarcosinate, stearoyl sarcosinate and oleoyl sarcosinate, polyoxyethylene sorbitan monostearate, isostearate and laurate, sodium lauryl sulfoacetate, N-lauroyl sarcosine, the sodium, potassium, and ethanolamine salts of N-lauroyl, N-myristoyl, or N-palmitoyl sarcosine, polyethylene oxide condensates of alkyl phenols, cocoamidopropyl betaine, lauramidopropyl betaine, palmityl betaine and the like.

The terms “lubricant” and “lubricants” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable pharmaceutical lubricant according to the present subject matter can be selected form but not limited to magnesium, aluminium , zinc or calcium stearate, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of benenate esters of glycerine (e.g. a mixture of glyceryl bihenehate, tribehenin and glyceryl behenate), magnesium stearate, myristic acid, palmitic acid, stearic acid, talc, tribehenin, sodium stearyl fumarate (SSF) and sucrose stearate.

The terms “plasticizer” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable pharmaceutical plasticizer according to the present subject matter can be selected form selected from TEC, Polyethylene Glycol, Tween80, Span 80, Sodium dioctyl sulfate, Sodium deoxycholate, Lecithin or their mixture thereof.
Still another embodiment of the present subject matter provides a composition wherein the organic solvent used in preparation of pharmaceutical composition is selected from isopropyl alcohol, ethanol, methanol, acetone, dichloromethane, acetonitrile, petroleum ether or their mixture thereof.

As used herein, the word “comprising” describes components that must be present, but leaves open the possibility that other unspecified components may also be present within the scope of the relevant term.

In one aspect there is provided a pharmaceutical tablet comprising the pharmaceutical composition as defined herein.

In one embodiment there is provided a pharmaceutical tablet comprising a pharmaceutical composition in the form of tablet core, wherein the tablet core is coated with a layer of coating. In one embodiment the coating is a film coating.

When the tablet has a film coating, the film coating may be applied using conventional methods. A coating can be used to provide protection against, for example, moisture ingress or degradation by light, to colour the formulation, or to modify or control the release of Cabozantinib (S)-malate from the formulation.

In one embodiment, the pharmaceutical composition is a pharmaceutical tablet composition (for oral administration).

In one embodiment, the pharmaceutical composition is a pharmaceutical tablet composition suitable for oral administration to a human.

In one embodiment, the pharmaceutical composition is a pharmaceutical tablet composition suitable for oral administration for the treatment of renal cell carcinoma and hepatocellular carcinoma.

In one embodiment, the pharmaceutical tablet comprises 20 mg, 40 mg and 60 mg Cabozantinib free base which is equivalent to 25 mg, 51 mg and 76 mg of Cabozantinib (S)-malate respectively.

In a further aspect, there is provided the use of a pharmaceutical composition, as defined herein, for the manufacture of a medicament.
In one embodiment, there is provided the use of a pharmaceutical composition, as defined herein, for the manufacture of a medicament for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma.

In one aspect, there is provided a pharmaceutical composition, as defined herein, for use as a medicament.
In one embodiment, a pharmaceutical composition is a pharmaceutical tablet.
In one embodiment, there is provided a method of treatment of advanced renal cell carcinoma and hepatocellular carcinoma.

Solid dispersions of the present application also include the solid dispersions obtained by combining Cabozantinib (S)-malate with a suitable non-polymeric excipient by employing techniques known in the art or procedures described or exemplified in any aspect of the instant application.
It is to be understood that each of the variously stated ranges is intended to be continuous so as to include each numerical parameter between the stated minimum and maximum value of each range.

Embodiments provided herein may be more fully understood by reference to the following examples. These examples are meant to be illustrative of pharmaceutical composition and dosage form provided herein, but is not in any way limiting.

Table 1
Example 1 -Pharmaceutical composition of Cabozantinib (S)-malate.
Sr. No. Ingredients % of ingredient by weight of core tablet

1 Cabozantinib (S)-malate 20-40%
2 Polymer (e.g. Copovidone, HPMC-AS, HPMC, HPC, Eudragit) 5-55%
3 Stabilizer (e.g. Magnesium aluminium metasilicate , Silicon dioxide) 20-55%
4 Diluents (e.g. MCC, Lactose) 5-50%
5 Disintegrant (e.g. Sodium starch glycolate, Crospovidone, croscarmellose sodium, L-substituted hydroxy propyl cellulose) 2-15%
6 Binder (e.g. Povidone , Copovidone) 1-20%
7 Surfactant (e.g. Polysorbate, Sodium Lauryl Sulphate) 1-20%
8 Lubricant(e.g. Magnesium stearate, Stearic acid, sodium stearyl fumarate) 0.2-2%
9 Optionally Film Coating 1-6%

Table 2 (Example 2-11 prepared by Hot melt extrusion)
Example No 2 3 4 5 6 7 8 9 10 11
Ingredient mg mg mg mg mg mg mg mg mg mg
Stage A (Dry mix for extrusion)
Cabozantinib S maleate 76.042 76.042 76.042 76.042 76.042 76.042 76.042 76.042 76.042 76.042
polyvinylpyrrolidone vinyl acetate (Kollidon VA 64) 152.084 - - 152.084 - - 152.084 - - 76.042
hydroxypropylmethyl cellulose acetate succinate (HPMC-AS) - 152.084 - - 152.084 - - 152.084 - -
hydroxypropyl cellulose - - 152.084 - - 152.084 - - 152.084 76.042
polysorbate 80 - - - 15.208 - - - - -
polyethyene glycol - - 15.208 - - - 15.208 - - 15.208
Triethyl citrate (TEC) - - - - 15.208 - - 15.208 15.208 -
Stage B (Lubrication)
Microcrystalline cellulose 22.813 - 11.406 22.813 - 11.406 22.813 22.813 11.406 11.406
Supertab 21 AN - 22.813 11.406 - 22.813 11.406 - - 11.406 11.406
Croscarmellose sodium 12.167 12.167 12.167 12.167 12.167 12.167 12.167 12.167 12.167 12.167
Sodium starch glycolate 6.083 6.083 6.083 6.083 6.083 6.083 6.083 6.083 6.083 6.083
Extra-granular
Croscarmellose sodium 12.167 12.167 12.167 12.167 12.167 12.167 12.167 12.167 12.167 12.167
Colloidal Silicon Dioxide 2.281 2.281 2.281 2.281 2.281 2.281 2.281 2.281 2.281 2.281
Magnesium Stearate (Hyqual) 1.141 1.141 1.141 1.141 1.141 1.141 1.141 1.141 1.141 1.141
Total 284.777 284.777 299.986 299.986 299.986 284.777 299.986 299.986 299.986 299.986

The procedure for Example 2 to Example 11 comprises of the steps:
1. Stage A material was sifted through suitable mesh and added into double cone blender and blended for 5 minutes and subsequently processed in HME.
2. The extrudates were milled through 1575 µ, 1143 µ and finally 610 µ screens.
3. Stage B material was sifted through suitable mesh and blended with milled extrudates in double cone blender for 10 minutes.
4. Extragranular material was sifted through suitable mesh and blended with step 3 material in double cone blender for 5 minutes.
5. Step 4 lubricated blend was compressed into tablets using compression machine.

Table 3
Example 12 and 13- Preparation by Spray Drying
Cabozantinib S-malate Example 12
% w/w Example 13
% w/w
Intragranular Part
Cabozantinib S-malate 26.40 29.02
Hydroxypropyl Cellulose 13.20 --
Copovidone -- 14.51
Dichloromethane (DCM) q.s q.s
Methanol q.s q.s
Extra granular Part
Microcrystalline cellulose 48.6 44.94
Sodium starch glycolate 8.70 8.70
Colloidal anhydrous silica 2.30 2.30
Magnesium stearate 0.80 0.53
Total Tablets Weight 100.00 100.00

The procedure for Example 12 and Example 13
1. Polymer was dissolved in DCM and methanol mixture along with the Cabozantinib S-malate and spray dried on spray dryer.
2. Sample solution was then sprayed and the solids separated from the process gas by a glass cyclone into a glass vial. The solids recovered were dried and then stored along with desiccant.
3. Extra granular material sifted through suitable mesh and blended with spray dried powder of step 2 in double cone blender for 10 minutes.
4. Lubricated blend was compressed into tablets on rotary tablet compression machine using suitable tooling and parameters.
Table 4
Example 14 to 18 – Preparation by Hot melt extrusion
Ingredient Example 14
% w/w Example 15
% w/w Example 16
% w/w Example 17
% w/w Example 18
% w/w
Intragranular Part
Cabozantinib S-malate 30.413 30.41 30.41 29.82 26.62
HPMC-AS 30.413 -- -- -- --
Polysorbate 80 3.041 -- 1.52 1.49 --
Magnesium aluminium metasilicate -- 30.41 30.41 29.82 53.24
Copovidone -- -- 15.21 14.91 --
Extra granular Part
Microcrystalline cellulose 25.133 -- 9.95 9.75 7.23
Sodium starch glycolate 8.000 -- -- -- --
Spray dried lactose -- 25.57 -- -- --
Crospovidone -- 10.00 10.00 9.80 8.75
Silicon dioxide 2.000 2.60 2.00 1.96 1.75
Sodium Lauryl Sulphate -- -- -- 1.96 1.96
Magnesium stearate 1.000 1.00 0.50 0.49 0.44
Total Tablets Weight 100.000 100.00 100.00 100.00 100.00

The procedure for Example 14 to Example 18 comprises of the steps:
1. Intragranular material was sifted through suitable mesh and added into double cone blender and blended for 5 minutes and subsequently processed in HME.
2. The extrudates were milled through 1575 µ, 1143 µ and finally 610 µ screens.
3. Extragranular material was sifted through suitable mesh and blended with step 2 material in double cone blender for 5 minutes.
4. Step 3 lubricated blend was compressed into tablets using compression machine.
Table 5
Example 19 and 20 - Top spray granulation Followed by compression
Name of Ingredients Example 19
% w/w Example 20
% w/w
Drug Polymer Solution
Cabozantinib S-malate 25.34 24.47
Copovidone 25.34 12.23
DCM q.s q.s
Methanol q.s q.s
Intra-granular
Microcrystalline cellulose 46.65 --
Mg Al metasilicate -- 39.32
Extra-granular
Sodium starch glycolate 2.00 --
Microcrystalline cellulose -- 11.57
Crospovidone -- 10.0
Colloidal anhydrous silica 0.20 1.93
Magnesium stearate 0.47 0.48
Tablet Weight 100.00 100.00

Table 6
Example 21, 22, 23 and 24 -Top spray granulation + Roller compaction and compression
Name of Ingredients Example 21
% w/w Example 22
% w/w Example 23
% w/w Example 24
% w/w
Drug binder solution
Cabozantinib S-malate 25.67 25.43 22.37 22.37
Copovidone 12.84 12.72 -- --
Amino Methacrylate Copolymer – NF (Eudragit EPO) -- -- 11.18 --
Hypromellose acetate succinate AQOAT (AS-LG) -- -- -- 11.18
Dichloromethane (DCM) q.s q.s q.s q.s
Methanol q.s q.s q.s q.s
Intragranular Part
Magnesium aluminium metasilicate 41.26 30.10 26.48 26.48
Microcrystalline cellulose -- 11.71 -- --
Mannitol (Pearlitol 50 C ) -- -- 6.18 6.18
Extra granular Part before roller compaction
Microcrystalline cellulose 5.06 5.02 -- --
Mannitol (Pearlitol 50 C ) -- -- 12.65 12.65
Crospovidone 5.06 5.02 5.44 5.44
Sodium Lauryl Sulphate 0.00 1.98 -- --
Silicon dioxide 1.01 1.00 0.88 0.88
Magnesium stearate 0.51 0.50 0.44 0.44
Extra granular Part after roller compaction
Crospovidone 5.06 5.02 5.44 5.44
Microcrystalline Cellulose (Ceolus UF 702) -- -- 7.62 7.62
Silicon dioxide 1.01 1.00 0.88 0.88
Sodium Lauryl Sulphate 2.00 -- -- --
Magnesium stearate 0.51 0.50 0.44 0.44
Total Weight 100.00 100.00 100.00 100.00

The procedure for Example 21, 22, 23 and 24
1. Copovidone/ Eudragit EPO was dissolved in DCM and methanol mixture along with the Cabozantinib S-malate and spray granulated onto the substrate (magnesium aluminium metasilicate/ magnesium aluminium metasilicate and microcrystalline cellulose/ mannitol). Obtained granules were collected and dried.
2. Extra granular material was sifted through suitable mesh & used for the lubrication of step 1 granules.
3. Lubricated granules obtained in step 2 were subjected to roller compaction, milled and passed through suitable mesh.
4. The granules obtained in step 3 were lubricated using extra granular material containing crospovidone, microcrystalline cellulose, silicon dioxide, sodium lauryl sulphate and magnesium stearate.
5. Lubricated blend of step 4 was compressed into tablets.
Table 7
Example 25 - Spray drying followed by Roller compaction and compression
Name of Ingredients % w/w
Intragranular Part
Cabozantinib S-malate 27.16
Copovidone 13.58
Mg Al metasilicate 32.14
Dichloromethane (DCM) q.s
Methanol q.s
Total Weight 72.88
Extragranular Part before roller compaction
Microcrystalline cellulose 7.94
Crospovidone 5.00
Silicon dioxide 1.07
Magnesium stearate 0.54
Total Weight 87.43
Extragranular Part after roller compaction
Microcrystalline cellulose 4.00
Crospovidone 5.00
Silicon dioxide 1.07
Sodium lauryl Sulphate (SLS) 2.00
Magnesium stearate 0.50
Total Weight 100.00
The procedure for Example 25
1. Copovidone was dissolved in DCM and methanol mixture along with the Cabozantinib S-malate to form a solution.
2. Magnesium aluminium metasilicate was added to the solution of step 1 and was fed to a spray dryer and sprayed into the chamber from a nozzle with a suitable diameter. The dried material was collected and sifted through suitable mesh.
3. Extra granular material containing microcrystalline cellulose, crospovidone, silicon dioxide & magnesium stearate were sifted through suitable mesh and used for the lubrication of step 2 granules.
4. Lubricated granules obtained in step 3 were subjected to roller compaction, milled and passed through suitable mesh.
5. The granules obtained in step 4 were lubricated using extra granular material containing microcrystalline cellulose, crospovidone, silicon dioxide, sodium lauryl sulphate and magnesium stearate
6. Lubricated blend of step 5 was compressed into tablets.
Table 8
Example 26 - Spray drying followed by granulation and compression
Name of Ingredients % w/w
Spray Drying
Cabozantinib S-Malate 100.00
Dichloromethane q.s.
Methanol q.s.
Total weight 100.00
Intra granular part
Cabozantinib S-Malate (Amorphous) 30.76
Crospovidone (Kollidon CL) 2.91
Silicon dioxide (Syloid 244FP) 0.97
Microcrystalline Cellulose (Avicel PH 102) 30.34
Anhydrous lactose (SuperTab 21AN) 7.48
Binder Solution
Copovidone (Kollidon VA 64) 4.85
Purified water -
Extra Granular Part
Microcrystalline Cellulose (Avicel PH 102) 16.37
Crospovidone (Kollidon CL) 2.91
Magnesium stearate (Ligamed MF-2-V) 0.49
Weight of Core Tablets 97.09
Film Coating
Opadry® 03K92254 Yellow 2.91
Purified water -
Weight of Coated Tablets 100.00

The procedure for Example 26
1. Cabozantinib S-malate was dissolved in DCM and methanol to form a solution and sprayed into the spray drying chamber from a nozzle with a suitable diameter. The dried material was collected and sifted through suitable mesh.
2. The output amorphous cabozantinib was mixed with crospovidone (Kollidon CL), silicon dioxide (Syloid 244FP), microcrystalline cellulose (Avicel PH 102), and anhydrous lactose (SuperTab 21 AN) in rapid mixer granulator and granulated using binder solution with suitable parameters.
3. The dried material was collected and sifted through suitable mesh.
4. The granules obtained in step 3 were mixed with extragranular part and compressed using suitable parameters.
5. Core tablets were coated using Opadry dispersion with suitable parameters.

Table 9 - Results of Examples 14-26
Ex Type of Process Polymer API to Polymer Ratio Form DT Dissolution
(DR in 30 min)
14 HME Hydroxypropyl methylcellulose acetate succinate 1:1 Amorphous 2 min 30 sec 25%
15 HME Magnesium aluminium metasilicate 1:1 Amorphous 30 sec 65%
16 HME Copovidone + magnesium aluminium metasilicate 1:0.5:1 Amorphous 30 sec 69%
17 HME Copovidone + magnesium aluminium metasilicate 1:0.5:1 Amorphous 30 sec 81%
18 HME Magnesium aluminium metasilicate 1:2 Amorphous 30 sec 84%
19 Top Spray Granulation Copovidone 1:1 Amorphous NLT 30 min 1%
20 Top Spray Granulation Copovidone 1:0.5 Amorphous 1 min 20 sec 28 %
21 Top Spray Granulation Copovidone + magnesium aluminium metasilicate 1:0.5:1.5 Amorphous 1 min 50 sec 92%
22 Top Spray Granulation Copovidone + magnesium aluminium metasilicate 1:0.5:1.18 Amorphous 1 min 30 sec 86%
23 Top Spray Granulation Eudragit EPO 2:1 Amorphous 50 sec 97%
24 Top Spray Granulation HPMC AS 2:1 Amorphous 1 min 40 sec 78%
25 Top Spray Granulation Copovidone 2:1 Amorphous 5 min 30 sec 60%
26 Wet granulation Copovidone 6:1 Amorphous 1 min 60 sec 90%

Dated this 22nd Sep, 2022

(Signature):

_______________
(Sonal Ben Parimal Patel)
For Alembic Pharmaceuticals Limited
,CLAIMS:We claim:
1. A pharmaceutical composition comprising a therapeutically effective amount of Cabozantinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carrier.
2. The pharmaceutical composition as per claim 1, wherein pharmaceutically acceptable carrier is selected from the group consisting of a polymer, a stabilizer, a diluent, a surfactant, a binder, a disintegrant, an adsorbent and a complexing agent.
3. The pharmaceutical composition as per claim 1, wherein the composition is in the form of solid dispersion.
4. The pharmaceutical composition as per claim 3, wherein solid dispersion is prepared by a process selected from the group consisting of adsorption process, solvent evaporation, hot melt extrusion, spray granulation, freeze drying, spray drying, lyophilization, complexation, anti-solvent precipitation and supercritical fluid (SCF) technology.
5. The pharmaceutical composition in the form of solid dispersion as per claim 3, wherein solid dispersion comprises Cabozantinib (S)-malate and at least one polymer selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate, copovidone, polyvinylpyrrolidone vinyl acetate, hydroxypropyl cellulose and amino methacrylate copolymer.
6. A process for preparing the solid dispersion as per claim 3 comprising:
a) providing a solution of Cabozantinib (S)-malate and at least one polymer and / or at least one pharmaceutically acceptable excipient in an inert solvent or mixture of solvents,
b) spraying the resultant solution on to the fluidized bed substrate,
c) simultaneous evaporation or removal of the solvent from the solution obtained in step a), and

e) mixing amorphous solid dispersion of Cabozantinib (S)-malate with extragranular excipients and processing the resultant mixture with roller compaction to obtain granules,
f) lubricating the granules obtained in step e) with extragranular material and formulating the mixture to obtain a suitable dosage form.
7. A process for preparing the solid dispersion as per claim 3 comprising:
a) preparing a solid dry mix of Cabozantinib (S)-malate, polymer and / or pharmaceutically acceptable excipient,
b) processing a dry mix obtained in step a) through hot melt extruder,
c) collecting extrudates containing amorphous solid dispersion of Cabozantinib (S)- malate and milling the extrudates to obtain granules,
g) mixing the granules containing amorphous solid dispersion of Cabozantinib (S)-malate with extragranular excipients,
h) lubricating the granules obtained in step g) with suitable excipient and formulating the mixture to obtain a suitable dosage form.
8. A process for preparing the solid dispersion as per claim 3 comprising
a) preparing a solution of Cabozantinib (S)-malate in suitable solvent(s),
b) removing the solvent from the solution to provide an amorphous Cabozantinib (S)-malate,
c) mixing the amorphous Cabozantinib (S)-malate with extragranular material and wet granulating using binder solution to obtain granules for preparing a suitable dosage form.

Dated this 22nd Sep, 2022
(Signature):

(Sonal Ben Parimal Patel)
For Alembic Pharmaceuticals Limited