Stable pharmaceutical composition of cabozantinib

Abstract

The present invention pertains to stable pharmaceutical compositions comprising cabozantinib or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient, which does not contain glidant(s). Preferably, the pharmaceutically acceptable salts of cabozantinib is cabozantinib S-malate. Furthermore, the present invention also covers liquid oral pharmaceutical composition and injectable dosage forms of cabozantinib or pharmaceutically acceptable salts thereof.

Description

[0001] Stable pharmaceutical composition of cabozantinib

[0002] Related applications:

[0003] This application claims the benefit of priority of our Indian patent application numbers 202341080012 filed on Nov 24, 2023 which is incorporated herein by reference. Field of the Invention:

[0004] The present invention pertains to stable pharmaceutical compositions comprising cabozantinib or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient, which does not contain a glidant(s). Preferably, the pharmaceutically acceptable salts of cabozantinib is cabozantinib S-malate. Furthermore, the present invention also covers liquid oral pharmaceutical composition and injectable dosage forms of cabozantinib or pharmaceutically acceptable salts thereof.

[0005] Background of the Invention:

[0006] Cabozantinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumour growth and angiogenesis, pathologic bone remodeling, and metastatic progression of cancer. Cabozantinib was evaluated for its inhibitory activity against a variety of kinases and was identified as an inhibitor of MET (hepatocyte growth factor receptor protein) and VEGF (vascular endothelial growth factor) receptors. In addition, cabozantinib inhibits other tyrosine kinases. Cabozantinib (S)-malate is chemically described as N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl) cyclopropane- 1,1- dicarboxamide, (2S)-hydroxybutanedioate. The molecular formula is C28H24FN3O5 and the molecular weight is 635.6 Daltons as malate salt. Cabozantinib (S)-malate salt is a white to off-white sold that is practically insoluble in water. The chemical structure of cabozantinib (s)-malate salt is: W02012009722 discloses tablet composition of Cabozantinib and W02012109510 discloses capsule tablet composition of Cabozantinib the entire contents of which is herein incorporated by reference.

[0007] Although therapeutic efficacy is the primary concern for a therapeutic agent, the pharmaceutical composition can be equally important to its development. Generally, formulation developers endeavor to discover a pharmaceutical composition that possesses desirable properties, such as satisfactory water-solubility (including rate of dissolution), storage stability, hygroscopicity, and reproducibility, all of which can impact the processability, manufacture, and / or bioavailability of the drug. Accordingly, discovery of pharmaceutical compositions that possess some or all of these desired properties is vital to drug development.

[0008] There exists a need to develop pharmaceutical compositions of cabozantinib which increases the stability of cabozantinib throughout shelf life. Wherein stored for at least 6 months at 40° C. / 75% RH (“relative humidity”) or at least 12 months at 25° C. / 60% RH or at least 24 months at 25° C. / 60% RH (“relative humidity”).

[0009] The inventors of the present invention have developed a stable formulation for the preparation of a pharmaceutical composition comprising cabozantinib and suitable pharmaceutical carriers or excipients which does not contain glidant(s) and a process for preparing the same.

[0010] The inventors of the present invention have chosen granulation technique for the preparation of a pharmaceutical composition comprising cabozantinib and suitable pharmaceutical carriers or excipients.

[0011] Without being bound by any theory, the inventors of the present invention have developed stable pharmaceutical compositions of cabozantinib, particularly formulations comprising cabozantinib (S)-malate as active ingredient that do not contain glidant(s) as pharmaceutical carrier or excipient, while allowing for substantially less complex and inexpensive preparation.

[0012] Further, in order to study the efficacy and safety of Cabozantinib in pediatric and geriatric patients, there is a need for appropriate formulations in order to allow for pediatric and geriatric studies and later for treatment. Such formulations suitable for pediatric and geriatric patients might also be suitable for other patients encountering problems with swallowing e.g. as a result of a disease or because of age or for psychological reasons.

[0013] It is, therefore, an unmet need to develop and provide a liquid formulation of cabozantinib that addresses the deficiencies of the marketed film-coated tablet in terms of a pediatric and geriatric application.

[0014] Summary of the Invention:

[0015] The present invention pertains to stable pharmaceutical compositions comprising cabozantinib or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient, which does not contain a glidant(s). Preferably, the pharmaceutically acceptable salts of cabozantinib is cabozantinib S -malate. Furthermore, the present invention encompasses manufacturing processes, and the use of the novel compositions of the present invention for prevention, treatment or prophylaxis of Renal cell carcinoma (RCC), Hepatocellular Carcinoma and Differentiated Thyroid Cancer in human patients in need thereof.

[0016] The term “cabozantinib” refers to cabozantinib free base, a pharmaceutically acceptable salt, solvate or hydrate thereof. For example, the “pharmaceutically acceptable salt” comprises cabozantinib salts, which are formed with inorganic or organic acids. The salt is preferably the (S)-malate salt.

[0017] The first embodiment of the present invention provides a stable pharmaceutical composition comprising cabozantinib as an active ingredient and at least one pharmaceutically acceptable carrier / excipient, which does not contain glidant(s).

[0018] The first aspect of first embodiment of the present invention provides a stable pharmaceutical composition comprising cabozantinib (S)-malate and at least one pharmaceutically acceptable carrier, which does not contain glidant(s).

[0019] The second embodiment of the present invention provides a stable pharmaceutical composition comprising cabozantinib (s)-malate and at least one pharmaceutically acceptable carrier, which does not contain glidant(s), wherein said cabozantinib is present in crystalline form.

[0020] The third embodiment of the present invention provides a stable pharmaceutical composition comprising a crystalline form of cabozantinib (s)-malate and at least one pharmaceutically acceptable excipient, wherein said pharmaceutical composition does not contain glidant(s).

[0021] The first aspect of the third embodiment of the present invention provides a pharmaceutical composition comprising a crystalline form of cabozantinib and one or more pharmaceutically acceptable excipients wherein said excipients are those which improve the stability, solubility / dissolution and permeability / absorption of the said pharmaceutical composition, wherein said pharmaceutical composition does not contain glidant(s).

[0022] The fourth embodiment of the present invention provides a stable pharmaceutical composition comprising a crystalline form of cabozantinib (s)-malate and at least one pharmaceutically acceptable excipient, wherein said excipients are those which are present in the form of intragranular and an extragranular, wherein said pharmaceutical composition does not contain glidant(s).

[0023] The first aspect of the fourth embodiment of the present invention an intragranular excipient are one or more selected from the groups comprising but are not limited to filler, diluents, binders and disintegrants.

[0024] The second aspect of the fourth embodiment of the present invention an extragranular excipient are one or more selected from the groups comprising but are not limited to filler, diluents, binders, disintegrants, lubricants.

[0025] The third aspect of the fourth embodiment of the present invention an intragranular excipients are comprised of at least a diluent and a disintegrant, wherein the diluent is at least one selected from the group comprising corn starch, optionally a granulated corn starch, lactose, mannitol, microcrystalline cellulose or a combination thereof and disintegrant is at least one selected from the group comprising croscarmellose sodium, crospovidone, sodium starch glycolate and hydroxy propyl cellulose or a combination there of.

[0026] The fourth aspect of the fourth embodiment of the present invention an extragranular excipients are comprised of at least a disintegrant, a diluents and a lubricant, wherein the diluent is at least one selected from the group comprising corn starch, optionally a granulated corn starch, lactose, mannitol, microcrystalline cellulose or a combination thereof and disintegrant is at least one selected from the group comprising croscarmellose sodium, crospovidone, sodium starch glycolate and hydroxy propyl cellulose or a combination there of and a lubricant is magnesium stearate.

[0027] The fifth embodiment of the present invention provides a stable pharmaceutical composition comprising a crystalline form of cabozantinib and at least one pharmaceutically acceptable excipient that is not a glidant(s), wherein said excipients comprising an intragranular excipients and extragranular excipients, wherein cabozantinib from about 5 % w / w to about 40 % w / w, a filler / diluent from about 20 % w / w to about 90 % w / w, disintegrant from about 1 % w / w to about 25 % w / w, a binder from about 0.1 % w / w to about 10 % w / w, a lubricant from about 0.01 % w / w to about 5 % w / w.

[0028] The first aspect of the fifth embodiment of the present invention provides a stable pharmaceutical composition comprising crystalline form of cabozantinib and pharmaceutically acceptable intragranular excipients and extragranular excipients, wherein cabozantinib from about 10 % w / w to about 30 % w / w, a filler / diluent from about 50 % w / w to about 80 % w / w, a disintegrant from about 3 % w / w to about 15 % w / w, a binder from about 1 % w / w to about 10 % w / w, a lubricant from about 0.1 % w / w to about 3 % w / w.

[0029] The second aspect of the fifth embodiment of the present invention provides a stable pharmaceutical composition comprising crystalline form of cabozantinib and at least one pharmaceutically acceptable excipient that is not a glidant(s), wherein said excipients are comprising an intragranular excipients and an extragranular excipients, wherein intragranular excipients comprising: a filler / diluent from about 30 % w / w to about 70 % w / w, a disintegrant from about 3 % w / w to about 15 % w / w, binder from about 1 % w / w to about 10 % w / w and extragranular excipients comprising: a filler / diluent from about 5 % w / w to about 30 % w / w, a disintegrant from about 3 % w / w to about 10 % w / w, a lubricant from about 0.1 % w / w to about 3 % w / w, and optionally comprises a coating.

[0030] The third aspect of the fifth embodiment of the present invention comprising an intragranular excipients and an extragranular excipients, wherein the intragranular excipients comprise: corn starch in an amount from about 15% w / w to about 30% w / w; lactose in an amount from about 15% w / w to 40% w / w; croscarmellose sodium in an amount from about 3% w / w to 15% w / w; hydroxypropyl cellulose in an amount from about 1 % w / w to about 10 % w / w and the extragranular excipients comprise: croscarmellose sodium in an amount from about 3% to 15% w / w; one or more diluent in an amount from about 8% w / w to 25% w / w selected from the group comprising granulated corn starch, lactose monohydrate, mannitol, microcrystalline cellulose; croscarmellose sodium in an amount from about 3% w / w to 15% w / w; magnesium stearate in an amount from about 0.5% w / w to 2% w / w and optionally comprises a coating, wherein the coating is opadry.

[0031] The fourth aspect of the fifth embodiment of the present invention comprising an intragranular excipients and an extragranular excipients, wherein intragranular portion comprising: a cabozantinib is 25.340 % w / w, a lactose monohydrate is 25.660 % w / w, a croscarmellose sodium is 5.000 % w / w, a corn starch is 25.670 % w / w, a hydroxypropyl cellulose is 2.000 %w / w, extragranular portion comprising: a granulated corn starch is 12.330 % w / w, a croscarmellose sodium is 3.000 % w / w, a magnesium stearate is 1.0 % w / w.

[0032] The fifth aspect of the fifth embodiment of the present invention comprising an intragranular excipients and an extragranular excipients, wherein intragranular portion comprising: a cabozantinib is 25.340 % w / w, a lactose monohydrate is 25.660 % w / w, a croscarmellose sodium is 5.000 % w / w, a corn starch is 28.000 % w / w, a hydroxypropyl cellulose is 2.000 %w / w, extragranular portion comprising: a granulated corn starch is 10.000 % w / w, a croscarmellose sodium is 3.000 % w / w, a magnesium stearate is 1.0 % w / w.

[0033] The sixth aspect of the fifth embodiment of the present invention comprising an intragranular excipients and an extragranular excipients, wherein intragranular portion comprising: a cabozantinib is 12.670 % w / w, a lactose monohydrate is 33.330 % w / w, a croscarmellose sodium is 5.000 % w / w, a corn starch is 28.000 % w / w, a hydroxypropyl cellulose is 2.000 %w / w, extragranular portion comprising: a granulated corn starch is 15.000 % w / w, a croscarmellose sodium is 3.000 % w / w, a magnesium stearate is 1.0 % w / w.

[0034] The seventh aspect of the fifth embodiment of the present invention comprising an intragranular excipients and an extragranular excipients, wherein intragranular portion comprising: a cabozantinib is 25.340 % w / w, a lactose monohydrate is 20.660 % w / w, a croscarmellose sodium is 5.000 % w / w, a corn starch is 28.000 % w / w, a hydroxypropyl cellulose is 2.000 %w / w, extragranular portion comprising: a granulated corn starch is 15.000 % w / w, a croscarmellose sodium is 3.000 % w / w, a magnesium stearate is 1.0 % w / w.

[0035] The eighth aspect of the fifth embodiment of the present invention comprising an intragranular excipients and an extragranular excipients, wherein intragranular portion comprising: a cabozantinib is 25.340 % w / w, a lactose monohydrate is 25.660 % w / w, a croscarmellose sodium is 5.000 % w / w, a corn starch is 30.000 % w / w, a hydroxypropyl cellulose is 2.000 %w / w, extragranular portion comprising: a granulated corn starch is 8.000 % w / w, a croscarmellose sodium is 3.000 % w / w, a magnesium stearate is 1.0 % w / w.

[0036] The ninth aspect of the fifth embodiment of the present invention comprising an intragranular excipients and an extragranular excipients, wherein intragranular portion comprising: a cabozantinib is 25.340 % w / w, a lactose monohydrate is 25.660 % w / w, a croscarmellose sodium is 5.000 % w / w, a corn starch is 28.000 % w / w, a hydroxypropyl cellulose is 2.000 %w / w, extragranular portion comprising: a mannitol is 10.000 % w / w, a croscarmellose sodium is 3.000 % w / w, a magnesium stearate is 1.0 % w / w.

[0037] The tenth aspect of the fifth embodiment of the present invention comprising an intragranular excipients and an extragranular excipients, wherein intragranular portion comprising: a cabozantinib is 25.340 % w / w, a lactose monohydrate is 25.660 % w / w, a croscarmellose sodium is 5.000 % w / w, a corn starch is 28.000 % w / w, a hydroxypropyl cellulose is 2.000 %w / w, extragranular portion comprising: a lactose monohydrate is 10.000 % w / w, a croscarmellose sodium is 3.000 % w / w, a magnesium stearate is 1.0 % w / w.

[0038] The eleventh aspect of the fifth embodiment of the present invention comprising an intragranular excipients and an extragranular excipients, wherein intragranular portion comprising: a cabozantinib is 25.340 % w / w, a lactose monohydrate is 25.660 % w / w, a croscarmellose sodium is 5.000 % w / w, a corn starch is 28.000 % w / w, a hydroxypropyl cellulose is 2.000 %w / w, extragranular portion comprising: a microcrystalline cellulose is 10.000 % w / w, a croscarmellose sodium is 3.000 % w / w, a magnesium stearate is 1.0 % w / w.

[0039] The sixth embodiment of the present invention provides a process for preparing a pharmaceutical composition comprising a crystalline form of cabozantinib wherein said process for the preparation of pharmaceutical composition comprises a granulation technique.

[0040] The first aspect of the sixth embodiment of the present invention wherein said granulation technique preferably comprises wet granulation.

[0041] The seventh embodiment of the present invention provides stable solid oral pharmaceutical compositions comprising cabozantinib and one or more pharmaceutically acceptable excipients wherein the strength of cabozantinib is present in the range of about from 2.5 mg to 200mg, corresponding to 2.5mg, 5mg, lOmg, 15mg, 20mg, 40mg, 60mg, 80mg, lOOmg, 120mg, 140mg, 160mg, 180mg or 200mg equivalent of cabozantinib free base.

[0042] The first aspect of seventh embodiment of the present invention provide stable solid oral pharmaceutical composition comprising lower strengths of cabozantinib and one or more pharmaceutically acceptable excipients, wherein the lower strength of cabozantinib is present in range of about from 2.5 mg to 15 mg, corresponding to 2.5mg, 5mg, lOmg, or 15mg equivalent of cabozantinib free base.

[0043] The second aspect of seventh embodiment of the present invention provide stable solid oral pharmaceutical composition comprising higher strengths of cabozantinib and one or more pharmaceutically acceptable excipients, wherein the higher strength of cabozantinib is present in the range of about from 80 mg to 200 mg, corresponding to 80mg, lOOmg, 120mg, 140mg, 160mg, 180mg or 200mg equivalent cabozantinib free base.

[0044] The eight embodiment of the present invention provides stable solid oral tablet or capsule dosage form comprising cabozantinib and one or more pharmaceutically acceptable excipients, wherein said tablet or capsule dosage forms are interchangeable. Means tablet dosage form can be used for all the approved indications of cabozantinib capsule and “vice- versa”.

[0045] The ninth embodiment of the present invention relates to a process for preparing a solid dosage form comprising a crystalline form of cabozantinib and one or more pharmaceutically acceptable excipients. The first aspect of the ninth embodiment of the present invention relates to a process for preparing a solid dosage form comprising a crystalline form of cabozantinib and one or more pharmaceutically acceptable excipients comprising the following steps:

[0046] 1. sifting & blending cabozantinib (s)-malate, diluents and disintegrants.

[0047] 2. sifting & blending binders in solvent to prepare binder solution

[0048] 3. granulating the blend obtained in step (1) by using binder solution of obtained in step (2);

[0049] 4. sifting & mixing extra granular excipients such as disintegrants, diluents and lubricants.

[0050] 5. further processing the granules obtained from step (4) for the preparation of tablet.

[0051] The tenth embodiment of the present invention is to provide stable pharmaceutical composition wherein the pharmaceutical composition comprising liquid oral dosage form or liquid or lyophilized injectable dosage form.

[0052] The eleventh embodiment of the present invention provides stable ready-to-use or ready to dilute or powder for solution forms of oral liquid dosage form comprising cabozantinib and one or more pharmaceutically acceptable excipients wherein said excipients are those which improve the stability of the said pharmaceutical composition.

[0053] The first aspect of eleventh embodiment of the present invention provides stable ready-to-use or ready to dilute or powder for solution forms of oral liquid dosage form comprising cabozantinib, wherein, said stability improving excipients are one or more selected from a solubilizing agent, buffering agent, thickening agents, chelating agent, antioxidant, preservative, anti-foaming agents, Sweetener, flavoring agent and pH adjusting agents and any other pharmaceutical excipients for improving stability.

[0054] The second aspect of eleventh embodiment of the present invention provides liquid oral pharmaceutical composition comprising cabozantinib or its pharmaceutically acceptable salts, wherein said pharmaceutical composition does not contain d-a-tocopheryl polyethylene glycol succinate

[0055] The twelfth embodiment of the present invention provides stable ready-to-use or ready to dilute or powder for solution forms of oral liquid dosage form comprising cabozantinib wherein, the diluent or solvent in liquid dosage form is aqueous or non-aqueous and further provides process for preparation.

[0056] The first aspect of the twelfth embodiment of the present invention relates to a process for the preparation of stable ready-to-use or ready to dilute or powder for solution forms of oral liquid form by using a processes well known in the art for the preparing oral liquids, such as mixing, solubilizing and maintain the pH of oral solution of cabozantinib and one are more pharmaceutically acceptable excipients suitable for preparing oral liquid solution and finally aseptically filling in a suitable bottle.

[0057] The thirteenth embodiment of the present invention provides stable ready-to-use or ready to dilute or powder for solution forms of oral liquid dosage form comprising cabozantinib and one or more pharmaceutically acceptable excipients wherein the strength of cabozantinib present in said ready-to-use or ready to dilute oral liquid dosage form ranges about from 2.5 mg to 200mg, corresponding to 2.5mg, 5mg, lOmg, 15mg, 20mg, 40mg, 60mg, 80mg, lOOmg, 120mg, 140mg, 160mg, 180mg or 200mg equivalent of cabozantinib free base.

[0058] The first aspect of thirteenth embodiment of the present invention provide stable ready-to-use or ready to dilute or powder for solution forms of oral liquid dosage form comprising lower strengths of cabozantinib and one or more pharmaceutically acceptable excipients wherein the lower strength of cabozantinib present in said ready-to-use or ready to dilute oral liquid dosage form ranges about from 2.5 mg to 15 mg, corresponding to 2.5mg, 5mg, lOmg or 15mg) equivalent of cabozantinib free base.

[0059] The second aspect of thirteenth embodiment of the present invention provide stable ready-to-use or ready to dilute or powder for solution forms of oral liquid dosage form comprising higher strengths of cabozantinib and one or more pharmaceutically acceptable excipients wherein the higher strength of cabozantinib present in said ready-to-use or ready to dilute oral liquid dosage form ranges about from 80 mg to 200 mg, corresponding to 80mg, lOOmg, 120mg, 140mg, 160mg, 180mg or 200mg equivalent of cabozantinib free base. The fourteenth embodiment of the present invention provides stable ready-to-use or ready to dilute or powder for solution forms of oral liquid dosage form comprising cabozantinib and one or more pharmaceutically acceptable excipients which is buffered to a pH of about 2.0 to about 8.0 to further increase the stability of the said pharmaceutical composition.

[0060] The fifteenth embodiment of the present invention provides stable dosage form comprising parenteral dosage form, selected from but are not limited to lyophilized powder formulation for injection or liquid injectable formulation for injection of cabozantinib and one or more pharmaceutically acceptable excipients.

[0061] The first aspect of fifteenth embodiment of the present invention provides stable dosage form comprising parenteral dosage form, selected from but are not limited lyophilized powder formulation for injection or liquid injectable formulation for injection of cabozantinib, wherein cabozantinib used for the preparation of the present invention is amorphous, or in crystalline forms, or in mixture of amorphous and crystalline form. Crystalline forms may be anhydrous, solvate or hydrate forms.

[0062] The second aspect of fifteenth embodiment of the present invention provides stable parenteral pharmaceutical composition liquid injectable injection.

[0063] The third aspect of fifteenth embodiment of the present invention provides stable parenteral pharmaceutical composition prepared by specialized techniques like and not limited to “Lyophilization” or “Freeze drying”.

[0064] The sixteenth embodiment of the present invention provides stable dosage form comprising parenteral dosage form, selected from but are not limited to lyophilized powder formulation for injection or liquid injectable formulation for injection of cabozantinib and one or more pharmaceutically acceptable excipients wherein said excipients are those which improve the solubility and stability of the said pharmaceutical composition.

[0065] The first aspect of sixteenth embodiment of the present invention provides stable dosage form comprising parenteral dosage form, selected from but are not limited to lyophilized powder formulation for injection or liquid injectable formulation for injection of cabozantinib and one or more pharmaceutically acceptable excipients wherein said solubility and stability improving excipients are one or more selected from, but are not limited to a solubilizing agent, buffering agent, stabilizing agent, chelating agent, anti-oxidant, preservative, bulking agent, surfactant / detergent and pH adjusting agents and any other pharmaceutical excipients for improving stability.

[0066] The second aspect of sixteenth embodiment of the present invention comprising: (i) cabozantinib or its pharmaceutically acceptable salts; (ii) a solvent system containing a pharmaceutically acceptable solvent suitable for injection selected from the group comprising of Cl -4 alkyl alcohol, polyethylene glycol, dimethylsulfoxide, N- methyl-2-pyrrolidone, dimethylacetamide, ethyl lactate or combination thereof; (iii) at least one solubilizing agent; and (iv) optionally, a pH adjusting agent; and wherein the injection is administered intravenously or subcutaneously.

[0067] The third aspect of sixteenth embodiment of the present invention comprising: (i) cabozantinib or its pharmaceutically acceptable salts; (ii) a solvent system containing a pharmaceutically acceptable solvent suitable for injection selected from the group comprising of ethanol, propylene glycol, polyethylene glycol or combination thereof; (iii) polysorbate 80 as a solubilizing agent; and (iv) optionally, a pH adjusting agent; and wherein the injection is administered intravenously or subcutaneously.

[0068] The fourth aspect of sixteenth embodiment of the present invention the injectable formulation of injection administration comprising about 2.5 mg / ml to about 20 mg / ml of cabozantinib; 200 mg / ml to 400 mg / ml of polysorbate 80; Q.S Ethanol and optionally about 200 mg / ml to 300 mg / ml of propylene glycol; 200 mg / ml to 300 mg / ml of polyethylene glycol and sufficient quantity Glacial Acetic acid for pH adjustment to pH 3-4.

[0069] The eighteenth embodiment of the present invention provides stable parenteral dosage form selected from but are not limited to lyophilized powder formulation for injection or liquid injectable formulation for injection of cabozantinib and one or more pharmaceutically acceptable excipients wherein the strength of cabozantinib present in said stable parenteral dosage form selected from ranges about from 2.5 mg to 200mg, corresponding to 2.5mg, 5mg, lOmg, 15mg, 20mg, 40mg, 60mg, 80mg, lOOmg, 120mg, 140mg, 160mg, 180mg or 200mg) equivalent of cabozantinib free base. The nineteenth embodiment of the present invention provides stable parenteral dosage form selected from but are not limited to lyophilized powder formulation for injection or liquid injectable formulation for injection of cabozantinib and one or more pharmaceutically acceptable excipients which is buffered to a pH of about 2.0 to about 8.0 to further increase the stability of the said pharmaceutical composition.

[0070] The twentieth embodiment of the present invention discloses a pharmaceutical formulation comprising a crystalline form of cabozantinib for use as medicament for the treatment or prophylaxis of Renal cell carcinoma (RCC), Hepatocellular Carcinoma, or Differentiated Thyroid in human patients in need thereof.

[0071] The present invention may be embodied in other specific form without departing its spirit or essential characteristics. The described embodiments are to be considered in all respect only as illustrative and not restrictive. All changes which come within the meaning and range of equivalency of the claims are to be embraced within the scope.

[0072] Detailed Description of the Invention:

[0073] The present invention pertains to a stable pharmaceutical composition comprising cabozantinib or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient, which does not contain glidant(s). Preferably, the pharmaceutically acceptable salts of cabozantinib is cabozantinib S -malate. Furthermore, the present invention encompasses manufacturing processes and use of stable compositions of the present invention for prevention, treatment or prophylaxis of Renal cell carcinoma (RCC), Hepatocellular Carcinoma or Differentiated Thyroid Cancer in human patients in need thereof.

[0074] The disclosure herein is not limited to the particular systems, devices and methods described, as these may vary. The terminology used in the description is for the purpose of describing the particular versions or embodiments only and is not intended to limit the scope.

[0075] The term “active ingredient”, “drug”, “biologically active molecule”, “biologically active moiety” or “biologically active agent”, when used herein means any substance which can affect any physical or biochemical properties of a biological organism, including but not limited to viruses, bacteria, fungi, plants, animals, and humans. In particular, as used herein, Active ingredient include any substance intended for diagnosis, cure mitigation, treatment, or prevention of disease in humans or other animals, or to otherwise enhance physical or mental well-being of humans or animals or to have direct effect in restoring, correcting or modifying physiological functions in human beings. As used herein active substance is preferably a cabozantinib. Further wherever cabozantinib is present it encompasses the cabozantinib free base and it pharmaceutically acceptable salts, preferably S -Malate salt.

[0076] The term "stable" as used herein refers physical and / or chemical stability.

[0077] The term "therapeutically effective amount" of a compound as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications. An amount adequate to accomplish this is defined as "therapeutically effective amount". Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician.

[0078] The term “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or “pharmaceutically acceptable inactive ingredient” as used herein includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except in so far as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0079] The term “about” as used herein will compensate for variability allowed for in the pharmaceutical industry and inherent in pharmaceutical products, such as differences in product strength due to manufacturing variation and time-induced product degradation. In one embodiment the term allows for any variation which in the practice of pharmaceuticals would allow the product being evaluated to be considered pharmaceutically equivalent or bioequivalent to the recited strength. In another embodiment the term allows for any variation within ±10% of the recited strength or concentration of the formulation.

[0080] The term “Pharmaceutically acceptable salts” as used herein of cabozantinib may be formed as acid addition salts, for example with organic or inorganic acids. Suitable inorganic acids include but are not limited to halogen acids such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids include but are not limited to carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, benzoic acid, salicylic acid, cinnamic acid, or other organic protonic acids, such as ascorbic acid. Useful salt of cabozantinib for preparing present inventive compositions herein is (S)-malate salt.

[0081] The invention can be defined based on several principal embodiments which can be combined in any manner physically and mathematically possible to create additional principal embodiments.

[0082] Presently useful compositions may include one or more components in amounts effective to facilitate the usefulness and effectiveness of the present methods and / or the presently useful compositions. Examples of such components include, filler / diluent, disintegrant, binder, lubricants, buffering agent, chelating agent, anti-oxidant, preservative, bulking agent, surfactant / detergent Sweeteners, flavoring agents and pH adjusting agents without limitation, one or more selected from and any other pharmaceutical excipients for improving stability with the proviso that the pharmaceutical composition does not include glidant(s).

[0083] The pharmaceutical composition according to the invention typically comprises at least one filler / diluent / adsorbents. Suitable diluents / adsorbents include monosaccharides and oligosaccharides such as glucose, fructose, saccharose, lactose (anhydrous and monohydrate), raffinose, trehalose and dextrates, sugar alcohols such as mannitol, sorbitol, maltitol, xylitol and lactitol, compressible sugar, microcrystalline cellulose, magnesium aluminium metasilicate, pregelatinized starch, granulated corn / maize starch, powdered cellulose, silicified microcrystalline cellulose, silicon dioxide, crospovidone, croscarmellose sodium, calcium hydrogen phosphate, calcium carbonate, calcium lactate and mixtures thereof.

[0084] The diluents / filler are used interchangeably in the present invention. The preferred diluent / filler is at least one selected from the group consisting of silicified microcrystalline cellulose, microcrystalline cellulose, magnesium aluminium metasilicate, mannitol, granulated corn starch and lactose monohydrate.

[0085] The term “bulking agent” refers to a substance or component that is chemically compatible with the active pharmaceutical ingredient and with further excipients of a composition, and that adds mass to a lyophilized composition. Some suitable bulking agents for pharmaceutical compositions according to the present invention is for example but not limited to mannitol, sucrose, fructose, mannose, trehalose, L-proline, glycine and polyvinylpyrrolidone.

[0086] The binder is used in a pharmaceutical composition to improve the cohesion and plasticity of the powder mixture, which enhances the processability of the tablet and reduces the risk of tablet breakage during manufacture. The binders are selected from but are not limited to cellulose derivatives such as hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose sodium, microcrystalline cellulose, gelatin, starch paste, pregelatinized starch, povidone or polyvinylpyrrolidone and sucrose. The preferred binder in a present pharmaceutical composition is one or more selected from hydroxypropyl cellulose and povidone. The most preferred binder in a present pharmaceutical composition is hydroxypropyl cellulose.

[0087] The disintegrating agents suitable for use in the present formulations include which facilitate the breakup of a tablet when it is placed in aqueous environment. Disintegrants once in contact with water or gastric juice, swell, hydrate, change in volume or form to produce a disruptive force that opposes the efficiency of the binder / s causing the compressed table to break apart. The disintegrants are selected from maize starch, potato starch, carboxymethylstarch, sodium starch glycolate, croscarmellose sodium, crospovidones, sodium carboxymethylcelluloses, sodium alginate, microcrystalline cellulose, methacrylic acid copolymer, potassium polacrilin. The most preferred disintegrant in a present pharmaceutical composition is one or more selected from croscarmellose sodium and crospovidone.

[0088] Lubricants are used in the tablet formulation to reduce the friction during the compression stages and to prevent the sticking of the tablet to the punch faces. Lubricant is selected from stearic acid (calcium stearate and magnesium stearate), vegetable oils (corn oil), mineral oils, polyethylene glycol, inorganic salts (such as sodium chloride), organic salts (sodium benzoate, sodium acetate), and polyvinyl alcohols. The most preferred lubricant is magnesium stearate.

[0089] Coating is a process by which an essentially dry, outer layer of coating material is applied to the surface of a dosage form in order to confer specific benefits over uncoated variety. Coating may be carried out by using coating agents such as Opadry Yellow, Opadry Black, Opadry Red and Opadry White.

[0090] Buffer solutions particularly maintain the solution dosage forms at a particular ion concentration and pH, some suitable buffer components, for example, and without limitation, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminum hydroxide / sodium bicarbonate coprecipitate, mixture of an amino acid and a buffer, a mixture of aluminum glycinate and a buffer, a mixture of an acid salt of an amino acid and a buffer, and a mixture of an alkali salt of an amino acid and a buffer. Additional buffering agents include citric acid, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, phosphoric acid, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, disodium phosphate anhydrous, tripotassium phosphate, sodium acetate may be employed to maintain a suitable pH in the present invention.

[0091] Surfactants offer many advantages. One of these is the use of surfactants becomes inevitable to reduce the interfacial tension between the medium and the drug and to increase solubility of drugs. Since carfilzomib has low molarity, the choice of surfactant is of great importance. Suitable the surfactants are selected from the group comprising macrogol 15 hydroxystearate, macrogolglycerol ricinoleate 35, polyoxyethylene sorbitan esters (polysorbate), sodium lauryl sulphate, propylene glycol, glyceryl oleate, tocopherol, ascorbyl palmitate, citric acid, polyethoxylated fatty acid esters, polyoxyethylene hydrogenated castor oil, sorbitan esters, docusate sodium, nonoxynol or mixtures thereof.

[0092] Sweetening agents illustratively include glucose, fructose, sucrose, xylitol, tagatose, sucralose, maltitol, isomaltulose, Isomalt™ (hydrogenated isomaltulose), lactitol, sorbitol, erythritol, trehalose, maltodextrin, polydextrose, and the like. Other sweetening agents illustratively include glycerin, inulin, maltol, acesulfame and salts thereof, e.g., acesulfame potassium, alitame, aspartame, neotame, sodium cyclamate, saccharin and salts thereof, e.g., saccharin sodium or saccharin calcium, neohesperidin dihydrochalcone, stevioside, thaumatin, and the like. Preservatives include anti-microbials, anti-oxidants, and agents that enhance sterility. Exemplary preservatives include ascorbic acid, ascorbyl palmitate, BHA, BHT, citric acid, EDTA and its salts, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, parabens (such as methylparaben, ethylparaben, propylparaben, butylparaben and their salts), benzoic acid, sodium benzoate, potassium sorbate, vanillin, and the like.

[0093] The flavoring agent or flavorant to enhance the taste or aroma of the formulation in liquid form. Suitable natural or synthetic flavoring agents can be selected from standard reference books, for example Fenaroli's Handbook of Flavor Ingredients, 3rd edition (1995). Non-limiting examples of suitable natural flavors, some of which can readily be simulated with synthetic agents or combinations thereof, include anise, cinnamon, cacao, orange, peppermint, cherry (in particular wild cherry), grape, bubblegum, vanilla, and mixed berry. Flavoring agents can be used singly or in combinations of two or more.

[0094] Suspending agents referred in the present invention are the compounds which are added to increase the viscosity of the solution, which is necessary to prevent sedimentation of the suspended particles. Suspending agents also act as thickening agents therefore sometimes they are also referred as thickening agents as well. Examples of suitable suspending agent are but not limited to sodium alginate, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, CMC, Na-CMC, microcrystalline cellulose, tragacanth, xanthan gum, bentonite, carageenan, guar gum, colloidal silicon dioxide. The preferred thickening agent is MCC & Na-CMC Dispersion and xanthan gum.

[0095] Anti-foaming agents are used in liquid dosage forms to reduce or prevent the formation of foam during manufacturing. Examples of antifoaming agents include simethicone emulsions, fatty acid esters, polysorbates, ethanol, and the like.

[0096] The liquid composition of the present invention comprises at least one solvent. Nonlimiting examples of solvent are ethanol, pentane, 2-methylbutane (isopentane), heptane, hexane, methanol, 2-methoxyethanol, isopropanol, n-butanol, t-butyl alcohol, octanol, ethyl acetate, 2-methoxyethyl acetate, butyl acetate, benzyl benzoate, benzene, toluene, diethyl ether, 2-ethoxyethyl ether, ethylene glycol dimethyl ether, methyl t-butyl ether, formaldehyde, glutaraldehyde, acetone, 3 -pentanone (diethyl ketone), ethylene glycol, propylene glycol, acetic acid, trifluoroacetic acid, phosphoric acid, acetic anhydride, piperidine, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide (DMSO), benzonitrile, acetonitrile, hydrazine, di chloromethane, chloroform, carbon tetrachloride, 1 ,2- di chlorobenzene, 1,2-di chloroethane, tetrachloroethylene and 1 -chlorobutane, tetrahydrofuran, 1,4-di oxane; glycerin / glycerol, Polyethylene glycol (PEG) e.g.: PEG 400 and Polypropylene glycol (PPG), e.g. PPG 400, PPG 1200 and PPG 2000.

[0097] The use of the terms "a," "an" and "the" and similar references in the context of this disclosure (especially in the context of the following) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., such as, preferred, preferably) provided herein, is intended merely to further illustrate the content of the disclosure and does not pose a limitation on the scope of the invention. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present disclosure.

[0098] The inventors of the present invention found that the flow properties (Bulk density, Tap density, Hausner’s ratio and compressibility index) of the inventive pharmaceutical composition during preparation could be improved without the use of glidant(s).

[0099] EXAMPLES

[0100] Table 01: (Example 1-3)

[0101] Table 02: (Example 4-6)

[0102] Manufacturing process for (Example 1-6):

[0103] 1. Cabozantinib (s)-malate, lactose monohydrate, croscarmellose sodium and corn starch were co-sifted through suitable sieve and the sifted material was loaded in rapid mixer granulator and mixed well.

[0104] 2. binder solution was prepared by dissolving hydroxyl propyl cellulose in water and stirring was continued till the clear solution was obtained.

[0105] 3. granulation: granulation of blend obtained from step (1) was done by using binder solution obtained from step (2); 4. granules formed in step (3) were dried at suitable temperature to obtain suitable loss on drying (LOD);

[0106] 5. dried granules of step (4) were sifted and milled and passed through suitable sieve;

[0107] 6. extra granular ingredients such as disintegrant croscarmellose sodium and diluents granulated corn starch, microcrystalline cellulose, lactose monohydrate and mannitol as exemplified in the above tables were sifted through suitable sieve.

[0108] 7. granules of step (5) and extra granular ingredients of step (6) were mixed and blended in a suitable blender;

[0109] 8. lubrication: magnesium stearate was added to granules of step (7) and blended in a suitable blender. 9. The blend of step (8) was compressed using suitable tooling to form uncoated tablets and was film coated.

[0110] Table 3: (Liquid oral Solution - Example 7-9)

[0111] Manufacturing process for (Example 7-9):

[0112] 1. A required quantity of cabozantinib S -malate, benzyl alcohol, propylene glycol, sucralose powder, medium-chain triglycerides, polyethylene glycol, sesame oil, strawberry flavor, and ethanol was weighed.

[0113] 2. Approximately 50% of the weighed quantity of medium-chain triglycerides or polyethylene glycol, or sesame oil was transferred into a suitable mixing vessel. Benzyl alcohol was added, and the mixture was stirred until a clear solution was obtained.

[0114] 3. Cabozantinib S -malate was introduced into the clear solution from step 2, and stirring was continued until a homogeneous and clear solution was achieved.

[0115] 4. The weighed quantity of sucralose powder was dissolved in ethanol by stirring until a clear solution was formed.

[0116] 5. The sucralose solution from step 4 was gradually added to the cabozantinib- containing solution obtained in step 3. Stirring was continued until a clear and homogeneous solution was obtained.

[0117] 6. Strawberry flavor was incorporated into the solution from step 5, followed by stirring until a clear and uniform solution was achieved. 7. The final solution was measured, and the volume was adjusted to the required batch size by adding the remaining quantity of medium-chain triglycerides, polyethylene glycol, or sesame oil as necessary.

[0118] Table 4: (Liquid oral suspension Example 10 and 11) Manufacturing process for (Example 10 & 11):

[0119] The preparation of the cabozantinib suspension involves the following sequential steps:

[0120] 1. Suspending Agent Phase

[0121] • A required quantity of purified water was taken in a suitable mixing vessel and stirred continuously. • Xanthan gum or sodium carboxymethylcellulose (CMC) combined with microcrystalline cellulose was slowly added under stirring.

[0122] • Stirring was continued until a clear and homogeneous solution was formed.

[0123] 2. Drug Dispersion Phase

[0124] • A separate quantity of purified water was taken in a mixing vessel and stirred continuously. • Glycerin and polysorbate 80 or sorbitol, along with polyvinyl alcohol, were added sequentially under stirring.

[0125] • Stirring was continued until a clear solution was obtained.

[0126] • Cabozantinib was then added to the solution under stirring, followed by 15 minutes of mixing.

[0127] • Homogenization of the mixture was performed at 3500 RPM for an additional 15 minutes. uffer Phase

[0128] • A required quantity of purified water was taken in a separate vessel and stirred.

[0129] • Trisodium citrate dihydrate or disodium phosphate anhydrous was added under continuous stirring until a clear solution was achieved.

[0130] • Citric acid monohydrate or sodium dihydrogen phosphate anhydrous was then introduced into the solution and stirred until completely dissolved.

[0131] • Sodium benzoate or a combination of methyl paraben and propyl paraben was added under stirring until fully dissolved.

[0132] • Sucralose powder and simethicone (30% emulsion) were added to the solution and stirred until a clear, homogeneous solution was formed. ulk Solution

[0133] • The buffer phase solution (Step 7) was gradually added to the drug dispersion phase solution (Step 3) under continuous stirring. Stirring was continued until a uniform solution was obtained.

[0134] • The suspending agent phase solution (Step 1) was then added to the mixture under stirring.

[0135] • Stirring was continued for 15 minutes, followed by homogenization for 25 minutes at 3500 RPM. inalization

[0136] • A flavoring agent was added to the bulk solution obtained in Step 9, and stirring was continued for an additional 15 minutes. • The volume of the suspension was measured and adjusted to the target batch volume using purified water.

[0137] • The final suspension was mixed thoroughly for 30 minutes to ensure uniformity and homogeneity.

[0138] 5 Table 05: (Injectable dosage forms Example 12 - 17)

[0139] Manufacturing process for (Example 12 & 17):

[0140] 1. A required quantity of ethanol was measured and transferred into a suitable mixing vessel. Propylene glycol or polyethylene glycol was optionally added to the ethanol 0 under continuous stirring. Stirring was maintained until a clear solution was obtained.

[0141] 2. Polysorbate 80 was added to the solution obtained in Step 1 under continuous stirring. Stirring was continued until a clear and homogenous solution was formed.

[0142] 3. If necessary, the pH of the solution from Step 2 was adjusted to a range of pH 3-4 by the gradual addition of glacial acetic acid under continuous stirring. 5 4. The volume of the solution from Step 3 was adjusted to the desired batch size using ethanol. The resulting solution was filtered through a 0.2 pm filter to ensure sterility and clarity.

[0143] 5. The filtered solution was filled into vials at a specific fill volume appropriate to the required strength of the formulation. 0 In vitro dissolution study

[0144] Dissolution studies were performed separately in accordance with the dissolution method. The dissolution conditions were 900 ml of 0.01 N HC1 with 0.375% Triton X-100 (degassed) with USP type II dissolution test apparatus at a speed of 75 rpm. The sample (10 ml) was withdrawn at regular time intervals (15, 30, and 45 Min.) and replaced the same with fresh dissolution medium. The samples were estimated for amount of drug dissolved by measuring their absorbance. The amount of drug released was calculated and plotted against time in below table.

[0145] Table 06:

[0146] Content of Related substance or Impurity: (% w / w by HPLC):

[0147] Stability samples of present invention pharmaceutical composition comprising cabozantinib and a pharmaceutically acceptable carrier were evaluated for related substance or impurities by HPLC. Wherein the said pharmaceutical composition has a Acid impurity, Hydroxy impurity, Dimer-2 impurity and Any unspecified degradation products of less than about 1.0 % as measured by HPLC are tabulated below.

[0148] Table 07:

[0149]

Claims

Claims1. A pharmaceutical composition comprising cabozantinib or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, wherein the composition does not include a glidant and is in the form of a solid dosage form, and the dosage form is selected from the group consisting of a tablet and a capsule.

2. The pharmaceutical composition as claimed in claim 1, wherein the cabozantinib or its pharmaceutically acceptable salt is present in an amount ranging from 2.5 mg to 200mg, corresponding to 2.5mg, 5mg, lOmg, 15mg, 20mg, 40mg, 60mg, 80mg, lOOmg, 120mg, 140mg, 160mg, 180mg or 200mg equivalent of cabozantinib free base.

3. The pharmaceutical composition as claimed in claim 1, cabozantinib is cabozantinib S-Malate salt.

4. The pharmaceutical composition as claimed in claim 1, pharmaceutically acceptable excipients comprising intragranular excipients and extragranular excipients.

5. The pharmaceutical composition as claimed in claim 4, wherein the intragranular excipients comprise: filler / diluent in an amount from about 30 % w / w to about 70 % w / w; disintegrant in an amount from about 3 % w / w to about 15 % w / w; binder in an amount from about 1 % w / w to about 10 % w / w and the extragranular excipients comprise filler / diluent in an amount from about 5 % w / w to about 30 % w / w; disintegrant in an amount from about 3 % w / w to about 15 % w / w and a lubricant in an amount from about 0.1 % w / w to about 3 % w / w and optionally comprises a coating.

6. The pharmaceutical composition as claimed in claim 4, wherein the intragranular excipients comprise: corn starch in an amount from about 15% w / w to about 30% w / w; lactose in an amount from about 15% w / w to 40% w / w; croscarmellose sodium in an amount from about 3% w / w to 15% w / w; hydroxypropyl cellulose in an amount from about 1 % w / w to about 10 % w / w and the extragranular excipients comprise: croscarmellose sodium in an amount from about 3% to 15% w / w; one or more diluent in an amount from about 8% w / w to 25% w / w selected from the group comprising granulated com starch, lactose monohydrate, mannitol, microcrystalline cellulose; croscarmellose sodium in an amount from about 3% w / w to 15% w / w; magnesium stearate in an amount from about 0.5% w / w to 2% w / w and optionally comprises a coating, wherein the coating is opadry.

7. The pharmaceutical composition as claimed in claim 5, wherein the solid dosage form is prepared by using a process comprising a wet granulation method.

8. A liquid oral pharmaceutical composition comprising cabozantinib or its pharmaceutically acceptable salts, wherein said pharmaceutical composition does not contain d-a-tocopheryl polyethylene glycol succinate.

9. A pharmaceutical composition comprising cabozantinib, wherein the pharmaceutical composition is an injectable dosage form.

10. The pharmaceutical composition as claimed in claim 9 comprising: (i) cabozantinib or its pharmaceutically acceptable salts; (ii) a solvent system containing a pharmaceutically acceptable solvent suitable for injection selected from the group comprising of Cl -4 alkyl alcohol, polyethylene glycol, dimethylsulfoxide, N- methyl-2-pyrrolidone, dimethylacetamide, ethyl lactate or combination thereof; (iii) at least one solubilizing agent; and (iv) optionally, a pH adjusting agent; and wherein the injection is administered intravenously or subcutaneously.

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