FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions of taxane and its derivatives, cyclodextrins derivative, wherein the composition is free of surfactants and glycols.

BACKGROUND OF THE INVENTION

A taxane is a type of mitotic inhibitor and a type of antimicrotubule agent. They are used to treat cancer. Taxanes interfere with microtubules (cellular structures that help move chromosomes during mitosis). Taxanes include a class of chemotherapy compounds that includes paclitaxel, docetaxel and cabazitaxel. As antimicrotubule agents, taxanes inhibit the normal process of reorganisation of the microtubule network essential for cellular function, which leads to of mitosis (cell division).

Taxane derivatives, such as paclitaxel, docetaxel and cabazitaxel are well known and established drugs in the treatment of malignant tumors. For example, paclitaxel is marketed by Bristol-Myers-Squibb under the trade name Taxol®, docetaxel is marketed by Sanofi-Aventis under the trade name Taxotere ^® and cabazitaxel is marketed under the trade name Jevtana ^® Kit. The low solubility of paclitaxel, docetaxel and cabazitaxel are well documented and is the major cause for preparation of the formulation for injection containing surfactant.

US5403858 A, US5698582 A, US5922754 A, and Auspar of Cabazitaxel, disclose the use of polysorbates, polyoxyethylene glycol esters and

polyethoxylated castor oils as suitable surfactants respectively.

The currently marketed formulation of Taxotere ^® is fairly complicated in manufacturing as it involves preparation of a solution of docetaxel in polysorbate 80 and ethanol with subsequent evaporation of ethanol and filling of the viscous solution. This process requires special equipment in term of evaporation, filtration and filling. The marketing composition of docetaxel is complicated to

manufacture and require special equipment. Moreover, said marketed formulations contain ethanol, therefore it is not possible to exclude the risk of alcoholism, especially when a patient is submitted to repetitive treatments.

Jevtana is supplied as a kit comprising of drug with surfactant polysorbate 80 and other diluent vial comprising ethanol in water for injection. The drug vials prior to use has to be reconstituted with the diluent vial making sure that the polysorbate 80 is properly reconstituted but without significant foaming. This solution then has to be further diluted by injection of the appropriate amount of solution into an infusion bag. The currently marketed formulation contains an overfill for both the drug vial and the solvent vial. Thus apart from the handling this implies a risk for the proper dosing to the patient.

To overcome the above complications, research on compositions comprising taxanes with cyclodextrins have been disclosed. WO2014122498 A1 publication discloses lyophilized and liquid composition comprising cabazitaxel and sulfobutyl ether beta cyclodextrins, wherein the composition exhibited desirable stability in aqueous media, without need of ethanol and surfactants.

US848151 1 B1 and US8765716 B1 publications disclose inclusion complexes of docetaxel and hydroxypropyl-beta-cyclodextrin or sulfobutyl-beta- cyclodextrin in a ratio of 1 : 10-150.

WO2016149162 A1 publication disclose liquid pharmaceutical

composition comprising, a taxane complexed with a beta-cyclodextrin or beta- cyclodextrin derivative, a low molecular weight polyethylene glycol, an alcohol suitable for parenteral administration, and water.

W020161 13752 A1 publication disclose liquid pharmaceutical

composition, comprising cabazitaxel, at least one solubilizer such as

polyethylene glycol and a solvent such as ethanol.

Considering the above drawbacks of taxanes and its derivatives of using surfactants and polyoxyl castor oil derivatives, alternate compositions with glycols, polyalkylene glycols, cyclodextrins and its derivatives have been developed. However there still remains a lacuna to develop a composition to void the above drawbacks of existing formulations such as side effects, reconstitution procedure and multiple dilutions, patient non-compliance issues. Therefore, the present composition is quintessential to address the above issues.

SUMMARY OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising taxane or its derivatives, cyclodextrins derivative, and optionally with other pharmaceutically acceptable excipients, wherein the composition is free of surfactants and glycols. Taxane or its derivatives include paclitaxel, docetaxel, cabazitaxel, its derivatives or any mixtures thereof.

One aspect relates to the pharmaceutical composition, wherein cyclodextrins derivative include but not limited to beta-cyclodextrin, gama - cyclodextrin, hydxoxyalkyl-beta-cyclodextrin, hydxoxypropyl-beta-cyclodextrin, hydroxypropyl-gama-cyclodextrin, dimethyl-beta-cyclodextrin, methylated-beta- cyclodextrin, carboxymethyl-beta-cyclodextrin, sulfoalkyl-beta-cyclodextrin, sulfobutylether-beta-cyclodextrin, modified cyclodextrins and its derivatives or any mixtures thereof; optionally other excipients include but not limited to acidifying agent/ pH modifier, chelating agent, solvent/ co-solvent, tonicity modifier, antioxidant/preservative or any mixtures thereof.

Another aspect relates to the pharmaceutical composition wherein, the composition is free of surfactants such as polyethoxylated sorbitan fatty ester such as polysorbate 80, polyethoxylated castor oils its derivatives or mixtures thereof, glycols such as polyethylene glycol, propylene glycol and the like or any mixtures thereof.

Another aspect details, pharmaceutical composition according to the present invention is lyophilized composition, liquid composition, ready to dilute, ready to use, ready to infuse compositions and the like.

Another aspect relates to a pharmaceutical composition comprising paclitaxel, docetaxel, cabazitaxel or its derivatives, cyclodextrins derivative, and optionally with other pharmaceutically acceptable excipients, the composition is free of surfactants. Another alternate aspect relates to a pharmaceutical composition wherein it increases rate of administration and reduced administration duration to the patient, wherein the composition comprises of taxane or its derivatives, cyclodextrins derivative, and optionally pharmaceutically acceptable excipients, the composition is free of surfactants and glycols; the pharmaceutical

composition is lyophilized composition, liquid composition, ready to dilute, ready to use, ready to infuse compositions, wherein composition is in the concentration of about 0.1 mg/ml_ to about 7.0 mg/ml_.

Another aspect relates to a pharmaceutical composition with increased rate of administration and reduced administration duration to the patient, wherein

a. the composition comprises of cabazitaxel or its pharmaceutically

acceptable salt, sulfobutyl ether beta cyclodextrin, and optionally pharmaceutically acceptable excipients;

b. the composition is free of surfactants and glycols;

c. the pharmaceutical composition is lyophilized composition, liquid

composition, ready to dilute, ready to use, ready to infuse compositions; d. the composition is in the concentration of about 0.1 mg/ml_ to about 7.0 mg/ml_.

Another aspect relates to the pharmaceutical composition according to the above embodiments is used to treat cancer, carcinoma or malignant disease such as carcinoma of the ovary, prostate cancer, breast cancer, and related conditions thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising taxane or its derivatives, cyclodextrins derivative, and

pharmaceutically acceptable excipients, wherein the composition is free of surfactants and glycols. Taxane or its derivatives include paclitaxel, docetaxel, cabazitaxel, its derivatives or any mixtures thereof. The present invention relates to pharmaceutical composition comprising paclitaxel, or pharmaceutically acceptable salts thereof with at least one cyclodextrins derivative, optionally with other pharmaceutically acceptable excipients, and wherein the composition is free of surfactants and glycols.

The present invention relates to pharmaceutical composition comprising docetaxel, or pharmaceutically acceptable salts thereof with at least one cyclodextrins derivative, optionally with other pharmaceutically acceptable excipients, and wherein the composition is free of surfactants and glycols.

The present invention relates to pharmaceutical composition comprising cabazitaxel, or pharmaceutically acceptable salts thereof with at least one cyclodextrins derivative, optionally with other pharmaceutically acceptable excipients, and wherein the composition is free of surfactants and glycols.

The term "active ingredient" or "drug" refers to a substance that has a physiological effect when ingested or otherwise introduced into the body, in particular or a chemical substance used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well- being.

The term "excipient" or "pharmaceutically acceptable excipient" or "adjuvant" means a component of a pharmaceutical product that is not a pharmacologically active ingredient, such as diluent, bulking agent, carrier, acidifying agent, pH modifier, chelating agent, solvent, co-solvent, tonicity modifier, antioxidant, preservative and the like added to a drug to increase or aid its effect. The excipients or adjuvants that are useful in preparing

pharmaceutical compositions are generally safe, non- toxic, and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. The term includes one or more excipients or adjuvants.

The term "composition" is intended to encompass a combination including active ingredients and pharmaceutically acceptable excipients, as well as any product which results, directly or indirectly, from combination, complexation, or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions involving one or more of the ingredients.

The term "formulation" or "dosage form" or "composition" refers to finished pharmaceutical products that are suitable for administration, including, but not limited to, injections, etc. The term composition relates to aqueous compositions and or its related compositions as known in the art.

The term "optional" or "optionally" means that the subsequently described element, component or circumstance may or may not be present, so that the description includes instances where the element, component, or circumstance is included and instances where it is not.

The term "stability" or "stable" as used herein includes both physical and chemical stability. Stability parameters include but not limited to potency, stable pH value and other physico-chemical parameters.

"Carrier" or "vehicle" or "solvent" as used herein refers to

pharmacologically inert materials that provide a more or less fluid matrix, suitable for topical drug administration. Carriers and vehicles useful herein include any such materials known in the art, which are nontoxic and do not interact with other components of a pharmaceutical formulation or drug delivery system in a deleterious manner. The formulations of the present invention are particularly suitable for parenteral administration. Formulations suitable for parenteral dosage forms such as injectable like intravenous, intramuscular or subcutaneous, implants and the like. Other parenteral ingredients used in the formulation are generally those commonly used and recognized by persons skilled in the art of parenteral formulations.

"Pharmaceutically-acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts, solvate, hydrate, esters and the like thereof. Pharmaceutically-acceptable salt forms of compounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Pharmaceutically acceptable salts are those forms of compounds, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

Any recitation of ranges of values set forth below is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. Furthermore, all references, including patent applications, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

In one aspect the pharmaceutical composition comprises of cyclodextrins derivative as one of the component which will form an inclusion complex with the taxane or its derivative. This theory has been disclosed in Ren et al., US848151 1 B2 and US8765716 B2 that current study showed that application of cyclodextrin inclusion technology can not only enhance docetaxel stability, enhance its solubility, but also can significantly enhance the drug activity and reduce toxic and side effects, which publications are incorporated herein in their entirety. Likewise, compositions of the present invention would form inclusion complexes of paclitaxel, docetaxel, and cabazitaxel with cyclodextrins derivatives.

Cyclodextrins derivatives include but not limited to beta-cyclodextrin, gama -cyclodextrin, hydxoxyalkyl-beta-cyclodextrin, hydxoxypropyl-beta- cyclodextrin, hydroxypropyl-gama-cyclodextrin, dimethyl-beta-cyclodextrin, methylated-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, sulfoalkyl-beta- cyclodextrin, sulfobutyl-ether-beta-cyclodextrin (SBECD), modified cyclodextrins or its derivatives or any mixtures thereof.

Pharmaceutically acceptable excipient includes acidifying agent, pH modifier, chelating agent, solvent, co-solvent, tonicity modifier, antioxidant, preservative and the like or any mixtures thereof. Acidifying agents or pH modifier include but not limited to ascorbic acid, boric acid, citric acid, tartaric acid, lactic acid, oxalic acid, formic acid, benzene sulphonic acid, benzoic acid, maleic acid, malonic acid, glutamic acid, succinic acid, aspartic acid, diatrizoic acid, acetic acid and the like or mixtures thereof.

Chelating agent include but not limited to ethylene diamine tetraacetic acid (EDTA) and acceptable salts thereof, ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) and acceptable salts thereof, and 8- Amino-2-[(2-amino-5-methylphenoxy) methyl]-6-methoxyquinoline-N,N,N',N'- tetraacetic acid, tetrapotassium salt (QUIN-2) and acceptable salts thereof.

Solvent or co-solvent include but not limited to alkanols, water; lower alkanols like C1 - C4 alkanols; it includes ethanol, dehydrated alcohol, absolute alcohol and the like or any mixtures thereof.

Tonicity modifier include those commonly used in the parenteral preparations but not limited to sodium chloride, dextrose, mannitol, glycerol and the like or any mixtures thereof.

Antioxidant or preservative include but not limited to ascorbic acid, acetylcysteine, sulfurous acid salts (bisulfite, metabisulfite), monothioglyercol, phenol, metacresol, benzyl alcohol, parabens (methyl, propyl, butyl), benzalkonium chloride, chlorobutanol, thimerosal and the like or any mixtures thereof.

In another aspect the composition is free of surfactants such as polyethoxylated sorbitan fatty ester such as polysorbate 80 its derivatives or mixtures thereof, polyethoxylated castor oils its derivatives or mixtures thereof, glycols such as polyethylene glycol, propylene glycol and the like or any mixtures thereof.

In another aspect, the pharmaceutical composition is lyophilized composition, liquid composition, ready to dilute, ready to use, ready to infuse compositions and the like. The pharmaceutical composition comprising taxane include liquid composition, ready to dilute, ready to use, ready to infuse compositions can be diluted with a suitable diluent before administration.

In one embodiment, the pharmaceutical composition is a ready to use and/or ready to infuse formulation. A ready to use composition is a formulation that is suitable for administration with or without further dilution.

In one embodiment, the pharmaceutical composition is a ready to dilute formulation. A ready to dilute composition is a formulation that is suitable for administration after dilution with a suitable diluent.

Suitable diluents include, but are not limited to, water, saline, dextrose, water for injection and the like or mixtures thereof. The lyophilized powder comprising of the taxane can also be reconstituted directly with a suitable diluent before administration. Suitable diluents include, but are not limited to, water, saline, dextrose, and water for injection.

In one more aspect, pharmaceutical composition comprises of taxane and cyclodextrins derivative.

In another aspect, pharmaceutical composition comprises of paclitaxel and cyclodextrins derivative.

In another aspect, pharmaceutical composition comprises of docetaxel and cyclodextrins derivative.

In another aspect, pharmaceutical composition comprises of cabazitaxel and cyclodextrins derivative.

In one more aspect, pharmaceutical composition comprises of taxane, a cyclodextrins derivative, and optionally acidifying or buffering agent.

In another aspect, pharmaceutical composition comprises of paclitaxel, cyclodextrins derivative and optionally acidifying or buffering agent.

In another aspect, pharmaceutical composition comprises of docetaxel, cyclodextrins derivative and optionally acidifying or buffering agent.

In another aspect, pharmaceutical composition comprises of cabazitaxel, cyclodextrins derivative and optionally acidifying or buffering agent. In alternate aspect, pharmaceutical composition comprises of taxane, cyclodextrins derivative, optionally acidifying or buffering agent and chelating agent.

In another aspect, pharmaceutical composition comprises of paclitaxel, cyclodextrins derivative, optionally acidifying or buffering agent and chelating agent.

In another aspect, pharmaceutical composition comprises of docetaxel, cyclodextrins derivative, optionally acidifying or buffering agent and chelating agent.

In another aspect, pharmaceutical composition comprises of cabazitaxel, cyclodextrins derivative, optionally acidifying or buffering agent and chelating agent.

In one more aspect pharmaceutical composition comprises of paclitaxel, sulfobutylether β-cyclodextrin, optionally acidifying or buffering agent and chelating agent.

In one more aspect pharmaceutical composition comprises of docetaxel, sulfobutylether β-cyclodextrin, optionally acidifying or buffering agent and chelating agent.

In one more aspect pharmaceutical composition comprises of

cabazitaxel, sulfobutylether β-cyclodextrin, optionally acidifying or buffering agent and chelating agent.

The compositions have a pH between about 2 to about 8, example between about 2.5 to about 7.5.

Another specific aspect details the process of preparation of

compositions, the process includes:

a) required quantity of cyclodextrins derivative is taken in water and mixed;

b) taxane or its derivatives is taken and mixed with suitable solvent; c) the above drug solution is added to the cyclodextrins solution and mixed, optionally acidifying agent or pH modifier or chelating agent may be added;

d) the above solution is purged with nitrogen and filled into suitable

container and/or optionally lyophilized to obtain a lyophilized product.

Another specific aspect details the process of preparation of

compositions, the process includes:

a) required quantity of cyclodextrins derivative is taken in water and mixed;

b) cabazitaxel or its derivatives is taken and mixed with suitable solvent; c) the above drug solution of step b) is added to the cyclodextrins

solution and mixed, optionally acidifying agent or pH modifier or chelating agent may be added;

d) the above solution is purged with nitrogen and filled into suitable

container and/or optionally lyophilized to obtain a lyophilized product.

In further aspects the concentration of taxanes used in the composition is between about 0.1 mg/ml_ to about 7.0mg/ml_.

The concentration of paclitaxel used in the composition is between about 0.1 mg/ml_ to about 7.0mg/ml_.

The concentration of docetaxel used in the composition is between about 0.1 mg/mL to about 7.0mg/ml_.

The concentration of cabazitaxel used in the composition is between about 0.1 mg/mL to about 7.0mg/ml_.

Further aspects relate to pharmaceutical composition which includes increased rate of administration and reduced administration duration to the patient, wherein the composition comprises of taxane or its derivatives, cyclodextrins derivative, and optionally pharmaceutically acceptable excipients, the composition is free of surfactants and glycols.

In some aspects of the invention, the taxane is administered

intravenously as part of an intravenous infusion. Contemplated infusion volumes are preferably less, with each volume varying about +/-10% or +/-15% being preferred in some aspects. In alternative aspects of the invention, the intravenous administration volume is suitable for IV bolus administration and may also include an amount of pharmaceutically acceptable diluent. As such, smaller volumes are required to deliver therapeutic doses to patients and the patients are spared exposure to excess fluid and sodium during therapy.

Another aspect relates to a pharmaceutical composition with increased rate of administration and reduced administration duration to the patient, wherein

a. the composition comprises of cabazitaxel or its pharmaceutically

acceptable salt, sulfobutyl ether beta cyclodextrin, and optionally pharmaceutically acceptable excipients;

b. the composition is free of surfactants and glycols;

c. the pharmaceutical composition is lyophilized composition, liquid

composition, ready to dilute, ready to use, ready to infuse compositions; d. the composition is in the concentration of about 0.1 mg/ml_ to about 7.0 mg/ml_.

The composition would allow to increase rate of administration and reduced administration duration to the patient when compared to the existing formulations, hence thereby providing ease of administration to the patients depending on these type of compositions.

The composition would reduce the handling difficulties and reconstitution challenges. Ready to use and/or ready to dilute compositions will minimize dosing errors resulting from reconstitution steps. Hence, ready to use and/or ready to dilute compositions reduce the time required for administration.

In another aspect the present innovative composition being aqueous would reduce administration of high toxic excipients, thereby providing higher concentration of the drug in lower volumes, increase rate of administration and reduced administration duration to the patient when compared to the existing formulations. In one embodiment, ready to use and/or ready to dilute compositions may be in the concentration range from about 0.1 mg/mL to about 7 mg/mL and preferred volume of not more than about 700 mL.

In another embodiment, ready to use and/or ready to dilute compositions may be in the concentration range from about 0.1 mg/mL to about 0.26mg/mL and preferred volume of not more than about 250 mL.

In one more embodiment, ready to use and/or ready to dilute

compositions may be in the concentration range from about 1 mg/mL to about 5 mg/mL and preferred volume of not more than about 250 mL.

In one more aspect the pharmaceutical composition according to above embodiments include lyophilized composition, liquid composition, ready to dilute, ready to use, ready to infuse compositions and the like.

In one more aspect the pharmaceutical composition according to above embodiments include lyophilized composition, liquid composition, ready to dilute, ready to use composition, ready to infuse composition, wherein composition is in the concentration of about 0.1 mg/mL to about 7.0 mg/mL.

The pharmaceutical composition according to the above embodiments is used to treat cancer, carcinoma or malignant disease such as carcinoma of the ovary, prostate cancer, breast cancer, and related conditions thereof.

Taxanes with or without other therapeutically active agents may also be used in combination or prior to administering taxane comprising composition without departing from the present invention or to prevent side effects (e.g., hypersensitivity reactions, gastrointestinal symptoms) associated with the administration of the inventive compositions. These agents may optionally be added to the compositions. Preferably the therapeutically active agents synergistically enhance the effect of Taxanes. Examples of therapeutic agents that may be used in conjunction with the pharmaceutical compositions of the present invention include, but are not limited to alkylating agents, antihistamines, hormonal agents, H ₂ antagonists, steroids, plant-derived agents, biologic agents, platinum containing anticancer agents, interleukins, interferons, cytokines, immuno-modulating agents, monoclonal antibodies, other anticancer agents and combinations thereof.

In another embodiment the present invention is presented in an ampoule, a vial, IV bag, or a suitable parenteral container that provides the composition comprising taxane or its derivatives, cyclodextrins derivative, and optionally with other pharmaceutically acceptable excipients, the composition is free of surfactants or glycols.

In another embodiment the present invention is presented in an ampoule, vial, IV bag, or a suitable parenteral container that provides the solution composition or alternately lyophilized composition comprising, taxane or its derivatives, cyclodextrins derivative, and optionally with other pharmaceutically acceptable excipients, the composition is free of surfactants or glycols.

In another specific embodiment the present invention provides a ready to use solution in bag or IV bag comprising a separate single dose container containing solution comprising taxane or its derivatives, cyclodextrins derivative, and optionally with other pharmaceutically acceptable excipients, the composition is free of surfactants or glycols with suitable diluents such as dextrose, sodium chloride, mannitol and the like.

In another specific embodiment the present invention provides a ready to infuse solution in bag or IV bag comprising a separate single dose container containing solution comprising taxane or its derivatives, cyclodextrins derivative, and optionally with other pharmaceutically acceptable excipients, the composition is free of surfactants or glycols, with suitable diluents such as dextrose, sodium chloride, mannitol and the like.

In another embodiment, the composition comprises a kit comprising the pharmaceutical composition with increased rate of administration and reduced administration duration to the patient, wherein,

a. the composition comprises of cabazitaxel or its pharmaceutically

acceptable salt, sulfobutyl ether beta cyclodextrin, and optionally pharmaceutically acceptable excipients; b. the composition is free of surfactants and glycols;

c. the pharmaceutical composition is lyophilized composition, liquid

composition, ready to dilute, ready to use, ready to infuse compositions; d. the composition is in the concentration of about 0.1 mg/ml_ to about 7.0 mg/ml_;

the composition is presented in a suitable parenteral container, wrapped over or covered with a suitable secondary packaging system.

To further illustrate the invention, the following examples are provided. It is to be understood that these examples are provided for illustrative purposes and are not to be construed as limiting the scope of the invention. It is to be further understood that, in the examples the functions of individual ingredients are sometimes listed for illustration purposes.

Examples:

Example 1 : Compositions with 1 mg/ml_ [Ready to dilute and/or ready to infuse compositions]

Stability Details of CA1 Composition:

*-Clear Colorless slightly viscous solution Stability Details of CA2 Composition:

*-Clear Colorless slightly viscous solution

Considering the stability details of CA1 composition without pH adjustment and CA2 composition with pH adjustment by using citric acid, the stability data results of both real time and accelerated conditions were found to be satisfactory.

Further it was found that pH did not impact the composition stability and hence further studies with new composition were carried out.

Example 2: Compositions with 0.26mg/ml_ [Ready to infuse composition]

Stability Details of CA3 composition:

The stability data of CA3 composition, a ready to infuse composition at accelerated condition 25°C/ 60%RH was found to be satisfactory and pH and no change in description, pH of stability samples, and total impurities are well comparable and within specification.

Example 3: Compositions with 3 mg/ml_ [Ready to dilute composition]

Stability Details of CA4 compositions:

The stability data of CA4 composition, a ready to dilute composition at

accelerated condition 25°C/ 60%RH was found to be satisfactory and pH and no change in description, pH of stability samples, and total impurities are well comparable and within specification.

In view of the above stability details, it is evident that the proposed compositions CA1 , CA2, CA3 and CA4 are stable, easy to use and administer for the patients unlike that of the available compositions. Further it was concluded that there is no impact of citric acid on the formulation stability. The stability data results of both real time (2-8°C) and accelerated condition (25°C/60 % RH) were found to be satisfactory.