PRIORITY CLAIM

[0001] This Application claims the benefit of U. S. Provisional Application No 63/334,357 filed April 25, 2022, which application is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to a field of an oral liquid pharmaceutical compositions in general, and in particular to an oral liquid pharmaceutical composition of nilotinib and a process for preparing the same.

[0003]

BACKGROUND OF THE INVENTION

[0004] Nilotinib is 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4- methyl-lH-imidazol-l-yl) -3-(trifluoromethyl)phenyl] benzamide. A particularly useful salt of nilotinib is nilotinib hydrochloride monohydrate. These therapeutic compounds have utility as inhibitors of the protein tyrosine kinase (TK) activity of Bcr-Abl. Examples of conditions that may be treated by such therapeutic compounds include, but are not limited to, chronic myeloid leukemia and gastrointestinal stromal tumors.

[0005] Tasigna™ oral capsule (nilotinib) has been developed for chronic myeloid leukemia and gastrointestinal stromal tumors. Nilotinib is commercially available as 50mg oral capsule, lOOmg oral capsule, 150mg oral capsule and 200mg oral capsule. Nilotinib is very slightly soluble drug in water and slightly soluble drug in alcohol, belonging to the BCS class IV, and its solubility in water is 0.2pg/ml. In order to ensure bioavailability, the Nilotinib capsules developed by Novartis use micronized Nilotinib along with Poloxamer 188 as a solubilizer to increase the solubility of the drug. Novartis further discloses, problem of nilotinib overdose in combination with alcohol.

[0006] It is important that pharmaceutical products be effective and safe. Even if a pharmaceutical product is effective and safe immediately after production, if the drug is easily decomposed or denatured during distribution, it is not effective and safe as a pharmaceutical product. Therefore, the stability of the drug is extremely important for pharmaceutical products. [0007] However, in the case of oral solid formulations, there has been a defect that it is difficult for young children to take them, and there has further been a problem that since very slightly soluble drugs dissolve only in a low concentration, thus a single dose of the solution becomes too large. Moreover, Tasigna™ label suggested complex process such as, to open capsule and sprinkle on applesauce with patients having difficulty in swallowing and time limit to use said mixture is 15 minutes.

[0008] The concentration of therapeutic compound in the pharmaceutical composition is present in an amount, e.g., in a therapeutically effective amount, which will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to one of ordinary skill in the art. Furthermore, it is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular recipient, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the pharmaceutical compositions. The therapeutic compound may be administered once, or may be divided into a number of smaller doses to be administered at varying intervals of time. Thus, an appropriate amount, e.g., an appropriate therapeutically effective amount, is known to one of ordinary skill in the art.

[0009] After rigorous experimentation it was surprisingly found that oral liquid compositions comprising nilotinib or its salt thereof, in aqueous solution form provide the desired stability profile. The said composition is cost effective, safe and process of obtaining it is less complex. The present inventors have also surprisingly found that aqueous oral nilotinib can be stored at room temperature and inhibit the formation of the impurity, while maintaining a functioning solution.

SUMMARY OF THE INVENTION

[0010] In accordance with the principal aspect of the present invention, there is provided oral pharmaceutical composition comprising nilotinib that exhibits aqueous oral solution.

[0011] One aspect of the invention is an aqueous oral solution comprising (i) Nilotinib,

(ii) a cyclodextin comprising cyclodextrin, a derivative of cyclodextrin, or any combination thereof, and (iii) optionally one or more excipient, where the solution is stored at ambient temperature (e.g., 25° C.) and 60% relative humidity. The solution is formulated such that it remains a solution during storage and the nilotinib does not precipitate out.

[0012] Yet another aspect is a method of dispensing to a patient an aqueous oral solution comprising (i) nilotinib, (ii) a cyclodextin comprising cyclodextrin, a derivative of cyclodextrin, or any combination thereof, and (iii) optionally one or more acid.

[0013] In another aspect, the present invention relates to an aqueous oral solution comprising nilotinib and one or more cyclodextin comprising cyclodextrin, a derivative of cyclodextrin, wherein the solution is free or substantially free (e.g. contains less than about 10% v/v, such as less than about 5% v/v, less than about 2.5% v/v, less than about 2% v/v, less than about 1.5% v/v, less than about 1% v/v, less than about 0.5% w/v, less than about 0.3% v/v, less than about 0.2% v/v, less than about 0.1% v/v, less than about 0.05% v/v, or less than about 0.01% v/v) of alcohol.

[0014] Yet another aspect is a method of dispensing to a patient an aqueous oral solution comprising (i) nilotinib, (ii) a cyclodextin comprising cyclodextrin, a derivative of cyclodextrin, or any combination thereof, (iii) optionally one or more polyol.

[0015] In other aspect, the liquid composition comprises about 10% (w/v) to about 50% (w/v) of polyol (also known as sugar alcohol), or about 15% (w/v) to about 50% (w/v) of polyol. Exemplary polyols that can be used in the inventive compositions include sorbitol, xylitol, maltitol, glycerine, propylene glycol, erythritol and combinations thereof. In other embodiments, the liquid composition comprises about 15% (w/v) to about 40% (w/v) sorbitol or 15% (w/v) to about 25% (w/v) sorbitol, or about 16% (w/v) to about 26% (w/v) sorbitol or about 18% (w/v) to about 24% (w/v) sorbitol and in other embodiments, the liquid composition comprises about 21% (w/v) sorbitol. In other embodiments the liquid composition comprises about 15% (w/v) to about 40% (w/v) of a combination of sorbitol and maltitol. In other embodiments, the liquid composition comprises about 15% (w/v) to 25% (w/v) of maltitol and in other embodiments, the composition comprises about 20% (w/v) maltitol. In other embodiments the liquid composition comprises about 1% (w/v) to about 25% (w/v) of glycerine, and in other embodiments the liquid composition comprises about 5% (w/v) glycerine. In other embodiments the liquid composition comprises about 5% to about 50% propylene glycol (w/v).

[0016] In certain aspects, the co- solvents are organic solvents such as propylene glycol, polyethylene glycol, and combinations thereof that are pharmaceutically acceptable based on the desired formulation.

[0017] In certain aspects, the formulation contains from about 5% to about 50% by weight propylene glycol.

[0018] In one aspect of any of the aqueous oral solutions described herein, the solution may comprise a sweetener, such as sucralose, sucrose, or sodium saccharin. In one embodiment, the solution comprises from about 0 to about 1% w/v sweetener. In one embodiment, the solution comprises from about 0.001 to about 1% w/v sucralose, such as about 0.025% w/v sucralose.

[0019] In other aspects, the sweetener of the liquid composition is an artificial sweetener (also known in the art as a “high intensity sweetener”). Exemplary artificial sweeteners include sucralose, acesulfame potassium, aspartame, and the saccharins. In other embodiments, the artificial sweetener is selected from sucralose and saccharin. In other embodiments, the sucralose is present at a concentration of about 0.35% (w/v); in other embodiments, the concentration of sucralose is from about 0.1% (w/v) to about 0.8% (w/v). In other embodiments, the concentration of saccharin is about 0.05% (w/v) to about 0.25% (w/v) or 0.2% (w/v) to about 0.8% (w/v) and in other embodiments, the concentration of saccharin is about 0.15% (w/v).

[0020] In one aspect of any of the aqueous oral solutions described herein, the solution comprises from about 0.05 to about 1.0% w/v of nilotinib, such as from about 0.1 to about 0.5% w/v of nilotinib, or from 0.1 to about 0.35% w/v of nilotinib.

[0021] In one aspect of any of the aqueous oral solutions described herein, the solution comprises about 0.33% w/v of nilotinib. In another embodiment, the solution comprises about 0.2% w/v of nilotinib.

[0022] In one aspect of any of the aqueous oral solutions described herein, the one or more acid. Suitable acids include but are not limited to acetic acid, ascorbic acid, citric acid, fumaric acid, lauric acid, glacial, sorbic acid, malic acid, succinic acid, tartaric acid, phosphoric acid, hydrochloric acid, amino acid and mixtures thereof. Organic acids, which enhance the taste of the solution, are especially useful. Citric acid, for example, adds tartness that is a taste enhancer, and may play a role in overall stability of the solution. Suitable amino acid include but are not limited to lysine, alanine, glutamic acid, tryptophan and mixture thereof. The concentration of the acid in the solvent system is in the range of about 0.1% to about 5.0% or about 0.25% to about 3.0% or about 0.5% to about 2% or about 1%.

[0023] In one aspect of any of the aqueous oral solutions described herein, the one or more preservatives comprise Bronopol, Imidurea, Potassium Sorbate, Phenoxyethanol, Phenylmercuric Acetate, Butylparaben, Benzyl Alcohol, Phenylmercuric Borate, Chlorocresol, Benzethonium Chloride, Phenylethyl Alcohol, Benzalkonium Chloride, Methylparaben, Hexetidine, Chlorobutanol, Ethylparaben, Propylparaben, Sodium Benzoate, Potassium Benzoate, Sorbic Acid, Cresol, Propylparaben Sodium, Cetylpyridinium Chloride, Phenylmercuric Nitrate, Chloroxylenol, Propionic Acid, Phenol, Thimerosal, Sulfur Dioxide, Boric Acid, Edetic Acid, Sodium Propionate, Calcium Chloride, Sodium Acetate, Sodium Sulfite, Benzoic Acid, Monothioglycerol, Cetrimide, Calcium Acetate, Butylene Glycol, Sodium Metabisulfite, Alcohol, Propyl Gallate, Potassium Metabisulfite, Sodium Lactate, Chlorhexidine, Calcium Lactate, Pentetic Acid, Glycerin, Propylene Glycol Alginate, Sodium Borate, Magnesium Trisilicate, Isopropyl Alcohol, Dimethyl Ether, Propylene Glycol, Butylated Hydroxyanisole, Pyrrolidone, Lactic Acid, Sodium Lauryl Sulfate and Dimethyl Sulfoxide or a combination thereof. In another embodiment of any of the aqueous oral solutions described herein, the one or more preservatives comprise methylparaben, propylparaben, or a combination thereof. For instance, the oral solution may comprise methylparaben and propylparaben.

[0024] For instance, the oral solution may comprise methylparaben and propylparaben. The solution includes an effective amount of preservatives (such as methylparaben, propylparaben, sodium benzoate, sodium methylparaben, or a combination thereof) to inhibit microbial contamination of the solution. In one embodiment, the solution includes from about 0.01 to about 4% (such as from about 0.05 to about 1% or from about 0.05 to about 0.5%) of preservatives, such as methylparaben, propylparaben, or a combination thereof. In another embodiment, the solution includes from about 0.1 to about 0.2% of preservatives, such as methylparaben, propylparaben, or a combination thereof.

[0025] In one aspect of any of the aqueous oral solutions described herein, the solution comprises one or more flavoring agents, such as, e.g., natural grape flavor. Other suitable flavoring agents include but are not limited to, cotton candy, raspberry, strawberry, lemonlime, apple, mint, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry, grape flavors, tutti-frutti, cherry flavors, combinations thereof, and the like. In one embodiment, the solution comprises from about 0.01 to about 2% w/v flavoring agent (e.g., natural grape flavor), such as about 1.0% w/v flavoring agent.

[0026] In some aspects, the stable oral liquid pharmaceutical compositions of the present application comprises of at least one solubilisers selected from the group of nonionic, anionic, cationic and zwitterionic surfactants or mixtures thereof.

[0027] Suitable non-limiting examples of the solubiliser(s) used in the compositions of the present application includes, but not limited to, polyethoxylated fatty acids like esters of lauric acid, oleic acid, and stearic acid, PEG-fatty acid diesters like PEG-20 dilaurate, PEG- fatty acid mono- and di-ester mixtures, alcohol-oil transesterification products like PEG-35 castor oil, Polyoxy 35 castor oil, polyoxyl 40 hydrogenated castor oil, etc., polyglycerized fatty acids like poly glyceryl oleate, etc., propylene glycol fatty acid esters like propylene glycol monolaurate etc, mixtures of propylene glycol esters-glycerol esters like oleic acid esters of propylene glycol and glycerol, etc., sterol and sterol derivatives like PEG-24 cholesterol ether etc, polyethylene glycol sorbitan fatty acid esters like PEG-20 sorbitan monolaurate etc, polyethylene glycol alkyl ethers like PEG-3 oleyl ether, etc., sugar esters like sucrose monopalmitate etc, polyethylene glycol alkyl phenols like Octoxynol-1 etc, sorbitan fatty acid esters like sorbitan monolaurate, lower alcohol fatty acid esters like ethyl oleate, etc., anionic surfactants include fatty acid salts and bile salts. Additional exemplary solubilisers include, but are not limited to: polyoxyethylene alkylethers; polyethylene glycol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; poly glycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides Ionic surfactants include sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, and sodium taurocholate; Gelucire® 44/14, etc.

[0028] The at least one solubilisers be present in the stable oral liquid pharmaceutical compositions disclosed herein in a variety of concentrations. For example, the stable oral liquid pharmaceutical compositions disclosed herein can comprise at least one solubilisers of at least 1% by weight, at least 2% by weight, at least 5% by weight, at least 10% by weight, at least 15% by weight, at least 20% by weight, or a percentage between any two of the above values, based on the total weight of the composition. In some embodiments, the nilotinib composition of present application comprises of at least one solubilisers in an amount of from about 1 % to about 20% by weight, or from about 2% to about 15% by weight, or from about 2% to about 10% by weight, or from about 3% to about 10% by weight, based on the total weight of the composition.

[0029] In one aspect of any of the aqueous oral solutions described herein, the pH of the aqueous oral solution ranges from about 2 to about 7. In another of any of the aqueous oral solutions described herein, the pH of the aqueous oral solution ranges from about 2.5 to about 4. For instance, the pH may be 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, or 3.5.

[0030] In some aspects, the stable oral liquid pharmaceutical compositions of the present application may comprises of at least one buffering agents. Non-limiting examples of buffering agents include, but are not limited to sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminum hydroxide/sodium bicarbonate co precipitate, 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, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts.

[0031] In one aspect of any of the aqueous oral solutions described herein, the solution may comprises anti-oxidant. The anti-oxidant included in the formulations of the invention may further be selected from e.g., propyl gallate, lecithin, Vitamin E tocopherol, sesamin, sesamol, sesamolin, alpha tocopherol, ascorbic acid, ascorbyl palmitate, fumaric acid, malic acid, and sodium metabisulphite, disodium EDTA, and combinations of any of the foregoing. [0032] Another aspect of the present invention is to provide an aqueous oral solution composition containing, while having a reduced bitter taste of the drug.

[0033] A further aspect of the present invention is to provide a syrup composition which is easy to take.

[0034] The details of one or more aspect of the inventions are set forth in the description below. Others features, objects and advantages of the inventions will be apparent from the description and claims.

[0035] DETAILED DESCRIPTION

[0036] Before the present formulations and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. [0037] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.

[0038] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

[0039] It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a. compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.

[0040] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

[0041] In accordance with the principal aspect of the present invention, there is provided oral pharmaceutical composition comprising nilotinib that exhibits aqueous oral solution.

[0042] One aspect of the invention is an aqueous oral solution comprising (i) Nilotinib, (ii) cyclodextrin, and (iii) optionally one or more excipient, where the solution is stored at ambient temperature (e.g., 25° C.) and 60% relative humidity. The solution is formulated such that it remains a solution during storage and the nilotinib does not precipitate out.

[0043] Yet another aspect is a method of dispensing to a patient an aqueous oral solution comprising (i) nilotinib, (ii) a cyclodextin comprising cyclodextrin, a derivative of cyclodextrin, or any combination thereof, and (iii) optionally one or more acid.

[0044] In another aspect, the present invention relates to an aqueous oral solution comprising nilotinib and one or more cyclodextrin, wherein the solution is free or substantially free (e.g. contains less than about 10% v/v, such as less than about 5% v/v, less than about 2.5% v/v, less than about 2% v/v, less than about 1.5% v/v, less than about 1% v/v, less than about 0.5% w/v, less than about 0.3% v/v, less than about 0.2% v/v, less than about 0.1% v/v, less than about 0.05% v/v, or less than about 0.01% v/v) of alcohol.

[0045] Yet another aspect is a method of dispensing to a patient an aqueous oral solution comprising (i) nilotinib, (ii) a cyclodextin comprising cyclodextrin, a derivative of cyclodextrin, or any combination thereof, (iii) optionally one or more polyol.

[0046] In other aspect, the liquid composition comprises about 10% (w/v) to about 50% (w/v) of polyol (also known as sugar alcohol), or about 15% (w/v) to about 50% (w/v) of polyol. Exemplary polyols that can be used in the inventive compositions include sorbitol, xylitol, maltitol, glycerine, propylene glycol, erythritol and combinations thereof. In other embodiments, the liquid composition comprises about 15% (w/v) to about 40% (w/v) sorbitol or 15% (w/v) to about 25% (w/v) sorbitol, or about 16% (w/v) to about 26% (w/v) sorbitol or about 18% (w/v) to about 24% (w/v) sorbitol and in other embodiments, the liquid composition comprises about 21% (w/v) sorbitol. In other embodiments the liquid composition comprises about 15% (w/v) to about 40% (w/v) of a combination of sorbitol and maltitol. In other embodiments, the liquid composition comprises about 15% (w/v) to 25% (w/v) of maltitol and in other embodiments, the composition comprises about 20% (w/v) maltitol. In other embodiments the liquid composition comprises about 1% (w/v) to about 25% (w/v) of glycerine, and in other embodiments the liquid composition comprises about 5% (w/v) glycerine. In other embodiments the liquid composition comprises about 5% to about 50% propylene glycol (w/v).

[0047] In certain aspects, the co- solvents are organic solvents. Organic solvent include but are not limited to propylene glycol, polyethylene glycol, and combinations thereof that are pharmaceutically acceptable based on the desired formulation.

[0048] In certain aspects, the formulation contains from about 5% to about 50% by weight propylene glycol.

[0049] In one aspect of any of the aqueous oral solutions described herein, the solution may comprises a sweetener, such as sucralose, sucrose, or sodium saccharin. In one embodiment, the solution comprises from about 0 to about 1% w/v sweetener. In one embodiment, the solution comprises from about 0.001 to about 1% w/v sucralose, such as about 0.025% w/v sucralose.

[0050] In other aspects, the sweetener of the liquid composition is an artificial sweetener (also known in the art as a “high intensity sweetener”). Exemplary artificial sweeteners include sucralose, acesulfame potassium, aspartame, and the saccharins. In other embodiments, the artificial sweetener is selected from sucralose and saccharin. In other embodiments, the sucralose is present at a concentration of about 0.35% (w/v); in other embodiments, the concentration of sucralose is from about 0.1% (w/v) to about 0.8% (w/v). In other embodiments, the concentration of saccharin is about 0.05% (w/v) to about 0.25% (w/v) or 0.2% (w/v) to about 0.8% (w/v) and in other embodiments, the concentration of saccharin is about 0.15% (w/v).

[0051] In one aspect of any of the aqueous oral solutions described herein, the solution comprises from about 0.05 to about 1.0% w/v of nilotinib, such as from about 0.1 to about 0.5% w/v of nilotinib, or from 0.1 to about 0.35% w/v of nilotinib. [0052] In one aspect of any of the aqueous oral solutions described herein, the solution comprises about 0.33% w/v of nilotinib. In another embodiment, the solution comprises about 0.2% w/v of nilotinib.

[0053] In one aspect of any of the aqueous oral solutions described herein, the one or more acid. Suitable acids include but are not limited to acetic acid, ascorbic acid, citric acid, fumaric acid, lauric acid, glacial, sorbic acid, malic acid, succinic acid, tartaric acid, phosphoric acid, hydrochloric acid, amino acid and mixtures thereof. Organic acids, which enhance the taste of the solution, are especially useful. Citric acid, for example, adds tartness that is a taste enhancer, and may play a role in overall stability of the solution. Suitable amino acid include but are not limited to lysine, alanine, glutamic acid, tryptophan and mixture thereof. The concentration of the acid in the solvent system is in the range of about 0.1% to about 5.0% or about 0.25% to about 3.0% or about 0.5% to about 2% or about 1%.

[0054] In one aspect of any of the aqueous oral solutions described herein, the one or more preservatives comprise Bronopol, Imidurea, Potassium Sorbate, Phenoxyethanol, Phenylmercuric Acetate, Butylparaben, Benzyl Alcohol, Phenylmercuric Borate, Chlorocresol, Benzethonium Chloride, Phenylethyl Alcohol, Benzalkonium Chloride, Methylparaben, Hexetidine, Chlorobutanol, Ethylparaben, Propylparaben, Sodium Benzoate, Potassium Benzoate, Sorbic Acid, Cresol, Propylparaben Sodium, Cetylpyridinium Chloride, Phenylmercuric Nitrate, Chloroxylenol, Propionic Acid, Phenol, Thimerosal, Sulfur Dioxide, Boric Acid, Edetic Acid, Sodium Propionate, Calcium Chloride, Sodium Acetate, Sodium Sulfite, Benzoic Acid, Monothioglycerol, Cetrimide, Calcium Acetate, Butylene Glycol, Sodium Metabisulfite, Alcohol, Propyl Gallate, Potassium Metabisulfite, Sodium Lactate, Chlorhexidine, Calcium Lactate, Pentetic Acid, Glycerin, Propylene Glycol Alginate, Sodium Borate, Magnesium Trisilicate, Isopropyl Alcohol, Dimethyl Ether, Propylene Glycol, Butylated Hydroxyanisole, Pyrrolidone, Lactic Acid, Sodium Lauryl Sulfate and Dimethyl Sulfoxide or a combination thereof. In another embodiment of any of the aqueous oral solutions described herein, the one or more preservatives comprise methylparaben, propylparaben, or a combination thereof. Lor instance, the oral solution may comprise methylparaben and propylparaben.

[0055] Lor instance, the oral solution may comprise methylparaben and propylparaben.

The solution includes an effective amount of preservatives (such as methylparaben, propylparaben, sodium benzoate, sodium methylparaben, or a combination thereof) to inhibit microbial contamination of the solution. In one embodiment, the solution includes from about 0.01 to about 4% (such as from about 0.05 to about 1% or from about 0.05 to about 0.5%) of preservatives, such as methylparaben, propylparaben, or a combination thereof. In another embodiment, the solution includes from about 0.1 to about 0.2% of preservatives, such as methylparaben, propylparaben, or a combination thereof.

[0056] In one aspect of any of the aqueous oral solutions described herein, the solution comprises one or more flavoring agents. Suitable flavoring agents include but, are not limited to, cotton candy, raspberry, strawberry, lemon-lime, apple, mint, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry, grape flavors, tutti-fruti, cherry flavors, combinations thereof; and the like. In one embodiment, the solution comprises from about 0.01 to about 2% w/v flavoring agent (e.g., natural grape flavor), such as about 1.0% w/v flavoring agent.

[0057] In some aspects, the stable oral liquid pharmaceutical compositions of the present application comprises of at least one solubilisers selected from the group of nonionic, anionic, cationic and zwitterionic surfactants or mixtures thereof.

[0058] Suitable non-limiting examples of the solubiliser(s) used in the compositions of the present application includes, but not limited to, polyethoxylated fatty acids like esters of lauric acid, oleic acid, and stearic acid, PEG-fatty acid diesters like PEG-20 dilaurate, PEG- fatty acid mono- and di-ester mixtures, alcohol-oil transesterification products like PEG-35 castor oil, Polyoxy 35 castor oil, polyoxyl 40 hydrogenated castor oil, etc., polyglycerized fatty acids like poly glyceryl oleate, etc., propylene glycol fatty acid esters like propylene glycol monolaurate etc, mixtures of propylene glycol esters-glycerol esters like oleic acid esters of propylene glycol and glycerol, etc., sterol and sterol derivatives like PEG-24 cholesterol ether etc, polyethylene glycol sorbitan fatty acid esters like PEG-20 sorbitan monolaurate etc, polyethylene glycol alkyl ethers like PEG-3 oleyl ether, etc., sugar esters like sucrose monopalmitate etc, polyethylene glycol alkyl phenols like Octoxynol-1 etc, sorbitan fatty acid esters like sorbitan monolaurate, lower alcohol fatty acid esters like ethyl oleate, etc., anionic surfactants include fatty acid salts and bile salts. Additional exemplary solubilisers include, but are not limited to: polyoxyethylene alkylethers; polyethylene glycol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; poly glycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides Ionic surfactants include sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, and sodium taurocholate; Gelucire® 44/14, etc.

[0059] The at least one solubilisers be present in the stable oral liquid pharmaceutical compositions disclosed herein in a variety of concentrations. For example, the stable oral liquid pharmaceutical compositions disclosed herein can comprise at least one solubilisers of at least 1% by weight, at least 2% by weight, at least 5% by weight, at least 10% by weight, at least 15% by weight, at least 20% by weight, or a percentage between any two of the above values, based on the total weight of the composition. In some embodiments, the nilotinib composition of present application comprises of at least one solubilisers in an amount of from about 1 % to about 20% by weight, or from about 2% to about 15% by weight, or from about 2% to about 10% by weight, or from about 3% to about 10% by weight, based on the total weight of the composition.

[0060] In one aspect of any of the aqueous oral solutions described herein, the pH of the aqueous oral solution ranges from about 2 to about 7. In another of any of the aqueous oral solutions described herein, the pH of the aqueous oral solution ranges from about 2.5 to about 4. For instance, the pH may be 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, or 3.5.

[0061] In some aspects, the stable oral liquid pharmaceutical compositions of the present application may comprises of at least one buffering agents. Non-limiting examples of buffering agents include, but are not limited to sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminum hydroxide/sodium bicarbonate co precipitate, 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, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts.

[0062] In one aspect of any of the aqueous oral solutions described herein, the solution may comprises anti-oxidant. The anti-oxidant included in the formulations of the invention may further be selected from e.g., propyl gallate, lecithin, Vitamin E tocopherol, sesamin, sesamol, sesamolin, alpha tocopherol, ascorbic acid, ascorbyl palmitate, fumaric acid, malic acid, and sodium metabisulphite, disodium EDTA, and combinations of any of the foregoing. [0063] Another aspect of the present invention is to provide an aqueous oral solution composition containing, while having a reduced bitter taste of the drug. [0064] ‘Nilotinib” as used herein encompasses base form as well as its pharmaceutically acceptable salts, complexes, polymorphs, hydrates, solvates, enantiomers or racemates. The solid state form of nilotinib used in the composition of the present application is not critical. For example, nilotinib can be amorphous or crystalline.

[0065] The term “pharmaceutically acceptable salts” as used herein includes those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, which are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the pharmaceutically active substance, having a freebase function, with a suitable organic acid or inorganic acid.

[0066] As used herein, an “effective amount” or a “therapeutically effective amount” of a drug refers to a non-toxic, but sufficient amount of the drug, to achieve therapeutic results in treating a condition for which the drug is known to be effective. In this instance, an effective amount is an amount of nilotinib which is sufficient to treat leukemia in a patient in need thereof. The term "nilotinib" or a pharmaceutically acceptable salt thereof refers to nilotinib free base or any pharmaceutically acceptable salt of nilotinib, the pharmaceutical composition of the present invention may include nilotinib in amounts ranging from about 0.05 % w/v to about 20 % w/v of the composition.

[0067] The term “liquid composition” refers to a liquid composition that is ingested with or without further mixing with aqueous or suitable media before oral administration.

[0068] The term “stable composition(s)” as used herein, refers to a composition that does not show any precipitation in Simulated Gastric Fluid (SGF) at pH 1.2, temperature of 37° C.+0.5 ⁰ C. and under stirring at a speed of 50 rpm at least for 60 minutes. Also the term “stable composition(s)” refers to a composition which upon subjected to stability evaluation at 40° C. and 75% RH (relative humidity) or 25° C. and 60% RH (relative humidity), is substantially free of impurities, or comprises not more than 5% impurities, or comprises impurities levels which are acceptable by regulatory bodies such as US FDA.

[0069] Cyclodextrins are compounds made up of sugar molecules bound together in a ring and are composed of 5 or more a-D-glucopyranoside units linked 1— >4. Cyclodextrins are produced from starch by means of enzymatic conversion. Three major non-substituted cyclodextrins are known, containing each a different number of glucose monomers ranging from six to eight in a ring, creating a conical shape. The so-called a-cyclodextrin is a sixmembered sugar ring molecule, P-cyclodextrin is a seven- membered sugar ring molecule and y-cyclodextrin is an eight-membered sugar ring molecule. Suitable solubility enhancers include, without limitation, are beta cyclodextrin, hydroxyl beta cyclodextrin, betadex sulfobutyl ether cyclodextrin, methyl beta cyclodextrin, 2,6- dimethyl betacyclodextrin, hydroxyethyl betacyclodextrin, a-cyclodextrin, y-cyclodextrin.

[0070] Unless otherwise stated all concentrations mentioned herein are based on total weight of the composition.

[0071] As used herein, the term “flavoring agent” is intended to mean a compound used to impart a pleasant flavor and often odor to a pharmaceutical preparation. Exemplary flavoring agents include synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits and so forth and combinations thereof. These may also include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil. Other useful flavoring agents include vanilla, citrus oil, including lemon, orange, grape (e.g., natural grape), lime and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. The amount of flavoring agent may depend on a number of factors, including the organoleptic effect desired.

[0072] The inventive composition also comprises a sweetener. Various sweeteners are contemplated, including but not limited to simple sugars such as sucrose, dextrose, fructose, maltose, and the like. In other embodiments, the inventive composition is “low calorie” or “light”, “sugar-free”, or “calorie-free.” As discussed above, the sweetener in the inventive compositions may be a so-called “artificial sweetener” (also known as “high-intensity sweetener”), such as sucralose, acesulfame potassium, saccharin, and aspartame, or any combination thereof. The use of such artificial sweeteners is desirable for adding sweetness without the addition of calories. Also as discussed above, the polyol in the inventive composition may also provide some sweetening and the lower calorie content of polyols, and lower glycemic index (compared to simple sugars) make the inventive compositions suitable for low calorie diets. Additionally, the inventive compositions that are low calorie and/or low glycemic index would be suitable for diabetic patients.

[0073] One of skill in the art will recognize that the “sugar-free” means that a product contains no amount of, or only trivial or “physiologically inconsequential” amounts of sugars. In this regard, “sugar free” means less than 0.5 g of sugars per serving. “Calorie free” means fewer than 5 calories per serving. Examples of synonyms for “free” include “without,” “no” and “zero.” Those products sweetened only with artificial sweeteners and/or sugar alcohols (and containing no other sugars) can be classified as “sugar-free.” The term “low calorie” is understood to mean 40 calories or less per reference amount.

[0074] Other additives conventionally used in pharmaceutical compositions can be included, and these additives are well known in the art. Such additives include pharmaceutically acceptable detackifiers, anti-foaming agents, chelating agents, viscomodulators, tonicifiers, flavorants, colorants odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired, keeping in mind the possibility that any such additives should preferably not negatively impact the stability of the final formulation.

[0075] Suitable coloring agents include red, black, and yellow iron oxides and FD&C dyes such as FD&C Blue No. 2, FD&C Red No. 40, and the like. Suitable taste-masking agents include sodium bicarbonate, ion-exchange resins, cyclodextrin inclusion compounds, adsorbates, and the like.

[0076] It is recognized that pharmaceutical excipients may perform more than one function and are therefore characterized as having different uses depending on the particular application. While the use of an excipient in the context of a particular formulation may determine the function of the excipient, the inclusion of any particular excipient into any one or more categories as set forth above is not meant to limit the function of that excipient.

[0077] The following examples are provided to enable one of ordinary skill in the art to prepare dosage forms of the invention and should not be construed as limiting the scope of the invention.

[0078] Example 1-7

[0079] Table No. 1

[0080] Manufacturing Process for Example 1- 8:

Step-1: Propylene glycol and Nilotinib Hydrochloride Monohydrate is taken into a beaker and mixed using a stirrer until a clear solution is obtained.

Step-2: Purified water is taken in another breaker and Citric acid anhydrous is added and mixed, using a stirrer. Further to it, Sulfobutylether beta cyclodextrin is added with mixing until a clear solution was obtained.

Step-3: Step-2 solution is added to step-1 with mixing.

Step-4: Methylparaben sodium, propylparaben sodium, tutti frutti and liquid maltitol are sequentially added into purified water and mixed using a stirrer until a clear solution is obtained.

Step-5: Step-4 solution is added to step-3 and mixed using a stirrer.

Step-6: The volume of the Step 5 solution was adjusted using purified water up to 100%.