MONTELUKAST SODIUM AND LEVOCETIRIZINE HYDROCHLORIDE

FIELD OF INVENTION

The present invention relates to the stable mouth dissolving tablet composition.

The present invention specifically relates to composition of montelukast and levocetirizine or its pharmaceutically acceptable salts. The present invention specifically relates to composition of montelukast sodium and levocetirizine hydrochloride taste masked mouth dissolving tablets.

The present invention more specifically relates to composition and process for the preparation of montelukast sodium and levocetirizine hydrochloride taste masked mouth dissolving tablets.

BACKGROUND OF INVENTION

Montelukast sodium is an active ingredient of products used for the treatment of respiration diseases, mainly asthma and nasal allergy. Montelukast sodium, chemically the sodium salt of [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]- 3-[2-(l-hydroxy-l- methylethyl)phenyl]propyl]thio] -methyl] cyclopropane acetic acid. Montelukast Sodium has a chemical formula of CssfLsClNNaCLS and a molecular mass of 608.18 g/mol. It has a structural formula of:

Levocetirizine dihydrochloride is a third generation non- sedative antihistamine, developed from cetirizine, which is a second generation antihistamine. Levocetirizine is the active enantiomer of cetirizine, is more effective than cetirizine itself, and has fewer side effects. Levocetirizine and its salts including its dihydrochloride are known and are effective in the treatment of allergies, including but not limited to, chronic and acute allergic rhinitis, allergic conjunctivitis, pruritus, urticaria and the like. The chemical name of levocetirizine is (R)-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl] ethoxy] acetic acid dihydrochloride. Levocetirizine dihydrochloride is the R enantiomer of cetirizine hydrochloride, a racemic compound with antihistaminic properties. Levocetirizine dihydrochloride has a chemical formula of C ₁₂ H ₂₅ CIN ₂ O ₃ .2HCI and a molecular mass of 461.82 g/mol. It has a structural formula of:

WO 2010/107404 discloses stable pharmaceutical combinations, methods for preparing these combinations and their medical use. It also discloses pharmaceutical composition comprising levocetirizine or a pharmaceutically acceptable salt, ester, solvate, derivative, polymorph or hydrate thereof, montelukast or a pharmaceutically acceptable salt, ester, solvate, derivative, polymorph or hydrate thereof, mannitol and optionally at least one pharmaceutically acceptable excipient selected from stabilizing agent, diluent, binder, disintegrant, lubricant, glidant and surface active agent.

WO 2012/064304 discloses pharmaceutical formulation comprising montelukast formulation comprising montelukast as active agent; a lubricant selected from a group comprising silicone oil, siliconized talc or liquid paraffin or binary or ternary combinations thereof, levocetirizine dihydrochloride formulation comprising levocetirizine dihydrochloride as active agent; a lubricant selected from a group comprising magnesium stearate and/or colloidal silicone dioxide or binary combinations thereof, at least one other pharmaceutically acceptable excipient selected from a group comprising disintegrants, viscosity enhancing components, filling agents, drying agents, lubricants, diluents, binders, glidants, stabilizing agents, antifoaming agents, wetting agents, effervescent mixtures, sweeteners and flavoring agents.

WO 2012/064305 discloses a bilayer tablet of montelukast and levocetirizine comprising atleast two different diluents. WO 2013/012199 discloses capsule formulation for preventing or treating allergic rhinitis and asthma, which comprises two separate layers of montelukast layer comprising montelukast or a pharmaceutically acceptable salt thereof and levocetirizine layer comprising levocetirizine or a pharmaceutically acceptable salt thereof; and a method for the preparation thereof.

WO 2013/055177 discloses a hard capsule composite formulation comprising a capsule having one or more tablets placed in the capsule. This publication also discloses that montelukast containing coated tablet together with a levocetirizine containing coated tablet charged in one capsule body.

WO 2013/103262 discloses a pharmaceutical formulation for oral administration, which comprises two particle parts: (a) a first particle part comprising levocetirizine or a pharmaceutically acceptable salt thereof and an organic acid; and (b) a second particle part comprising montelukast or a pharmaceutically acceptable salt thereof.

WO 2013/154390 discloses a hard capsule composite formulation comprising two or more pharmaceutically active ingredients, wherein each pharmaceutically active ingredient is contained in a multi-unit spheroidal tablet (MUST) and a plurality of the MUSTs per each pharmaceutically active ingredient are encapsulated in the hard capsule.

WO 2014/164281 discloses method of treating anaphylaxis in a patient in need thereof comprising administering to the patient an effective amount of a combination of levocetirizine and montelukast.

WO 2014/208915 discloses a complex granule formulation comprising: (a) a first granular part comprising levocetirizine or a pharmaceutically acceptable salt thereof, cyclodextrin or a derivative thereof, and an alkalinizing agent; and (b) a second granular part comprising montelukast or a pharmaceutically acceptable salt thereof, cyclodextrin or a derivative thereof, and an alkalinizing agent.

WO 2015/062466 discloses a granular composition which comprises montelukast sodium particles and levocetirizine hydrochloride particles; the montelukast particles comprise montelukast sodium, fillers, stabilizers, adhesion agent; the levocetirizine hydrochloride particles comprise levocetirizine hydrochloride, fillers, stabilizers, binders; the stabilizer is meglumine; the binder is h y d o x y p o p y 1 - b - c y c 1 o dc x t i n .

EP 3 222 279 Al discloses formulation comprising (a) levocetirizine or a pharmaceutically acceptable salt thereof mixed together with (b) montelukast or a pharmaceutically acceptable salt thereof, placed together in a single standard coated tablet with good long-term storage stability.

All the prior-art documents relate to different compositions of montelukast and levocetirizine. Inventors of the present invention have developed a taste masked stable mouth dissolving tablets of montelukast sodium and levocetirizine hydrochloride without using any stabilizing agents like chelating agents, antioxidants and alkalizing agents, using non- aqueous method. Inventors of the present invention have also developed a non-aqueous process for the preparation of montelukast sodium and levocetirizine hydrochloride mouth dissolving tablets.

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a taste masked stable mouth dissolving tablet of montelukast and levocetirizine or its pharmaceutically acceptable salts.

Another objective of the present invention is to provide a taste masked stable mouth dissolving tablet of montelukast sodium and levocetirizine hydrochloride.

Another objective of the present invention is to provide a process for the preparation of taste masked stable mouth dissolving tablet composition comprising montelukast sodium and levocetirizine hydrochloride, wherein the composition is free of stabilizing agents, using non-aqueous process.

SUMMARY OF INVENTION

Accordingly, the present invention provides a taste masked stable mouth dissolving tablet composition comprising montelukast and levocetirizine or its pharmaceutically acceptable salts. One embodiment of the present invention provides a taste masked stable mouth dissolving tablet composition comprising montelukast sodium and levocetirizine hydrochloride.

One embodiment of the present invention provides a taste masked stable mouth dissolving tablet composition comprising montelukast sodium and levocetirizine hydrochloride, wherein the composition is free of stabilizing agents.

Another embodiment of the present invention provides a taste masked stable mouth dissolving tablet composition comprising montelukast sodium and levocetirizine hydrochloride and one or more pharmaceutically acceptable excipients, wherein the composition is free of stabilizing agents.

Another embodiment of the present invention provides a taste masked stable mouth dissolving tablet composition comprising montelukast sodium and levocetirizine hydrochloride and one or more excipients selected from diluents, superdisintegrants, binders, lubricants, sweetners, taste-masking agents and flavouring agents, wherein the composition is substantially free of stabilizing agents.

Another embodiment of the present invention provides a taste masked stable mouth dissolving tablet composition comprising:

1 % to 10% of montelukast sodium,

1 % to 10% of levocetirizine hydrochloride,

10 % to 95% of diluents,

1 % to 10% of superdisintegrants,

1 % to 10% of binders and

10 % to 95% of one or more other excipients.

Another embodiment of the present invention provides a taste masked stable mouth dissolving tablet composition comprising:

1 % to 10% of montelukast sodium,

1 % to 10% of levocetirizine hydrochloride,

10 % to 95% of lactose,

1 % to 10% of croscarmellose sodium, 1 % to 10% of HPMC, and

10 % to 95% of one or more other excipients.

Yet another embodiment of the present invention provides a process for the preparation of taste masked stable Montelukast Sodium and Levocetirizine Hydrochloride mouth dissolving tablet by non-aqueous granulation process without using stabilizing agents.

Yet another embodiment of the present invention provides process for the preparation of taste masked stable mouth dissolving tablet of montelukast sodium and levocetirizine hydrochloride comprising:

(a) sifting montelukast sodium, levocetirizine hydrochloride, diluents, disintegrants and mixing these materials using blender,

(b) adding sweetners and flavors to the above blend,

(c) adding the lubricant to the above blend and mixing, and

(d) compressing the lubricated blend using compression machine.

Yet another embodiment of the present invention provides process for the preparation of taste masked stable mouth dissolving tablet of montelukast sodium and levocetirizine hydrochloride comprising:

(a) sifting montelukast sodium, levocetirizine hydrochloride, diluents, disintegrants and mixing these materials using rapid mixer granulator,

(b) granulating above mixture using binder solution,

(c) adding extra- granular excipients to the above granules,

(d) adding the lubricant to the above blend and mixing, and

(e) compressing the lubricated granules using compression machine.

Yet another embodiment of the present invention provides process for the preparation of taste masked stable mouth dissolving tablet of montelukast sodium and levocetirizine hydrochloride comprising:

(a) sifting Montelukast sodium, diluents, disintegrants and mixing these materials using rapid mixer granulator,

(b) granulating the above blend using non-aqueous binder solution, (c) sifting Levocetirizine hydrochloride, diluents, disintegrants and mixing these materials using rapid mixer granulator,

(d) granulating the above blend using non-aqueous binder solution, and

(e) mixing the Montelukast sodium granules and Levocetirizine hydrochloride granules along with extra-granular excipients and compressed into tablets.

DETAILED DESCRIPTION OF THE INVENTION

The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

The term“allergic rhinitis” refers to a symptomatic disorder of the nose induced by an IgE-mediated inflammation after allergen exposure of the membrane of the nose. Symptoms of allergic rhinitis include rhinorrhea, nasal obstruction, nasal itching, sneezing, ocular pruritis, etc. Allergic rhinitis and asthma can develop separately. However, there is a study showing that 58% of patients with allergic rhinitis have asthma and 85 to 95% of patients with asthma also suffer from allergic rhinitis, having high rates of complications between these two patient groups. Thus, there has been a need for developing a complex formulation which has improved stability and efficacy for the treatment of these two conditions.

The present invention is to provide a stabilized formulation of mouth dissolving tablets comprising antihistaminic and leukotriene receptor antagonist.

The specified combination includes levocetirizine or pharmaceutically acceptable salts, esters, solvates, derivatives, polymorphs or hydrates thereof as a non-sedative long acting Hl -antihistamine and montelukast or pharmaceutically acceptable salts, esters, solvates, derivatives, polymorphs or hydrates thereof as a leukotriene receptor antagonist and method of preparation thereof.

Levocetirizine is an antihistamine and montelukast is a leukotriene receptor antagonist. As described herein, synergy between levocetirizine and montelukast shortens the course of the disease processes, thereby decreasing morbidity and mortality. This combined therapy also can improve quality of life from the amelioration of symptoms/side effects/disease process itself, and can decrease health-care costs. Levocetirizine and montelukast each exhibits different therapeutic mechanisms, and they together can bring about a synergistic effect in the treatment of allergic rhinitis or asthma.

Cetirizine is (2-(4-((4-chlorophenyl)phenylmethyl)-l- piperazinyl)ethoxy)acetic acid, and its levorotatory and dextrorotatory mirror image enantiomers are known as "levocetirizine" and "dextrocetirizine," respectively.

Levocetirizine can be obtained via breakdown or asymmetric synthesis using a racemic mixture of cetirizine or a yeast biocatalytic hydrolysis. Levocetirizine possesses antihistamine properties, and hence is useful as an antiallergic, an antihistamine agent, as well as an anticonvulsant and a bronchodialator.

Montelukast is an antagonist for cysteinyl leukotriene receptor (CysLTl) which is used for the prevention and treatment of a leukotriene-mediated disease. In addition, montelukast is useful in the treatment of allergic rhinitis, atopic dermatitis, chronic urticaria, sinusitis, nasal polyp, chronic obstructive pulmonary disease, conjunctivitis including nasal conjunctivitis, migraine, cyst fibrosis, viral bronchiolitis and the like.

Montelukast Sodium is an alkaline stable whereas Levocetirizine Hydrochloride is an acid stable in nature. Separate granulation is performed to avoid not only Incompatibility between these two actives but also interaction between polyols such as Mannitol and Levocetirizine Hydrochloride.

The composition of the present invention consists of pharmaceutically acceptable excipients. Common excipients include diluents or bulking agents, superdisintegrants, binders, lubricants, sweetners, taste-masking agents, solvents and flavouring agents.

Diluents used in the compositions of present invention include, but not limited to lactose monohydrate, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and/or tribasic), calcium sulphate trihydrate, calcium sulphate dihydrate, calcium carbonate, kaolin, lactitol, powdered cellulose, dextrose, dextrates, dextrin, sucrose, maltose, fructose, mannitol, sorbitol and xylitol. Preferably used diluents are mannitol and lactose monohydrate. Superdisintegrants or disintegrants used in the compositions of present invention include, but not limited to low substituted hydroxypropyl cellulose (L-HPC), sodium starch glycolate, sodium croscarmellose, cross-linked polyvinylpyrrolidone, soy polysaccharide, cross-linked alginic acid, gellan gum, xanthan gum, calcium silicate and ion exchange resin. Preferably used superdisintegrant is croscarmellose sodium.

Binders used in the compositions of present invention include, but not limited to sugars such as starch (potato starch, corn starch, wheat starch), sucrose, glucose, dextrose, lactose, maltodextrin, methylene dichloride, natural and synthetic gums (e.g. acacia), gelatin, cellulose derivatives (e.g. microcrystalline cellulose, HPC, HEC, HPMC, carboxymethyl cellulose, methyl cellulose, ethyl cellulose), polyvinylpyrrolidone, polyethyleneglycols, waxes, calcium carbonate, calcium phosphate. Preferably used binder is hydroxypropylmethylcellulo se .

Preferably used solvents for the preparation of binder solution are Isopropyl alcohol and Methylene dichloride in a fixed ratio 60:40.

Lubricants used in the composition of present invention include, but not limited to metallic stearates (e.g. magnesium stearate, calcium stearate, aluminum stearate), esters of fatty acids (e.g. sodium stearyl fumarate), fatty acids (e.g. stearic acid), fatty acid alcohols, glyceryl beheanate, mineral oils, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols, metallic lauryl sulphates (e.g. sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc. Preferably used lubricant is magnesium stearate.

Taste masking of both actives is achieved by use of bitter masking agent, sweetener, sweetener enhancer and flavours.

Bitter masking agents used in the compositions of present invention is Carbomer 934, Carbomer 971, Carbomer 974, PEG-5M. Preferably used Bitter masking agents include mixture of excipients. Sweeteners exert sweet taste and examples are sugars such as sucrose, sucralose, lactose, and glucose, cyclamate and salts thereof, saccharin and salts thereof, ammonium glycyrrhizinate, neotame and aspartame. Preferably used sweeteners are sucralose, sucrose, neotame, aspartame etc.

The term “sweetener enhancer” includes compositions capable of enhancing or intensifying the perception of sweet taste of sweetener compositions or sweetened compositions. The phrase sweetness enhancer is synonymous with the terms“sweet taste potentiator,”“sweetness potentiator,” and“sweetness intensifier”. Generally, the sweetness enhancers provided herein enhance the sweet taste of sweeteners without providing any noticeable sweet taste by themselves at acceptable use levels; however, the sweetness enhancers may themselves provide sweet taste at higher concentrations.

Flavours are used to exert better sensory properties. Examples of Flavours are vanillin, vanilla extract, cinnamon, citrus, coconut, ginger, viridiflorol, almond, menthol (including menthol without mint), grape skin extract, and grape seed extract, orange, banana, peppermint, mango, strawberry etc. Preferably used flavours include orange, banana, peppermint, mango and strawberry.

Mouth dissolving tablet formulation is comprised of superdisintegrants and water soluble excipients to a greater extent to allow faster disintegration when it placed on the tongue. Flat faced tooling is used to make quick contact of tablet surface with the tongue and aid in faster hydration as well as disintegration in the oral cavity.

The present invention opted non-aqueous granulation process for the preparation of tablets due to tendency of Montelukast Sodium towards aqueous degradation.

Since Levocetirizine Hydrochloride possess low dose, high density diluent with bulk density more than 0.5 g/mL is used in Levocetirizine granulation part to achieve content uniformity instead of making hard granulation.

Moreover, bulk density of two embodiments namely Montelukast sodium and Levocetirizine Hydrochlorides dried granules is kept between 0.50 g/mL and 0.60 g/mL, preferably, between 0.5 g/mL and 0.55 g/mL to achieve content uniformity of both the active ingredients namely Montelukast sodium and Levocetirizine Hydrochloride at the time of die filling during compression of tablets. The present invention is illustrated in detail but not limiting to, the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

Example 1

Montelukast Part

Montelukast sodium and mannitol were co-sifted. Croscarmellose sodium and bitter masking agent were co-sifted. All these material were mixed together in rapid mixer granulator for 10 minutes. Mixed materials were granulated using hydroxypropylmethylcellulose solution in isopropyl alcohol and methylene dichloride.

Dried granules were dried in dryer till target LOD achieved between l%-2% w/w. After drying, dried granules were screened.

Levocetirizine Part

Levocetirizine Hydrochloride and Lactose were co-sifted. Croscarmellose sodium and bitter masking agent were co-sifted. All these material were mixed together in rapid mixer granulator for 10 minutes. Mixed materials were granulated using hyproxypropylmethylcellulose solution in isopropyl alcohol and methylene dichloride.

Dried granules were dried in dryer till target LOD achieved between l%-2% w/w. After drying, dried granules were screened.

Both Montelukast and Levocetirizine dried granules were mixed in blender for 10 minutes. Extra granular materials mannitol, croscarmellose sodium, Sweetener enhancer, sweetening agents and flavours were accurately weighed. Mannitol and croscarmellose sodium were co- sifted and mixed with dried granules comprising both active parts. Sweetener enhancer, Sweeteners and flavours were co-sifted and mixed in blender. Finally, granules were mixed with magnesium stearate in blender for 5 minutes.

The resulting blend was compressed into tablets using compression machine with appropriate tooling.

Example 2

Manufacturing process

Montelukast Part

Montelukast sodium and mannitol were co-sifted. Croscarmellose sodium and bitter masking agent were co-sifted. All these material were mixed together in rapid mixer granulator for 10 minutes. Mixed materials were granulated using hyproxypropylmethylcellulose solution in purified water.

Dried granules were dried in dryer till target LOD achieved between l%-2% w/w. After drying, dried granules were screened.

Levocetirizine Part

Levocetirizine Hydrochloride and lactose were co-sifted. Croscarmellose sodium and bitter masking agent were co-sifted. All these material were mixed together in rapid mixer granulator for 10 minutes. Mixed materials were granulated using hyproxypropylmethylcellulose solution in purified water.

Dried granules were dried in dryer till target LOD achieved between l%-2% w/w. After drying, dried granules were screened.

Both Montelukast and Levocetirizine dried granules were mixed in blender for 10 minutes. Extra granular materials mannitol, croscarmellose sodium, sweetener enhancer, sweetening agents and flavours were accurately weighed. Mannitol and croscarmellose sodium were co sifted and mixed with dried granules comprising both active parts. Sweetener enhancer, sweeteners and flavours were co-sifted and mixed in blender. Finally, granules were mixed with magnesium stearate in blender for 5 minutes.

The resulting blend was compressed into tablets using compression machine with appropriate tooling.

Batch was manufactured with aqueous granulation. Binder solution was prepared using water alone.

Example 3

Manufacturing process

Montelukast sodium and Levocetirizine Hydrochloride were co-sifted. Lactose and croscarmellose sodium were co-sifted. All these materials were mixed in blender for 10 minutes. Sweetener and flavour were co sifted and mixed in blender for 10 minutes. The resulting blend was mixed with magnesium Stearate in blender for 5 minutes. Finally, lubricated blend was compressed into the tablets using compression machine.

Example 4

Manufacturing process

Montelukast Part

Montelukast sodium and mannitol were co-sifted. Croscarmellose sodium and bitter masking agent were co-sifted. All these material were mixed together in rapid mixer granulator for 10 minutes. Mixed materials were granulated using hyproxypropylmethylcellulose solution in isopropyl alcohol and methylene dichloride.

Dried granules were dried in dryer till target LOD achieved between l%-2% w/w. After drying, dried granules were screened. Levocetirizine Part

Levocetirizine Hydrochloride and lactose were co-sifted. Croscarmellose sodium and bitter masking agent were co-sifted. All these material were mixed together in rapid mixer granulator for 10 minutes. Mixed materials were granulated using hyproxypropylmethylcellulose solution in isopropyl alcohol and methylene dichloride.

Dried granules were dried in dryer till target LOD achieved between l%-2% w/w. After drying, dried granules were screened.

Both Montelukast and Levocetirizine dried granules were mixed in blender for 10 minutes. Extra granular materials mannitol, croscarmellose sodium, sweetener enhancer, sweetening agents and flavours were accurately weighed. Mannitol and croscarmellose sodium were co- sifted and mixed with dried granules comprising both active parts. Sweetener enhancer, sweeteners and flavours were co-sifted and mixed in blender. Finally, granules were mixed with magnesium stearate in blender for 5 minutes.

The resulting blend was compressed into tablets using compression machine with appropriate tooling.

Example 5

Manufacturing process

Montelukast sodium and Levocetirizine Hydrochloride were co-sifted. Lactose and croscarmellose sodium were co-sifted. All these materials were mixed in rapid mixer granulator for 10 minutes. The blend was granulated using hyproxypropylmethylcellulose solution in isopropyl alcohol and methylene dichloride.

Dried granules were dried in dryer till target LOD achieved between l%- 2% w/w. After drying, dried granules were screened. Sweetener and flavour were co sifted and mixed with granules in blender for 10 minutes. The resulting blend was mixed with magnesium Stearate in blender for 5 minutes. Finally, lubricated blend was compressed into the tablets using compression machine.