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Title:
PHARMACEUTICAL COMPOSITION
Document Type and Number:
WIPO Patent Application WO/2009/122187
Kind Code:
A2
Abstract:
A pharmaceutical composition comprising a leukotriene-receptor antagonist optionally in combination with one or more pharmaceutical excipients, wherein the leukotriene-receptor antagonist comprises a plurality of particles, and wherein some or all of the particles are coated with a suitable coating material. A process for making the composition, particularly using fluid bed spray drying, is also disclosed.

Inventors:
LULLA AMAR (IN)
MALHOTRA GEENA (IN)
Application Number:
PCT/GB2009/000891
Publication Date:
October 08, 2009
Filing Date:
April 03, 2009
Export Citation:
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Assignee:
CIPLA LTD (IN)
LULLA AMAR (IN)
MALHOTRA GEENA (IN)
CURTIS PHILIP ANTHONY (GB)
Domestic Patent References:
WO2007077135A12007-07-12
WO2009120885A22009-10-01
Foreign References:
US20060134217A12006-06-22
JP2007211006A2007-08-23
JP2006316047A2006-11-24
Other References:
NANDA A ET AL: "AN UPDATE ON TASTE MASKING TECHNOLOGIES FOR ORAL PHARMACEUTICALS" JOURNAL OF THE INDIAN CHEMICAL SOCIETY, THE INDIAN CHEMICAL SOCIETY, CALCUTTA; IN, vol. 64, no. 1, 1 January 2002 (2002-01-01), pages 10-17, XP008043034 ISSN: 0019-4522
Attorney, Agent or Firm:
CURTIS, Philip Anthony (235 High Holborn, London WC1V 7LE, GB)
Download PDF:
Claims:

CLAIMS

1. A pharmaceutical composition comprising a leukotriene-receptor antagonist optionally in combination with one or more pharmaceutical excipients, wherein the leukotriene-receptor antagonist comprises a plurality of particles, and wherein some or all of the particles are coated with a suitable coating material.

2. A pharmaceutical composition according to claim 1, wherein the leukotriene-receptor antagonist in combination with one or more excipient is coated with suitable material.

3. A pharmaceutical composition according to claim 1 or 2, wherein the leukotriene- receptor antagonist comprises zafiriukast, montelukast, pranlukast, zileuton, or salts, solvates, derivatives, prodrugs, enantiomers, racemic mixtures, polymorphs thereof .

4. A pharmaceutical composition according to claim 3, wherein the leukotriene-receptor antagonist is montelukast sodium.

5. A pharmaceutical composition according to any preceding claim, which is provided in the form of an oral pharmaceutical composition comprising tablet, minitablet, dispersible tablet, chewable tablet, capsule, pills, powder, suspension, granules, sachet, sprinkles, preferably tablet.

6. A pharmaceutical composition according to any preceding claim, wherein coating material comprises a water soluble polymer, water insoluble polymer, water swellable polymer or mixture thereof.

7. A pharmaceutical composition according to any preceding claim, wherein coating material comprises a water soluble polymer selected from cellulose polymers; povidones; polyvinyl alcohols; alkyl celluloses such as methylcellulose; hydroxyalkyl celluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose; hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose; carboxyalkylcelluloses such as carboxymethylcellulose; alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose;

carboxyalkylalkylcelluloses such as carboxymethylethylcellulose; carboxyalkylcellulose esters; starches; pectins such as sodium carboxymethylamylopectin; chitin derivatives such as chitosan; polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar-agar, gum arabicum, guar gum and xanthan gum; or any combination thereof.

8. A pharmaceutical composition according to any preceding claim, wherein the coating material comprises a water insoluble polymer selected from acrylic polymers and copolymers, such as Eudragit ElOO, Eudragit EPO, Eudragit L30D-55, Eudragit FS30D, Eudragit RL30D, Eudragit RS30D, Eudragit NE30D and Acryl-Eze; polyvinylacetate, such as Kollicoat SR 3OD; cellulose derivatives such as ethyl cellulose and cellulose acetate, such as Surelease, Aquacoat ECD and Aquacoat CPD; or any combination thereof.

9. A pharmaceutical composition according to any preceding claim, wherein the coating material comprises a pharmaceutically acceptable wax, such as synthetic wax, microcrystalline wax, paraffin wax, carnauba wax, and beeswax; a glyceride, such as glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, polyethoxylated castor oil derivatives, hydrogenated vegetable oils, glyceryl mono, di or tribehenates, glyceryl tristearate, and glyceryl tripalmitate; a long-chain alcohol, such as stearyl alcohol, cetyl alcohol, and polyethylene glycol, or any combination thereof

10. A dosage formulation according to any preceding claim, wherein pharmaceutical excipient is selected from diluents, binders, water soluble polymers, water insoluble polymers, sweeteners, flavoring agents, fillers, disintegrants, glidants, lubricants, preservatives, stabilizers, anti-caking agents, colouring agents or mixtures thereof.

11. A dosage formulation according to any preceding claim further comprising an active ingredient selected from 5-lipooxygenase inhibitors, corticosteroids, FLAP inhibitors, antihistamines, long- acting beta-2 antagonist, or salts, solvates, derivatives, prodrugs, enantiomers, racemic mixtures, polymorphs thereof or any mixture thereof.

12. A process for making a dosage formulation as defined in any preceding claim, comprising:

(1) Coating a leukotriene-receptor antagonist with the coating material to form coated particles containing the leukotriene-receptor antagonist, (2) Optionally, mixing the coated particles obtained in step (1) with one or more pharmaceutical excipients, (3) Processing the particles to form the desired dosage formulation.

13. A process according to claim 12, wherein the leukotriene-receptor antagonist is coated with the coating material by fluidizing particles of the leukotriene-receptor antagonist, and spraying the coating material over the fluidized leukotriene-receptor antagonist.

14. A process according to claim 12, wherein the leukotriene-receptor antagonist is coated with the coating material by spray-drying, turbo-drying, pan coating.

15. A process according to claim 12, 13 or 14, wherein step (3) comprises compressing the mixture formed in step (2) to form tablets.

16. Use of a coating material to reduce and/or prevent the formation of a sulfoxide impurity of a leukotriene-receptor antagonist in a dosage formulation comprising the leukotriene-receptor antagonist.

17. Use of a coating material to mask the taste of a leukotriene-receptor antagonist in a dosage formulation comprising the leukotriene-receptor antagonist.

18. Use according to claim 16 or 17, wherein the leukotriene antagonist is montelukast sodium.

19. A dosage formulation substantially as herein described and illustrated with examples.

Description:

Pharmaceutical Composition

Field of the invention

The present invention relates to a pharmaceutical composition, especially a stable pharmaceutical composition. More particularly, the invention is directed to a stable pharmaceutical composition comprising leukotriene receptor antagonist and a method to manufacture the same.

Background and prior art Leukotriene receptor antagonists have been shown to be efficacious in the prophylaxis and chronic treatment of asthma in adults and pediatric patients and for the relief of symptoms of seasonal allergic rhinitis in adults and pediatric patients.

Leukotrienes are biologically active fatty acids derived from the oxidative metabolism of arachidonic acid. Leukotrienes work to contract airway smooth muscle, increase vascular permeability, increase mucus secretions, and attract and activate inflammatory cells in the airways of patients with asthma. The action of leukotriene can be blocked through either of two specific mechanisms: (1) inhibition of leukotriene production and/or (2) antagonism of leukotriene binding to cellular receptors.

Leukotriene-receptor antagonists have a unique profile in that they are a hybrid of antiinflammatory effects (antagonism of proinflammatory activities of leukotrienes) and bronchodilator effects (antagonism of leukotriene-induced smooth-muscle bronchoconstriction). Leukotriene-receptor antagonists are also effective in treating allergic rhinitis, which commonly coexists in patients with asthma.

US5565473 (to Merck Frosst Canada Inc, filed on February 23, 1995) teaches a process of preparation of leukotriene antagonists and their use as anti-asthmatic, anti-allergic, antiinflammatory, and cytoprotective agents. They are also said to be useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis, and allograft rejection.

WO0021536 (to Sheftell Fred D., filed on October 12, 1999) discusses a method of treatment using leukotriene antagonist drugs to prevent and treat recurrent primary headaches, which includes migraine headaches and cluster headaches.

WO2007005965 (to Teva Pharmaceutical Industries Limited, filed on July 5, 2006) describes a method of purifying montelukast sodium, isolating impurities like MLK-SO, MLK-D and formulating the same. The patent discloses that there are impurities present during the processing of montelukast sodium.

EP 1059917 (to Alza Corporation, filed on February 26, 1999) discloses a sustained-release delivery system and a method of administering leukotriene receptor antagonists in a rate- controlled dose over time.

US6221880 (to Schering Corporation, filed on October 6, 1999) teaches a pharmaceutical composition comprising a combination of a neurokinin antagonist and a leukotriene receptor antagonist and a method of treatment of allergic rhinitis and other respiratory diseases using the same.

WOO 160407 (to Asta Medica, filed on February 5, 2001) describes a pharmaceutical composition comprising a combination of a non sedating antihistamine and a leukotriene receptor antagonist or a FLAP antagonist to be administered topically and orally.

WO03035036 (to Merck Frosst Canada Inc, filed on October 22, 2002) discloses flowable and dispersible granule compositions for packaging. The patent further mentions that these granules can be medicated and can be directly or indirectly mixed with food or other comestibles.

WO2007092031 (to Teva Pharmaceutical Industries Limited, filed on May, 9 2006) discloses a pharmaceutical composition comprising montelukast sodium and excipients which reduce sulfoxide impurities. More particularly, the patent discloses that the impurity results from microcrystalline cellulose and thus a stable pharmaceutical composition devoid of microcrystalline was formulated into film-coated and chewable tablets.

However, the degradation of montelukast during storage and manufacture to its sulfoxide impurity still presents a problem in montelukast compositions of the state of the art. The degradation, inter alia, reduces the effective dosage of montelukast of the dosage form. Thus there still remains a need to formulate stable pharmaceutical composition of leukotriene antagonists. More particularly, there is a need for pharmaceutical compositions that contain a reduced amount of sulfoxide impurity.

Object of the invention

An object of the present invention is to provide a pharmaceutical composition comprising a plurality of coated leukotriene antagonist and manufacture of the same. Another object is to provide a stable pharmaceutical composition of this form.

Another object of the invention is to provide a process for the preparation of a coated leukotriene antagonist, which is capable of withstanding formulation and storage conditions that otherwise may cause its decomposition and degradation.

Yet another object of the invention is to provide a taste-masked composition of a leukotriene antagonist.

Further object of the invention is to provide a method of treatment and prevention of leukotriene-mediated diseases and disorder using the stable pharmaceutical composition.

Summary

According to first aspect of the present invention, there is provided a pharmaceutical composition comprising a plurality of coated leukotriene antagonist particles along with suitable pharmaceutical excipients to achieve an effective taste masked composition.

According to second aspect of the present invention, there is provided a process of manufacturing a pharmaceutical composition according to the present invention.

According to third aspect of the present invention, there is provided a pharmaceutical composition for use in the treatment/prophylaxis of conditions requiring alleviation of asthma, allergic rhinitis and related disorders.

According to fourth aspect of the present invention, there is provided a pharmaceutical composition comprising a plurality of coated leukotriene antagonist particles with at least one of the drugs of class selected from 5-lipooxygenase inhibitor, corticosteroids, antihistamine or neurokinin inhibitors.

The expression leukotriene antagonist, as used in this specification, encompasses the free from of the active material, and also its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its pharmaceutically acceptable enantiomers, its pharmaceutically acceptable derivatives, its pharmaceutically acceptable polymorphs or its pharmaceutically acceptable prodrugs. This especially applies to the preferred leukotriene antagonist, which is montelukast.

In a preferred embodiment, the at least some of the particles of the leukotriene receptor antagonist are at least partially coated with the coating material. The amount of coating material should be selected to provide taste-masking and improved stability of the pharmaceutical composition. It is an important feature of the invention that the coating does not substantially interfere with the release properties of the pharmaceutical composition, i.e., the composition should be an immediate release formulation, rather than a sustained release one.

Description

As described hereinbefore, montelukast compositions are subject to degradation during manufacture and storage. It is believed that the montelukast degrades into corresponding sulfoxide impurity. The sulfoxide is an inactive impurity, which reduces the effective dosage of montelukast when it is administered to patients.

Attempts have been made in the prior art to resolve the problem but there still remains a continuing need to provide a stable pharmaceutical composition of montelukast along with one or more pharmaceutical acceptable excipient/s.

The inventors have surprisingly found that by coating leukotriene antagonist with a suitable polymer the sulfoxide impurity level of montelukast or a salt thereof was significantly reduced.

Thus according to the present invention there is provided a stable pharmaceutical composition comprising a leukotriene-receptor antagonist optionally in combination with one or more pharmaceutical excipients, wherein the leukotriene-receptor antagonist, or combination of the leukotriene-receptor antagonist and the or each excipient, is coated with a suitable material.

The term "coating", as used herein, refers to a process for covering or surrounding a single or plurality of particle(s) with one or more layers of a coat forming material to stabilize the particle(s). The term "coated", as used herein, has a somewhat different meaning compared to "coating" and refers to a single or plurality of particle(s) which is covered with or surrounded by a coat forming material, wherein the coat forming material remains distinct from the single particle that it covers, and with whose aid the particle is stabilized. While the covering by the coat forming material does not necessarily need to be uniform or to cover or surround the entire particle surface, the covering by the coat forming material should be sufficient to impart improved stability. However, the coating can also completely cover or encase the particle in a substantially uniform layer. The coated particles as defined herein may include not only completely or partially coated particles but also mixtures thereof. It is also preferable that the coated particle, when dried, has no substantial gain in moisture relative to its uncoated form.

As used herein, the term "stable" means that the increase in the amount of the sulfoxide impurity within the montelukast or salt thereof coated in accordance with the present invention is less than the increase in the corresponding amount of sulfoxide impurity within uncoated montelukast or salt thereof stored and/or manufactured under the same conditions.

As used herein, unless otherwise defined, the term "sulfoxide impurity" refers to montelukast or a salt thereof wherein the sulfide group in the [beta] -position relative to the cyclopropane group has been oxidized to a sulfoxide group.

Leukotriene-receptor antagonists, which are non-steroidal, are also known as LTRAs or antiinflammatory bronchoconstriction preventors. According to the present invention the leukotrience antagonist may be, for example, zafirlukast, montelukast, pranlukast, zileuton, leucettamine A and related imidazole alkaloids from the marine sponge Leucetta micro or aphis, which is a specific leukorriene B4 (LTB4) receptor antagonist which inhibits human neutrophil aggregation, chemotaxis and degranulation induced by LTB4 and LY2931 1 1 (2- [2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy] -propoxy]- phenoxy] benzoic acid sodium salt). The various available salts, solvates, derivatives, prodrugs, enantiomers, racemic mixtures, polymorphs thereof of the various leukorriene antagonists mentioned above may be used. The preferred one is montelukast, preferably montelukast sodium

Montelukast sodium is the common name of the compound: [R-(E)J-I -[[[ 1 -[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(l -hydro-xy-1 - methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt. Montelukast sodium is a hygroscopic, optically active, and white to off-white powder. Montelukast sodium is freely soluble in methanol, ethanol, and water and practically insoluble in acetonitrile.

The present invention involves coating the leukotriene antagonist with suitable polymer such as water soluble polymers, water insoluble polymers, water swellable polymers or mixtures thereof. Said polymer may be selected from water soluble polymers like cellulose polymers, povidones, polyvinyl alcohols; water insoluble polymers like acrylic polymers; pharmaceutically acceptable waxes like synthetic wax, microcrystalline wax, paraffin wax, carnauba wax, and beeswax; glycerides, such as glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, polyethoxylated castor oil derivatives, hydrogenated vegetable oils, glyceryl mono, di or tribehenates, glyceryl tristearate, glyceryl tripalmitate; long-chain alcohols, such as stearyl alcohol, cetyl alcohol, and polyethylene glycol; and mixtures thereof.

Examples of suitable water soluble polymers include, but are not limited to, alkylcelluloses such as methylcellulose, hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose; hydroxyalkyl

alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose; carboxyalkylcelluloses such as carboxymethylcellulose ; alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose; carboxyalkylalkylcelluloses such as carboxymethylethylcellulose; carboxyalkylcellulose esters; starches; pectins such as sodium carboxymethylamylopectin; chitin derivatives such as chitosan; polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenans,galactomannans, tragacanth, agar-agar, gum arabicum, guar gum and xanthan gum. These polymers are used alone or in admixtures.

The water insoluble polymer that may be used, according to the present invention, comprises acrylic copolymers e.g. Eudragit ElOO or Eudragit EPO; Eudragit L30D-55, Eudragit FS30D, Eudragit RL30D, Eudragit RS30D, Eudragit NE30D, Acryl-Eze (Colorcon Co.); polyvinylacetate, for example, Kollicoat SR 3OD (BASF Co.); cellulose derivatives such as ethylcellulose, cellulose acetate e.g. Surelease (Colorcon Co.), Aquacoat ECD and Aquacoat CPD (FMC Co.). These polymers are used alone or in admixtures.

It would be appreciated to the skilled artisan that any suitable material known in the art can be used for coating according to the present invention which render the pharmaceutical composition stable during the storage and manufacture.

The present invention also encompasses a process for the preparation of the coated leukotriene antagonist(s). Coating advantageously involves spraying the coating solution over powder bed of leukotriene-receptor antagonist. The coated leukotriene antagonist particles are dried and then formulated into required dosage form.

Examples of coating processes or techniques which may be envisaged by the present invention includes spray drying, turbo drying, pan coating, fluidized bed coating. Fluidized bed coating methods, however, are preferred.

According to the present invention there is provided a formulation having a plurality of coated leukotriene antagonist(s) particles. The coated particles so obtained are then further mixed with other pharmaceutically acceptable excipients.

The pharmaceutically acceptable excipients comprise one or more diluents, one or more binders, one or more disintegrants, and/or one or more lubricants/glidants.

Suitable diluents may include, for example, calcium phosphate-dibasic, calcium sulfate, cellulose-microcrystalline, cellulose powders, dextrates, dextrins, dextrose excipients, fructose, lactitol, lactose, lactose anhydrous, tablettose, mannitol, Pearlitol SD 200, sorbitol, Microcelac, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners and equivalents thereof, and mixtures thereof. The amount of diluent is preferably in the range of 10% to 80% by weight of the composition.

Suitable binders may include, for example, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, polyvinyl alcohol, pullulan, microcelac, starch, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, alginate and other cellulose derivatives and equivalents thereof, and mixtures thereof. The amount of binder is preferably in the range of 2% to 10% by weight of the composition.

Suitable disintegrants may include, for example, hydroxypropyl cellulose, low substituted- hydroxypropylcellulose, L-HPC, carboxymethyl cellulose, calcium carboxymethylcellulose, sodiumcarboxymethycellulose, croscarmellose sodium, starch, crystalline cellulose sodium starch glycollate, starch, pregelatinized starch, crospovidone and equivalents thereof, and mixtures thereof. The amount of disintegrant is preferably in the range of 3% to 30% by weight of the composition.

Suitable lubricants/glidants may include, for example, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, and sucrose esters fatty acid, microcrystalline wax, colloidal silicon dioxide, and equivalents thereof, and mixtures thereof. The amount of lubricant/glidant is preferably in the range of 0.25% to 5% by weight of the composition.

Optionally the pharmaceutical composition may also include other pharmaceutical acceptable excipients such as anti-caking agents, coloring agents, which include, but are not limited to, red oxide of iron, yellow oxide of iron; ready color mix system, which includes, but is not

limited to, Opadry; and suitable pharmaceutically acceptable sweeteners and flavoring agents.

In another embodiment, the pharmaceutical composition comprising a plurality of coated leukotriene antagonist, a diluent; a disintegrant; a binding agent; lubricant/glidant and optionally suitable pharmaceutical excipients like anti-caking agent, colorant, sweetener, flavoring agent.

The pharmaceutical composition of the present invention may be administered in various preparations depending on the age, sex, and symptoms of the patient. The pharmaceutical compositions can be administered, for example, as tablets, capsules (either solid-filled, semisolid filled or liquid filled), pills, powders, liquids, suspensions, emulsions, granules, dispersible granules, powders for constitution, oral gels, elixirs, suppositories, topical composition includes inhalers, sprays, creams, lotions, gels and injection preparations (solutions and suspensions), and the like. Preferably the composition is a solid composition, especially a granule, tablet, chewable tablet, capsule, or pellet and the like. More preferably the composition is tablet. Preferably the tablet composition is especially film coated, sugar coated, chewable, multilayer, and dispersible and the like.

In a further embodiment, the pharmaceutical composition comprises plurality of coated montelukast sodium or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs along with one or more excipients which includes, but are not limited to, one or more diluents, one or more disintegrants, one or more lubricants and glidants.

Alternatively, the present invention may be in combination comprising coated leukotriene antagonist with atleast one of the drugs of class like 5-lipooxygenase inhibitors, corticosteroids, FLAP inhibitors, antihistamines, long-acting beta-2 antagonist or salts, solvates, derivatives, prodrugs, enantiomers, racemic mixtures, polymorphs thereof.

The present invention further provides a method of prophylaxis and/or treatment of asthma, COPD (chronic obstructive pulmonary disease) and related disorders; relief of symptoms of

seasonal allergic rhinitis and perennial allergic rhinitis; prevention of exercise-induced bronchospasm by use of a therapeutically effective amount of the coated drug in a suitable pharmaceutical composition of the present invention to a mammal in need thereof.

The following example is for the purpose of illustration of the invention only and is not intended in any way to limit the scope of the present invention.

Examples Formula 1:

Process

1. Sifted Montelukast Sodium was loaded in Fluid bed processor.

2. A coating solution was prepared by dissolving hypromellose in purified water and sprayed over powder bed continuously.

3. The coated particles obtained in (2) were dried and sieved.

Formula 2

Process

1. Sifted Coated Montelukast sodium, Levocetririzine Dihydrochloride, mannitol (Pearlitol SD200), microcelac, croscarmellose sodium, aspartame, strawberry flavor and magnesium stearate was loaded in a blender to form a dry mix.

2. Dry mix formed in Step 1 which was then compressed into tablet.

Formula 3

Process

1 Sifted Coated Montelukast sodium, Bambuterol Hydrochloride, mannitol (Pearlitol SD200), mannitol, croscarmellose sodium, aspartame, strawberry flavor and magnesium stearate was loaded in a blender to form a dry mix.

2 Dry mix formed in Step 1 which was then compressed into tablet.

Formula 4

Process

1. Sifted Coated Montelukast Sodium, mannitol, low substituted- hydroxypropylcellulose, activated dimethicone was loaded in fluidized bed processor.

2. A binder solution of Povidone in purified water was prepared.

3. Granules were prepared using the binder solution; dried and blended with L-HPC, aspartame, and magnesium stearate and compressed into tablets.

Formula 5

Process

1 Sifted Coated Montelukast sodium, mannitol (Pearlitol SD200), mannitol, croscarmellose Sodium, red oxide of Iron, aspartame, strawberry flavor, colloidal silicon dioxide and magnesium stearate was loaded in a blender to form a dry mix.

2 Dry mix formed in Step 1 which was then compressed into tablet.

Formula 6

Process

1 Sifted Coated Montelukast sodium, mannitol, crospovidone, low substituted- hydroxypropyl cellulose, yellow oxide of Iron, activated dimethicone and loaded in fiuidized bed processor.

2 A binder solution of Povidone in purified water was prepared.

3 Granules were prepared using the binder solution; dried and blended with low substituted-hydroxypropyl cellulose and magnesium stearate and compressed into tablets.

Formula 7

Process

For Montelukast Sodium Layer

1. Sifted Coated Montelukast Sodium, mannitol, crospovidone, low substituted- hydroxypropyl cellulose, activated dimethicone and yellow oxide of iron was loaded in fluidized bed processor.

2. A binder solution prepared by dissolving Povidone in purified water.

3. Granules were prepared using the binder solution; dried and blended with disintegrant, sweetener and lubricant and compressed to form a tablet layer.

For Levocetrizine Dihydrochloride Layer 4. Sifted Levocetrizine dihydrochloride, tabelettose, lactose, lactose anhydrous, avicel, red oxide of iron, Crospovidone and magnesium stearate was loaded in a blender to form a dry mix.

5. The dry mix obtained in Step 4 was compressed to form Levocetrizine dihydrochloride layer onto compressed Montelukast Sodium layer formed in Step 3 to form a bilayer tablet.

* Coated Montelukast Sodium mentioned in formulae 2 to 1 was prepared as described in formula 1.

Process :-

1. Montelukast sodium was coated with coating solution containing HPMC, Mannitol and purified water in fluidized bed granulator.

2. Coated montelukast sodium, mannitol, MCC, Crosspovidone, Aspartame, Cherry flavour and Aerosil were sifted and blended.

4. The blend of step 2 was then sifted and lubricated with magnesium stearate.

5. Lubricated granules then compressed into tablets.

Stability study data:

A comparative stability testing was carried out for the formulations comprising plain API and coated API (as per the invention) for the amount of sulfoxide impurity as shown in the table below.

The table above depicts that the amount of sulfoxide impurity in the formulation comprising coated montelukast sodium is relatively less than that in the formulation comprising uncoated montelukast sodium. This demonstrates the surprising improved stability of the pharmaceutical composition comprising coated montelukast sodium during storage and manufacture.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.

It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a preservative" includes a single preservative as well as two or more different preservatives; reference to a "surfactant" refers to a single surfactant or combination of two or more surfactants, and the like.