FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
"Stable Pharmaceutical Composition"
2. APPLICANT:
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.

Stable Pharmaceutical Composition
Field of the invention
The present invention relates to a pharmaceutical composition comprising leukotriene receptor antagonist. More particularly, the invention is directed to a stable pharmaceutical formulation and the 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 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 anti¬inflammatory 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.
US 5565473 teaches that process of preparation of leukotriene antagonists and its use as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis, and allograft rejection.


WO0021536 discuss a method of treatment using leukotriene (LT) antagonist drugs to prevent and treat recurrent primary headaches, which includes migraine headaches and cluster headaches.
WO2007005965 describes the method of purifying montelukast sodium, isolating impurities like MLK-SO, MLK-D and formulating the same. The patent discloses impurities during processing of montelukast sodium.
EP1059917 patent discloses a sustained-release delivery system and a method of administering leukotriene receptor antagonists in a rate-controlled dose over time.
US6221880 teach about pharmaceutical composition comprising combination of neurokinin antagonist and leukotriene receptor antagonist and method of treatment of the same.
WOO 160407 describe the pharmaceutical composition comprising combination of non sedating antihistamine and leukotriene receptor antagonist or FLAP antagonist to be administered topically and orally.
WO03035036 talks about flowable and dispersible granule composition for packaging. The patent further mentions that these granules can be medicated which can be directly or indirectly mixed with food or other comestibles.
WO2007092031 discloses about pharmaceutical composition comprising montelukast sodium and excipients which reduce sulfoxide impurities. More particularly, the patent discloses that impurity results from microcrystalline cellulose and thus a stable pharmaceutical composition devoid of microcrystalline was formulated into film-coated and chewable tablets.


Thus there still remains a need to formulate stable pharmaceutical composition of leukotriene antagonists. More particularly, pharmaceutical compositions that contain reduced amount of sulfoxide impurity.
Object of the invention
The object of the present invention is to provide a stable pharmaceutical composition comprising a plurality of coated leukotriene antagonist and manufacture of the same thereof.
Another object of the invention is to provide a process of preparation of coated leukotriene antagonist which is capable of withstanding formulation and storage conditions that can cause its decomposition and degradation.
Yet another object of the invention is to provide a taste masked composition of 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 stable pharmaceutical composition comprising a plurality of coated leukotriene antagonist or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs; along with suitable pharmaceutical excipients thereby achieving an effective taste masked composition.
According to second aspect of the present invention, there is provided a method of manufacturing a stable pharmaceutical composition according to the present invention.


According to third aspect of the present invention, there is provided a stable 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 with at least one of the drugs of class selected from 5-lipooxygenase inhibitor, corticosteroids, antihistamine or neurokinin inhibitors.
Description
Montelukast compositions are subject to degradation during manufacture and storage. It is believed that the montelukast degrades into corresponding sulfoxide. 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 need to provide a stable pharmaceutical composition of montelukast thereof along with pharmaceutical acceptable excipient.
The inventors have surprisingly found that by coating leukotriene antagonist with a suitable polymer the sulfoxide impurity level of corresponding montelukast or a salt was significantly reduced.
Thus according to the present invention there is provided a stable pharmaceutical composition comprising a plurality of coated leukotriene antagonist along with suitable pharmaceutical excipients.
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 will completely cover or encase the particle in a substantially uniform layer. It is also preferable that the coated particle, when dried, has no substantial gain in moisture relative to its uncoated form.
The term "stable", as used herein, refers to a coating process by which a particle(s) is/are stabilized.
According to the present invention, the composition further comprises pharmaceutically acceptable excipients. As used herein, "excipients" refers to a substance, or mixture of substances, that is used in the composition to give desirable physical characteristics to the formulation. As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other complications commensurate with a reasonable benefit/risk ratio.
In some embodiments, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized international pharmacopeia for use in animals, and more particularly in humans. Various pharmaceutically acceptable excipients can be used.
Leukotriene-receptor antagonists, which are non-steroidal, are also known as LTRAs or anti-inflammatory bronchoconstriction preventers. According to the present invention various leukotriene antagonist include but are not limited to zafirlukast, montelukast, pranlukast, zileuton, leucettamine A and related imidazole alkaloids from the marine sponge Leucetta micro or aphis, which is a specific leukotriene B4 (LTB4) receptor antagonist which inhibits human neutrophil aggregation, chemotaxis and degranulation


induced by LTB4 and LY293111 (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, enantioners, racemic mixtures, polymorphs thereof of the various leukotriene antagonists mentioned above may be used. The preferred one is montelukast sodium
Montelukast sodium is the common name of the compound: [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(l-hydro-xy-l-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. 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 along or in admixtures.
The water insoluble polymer that may be used, according to the present invention, comprises of acrylic copolymers e.g. Eudragit El 00 or Eudragit EPO; Eudragit L30D-55, Eudragit FS30D, Eudragit RL30D, Eudragit RS30D, Eudragit NE30D, Acryl-Eze (Colorcon Co.); polyvinylacetate, for example, Kollicoat SR 30D (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 along or in admixtures.
The pharmaceutical composition, according to the present invention, further describes a process for the preparation of the coated leukotriene antagonist(s). Coating 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 pluralities of coated leukotriene antagonist(s). The coated particles so obtained are then further mixed with other pharmaceutically acceptable excipients.
The pharmaceutically acceptable carrier comprises one or more pharmaceutically acceptable excipients, including 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.
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.
Suitable disintegrants may include, for example, hydroxypropyl cellulose, low substituted-hydroxypropylcellulose, L-HPC, carboxymethylcellulose, calcium carboxymethylcellulose, sodiumcarboxymethycellulose, croscarmellose sodium, starch, crystalline cellulose sodium starch glycollate, starch, pregelatinized starch, crospovidone and equivalents thereof, and mixtures thereof.
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.
Optionally the pharmaceutical composition may also include other pharmaceutical acceptable excipients such as anti-caking agents, coloring agents which includes, but are not limited to, red oxide of iron, yellow oxide of iron; ready color mix system, which includes, but are not limited to, Opadry and suitable pharmaceutically acceptable sweeteners and flavoring agents.


A 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 can 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, semi-solid 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, 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.
According to one embodiment, a 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 one of the drugs of class like 5-lipooxygenase inhibitors, corticosteroids, FLAP inhibitors, antihistamines, long-acting beta-2 antagonist or mixtures thereof.
The present invention further provides a method of prophylaxis and/or treatment of asthma, COPD 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.
Formula 1:

Sr. No. Ingredients Qty (mg)
1. Montelukast Sodium 4.16
Coating solution
2 Hypromellose 0.42
3. Purified water q.s.
Total weight 4.58
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

Sr. No Name of ingredients Qty/tab (mg)
DRY MIX *
1. * Coated Montelukast Sodium 4.58
2 Levocetirizine Dihydrochloride 2.50
3. Mannitol (Pearlitol SD 200) 57.62
4 Microcelac 50.0
5. Croscarmellose Sodium 10.0
6. Aspartame 2.00
7. Strawberry Flavor 1.30
8. Magnesium Stearate 2.00
Tablet weight 130 mg
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

Sr.
No Name of ingredients Qty/tab (mg)
1. * Coated Montelukast Sodium 4.16
2. Bambuterol Hydrochloride 5.00
3. Mannitol (Pearlitol SD 200) 90.10
4 Mannitol 20.00
5. Croscarmellose Sodium 6.50
6. Aspartame 0.74
7. Strawberry Flavor 1.00
8. Magnesium Stearate 2.5
Tablet weight 130 mg
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

Sr.No Name of ingredients Qty/tab (mg)
1.*
2. 3. Coated Montelukast Sodium
Mannitol
Low Substituted-Hydroxypropyl
Cellulose 4.15
155.20
6.00
4. 5. 6.
7. Activated Dimethicone Povidone Purified water. L-HPC 0.15 3.50 q.s. 6.00
8. 9. 10. Aspartame Strawberry Flavor Magnesium Stearate Tablet weight 1.00
2.00
2.00
180.00
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

Sr.No Name of ingredients Qty/tab (mg)
1.* Coated Montelukast Sodium 5.19
2. Mannitol (Pearlitol SD 200) 102.50
3. Mannitol 10.00
4 Croscarmellose Sodium 6.50
5. Red Oxide Of Iron 0.06
6. Aspartame 0.75
7. Strawberry flavor 1.00
8. Colloidal silicon dioxide 1.00
9. Magnesium Stearate 3.00
Tablet weight 130 mg
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

Sr.
No Name of ingredients Qty/tab (mg)
1. * 2. 3 4 Coated Montelukast Sodium
Mannitol
Crospovidone
Low Substituted-Hydroxypropyl Cellulose 10.40
148.00
4.00
4.00
5. Yellow oxide of Iron 0.4
6 7. 8. 9. Activated Dimethicone
Povidone
Purified water
Low-substituted-Hydroxypropyl Cellulose 0.20 7.00 q.s. 4.00
10. Magnesium Stearate Tablet weight 2.00 180 mg
Process
1 Sifted Coated Montelukast sodium, mannitol, crospovidone, low substituted-hydroxypropyl cellulose, yellow oxide of Iron, activated dimethicone and 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 low substituted-hydroxypropyl cellulose and magnesium stearate and compressed into tablets.


7

Sr.
No Name of ingredients Qty/tab (mg)
Montelukast sodium Layer
1. * Coated Montelukast Sodium 10.40
2. Mannitol 148.00
3 Crospovidone 4.00
4 Low Substituted-Hydroxypropyl Cellulose 4.00
5. Yellow oxide of Iron 0.4
6 Activated Dimethicone 0.20
7. Povidone 7.00
8. Purified water q.s.
9. Low-substituted-Hydroxypropyl Cellulose 4.00
10. Magnesium Stearate 2.00
Tablet weight 180 mg
Levocetirizine Dihydrochloride Layer
1. Levocetirizine dihydrochloride 5.00
2. Tablettose 16.50
3 Lactose 9.00
4 Lactose anhydrous 39.90
5. Avicel 25.00
6 Red oxide of Iron 0.10
7. Crospovidone 4.00
8. Magnesium stearate 0.50
Tablet weight 100.00


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 7 was prepared as described in formula 1.
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.

To,
The Controller of Patents,
The Patent Office, at Mumbai.