COMPLATE AFTER PROVISIONAL LEFT ON
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FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
PHARMACEUTICAL COMPOSITIONS OF MONTELUKAST
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near
Dinesh Hall, Ahmedabad 380 009, Gujarat,
India

The following specification particularly describes the invention and the manner in which it is to be performed.


PHARMACEUTICAL COMPOSITIONS OF MONTELUKAST
FIELD OF THE INVENTION
The present invention relates to stable pharmaceutical compositions of montelukast. More particularly, the present invention relates to pharmaceutical compositions of montelukast comprising less than 1.6 % by weight of an organoleptic additive.
BACKGROUND OF THE INVENTION
Montelukast is a leukotriene receptor antagonist which may be used for the treatment and prevention of leukotriene-mediated diseases and disorders such as asthma, allergic rhinitis, atopic dermatitis, chronic urticaria, sinusitis, nasal polyps, chronic obstructive pulmonary disease, conjunctivitis including rhinoconjunctivitis, migraine, cystic fibrosis, and wheezing secondary to viral bronchiolitis.
Montelukast is a known compound and its preparation is disclosed in, for example, U.S. 5,565,473 and US 5,614,632. Oral solid pharmaceutical compositions like tablets, capsules and granules of montelukast are also disclosed in the art. In addition to montelukast or its salt, such compositions comprise conventional excipients such as diluent, disintegrant, binder, lubricant, and organoleptic additives such as flavoring agent, sweetener or coloring agent.
US 2005/187244 discloses crystalline forms of montelukast sodium and process for preparation thereof. It also discloses solid and liquid compositions of montelukast sodium. It also discloses use of flavoring agent and sweetener in the compositions.
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US 2003/096840 disclose a novel formulation of montelukast sodium in the form of granular powder which may be ingested directly or mixed with food or other comestibles. It also discloses easily flowable and dispersible pharmaceutical composition which comprises granules having a substrate coated with montelukast sodium, and a lubricant. It also discloses the use of flavoring agent, sweetener and/or coloring agent in the composition.
Organoleptic additives like flavoring agents or sweeteners are mostly used to impart improved sensory characteristics to the pharmaceutical compositions. We have surprisingly found that by modifying the content of organoleptic additives in the composition, improved in-vitro dissolution of the composition can be achieved.
SUMMARY OF THE INVENTION
One embodiment discloses a stable pharmaceutical composition comprising
i) montelukast,
ii) less than 1.6 % by weight of the composition of an organoleptic
additive, and
iii) at least one pharmaceutically acceptable excipient; wherein the composition releases at least 60 % of montelukast after 30 minutes, when the composition is subjected to dissolution in 900 ml of pH 4.5 acetate buffer having 1% SLS using USP Type II apparatus with a paddle speed of 50 rpmat 37±0.5°C.
Another embodiment discloses a stable pharmaceutical composition comprising i) montelukast,
ii) less than 1.6 % by weight of the composition of aspartame and/or cherry flavor, and iii) at least one pharmaceutically acceptable excipient;
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wherein the composition releases at least 60 % of montelukast after 30 minutes, when the composition is subjected to dissolution in 900 ml of pH 4.5 acetate buffer having 1% SLS using USP Type II apparatus with a paddle speed of 50 rpm at 37±0.5°C.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows the comparative dissolution profiles of Comparative Example 1, Example 1, Reference Product-1 and Reference Product-2.
Figure 2 shows the comparative dissolution profiles of Example 2, Example 3 and Comparative Example 1.
DETAILED DESCRIPTION OF THE INVENTION
The term "montelukast" as used herein refers to montelukast free base or pharmaceutically acceptable salts, hydrates, solvates and enantiomers thereof or mixtures thereof. The preferred salt of montelukast is montelukast sodium. Montelukast may be present in amorphous form, crystalline form or mixtures thereof. Montelukast typically comprises from about 0.1% to about 20% by weight of the composition.
The term "organoleptic additive" as used herein refers to sweetener, flavoring agent or mixtures thereof. The organoleptic additive is present in an amount of less than 1.6 % by weight of the composition, preferably less than 0.5 % by weight of the composition.
The sweetener is selected from aspartame, saccharin sodium, acesulfame potassium, dried invert sugar, dextrose, glucose, fructose, galactose, levulose, maltose, neotame, sucralose or mixture thereof. Preferred sweetener is aspartame.
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The sweetener is present in an amount less than 1.6 % by weight of the composition.
The flavoring agent is selected from cherry, black current, pineapple, orange, strawberry, banana, vanilla, mint, menthol, citric acid, fumaric acid, tartaric acid, or mixture thereof. Preferred flavoring agent is cherry flavor. The flavoring agent is present in an amount less than 0.3 % by weight of the composition.
The pharmaceutical compositions as described herein may comprise of one or more pharmaceutically acceptable excipients selected from diluent, binder, disintegrant, glidant or lubricant.
Diluent may be selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrose, kaolin, magnesium carbonate, magnesium oxide; sugars such as lactose or sucrose; sugar alcohols such as mannitol, sorbitol or erythritol; and mixtures thereof. Preferred diluents are microcrystalline cellulose and mannitol. The diluent may be present in an amount ranging from 3 % to 90 % by weight of the composition.
Binder may be selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, gelatin, polymethacrylates, polyvinylpyrrolidone, pregelatinized starch, sodium alginate, gums, synthetic resins and the like. The binder may be present in an amount ranging from 0.1 % to 8 % by weight of the composition.
Disintegrant may be selected from croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone and mixtures thereof. Preferred disintegrant is croscarmellose sodium. The disintegrant may be present in an amount ranging from 1 % to 10 % by weight of the composition.
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Lubricant / glidant may be selected from talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate; and mixtures thereof. Preferred lubricant is magnesium stearate. The lubricant / glidant may be present in an amount ranging from 0.1 % to 6 % by weight of the composition.
Dissolution profile is carried out in 900 ml of pH 4.5 acetate buffer having 1% SLS using USP Type II apparatus with a paddle speed of 50 rpm at 37 ± 0.5°C. The embodiments disclosed herein show at least 60 % drug release after 30 min, preferably at least 70 % drug release after 30 min.
The pharmaceutical composition may be in the form of a tablet, a capsule, powder or granules. Tablet dosage form may be prepared by direct compression, dry granulation or wet granulation method.
One embodiment discloses a stable pharmaceutical composition comprises
(i) m ontelukast,
(ii) less than 1.6 % by weight of the composition of aspartame and/or cherry flavor, and
(iii)at least one pharmaceutically acceptable excipient; wherein the composition releases at least 60 % of montelukast after 30 minutes, when the composition is subjected to dissolution in 900 ml of pH 4.5 acetate buffer having 1% SLS using USP Type II apparatus with a paddle speed of 50 rpm at 37 ± 0.5 °C
Another embodiment discloses a stable pharmaceutical composition comprises (i) m ontelukast,
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(ii) 0.25 % by weight of the composition of aspartame, (iii)0.12 % by weight of the composition of cherry flavor, and (iv)at least one pharmaceutically acceptable excipient; wherein the composition releases at least 60 % of montelukast after 30 minutes, when the composition is subjected to dissolution in 900 ml of pH 4.5 acetate buffer having 1% SLS using USP Type II apparatus with a paddle speed of 50 rpm at 37±0.5°C.
Another embodiment discloses a process for preparing stable pharmaceutical composition of montelukast, wherein the process comprises
(a) mixing montelukast, less than 1 % by weight of the composition of aspartame and/or cherry flavor and at least one pharmaceutically acceptable excipient,
(b) lubricating the mixture, and
(c) compressing the mixture of step (b) into the tablet;
wherein the composition releases at least 60 % of montelukast after 30 minutes, when the composition is subjected to dissolution in 900 ml of pH 4.5 acetate buffer having 1% SLS using USP Type II apparatus with a paddle speed of 50 rpm at 37 ± 0.5 °C.
Yet another embodiment discloses a process for preparing stable pharmaceutical composition of montelukast, wherein the process comprises
(a) mixing montelukast, less than 1.6 % by weight of the composition of organoleptic additive and at least one pharmaceutically acceptable excipient,
(b) granulating the mixture to form granules,
(c) drying and lubricating the granules, and
(d) compressing the granules of step (d) into the tablet;
wherein the composition releases at least 60 % of montelukast after 30 minutes, when the composition is subjected to dissolution in 900 ml of pH 4.5 acetate
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buffer having 1% SLS using USP Type II apparatus with a paddle speed of 50 rpm at 37±0.5°C.
The pharmaceutical compositions as described herein may be illustrated by the following examples which are not to be construed as limiting the scope of the invention:
COMPARATIVE EXAMPLE 1

S.No Ingredients Mg / Tablet
1 Montelukast sodium 5.20
2 Mannitol 91.99
3 Microcrystalline cellulose 35.00
4 Croscarmellose sodium 11.25
5 Aspartame 2.20
6 Cherry flavor 0.38
7 Ferric oxide red 0.18
8 Magnesium stearate 3.75
Tablet Weight 150.000
Montelukast sodium, mannitol, microcrystalline cellulose (MCC), croscarmellose sodium, aspartame, and cherry flavor were sifted through appropriate sieve. Montelukast sodium was mixed with mannitol and MCC in geometric proportion followed by addition of remaining excipients to obtain a blend. The blend was lubricated by addition of magnesium stearate in a blender followed by compression into tablets.
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EXAMPLE 1

S.No Ingredients Mg / Tablet % w/w
1 Montelukast sodium 5.200 3.47
2 Mannitol 94,065 62.71
3 Microcrystalline cellulose 35.000 23.33
4 Croscarmellose sodium 11.250 7.50
5 Aspartame 0.375 0.25
6 Cherry flavor 0.180 0.12
7 Ferric oxide red 0.180 0.12
8 Magnesium stearate 3.750 2.50
Tablet Weight 150.000 100.00
Tablets comprising montelukast sodium were prepared by the same process as specified in Comparative Example 1.
EXAMPLE 2

S.No Ingredients Mg / Tablet % w/w
1 Montelukast sodium 5.200 3.47
2 Mannitol 94.245 62.83
3 Microcrystalline cellulose 35.000 23.33
4 Croscarmellose sodium 11.250 7.50
5 Cherry flavor 0,375 0.25
6 Ferric oxide red 0.180 0.12
7 Magnesium stearate 3.750 2.50
Tablet Weight 150.000 100.00
Tablets comprising montelukast sodium were prepared by the same process as specified in Comparative Example 1.
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EXAMPLE 3

S.No Ingredients Mg/ Tablet % w/w
1 Montelukast sodium 5.200 3.47
2 Mannitol 94.065 62.71
3 Micro crystal line cellulose 35.180 23.45
4 Croscarmellose sodium 11.250 7.50
5 Aspartame 0.375 0.25
6 Ferric oxide red 0.180 0.12
7 Magnesium stearate 3.750 2.50
Tablet Weight 150.000 100.00
Tablets comprising montelukast sodium were prepared by the same process as specified in Comparative Example 1.
Table 1: Comparison of dissolution profiles of Examples disclosed in the
specification

Time (min) Dissolution (% Drug dissolved)

Comparative Example 1 Example 1 Example 2 Exam ples Reference Product-1 Reference Product-2
5 29.8 57.1 49.9 58.6 53.7 65.8
10 38.1 64.3 60.0 53.3 65.1 73.9
15 40.7 69.2 61.8 60.9 69.7 79.3
20 43.0 71.1 63.2 64.7 67.3 83.7
30 46.5 74.1 65.7 65.8 76.5 86.9
45 49.0 73.2 67.9 61.2 79.8 89.3
60 51.6 76.9 69.9 70.3 81.1 90.8
(Dissolution profile is carried out in 900 ml of pH 4.5 acetate buffer having 1% SLS using USP Type II apparatus with a paddle speed of 50 rpm at 37 ± 0.5°C.)
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Reference Product-l is tablet dosage form marketed by Merck & Co., Inc, in Germany (Batch no. 260208). Reference Product-2 is tablet dosage form marketed by Merck & Co., Inc, in USA (Batch no: F6866) under the trade name Singulair®.
EXAMPLE 4

S.No Ingredients Mg/Tablet % w/w
1 Montelukast sodium 10.40 3.47
2 Mannitol 193.63 64.54
3 Microcrystalline cellulose 70.00 23.33
4 Croscarmellose sodium 17.00 5.67
5 Aspartame 0.75 0.25
6 Cherry flavor 0.36 0.12
7 Ferric oxide red 0.36 0.12
8 Magnesium stearate 7.50 2.50
Tablet Weight 300.00 100.00
Tablets comprising montelukast sodium were prepared by the same process as specified in Comparative Example 1.
EXAMPLE 5

S.No Ingredients Mg/Tablet % w/w
1 Montelukast sodium 10.40 3.47
2 Mannitol 188.13 62.71
3 Microcrystalline cellulose 70.00 23.33
4 Croscarmellose sodium 22.50 7.50
5 Aspartame 0.75 0.25
6 Cherry flavor 0.36 0.12
7 Ferric oxide red 0.36 0.12
8 Magnesium stearate 7.50 2.50
Tablet Weight 300.00 100.00
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Tablets comprising montelukast sodium were prepared by the same process as specified in Comparative Example 1.
Table 2: Dissolution Profile of Example 5

Time (min) Dissolution (% drug dissolved)
5 52.3
10 65.3
15 67.2
20 67.7
30 70.3
45 70.9
60 73.3
(Dissolution profile is carried out in 900 ml of pH 4.5 acetate buffer having 1% SLS using USP Type II apparatus with a paddle speed of 50 rpm at 37 ± 0.5°C.)
Table 3: Stability data of Example 5 in Alu-Alu Blister at 40°C -75% RH

Test Initial 3 Months 6 months
Related substances (%)
A) Known Impurities
I) Mok 3 Sulphoxide 0.10 0.07 0.09
II) Quid 8 0.04 0.05 0.03
111) Styrene 0.04 0.04 0.04
B) Any single unknown
impurity 0.06 0.06 0.11
C) Total impurities
(known + unknown) 0.4 0.5 0.5
Assay (% w/w) 99.8 100.2 100.7
Dated This 12tn Day of February, 2008
For Torrent Pharmaceuticals Ltd, Praveen Chand Gandhi
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We claim,
1. A stable pharmaceutical composition comprising
i) montelukast,
ii) less than 1.6 % by weight of the composition of an organoleptic
additive, and
iii) at least one pharmaceutical acceptable excipient; wherein the composition releases at least 60 % of montelukast after 30 minutes, when the composition is subjected to dissolution in 900 ml of pH 4.5 acetate buffer having 1% SLS using USP Type II apparatus with a paddle speed of 50 rpm at 37 ± 0.5 °C.
2. The composition of claim 1, wherein the organoleptic additive comprises a sweetener, a flavoring agent or mixture thereof.
3. The composition of claim 2, wherein the organoleptic additive is present in an amount less than 0.5 % by weight of the composition.
4. The composition of claim 2, wherein the sweetener is aspartame.
5. The composition of claim 2, wherein the flavouring agent is cherry flavor.
a
6. The composition of claim 1, wherein at least one pharmaceutically acceptable excipient is selected from the group consisting of diluent, disintegrant, binder, glidant and lubricant.
7. The composition of claim 6, wherein the disintegrant is croscannellose sodium.
8. The composition of claim 6, wherein the glidant or lubricant is magnesium
stearate.
9. A stable pharmaceutical composition as substantially described and
exemplified herein.
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