FIELD OF THE INVENTION
The present invention relates to stable oral pharmaceutical compositions of Montelukast.
The invention also relates to kit for dispensing of oral pharmaceutical compositions of
Montelukast.
BACKGROUND OF THE INVENTION
Asthma has close relationship with allergic respiratory disorders such as hay fever, allergic
rhinitis etc. The clinical symptoms produced in the course of allergic reaction are the result of
an early specific immune response and a late inflammatory reaction. The inhaled allergens
mediate the early phase by stimulating high affinity immunoglobulin (I g E) receptors e.g.
mast cells and basophils which in turn release histamine and cytokines. The cytokines
released from mast cells and basophils then mediate the late phase by recruiting
inflammatory cells into the nasal and upper respiratory tract passages. The influx of
eosinophils, macrophages, lymphocytes, neutrophils and platelets starts the vicious
inflammatory cycle. This late phase amplifies the initial immune response which in turn
triggers the release of more inflammatory cells.
Seasonal allergic rhinitis (hay fever) is caused by deposition of allergens on the nasal mucosa
resulting in an immediate hypersensitivity reaction. If the allergens (e.g. dust mite) are
carried to the lower airways (i.e. bronchioles), in susceptible subjects, the result is
bronchoconstriction of the airways (i.e. asthma). The allergen-induced release of leukotrienes
is critical in the pathophysiology of asthma. Leukotrienes are produced by mast cells,
eosinophils, neutrophils and alveolar macrophages. Leukotriene combines with receptors on
the respiratory tract cells, resulting in some symptoms of asthma such as respiratory tract
constriction, edema, and the increase of salivary secretion.
Various drugs like anti-inflammatory pharmaceuticals or bronchodilators are used for the
treatment of allergy related diseases and asthma. However, bronchodilators do not treat the
inflammatory reaction or lower the sensitivity of the respiratory tract. While anti-
inflammatory drugs are usually used as preventive medicine, the major anti-inflammatory
drugs in use nowadays are steroids, but the use of specific leukotriene receptor antagonists or
5-lipoxygenase pathway inhibitors are preferred which results in increased airflow and
reduction of symptoms in asthmatic patients.

U. S. Pat. No. 5,565,473 discloses a broad spectrum of compounds, which includes
Montelukast.
Montelukast is marketed as Singulair® in USA as oral tablets, granules and chewable tablets.
Oral tablet is not a convenient dosage form for some asthmatic patients, especially for
children below six years old and the geriatric patients. Geriatric patients may have difficulty
in swallowing tablet whereas tablet is usually grounded into powder before administration to
children. When the tablet is grounded into powder, impurities are introduced during the
grinding process and the drug dosage is difficult to control.
Montelukast as a granular dosage form is to be placed directly in the mouth; which can result
into unpleasant taste and grittiness in the mouth.
In another method of administration, Montelukast granules are dissolved in 1 teaspoonful (5
ml) of cold or room temperature baby formula or breast milk; or to be mixed with a spoonful
of one of the following soft foods at cold or room temperature; applesauce, mashed carrots,
rice, or ice cream, which is inconvenient and can result into inaccurate dosage administration.
Chewable tablets are masticated and swallowed at once, with a drink of water. These tablets
are sipped slowly for longer period of time, or otherwise, swallowed like conventional
tablets. This wrong usage would either lead to reduced therapeutic efficacy, or may lead to
mechanical obstruction of the ileum from impacted chewable tablets. Another major
disadvantage with the chewable tablet is unpleasant taste and grittiness mouth feel, leading to
poor patient compliance.
US patent application US 2006/0147482 discloses an oral liquid pharmaceutical composition
comprising leukotriene antagonist, a buffer agent, water, pharmaceutical alcohol, which may
be ethanol or propylene glycol and other additives.
US 2009/0247575 discloses a pharmaceutical composition for oral administration comprising
an exceptionally labile active agent, a stabilizing vehicle comprising liquid triglycerides and
a desiccant.
Montelukast compositions are susceptible to degradation during manufacture and storage.
This degradation is pronounced in the presence of agents such as UV light, heat, oxidizing
agents and/or water or moisture. This degradation of Montelukast leads to formation of
corresponding sulfoxide. The sulfoxide is an inactive impurity, which reduces the effective
dosage of Montelukast when it is administered to a patient. Montelukast undergoes photo-
isomerization to form inactive CIS isomer when exposed to UV Light. The CIS isomer is an
inactive impurity, which reduces the effective dosage of Montelukast when it is administered

to a patient. It also forms biologically inactive, non-absorbable S-enantiomer on exposure to
light and/or water.
Therefore, there exists a continuing need to develop stable oral pharmaceutical compositions
of Montelukast.
SUMMARY OF THE INVENTION
The invention provides stable oral pharmaceutical compositions comprising Montelukast, a
vehicle comprising mineral oil, desiccant and optionally pharmaceutically acceptable
additives.
Yet another embodiment provides stable oral liquid pharmaceutical compositions comprising
Montelukast, a vehicle comprising mineral oil, desiccant and optionally pharmaceutically
acceptable additives.
Yet another embodiment provides a kit for dispensing pharmaceutical compositions
comprising Montelukast, a vehicle comprising mineral oil, desiccant and optionally
pharmaceutically acceptable additives.
Yet another embodiment provides a kit for dispensing pharmaceutical compositions
comprising a first container comprising pharmaceutical composition of Montelukast and
optionally desiccant, a second container comprising a vehicle comprising mineral oil,
optionally desiccant and pharmaceutically acceptable additives, and instructions for use.
Montelukast and mineral oil occupy pre-measured volume into the respective unit of the kit.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides stable oral pharmaceutical compositions of Montelukast and a
kit containing pharmaceutical compositions of Montelukast.
The term "Montelukast" used herein refers to Montelukast as pharmaceutically acceptable
complexes, salts, polymorphs, hydrates, or solvates. Sodium salt of Montelukast is preferred.

As used herein with respect to pharmaceutical compositions, unless otherwise defined, the
term "stable" means that the amount of the corresponding sulfoxide within the montelukast in
the packaged pharmaceutical composition has not increased by more than 1.0 % by weight
from the initial amount of montelukast after storage at 40°C and 75% relative humidity for 3
months. In a preferred embodiment, the corresponding sulfoxide content has not increased by
more than 0.5% by weight of the initial amount of montelukast after storage at 40°C and 75%
relative humidity for 3 months. In the most preferred embodiment, the corresponding
sulfoxide content has not increased by more than 0.3% by weight of the initial amount of
montelukast after storage at 40°C and 75% relative humidity for 3 months.
As used herein with respect to pharmaceutical compositions, unless otherwise defined, the
term "stable" means that the amount of the corresponding CIS isomer within the montelukast
in the packaged pharmaceutical composition has not increased by more than 1.0 % by weight
from the initial amount of montelukast after storage at 40°C and 75% relative humidity for 3
months. In a preferred embodiment, the corresponding CIS isomer content has not increased
by more than 0.5% by weight of the initial amount of montelukast after storage at 40°C and
75% relative humidity for 3 months. In the most preferred embodiment, the corresponding
CIS isomer content has not increased by more than 0.3% by weight of the initial amount of
montelukast after storage at 40°C and 75% relative humidity for 3 months.
As used herein with respect to pharmaceutical compositions, unless otherwise defined, the
term "stable" means that the amount of the corresponding S-enantiomer within the
montelukast in the packaged pharmaceutical composition has not increased by more than 0.5
% by weight from the initial amount of montelukast after storage at 40°C and 75% relative
humidity for 3 months. In a preferred embodiment, the corresponding S-enantiomer content
has not increased by more than 0.3% by weight of the initial amount of montelukast after
storage at 40°C and 75% relative humidity for 3 months. In the most preferred embodiment,
the corresponding S-enantiomer content has not increased by more than 0.2% by weight of
the initial amount of montelukast after storage at 40°C and 75% relative humidity for 3
months.
The pharmaceutical compositions may be in the form of liquid. Alternatively the
pharmaceutical compositions are in form of powder or granules which can be reconstituted

(extemporaneous preparations) in the form of liquid. In one embodiment of the invention,
pharmaceutical compositions can be suspension or solution. In the preferred embodiment the
pharmaceutical composition is a suspension.
As used herein, the terms "suspension" and "solution" are interchangeable with each other.
"Suspension" encompasses a system in which a solid is dispersed in a liquid for example in
particles of larger than colloidal size. "Solution" encompasses any system in which one
substance is dissolved in another.
An extemporaneous preparation of a pharmaceutical composition is one performed at the
time of use, which is before the administration of the drug to the patient. The term
"extemporaneous preparation" also includes a preparation done by a pharmacist or other
healthcare practitioner and administered to a patient in a relatively short period of time after
the preparation. More preferably, an extemporaneous preparation is a pharmaceutical
composition that is not directly prepared by the pharmaceutical industry and put on the
market to be used as it is, but prepared at a time usually at a time close to the administration
to the patient.
The "stable oral pharmaceutical compositions" of the invention comprise Montelukast, a
vehicle comprising mineral oil, desiccant and optionally pharmaceutically acceptable
additives.
The mineral oil is a mixture of alkanes in the C15 to C40 range from a non-vegetable (mineral)
source. The mineral oil is employed in an amount ranging from about 1.0 % w/v to about
99.0 % w/v, preferably about 25.0 % w/v to about 99.0 % w/v and most preferably from
about 92.0 % w/v to about 99.0 % w/v based on the total volume of the composition.
The desiccants are selected from polyhydric alcohols, such as mannitol, sorbitol, xylitol,
isomalt and maltitol, as well as tribasic calcium phosphate, dibasic calcium phosphate,
calcium phosphate, kaolin, lactose, microcrystalline cellulose, powdered cellulose, precipitate
calcium carbonate, starch, dextrose, dextrate, sucrose, anhydrous silicon dioxide, anhydrous
ethanol, sodium metabisulfite, sodium sulfate, magnesium sulfate, magnesium oxide and

mixtures thereof. The preferred desiccants are colloidal silicon dioxide and magnesium oxide
and mixtures thereof.
These agents may be employed in an amount ranging from about 0.1 % w/v to about 30.0 %
w/v, preferably about 0.1 % w/v to about 10.0 % w/v and most preferably from about 0.1 %
w/v to about 5.0 % w/v based on the total volume of the composition.
The pharmaceutically acceptable additives may include sweeteners, flavours, and
preservatives.
Sweeteners are selected from sucrose, fructose, dipotassium glycirhizinate.
Artificial sweeteners like saccharin, saccharin sodium, aspartame; mannitol, xylitol or
acesulfame potassium and mixtures thereof are suitable for administration to children. The
sweeteners may be employed in an amount ranging from about 0.1% to about 10% w/v,
preferably about 0.1% to about 7% w/v and most preferably from about 0.1% w/v to about
2% w/v based on the total volume of the composition.
The preservatives are selected from butylated hydroxy toluene, butylated hydroxy anisole,
methyl parahydroxybenzoate, propyl parahydroxybenzoate and sodium benzoate and
mixtures thereof.
The amount of preservative to be used is less than about 0.1 % w/v. The preferred amount of
the preservative to be used is less than about 0.02 %w/v.
The flavoring agents may be selected from cherry, vanilla, strawberry, lemon, yoghurt,
cardamom, fennel, peppermint, or anise etc.
The term "pharmaceutically acceptable" means that which is useful in preparing a
pharmaceutical composition that is generally safe, non-toxic and neither biologically nor
otherwise undesirable and includes that which is acceptable for human pharmaceutical use.

The invention is also directed to kits comprising one or more pharmaceutical compositions of
the invention. In some embodiments, the kits of the invention comprise a container or other
means for holding the compositions of the invention.
In some embodiments, the kit comprises (a) a first container or other means for containing a
therapeutically effective amount of the Montelukast in form of powder or granules and (b) a
second container or other means for containing a vehicle comprising mineral oil. Optionally,
the kit can have additional containers or other means for containing comprising a
therapeutically effective amount of additional agents.
Powder or granules of montelukast and salt thereof can be prepared by methods known by
one of skill in the art.
Since the kit will contain at least one pharmaceutical active and the at least one vehicle, the
minimum number of containers in the given kit will be two. In a preferred embodiments, the
maximum number of containers in the kit will be less than or equal to five. In the most
preferred embodiment the number of containers in the kit will be two. The containers may be
formed in any size or shape useful for the mixing or transferring of components from one
container to another. Either or both of the first container and second container can be light-
protective containers.
In some embodiments, the kit comprises a container or other means for containing for the
separate compositions, such as, a divided bottle or a divided foil packet; however, the
separate compositions can also be contained within a single, undivided container.
As herein described the kit may contain mixing element for example a stirrer to physically
mix the Montelukast and a vehicle.
Typically, the kit contains printed labeling instructions. The printed labeling may provide
instructions for administering any of the compositions, using any of the kits, or performing
any other method herein described.
Suitable containers or other means for containing pharmaceutical composition(s) and
pharmaceutically acceptable carrier include, but are not limited to, bottles made of high-

density polyethylene (HDPE), polypropylene (PP), glass, and metal. Preferably the container
is an amber colored glass bottle with a child resistant cap.
In another preferred embodiment, the kit is a unit dose packet (sometimes referred to in the
art as a "sachet"), which is typically emptied into the mineral oil in preparing an oral
suspension.
The invention in another aspect provides a simple one-step transfer method for preparing a
pharmaceutical composition(s). A single dose sachet is designed to be emptied into the
mineral oil or alternatively the mineral oil is added to a bottle containing the single dose
pharmaceutical composition followed by gentle mixing for about 1-2 minutes result in a
homogeneous and uniform dispersion or solution of the drug.

Brief Manufacturing Procedure:
1. Dissolve Butylatedhydroxytoluene, Butylatedhydroxyanisole and in ½ quantity of
Mineral Oil light with stirring to get a clear solution.
2. Dissolve Silicon Dioxide in step-1 solution to get a clear solution.
3. Disperse Sucralose and Magnesium Oxide in step-2 solution with stirring to get
uniform suspension.
4. Disperse Montelukast Sodium in step-3 suspension with stirring.

5. Add Peppermint Oil to step 3 suspension with stirring and stir for 10 min.
6. Make up the volume to the required batch size with Mineral Oil light and stir to get
uniform suspension.

Brief Manufacturing Procedure:
1. Dissolve Butylatedhydroxytoluene, Butylatedhydroxyanisole and in ½ quantity of
Mineral Oil light with stirring to get a clear solution.
2. Dissolve Silicon Dioxide in step-1 solution to get a clear solution.
3. Disperse Saccharin and Magnesium Oxide in step-2 solution with stirring to get
uniform suspension.
4. Disperse Montelukast Sodium in step-3 suspension with stirring.
5. Add Peppermint Oil to step 3 suspension with stirring and stir for 10 min.
6. Make up the volume to the required batch size with Mineral Oil light and stir to get
uniform suspension.



Brief Manufacturing Procedure:
1. Dissolve Silicon Dioxide and 54 quantity of Mineral Oil to get a clear solution.
2. Disperse Magnesium Oxide in step-1 solution with stirring to get uniform suspension.
3. Disperse Montelukast Sodium in step-2 suspension with stirring.
4. Add Peppermint Oil to step 2 suspension with stirring and stir for 10 min.
5. Make up the volume to the required batch size with Mineral Oil light and stir to get
uniform suspension.
Example IV

Brief Manufacturing Procedure:
1. Dissolve Silicon Dioxide and 54 quantity of Mineral Oil to get a clear solution.
2. Disperse Magnesium Oxide in step-1 solution with stirring to get uniform suspension.
3. Disperse Montelukast Sodium in step-2 suspension with stirring.
4. Add Peppermint Oil to step 2 suspension with stirring and stir for 10 min.
5. Make up the volume to the required batch size with Mineral Oil light and stir to get
uniform suspension.

Stability Study of Montelukast Suspension prepared in accordance of Example 4:
Composition of Example 4 was subjected to stability studies at 40° C and 75% RH for 3
months. After one month, two month and three month sample was removed and checked for
various parameters. Data of 1, 2 and 3 month stability studies is shown in Table 1.


We Claim:
1. A stable liquid oral pharmaceutical composition comprising montelukast, a vehicle
comprising mineral oil, desiccant and optionally pharmaceutically acceptable
additives.
2. The composition of claim 1, wherein the liquid oral pharmaceutical composition is a
suspension.
3. The composition of claim 1, wherein the liquid oral pharmaceutical composition is a
solution.
4. The composition of claim 1, wherein the desiccant is selected from mannitol, sorbitol,
xylitol, isomalt, maltitol, tribasic calcium phosphate, dibasic calcium phosphate,
calcium phosphate, kaolin, lactose, microcrystalline cellulose, powdered cellulose,
precipitate calcium carbonate, starch, dextrose, dextrate, sucrose, anhydrous silicon
dioxide, anhydrous ethanol, sodium metabisulfite, sodium sulfate, magnesium sulfate,
magnesium oxide and mixtures thereof.
5. The composition of claim 4, wherein the desiccant is selected from colloidal silicon
dioxide, magnesium oxide and mixtures thereof.
6. The composition of claim 1, wherein the pharmaceutically acceptable additives are
selected from sweeteners, flavours, preservatives and mixtures thereof.
7. The composition of claim 1, wherein the composition contains not more than about
1.0 % by weight of sulfoxide degradation product after storage at about 40° C and
about 75% relative humidity for three months.
8. The composition of claim 1, wherein the composition contains not more than about
1.0 % by weight of corresponding Cis isomer of montelukast after storage at about
40° C and about 75% relative humidity for three months.
9. The composition of claim 1, wherein the composition contains not more than about
0.5 % by weight of S-enantiomer of montelukast after storage at about 40° C and
about 75% relative humidity for three months.
10. A kit for dispensing pharmaceutical composition comprising montelukast, a vehicle
comprising mineral oil, desiccant and optionally pharmaceutically acceptable
additives.

11. A kit for dispensing pharmaceutical composition comprising a first container
comprising pharmaceutical composition of montelukast and optionally desiccant, a
second container comprising a vehicle comprising mineral oil, optionally desiccant
and pharmaceutically acceptable additives, and instructions for use. montelukast and
mineral oil occupy pre-measured volume into the respective unit of the kit.

ABSTRACT

A stable liquid oral pharmaceutical composition comprising montelukast, a vehicle
comprising mineral oil, desiccant and optionally pharmaceutically acceptable additives is
provided. The invention also relates to kit for dispensing of oral pharmaceutical compositions
of Montelukast. The kit comprises montelukast, a vehicle comprising mineral oil, desiccant
and optionally pharmaceutically acceptable additives. The kit comprises a first container
comprising pharmaceutical composition of montelukast and optionally desiccant, a second
container comprising a vehicle comprising mineral oil, optionally desiccant and
pharmaceutically acceptable additives, and instructions for use. montelukast and mineral oil
occupy pre-measured volume into the respective unit of the kit.