MONTELUKAST ORAL SOLUBLE FILM FORMULATION
Field of the Invention
The present invention relates to an oral soluble film formulation comprising montelukast
sodium and one or more hydrophilic polymers and one or more pharmaceutically acceptable
excipients, and processes for the preparation of said formulation.
Background of the Invention
Oral Soluble Films (OSF) disintegrate, dissolve, or disperse quickly within a few
seconds after being placed in the mouth. They can be ingested without the need of water,
thereby eliminating the problem of swallowing tablets. Further, OSF may enhance the
bioavailability of drugs through pre-gastric absorption from the mouth, pharynx, and esophagus
by avoiding first pass liver metabolism. The multifaceted advantages of OSF formulations, such
as ease of self-administration without water and rapid disintegration and dissolution, provide
enhanced patient acceptance and compliance, particularly in patients where proper and complete
dosing can be difficult, for example, pediatric, geriatric, mentally ill, and uncooperative patients
and patients with nausea and vomiting.
Furthermore, there is a growing interest in OSF as an alternative to fast-dissolving tablets
to eliminate the patients' fear of choking. Although oral disintegrating tablets are readily
disintegrated, the disintegrated material remains largely insoluble until swallowing, which may
lead to choking.
Montelukast is a leukotriene antagonist and has the following chemical structure:
Montelukast was first disclosed in U.S. Patent No. 5,565,473. which further discloses the
use of montelukast in pulmonary disorders including diseases such as asthma, chronic
bronchitis, and related obstructive airway diseases; allergies and allergic reactions such as
allergic rhinitis, contact dermatitis, or allergic conjunctivitis; inflammation such as arthritis or
inflammatory bowel disease; pain; skin disorders such as psoriasis or atopic eczema; and
cardiovascular disorders such as angina, myocardial ischemia, hypertension, or platelet
aggregation.
Montelukast sodium is used for the treatment of asthma and to relieve symptoms of
seasonal allergies. Montelukast blocks the action of leukotriene on the cysteinyl leukotriene
receptor in the lungs and bronchial tubes by binding to these receptors. Therefore, it is highly
advantageous to formulate an oral soluble film formulation comprising montelukast sodium.
Summarv of the Invention
The present invention provides an oral soluble film formulation comprising a
therapeutically effective amount of montelukast or a pharmaceutically acceptable salt thereof
and one or more hydrophilic polymers and one or more pharmaceutically acceptable excipients.
The present invention also provides processes for the preparation of oral soluble film
formulation comprising a therapeutically effective amount of montelukast or a pharmaceutically
acceptable salt thereof and one or more hydrophilic polymers.
Detailed Description of the Invention
The term "montelukast or a pharmaceutically acceptable salt thereof', as employed
herein, refers to montelukast or pharmaceutically acceptable salts, solvates, derivatives,
polymorphs, hydrates, or enantiomers thereof. The salts may be derived from inorganic or
organic bases or acids including inorganic and organic acids. In particular, salts derived from
inorganic bases e.g, aluminium, ammonium, calcium, copper, ferric, ferrous, lithium,
magnesium, sodium, or zinc may be used.
The term "oral soluble film", as employed herein, refers to thin, flexible, non-friable
polymeric single-layer or multi-layer film strips containing montelukast or a pharmaceutically
3
acceptable salt thereof which is intended to be placed on the tongue for rapid disintegration and
dissolution in the saliva prior to swallowing for delivery of the drug into the GI tract or for
absorption from the buccal cavity.
The term "therapeutically effective amount", as employed herein, refers to the amount of
montelukast or pharmaceutically acceptable salt thereof contained in the oral soluble film
formulation which is sufficient to reduce, eliminate, treat, prevent or control the symptoms of a
disease or condition affecting a human for which montelukast is indicated. The dosage of
montelukast may be between 1 mg and 50 mg; particularly, it may be between 1 mg and 25 mg.
In particular, it may be between 1 mg and 15 mg.
The present invention can be explained by way of the following aspects.
A first aspect of the present invention provides an oral soluble film formulation
comprising a therapeutically effective amount of montelukast or a pharmaceutically acceptable
salt thereof, one or more hydrophilic polymers, and one or more pharmaceutically acceptable
excipients.
The hydrophilic polymers may include polymers that rapidly dissolve on the tongue or in
the buccal cavity, delivering the drug into the systemic circulation via dissolution, upon contact
with any liquid. These polymers are selected from natural and synthetic polymers and
combinations thereof. Examples of natural polymers include, but are not limited to, pullulan,
starch, gelatin, pectin, alginic acid, sodium alginate, dextrin, maltodextrin, polymerized resin,
carrageenan, xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, or
combinations thereof. Examples of synthetic polymers include, but are not limited to,
hydroxylpropyl methyl cellulose, sodium carboxymethyl cellulose, polyethylene oxide,
polyethylene glycol, hydroxypropyl cellulose, polyvinyl pyrrolidone, crosslinked polyvinyl
pyrrolidone, polyvinyl alcohol, carboxyvinyl copolymers, ethylene glycol and vinyl alcohol
graft copolymer, or combinations thereof.
Pharmaceutically acceptable excipients may be selected from plasticizers, disintegrants,
saliva stimulating agents, flavoring agents, sweetening agents, coloring agents, preservatives,
antioxidants, surfactants, buffering agents, solvents, or combinations thereof.
The plasticizers may be selected from the group comprising glycerine, ' sorbitol,
propylene glycol, polyethylene glycol, triacetin, tri ethyl citrate (TEC), acetyl tri ethyl citrate
(ATEC), other citrate esters, or combinations thereof.
The disintegrants may be selected from the group comprising alginic acid,
microcrystalline cellulose, cross-linked cellulose, modified starches such as sodium
carboxymethyl starch, cross-linked polymers such as polyvinyl pyrrolidone, cross-linked
starches such as sodium starch glycolate, cross-linked cellulosic polymers such as sodium
carboxymethyl cellulose, or combinations thereof.
The saliva stimulating agents may be selected from the group comprising acidic agents
such as phosphoric acid, adipic acid, succinic acid, citric acid, malic acid, tartaric acid, fumaric
acid, lactic acid, acetic acid, cinnamic acid, ascorbic acid, or combinations thereof.
The flavoring agents may be selected from the group comprising essential oils or water
soluble extracts of menthol, wintergreen, strawberry, peppermint, sweet mint, spearmint,
vanillin, cherry, chocolate, cinnamon, clove, lemon, orange, bubble gum flavor, other common
flavors, or combinations thereof.
The sweetening agents may be selected from the group comprising dextrose, lactose,
mannitol, erythritol, sucrose, xylitol, malitol, acesulfame potassium, talin, glycyrrhizin,
sucralose, aspartame, saccharin, or combinations thereof.
The coloring agents may be selected from the group consisting of FD&C approved
coloring agents; natural coloring agents; natural juice concentrates; pigments such as titanium
oxide, silicon dioxide, and zinc oxide; or combinations thereof.
The preservatives may be selected from the group comprising benzoic acid, sodium
benzoate, ethylene diamine tetra acetic acid and its salts (e.g. sodium EDTA), sorbic acid,
benzethonium chloride, benzalkonium chloride, bronopol, butyl paraben, methyl paraben, ethyl
paraben, propyl paraben, thiomerosol, sodium propionate, chlorhexidine, chlorobutanol,
chlorocresol, cresol, imidurea, phenol, phenylmercuric salts, potassium sorbate, propylene
glycol, or combinations thereof.
The antioxidants may be selected from the group comprising butylated hydroxyl-anisole
(BHA), sodium ascorbate, butylated hydroxyl toluene (BHT), sodium sulfite, gallates (e.g.
propyl gallate), tocopherol, citric acid, malic acid, ascorbic acid, acetyl cysteine, fumaric acid,
lecithine, ascorbyl palmitate, ethylene diamine tetra acetic acid and its salts (e.g. sodium
EDTA), or combinations thereof.
The surfactants may be selected from the group comprising sodium lauryl sulfate; mono
and diglycerides of fatty acids and polyoxyethylene sorbitol esters such as polyoxyethylene (20)
sorbitan monostearate (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate
SO), or derivatives thereof; or combinations thereof.
The buffering agents may be selected from the group comprising potassium hydrogen
phosphate, ascorbic acid, sodium hydroxide, citric acid, sodium citrate, calcium carbonate,
magnesium oxide, sodium bicarbonate, tartaric acid, fumaric acid, malic acid, or combinations
thereof.
The solvents may be selected from the group comprising water, isopropyl alcohol,
methylene chloride, acetone, methanol, ethanol, or combinations thereof.
A second aspect of the present invention provides a process for the preparation of an oral
soluble film formulation comprising a therapeutically effective amount of montelukast or a
pharmaceutically acceptable salt thereof, one or more hydrophilic polymers, and one or more
pharmaceutically acceptable excipients, wherein the process comprises the steps of:
a) dissolving or dispersing montelukast or a pharmaceutically acceptable salt thereof in one
or more suitable solvents to obtain a solution or dispersion;
b) dissolving or dispersing one or more hydrophilic polymers in the solution or dispersion
of step a);
c) dissolving or dispersing pharmaceutically acceptable excipients in the solution or
dispersion of step b) to obtain a final solution or dispersion; and
d) layering the final solution or dispersion of step c) onto a film casting device to obtain
said film.
According to one embodiment of this aspect, there is provided a process for the
preparation of an oral soluble film formulation comprising a therapeutically effective amount of
montelukast or a pharmaceutically acceptable salt thereof, one or more hydrophilic polymers,
6
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OR 0 & &l L. 'GINbL , l - and one or more pharmaceutically acceptable excipients. wherein the process comprises the
steps of:
a) dissolving or dispersing montelukast or a pharmaceutically acceptable salt thereof in one
or more suitable solvents to obtain a solution or dispersion;
b) dissolving or dispersing one or more hydrophilic polymers in the solution or dispersion
of step a);
c) dissolving or dispersing pharmaceutically acceptable excipients selected from
plasticizers, disintegrants, saliva stimulating agents, flavoring agents, sweetening agents,
coloring agents, preservatives, antioxidants, surfactants, buffering agents, or
combinations thereof in the solution or dispersion of step b) to form a final solution or
dispersion; and
d) layering the final solution or dispersion of step c) onto a film casting device to obtain
said film.
A third aspect of the present invention provides a process for the preparation of an oral
soluble film formulation comprising a therapeutically effective amount of montelukast or a
pharmaceutically acceptable salt thereof, one or more hydrophilic polymers, and one or more
pharmaceutically acceptable excipients, wherein the process comprises the steps of:
a) dissolving or dispersing one or more hydrophilic polymers in one or more suitable
solvents to obtain a solution or dispersion;
b) dissolving or dispersing one or more pharmaceutically acceptable excipients in the
solution or dispersion of step a);
c) dissolving or dispersing montelukast or a pharmaceutically acceptable salt thereof in one
or more suitable solvents to obtain a drug solution or dispersion;
d) mixing the drug solution or dispersion of step c) with the solution or dispersion of step b)
to form a final solution or dispersion; and
e) layering the final solution or dispersion of step d) onto a film casting device to obtain
said film.
According to one embodiment of this aspect, there is provided a process for the
preparation of an oral soluble film formulation comprising a therapeutically effective amount of
montelukast or a pharmaceutically acceptable salt thereof, one or more hydrophilic polymers,
and one or more pharmaceutically acceptable excipients, wherein the process comprises the
steps of:
a) dissolving or dispersing one or more hydrophilic polymers in one or more suitable
solvents to obtain a solution or dispersion;
b) dissolving or dispersing one or more pharmaceutically acceptable excipients selected
from plasticizers, disintegrants, saliva stimulating agents, flavoring agents, sweetening
agents, coloring agents, preservatives, antioxidants, surfactants. buffering agents, or
combinations thereof in the solution or dispersion of step a);
c) dissolving or dispersing montelukast or a pharmaceutically acceptable salt thereof in one
or more suitable solvents to obtain a drug solution or dispersion;
d) mixing the drug solution or dispersion of step c) with the solution or dispersion of step b)
to form a final solution or dispersion; and
e) layering the final solution or dispersion of step d) onto a film casting device to obtain
said film.
The oral soluble film formulation of the present invention may be characterized by one
or more parameters which may include organoleptic evaluation, film thickness, tensile strength,
folding endurance and in-vitro disintegration time.
The term "organoleptic evaluation" as used herein, refers to the surface appearance (e.g.
clarity and transparency) and the tactile characteristics (e.g. flexibility and uniformity) of the
oral soluble film formulations.
The term "film thickness" as used herein, refers to the thickness of the dry film when
measured by a film thickness gauge. The film thickness is between 0.01 mm and 1 mm.
The term "tensile strength" as used herein, refers to a physical property of the film that
requires a load to cause deformation failure of the film. The tensile strength is between 0.1
~ g / c mand~ 5 ICg/cm2.
The term "folding endurance" as used herein, refers to a physical property of the film
that is measured by repeated folding of the film strip at the same place until the strip breaks. The
number of times the film is folded without breaking is computed as the value for folding
endurance. The folding endurance is between 10 and 1000.
The term "in-vitro disintegration time" as used herein, refers to the time in seconds at
which a film breaks when brought into contact with water or saliva. The in-vifro disintegration
time is between 1 second and 120 seconds.
While the present invention has been described in terms of its specific aspects, certain
modifications and equivalents will be apparent to those skilled in the art and are intended to be
within the scope of the present invention.
In the following section, aspects are described by way of examples to illustrate the
processes of the invention. However, these are not intended in any way to limit the scope of the
present invention. Several variants of these examples would be evident to persons ordinarily
skilled in the art.
EXAMPLES
Example 1
Procedure:
1. Montelukast sodium was dissolved in purified water to obtain a uniform primary solution.
2. Ethylene glycol and vinyl alcohol graft copolymer was dispersed in the primary solution of
step 1 to obtain a secondary dispersion.
3. Sucralose, polysorbate 80, and bubble gum flavor were dispersed in the secondary dispersion
of step 2 to obtain a final dispersion.
4. The final dispersion of step 3 was de-aerated and layered onto film-forming rollers or plates
to obtain films.
Ingredients
Montelukast Sodium
Ethylene Glycol and Vinyl Alcohol Graft
Copolymer
Sucralose
Polysorbate 80
Bubble Gum Flavor
Purified Water
Quantity
mglfilm
10.4
-
21.0
0.2
2.5
2.0
q.s.
, R I G ~ ~ b7i
5. The films of step 4 were dried and cut into sttrpsdf desired size and shape.
Characterization of the film:
I
Tensile Strength 1 0.9 kg/cm2
Organoleptic Evaluation
Disintegration Time
I
Thickness 1 0.5 mm
Transparent, flexible, uniform in appearance
1-2 minutes
Example 2
Procedure:
1. Montelukast sodium was dissolved in purified water to obtain a uniform primary solution.
2. Polyvinyl alcohol and polyvinyl pyrrolidone were dispersed in the primary solution of step 1
to obtain a secondary dispersion.
3. Glycerine, sucralose, and bubble gum flavor were dispersed in the secondary dispersion of
step 2 to obtain a final dispersion.
4. The final dispersion of step 3 was de-aerated and layered onto film-forming rollers or plates
to obtain films.
5. The films of step 4 were dried and cut into film strips of desired size and shape.
Ingredients
Montelukast Sodium
Polyvinyl Alcohol
Polyvinyl Pyrrolidone
Glycerine
Sucralose
Bubble Gum Flavor
Purified Water
Characterization of the film:
Quantity
mglfilm
4.2
25.2
6.3
5.3
0.2
2.0
q.s.
Organoleptic Evaluation
Disintegration Time
Thickness
Transparent, flexible, uniform in appearance
1-2 minutes
0.5 mm
Example 3
Procedure:
1. Montelukast sodium was dissolved in purified water to obtain a uniform primary solution.
2. Pullulan was dispersed in the primary solution of step 1 to obtain a secondary dispersion.
3. Glycerine, polysorbate 80, and sucralose were dispersed in the secondary dispersion of step
2 to obtain a final dispersion.
4. The final dispersion of step 3 was de-aerated and layered onto film-forming rollers or plates
to obtain films.
5. The films of step 4 were dried and cut into film strips of desired size and shape.
Ingredients
Montelukast Sodium
Pullulan
Glycerine
Polysorbate 80
Sucralose
Purified Water
Characterization of the film:
Quantity
mglfilm
4.2
42.0
14.0
4.2
0.2
q.s.
I Organoleptic Evaluation 1 Transparent, flexible, uniform in appearance I
I
Disintegration Time 1 1-2 minutes 1
I
Thickness 1 0.5 mm
Example 4 -
Ingredients I i Quantity
I Montelukast Sodium 1 4.2 1
Hydroxypropyl Methyl Cellulose 10.6
Glycerine
I Sucralose
2.8
Crosslinked Polyvinyl Pyrrolidone 3.9
I
Procedure:
1. Montelukast sodium was dissolved in purified water to obtain a uniform primary solution.
2. Hydroxypropyl methyl cellulose was dispersed in the primary solution of step 1 to obtain a
secondary dispersion.
3. Glycerine, crosslinked polyvinyl pyrrolidone, sucralose, and bubble gum flavor were
dispersed in the secondary dispersion of step 2 to obtain a final dispersion.
4. The final dispersion of step 3 was de-aerated and layered onto film-forming rollers or plates
to obtain films.
5. The films of step 4 were dried and cut into film strips of desired size and shape.
Bubble Gum Flavor
I
Characterization of the film:
2.0
Purified Water
1
q.s.
Organoleptic evaluation
Disintegration Time
Tensile strength
Thickness
Transparent, flexible
1-2 minutes
2.5 ~glcm*
0.5 mm
C
WE CLAIM: - DELI 3 '
11
1. An oral soluble film formulation comprising a therapeutically effective amount of
montelukast or a pharmaceutically acceptable salt thereof. one or more hydrophilic
polymers, and one or more pharmaceutically acceptable excipients.
2. The oral soluble film according to claim 1, wherein the pharmaceutically acceptable
excipients are selected from plasticizers, disintegrants, saliva stimulating agents,
flavoring agents. sweetening agents, coloring agents, preservatives, antioxidants,
surfactants, buffering agents, solvents as herein described.
3. A process for the preparation of oral soluble film formulation according to claim 1,
wherein the process comprises the steps of:
a) dissolving or dispersing montelukast or a pharmaceutically acceptable salt thereof
in one or more suitable solvents to obtain a solution or dispersion;
b) dissolving or dispersing one or more hydrophilic polymers in the solution or
dispersion of step (a);
c) dissolving or dispersing pharmaceutically acceptable excipients in the solution or
dispersion of step (b) to obtain a final solution or dispersion; and
d) layering the final solution or dispersion of step (c) onto a film casting device to
obtain said film.
4. The process for the preparation of oral soluble film formulation according to claim 3,
wherein the pharmaceutically acceptable excipients are selected from plasticizers,
disintegrants, saliva stimulating agents, flavoring agents, sweetening agents, coloring
agents, preservatives, antioxidants, surfactants, buffering agents, solvents as herein
described.
5. A process for the preparation of oral soluble film formulation according to claim 1,
wherein the process comprises the steps of:
a) dissolving or dispersing one or more hydrophilic polymers in one or more
suitable solvents to obtain a solution or dispersion;
b) dissolving or dispersing one or more pharmaceutically acceptable excipients in
the solution or dispersion of step a);
o R l ~ l ~ A L
\ 17 6 2 D3 ELI i i u h t ~
c) dissolving or dispersing mont'elu a s t ~ p h a n n a c e ~ t i c aalccle~p table salt tb ereof
in one or more suitable solvents to obtain a drug solution or dispersion;
d) mixing the drug solution or dispersion of step c) with the solution or dispersion of
step b) to form a final solution or dispersion; and
e) layering the final solution or dispersion of step d) onto a film casting device to
obtain said film.
6. The process for the preparation of oral soluble film formulation according to claim 5,
wherein the pharmaceutically acceptable excipients are selected from plasticizers.
disintegrants, saliva stimulating agents, flavoring agents, sweetening agents, coloring
agents, preservatives, antioxidants, surfactants, buffering agents, solvents as herein
described.
7. The oral soluble oral soluble film formulation comprising a therapeutically effective
amount of montelukast or a pharmaceutically acceptable salt thereof, one or more
hydrophilic polymers, and one or more pharmaceutically acceptable excipients and the
processes for the preparation thereof substantially as described and illustrated by
examples herein.