FIELD OF INVENTION

The present invention relates to the orally dissolving strip formulations of montelukast or pharmaceutical^ acceptable salts thereof, and further relates to the process for the preparation thereof.

BACKGROUND OF THE INVENTION

Montelukast is described chemically as (R,E)-2-(l-((l-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propylthio)methyl)cyclopropyl)acetic acid, and is provided as a monosodium salt (I) which is represented by the formula as follows

Montelukast sodium is a hygroscopic, optically active, and white to off-white powder. Montelukast sodium is freely soluble in ethanol, methanol, and water and practically insoluble in acetonitrile.

Montelukast sodium is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLTl receptor. Leukotrienes are biologically active fatty acids derived from the oxidative metabolism of arachidonic acid. Leukotrienes contract air way smooth muscles, increase vascular permeability, increase mucus secretions and activate inflammatory cells in the airways of patients with asthma.

US patent 5,565,473 (Merck Frost Canada) teaches a process of preparation of leukotriene receptor antagonists and their use as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents.

Example- 161 along with the example-146 in the US patent 5,565,473 discloses the synthesis of montelukast sodium.

Montelukast is commercially available in the formulations of conventional oral solid dosage forms as oral granules of 4mg strength, chewable tablets of 4mg and 5mg strengths and film coated tablets of 10mg strength as Singluair® from Merck and Co., Inc. Film coated 10mg Singluair tablets contain 10.4mg montelukast sodium along with the inactive ingredients microcrystalline cellulose, lactose monohydrate (89.3 mg), croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The film coating consists of: hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, red ferric oxide, yellow ferric oxide, and carnauba wax. The chewable tablets 4mg and 5mg contain 4.2 and 5.2 mg montelukast sodium, respectively along with the inactive ingredients mannitol, microcrystalline cellulose, hydroxypropyl cellulose, red ferric oxide, croscarmellose sodium, cherry flavor, aspartame, and magnesium stearate. The oral granules 4mg contain 4.2mg montelukast sodium along with the inactive ingredients mannitol, hydroxypropyl cellulose, and magnesium stearate.

The form of preparing and dispensing of the conventional oral solid dosage forms of montelukast has many disadvantages that includes a large proportion of adjuvants are added to the conventional oral solid dosage forms and further needs the additional storage space.

Despite disclosure of various formulations like film coated tablets, chewable tablets and oral granules, however, still there exists a need for a convenient and patient friendly dosage form as well as to overcome the existing disadvantages of the stability, storage and difficulty in administration.

Inventors of the present application have provided here as an alternative to the conventional oral dosage forms, as orally dissolving strip formulation of montelukast or pharmaceutically acceptable salts thereof, which not only addresses the existing disadvantages of the stability, storage and difficulty in administration but also provide convenient and patient friendly dosage form.

SUMMARY OF THE INVENTION

In one aspect of the present invention, it relates to orally dissolving strips of montelukast or pharmaceutically acceptable salts thereof comprising montelukast or pharmaceutical^ acceptable salts thereof, water soluble polymeric component, and at least one pharmaceutically acceptable excipient.
In another aspect according to the present invention, it relates to orally dissolving strips of montelukast or pharmaceutically acceptable salts thereof, comprising montelukast or pharmaceutically acceptable salts thereof, water soluble polymeric component and at least one pharmaceutically acceptable excipient,
wherein the water soluble polymeric component comprises hydroxypropylmethyl cellulose.

In yet another aspect according to the present invention, it relates to orally dissolving strips of montelukast or pharmaceutically acceptable salts thereof, comprising montelukast or pharmaceutically acceptable salts thereof, water soluble polymeric component and at least one pharmaceutically acceptable excipient, wherein the water soluble polymeric component comprises polyethylene oxide, hydroxypropylmethyl cellulose and maltodextrin.

In another aspect of the present invention, it relates to orally dissolving strips of montelukast or pharmaceutically acceptable salts thereof, comprising montelukast or pharmaceutically acceptable salts thereof, acidic substance, water soluble polymeric component and at least one pharmaceutical acceptable excipient, wherein the water soluble polymeric component is hydroxypropylmethyl cellulose.

In a further aspect of the present invention, it relates to orally dissolving strips of montelukast or pharmaceutically acceptable salts thereof, comprising montelukast or pharmaceutically acceptable salts thereof, acidic substance, water soluble polymeric component and at least one pharmaceutically acceptable excipient, wherein the acidic substance is citric acid.

In a further aspect of the present application, it relates to a process for preparing montelukast orally dissolving strip comprising the steps of-

a. preparing an orally dissolving strip composition of montelukast or pharmaceutically acceptable salts thereof comprising montelukast or pharmaceutically acceptable salts thereof, water soluble polymeric component and at least one pharmaceutically acceptable excipient, wherein the water soluble polymeric component comprises polyethylene oxide, hydroxypropylmethyl cellulose and maltodextrin.

b. The composition prepared as per the step a.) is subjected to get layered on the heat stable polymer sheet.

c. Layered composition on polymer sheet of step b) dried for a time ranging between 5 to 30 minutes at about 75-1052C.

d. Collecting the dried and silted orally dissolving unit strip of montelukast or pharmaceutically acceptable salts.

In a further aspect of the present application, it relates to a process for preparing montelukast orally dissolving strip comprising the steps of-

a. preparing an orally dissolving strip composition of montelukast or pharmaceutically acceptable salts thereof comprising montelukast or pharmaceutically acceptable salts thereof, citric acid, water soluble polymeric component and at least one pharmaceutically acceptable excipient, wherein
the water soluble polymeric component is hydroxypropylmethyl cellulose.

b. The composition prepared as per the step a.) is subjected to get layered on the heat stable polymer sheet.

c. Layered composition on polymer sheet of step b) dried for a time ranging between 5 to 30 minutes at about 50-602C

d. Collecting the dried and silted orally dissolving unit strip of montelukast or pharmaceutically acceptable salts.

In a further aspect of the present application, it relates to oral montelukast strip formulation, which has features as - Oral Strip thickness in the range of 0.13 to 0.20 mm, weight in the range of 45 to 130 mg, and surface area 450 to 1200mm, which is useful as in the treatment of cardidvascular diseases such as angina pectoris, hypertension, congestive cardiac paralysis and the like.

Further aspects of the present invention are demonstrated in detailed description section as well as examples.

DESCRIPTION OF THE INVENTION

Reference will now be made in detail to the presently preferred embodiments of the invention, which, together with the following examples, serve to explain the principles of the invention. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, and it is to be understood that other embodiments may be utilized, and that various structural, biological, and chemical changes may be made without departing from the spirit and scope of the present invention.

The present invention relates to the rapid orally dissolving strips of montelukast or pharmaceutically acceptable salts thereof, comprising montelukast or pharmaceutically acceptable salts thereof, water soluble polymeric component, and at least one pharmaceutically acceptable excipient.

As used the "water soluble polymeric component" refers to a polymeric component that comprises "water soluble polymer" that is at least partially soluble in water and fully or predominantly soluble in water or swellable in water.

The "water soluble polymer" may be partially water soluble polymer or predominantly water soluble polymer, water swellable polymer or a combination of water soluble and water swellable polymer. The polymers may include cellulose or cellulose derivatives. Suitable examples of water soluble polymer includes but are not limited to, polyethylene oxide, pullulan, hydroxypropylmethyl cellulose (HPMC), Hydroxypropyl cellulose (HPC), carboxymethyl cellulose, polyvinyl alcohol, Water-swellable polysaccharides such as starch, starch derivatives such as polymers of dextrose like maltodextrin, carrageenan, xanthan gum, locus bean gum, acacia gum, chitosan, alginates, hyaluronic acid, pectin and combinations thereof. In accordance with the present invention "water soluble polymeric component" desirably ranges from about 25% to 70% w/w of the total weight of the dosage form. In a particular embodiment of the present invention, about 45% w/w of the water soluble polymeric component of the total weight of the dosage form.

The water soluble polymers utilized in the strip formulation are hydrophilic cellulosic polymer, maltodextrin and polyethylene oxide or combinations thereof. The Polyethylene oxide polymer in combination with a hydrophilic cellulosic polymer and Maltodextrin achieves flexible, strong films. The cellulosic polymers used in combination with Polyethylene oxide and Maltodextrin are selected from but are not limited to HPC, and HPMC.

In accordance with the present invention polyethylene oxide desirably ranges from about 5% to 20% by weight of the water soluble polymeric component, preferably from about 5% to 10% by weight of the total weight of the dosage form.

In accordance with the present invention the cellulosic polymer preferably used is Hydroxypropylmethyl cellulose (HPMC). The low viscosity grade HPMC used is preferably in the range of about 5 to 15 cps. In one embodiment of the invention, the brand name (Methocel E15 Premium LV) was used.

Hydroxypropylmethyl ranges from about 10% to 60% by weight of the water soluble polymeric component, preferably from about 15% to 45% by weight of the total weight of the dosage form.

A further embodiment of the invention, another water soluble polymeric component comprises Maltodextrin. Maltodextrin polymer appears to increase the viscosity of the solution present in the formulation that apparently aids in providing the flexibility and tensile strength to the dried films of the montelukast strip formulation of the present invention. The range of the maltodextrin may vary from about 8% to 30% by weight of the total weight of the dosage form.

In another embodiment of the present invention, it relates to orally dissolving strips of montelukast or pharmaceutically acceptable salts thereof, comprising montelukast or pharmaceutically acceptable salts thereof, acidic substance, water soluble polymeric component and at least one pharmaceutical acceptable excipient, wherein the water soluble polymeric component is hydroxypropylmethyl cellulose.

The composition of montelukast comprises an acidic substance selected from group consisting of citric acid, tartaric acid, malic acid and phosphoric acid.

In a further embodiment of the present invention, it relates to orally dissolving strips of montelukast or pharmaceutically acceptable salts thereof, comprising montelukast or pharmaceutically acceptable salts thereof, acidic substance, water soluble polymeric component and at least one pharmaceutically acceptable excipient, wherein the acidic substance is citric acid.

The composition of the montelukast strip comprises plasticizer, which is utilized to impart flexibility, enhance elasticity and decrease brittleness. Preferred Plasticizers in the formulation of the present invention include triacetine, citrate derivatives (such as triethyl, tributyl, acetyl tributyl, acetyl triethyl, trioctyl, acetyl trioctyl, trihexyl citrate, etc.), dibutyl sebacate, glycerol, polyethylene glycol (polyethylene glycol 400), propylene glycol or combinations thereof.

Flavors may be chosen from natural and synthetic flavouring liquids. An illustrative list of such agents includes volatile oils, synthetic flavor oils, flavouring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. A non-limiting representative list of examples includes mint oils, cocoa, and citrus oils such as lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, grape, vanilla, strawberry, raspberry, cherry, plum, pineapple, apricot or other fruit flavours.

Other useful flavourings include aldehydes and esters such as benzaldehyde (cherry, almond), citral i.e., alphacitral (lemon, lime), neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C-12 (citrus fruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanol (green fruit), and 2-dodecenal (citrus, mandarin), combinations thereof and the like.
The sweeteners may be chosen from the following non-limiting list: glucose (corn syrup), dextrose, invert sugar, fructose, and combinations thereof; saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, xylitol, and the like. Also contemplated are hydrogenated starch hydrolysates and the synthetic sweetener 3,6-dihydro-6-methyl-l-l-l,2,3-oxathiazin-4-one-2,2-dioxide, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof.

Also colour additives can be used in preparing the strips. A colouring agent, which may be provided in a dosage form of the present invention, includes pharmaceutically acceptable natural or artificially synthesized dyes. A great variety of such pharmaceutically acceptable dyes have been known to be suitable for use in pharmaceutical compositions, for example natural dyes such as annatto extract, anthocyanins, beta-carotene, beta APO 8, carotenal, black currant, burnt sugar, canthaxanthin, caramel, carbo medicinalis, carmine, carmine blue, carminic acid, carrot, chlorophyll, chlorophyllin, cochineal extract, copper-chlorophyll, copper-chlorophyllin, curcumin, curcumin/CU-chloro, elderberry, grape, hibiscus, lutein, mixed carotenoids, paprika, riboflavin, spinach, stinging nettle, titanium dioxide, turmeric, natural colors, aronia/redfruit, beet juice colors, paprika extract, paprika oleoresin; or artificial dyes such as allura red, Brilliant blue FCF, amaranth, carmoisine, fast red E, erythrosine, green S, patent blue V, ponceau 4R, quinoline yellow, red 2G, sunset yellow, and tartrazine.

The following examples illustrate methods of preparing rapid orally dissolving strips of montelukast or pharmaceutically acceptable salts thereof, in accordance with certain non-limiting aspects of the invention.

The composition of the montelukast strip comprises use of solvent, which may be selected from C2-C4 alcohols selected from ethyl alcohol, isopropyl alcohol, purified water and combinations thereof. In one of the particular embodiment, purified water was used.

The diluents used in the montelukast strip formulation are selected from but not limited to mannitol, macrocrystalline cellulose (MCC), lactose and combinations thereof. In one of the particular embodiment, mannitol was used.

In yet another aspect of the present application, it relates to a process for preparing montelukast orally dissolving strip comprising the steps of-

a. Preparing an orally dissolving strip composition of Montelukast sodium comprising dissolving montelukast sodium in water.

b. Adding water soluble polymeric component, mannitol and sucralose.

c. Stirring the solution at room temperature.

d. Adding plasticizer followed by flavoring agent and optionally adding coloring agent

e. The composition prepared as per the step d.) is subjected to be layered on the heat stable polymer sheet

f. Layered composition on polymer sheet of step e) dried for a time ranging between 5 to 30 minutes at about 60-905C.

g. Recovering the dried and cut orally dissolving unit strip of Montelukast sodium.

In yet another aspect of the present application, it relates to a process for preparing montelukast orally dissolving strip comprising the steps of-

a. Preparing an orally dissolving strip composition of Montelukast sodium comprising dissolving montelukast sodium in isopropyl alcohol.

b. Adding water soluble polymeric component, citric acid and sucralose to step a.

c. Stirring the solution at room temperature.

d. Adding plasticizer followed by flavoring agent and optionally adding coloring agent

e. The composition prepared as per the step d.) is subjected to be layered on the heat stable polymer sheet

f. Layered composition on polymer sheet of step e) dried for a time ranging between 5 to 30 minutes at about 50-609C.

g. Recovering the dried and cut orally dissolving unit strip of Montelukast sodium.

In a further aspect of the present application, it relates to an oral montelukast strip formulation, which has features as - Oral Strip thickness in the range of 0.04 to 0.11 mm, weight in the range of 30 to 70 mg, and surface area 400 to 1100 square mm.

The oral strip according to the invention may have any shape but not limited to oblong, circular, square, rectangular, triangular or mutliangular. The shape may not be as important as the surface area and the compliance to the drug content required for therapeutic purpose as long as strip weight, tensile strength and other physical parameters are well in the acceptable ranges.

Certain specific aspects and embodiments of the present application relating to methods of preparing orally dissolving strips formulation of montelukast or pharmaceutically acceptable salts shall be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

EXPERIMENTAL DETAILS

The process for preparation according to the present invention of an orally dissolving strip formulation of montelukast sodium may be demonstrated by examples as given below.

Example-1: Montelukast strip formulation (10mg Unit)
The process for the preparation of the orally dissolving strip formulation of montelukast sodium involves the following steps.

1. About 80 ml of Purified water was taken in a glass beaker, and then montelukast sodium (~10.40 gm) is added to it and stirred for 40 minutes.

2. Sucralose (2.73gm), Mannitol (3 gm) Maltodextrin (4.00gm), Polyethylene oxide (l.OOgm), were added to the contents of step 1 gradually and stepwise and stirred the contents for about 5-20 minutes.

3. Hydroxy Propyl methyl cellulose solution (17.85 gm in 220 gm water) was added to the contents of step 2 and stirred for 5-15 minutes.

4. Glycerol (10 gm), Color (0.02gm) and flavor (2.5 gms) were added stepwise to the contents of step 3 and stirred for 10 minutes

5. The solution was subjected to deaeration.

6. The Step No. 5 composition is subjected to layering on the heat stable polyester sheet and allowed to dry for 10 to 25 minutes at 852C.

7. Slit the above dried montelukast sodium strip of size equivalent to unit dose containing 10 mg of Montelukast.

Slitted Unit Strip physical parameters:

Example- 2: Montelukast sodium strip formulation (5 mg Strip Unit)
The process for the preparation of an orally dissolving strip formulation of montelukast sodium containing 5 mg drug involves the steps similar to the steps as mentioned in the above example within the dose proportion quantities as per the example. The observed slit Unit Strip physical parameters were -

Example- 3: Montelukast sodium strip formulation (5 mg Strip Unit)

The process for the preparation of the orally dissolving strip formulation of montelukast sodium involves the following steps.

1. About 80 ml of Purified water was taken in a glass beaker, and then montelukast sodium (~5.2 gm) is added to it and stirred for 40 minutes.

2. Sucralose (2.73gm), Mannitol (8.2 gm) Maltodextrin (4.00gm), Polyethylene oxide (l.OOgm), were added to the contents of step 1 gradually and stepwise and stirred the contents for about 5-20 minutes.

3. Hydroxy Propyl methyl cellulose solution (17.85 gm in 220 gm water) was added to the contents of step 2 and stirred for 5-15 minutes.

4. Glycerol (10 gm), Color (0.02gm) and flavor (2.5 gms) were added stepwise to the cpntents of step 3 and stirred for 10 minutes

5. The solution was subjected to deaeration.

6. The Step No. 5 composition is subjected to layering on the heat stable polyester sheet and allowed to dry for 10 to 25 minutes at 85eC.

7. Slit the above dried montelukast sodium strip of size equivalent to unit dose containing 5 mg of Montelukast.

Slitted Unit Strip physical parameters:

Example-4

Montelukast strip formulation (lOmg Unit)

The process for the preparation of the orally dissolving strip formulation of montelukast sodium involves the following steps.

1. About 80 ml of isopropyl alcohol was taken in a glass beaker, and then montelukast sodium (~10.40 gm) is added to it and stirred for 40 minutes.

2. Sucralose (2.73gm), citric acid (lgm), were added to the contents of step 1 gradually and stepwise and stirred the contents for about 5-20 minutes.

3. Hydroxy Propyl methyl cellulose solution (17.85 gm in 220 gm isopropyl alcohol) was added to the contents of step 2 and stirred for 5-15 minutes.

4. Glycerol (10 gm), poly ethylene glycol (3 gm), Color (0.02gm) and flavor (2.5 gms) were added stepwise to the contents of step 3 and stirred for 10 minutes

5. The solution was subjected to deaeration.

6. The Step No. 5 composition is subjected to layering on the heat stable polyester sheet and allowed to dry for 10 to 25 minutes at 50SC- 60C.

7. Slit the above dried montelukast sodium strip of size equivalent to unit dose containing 10 mg of Montelukast.

Slitted Unit Strip physical parameters:

Example-5
Montelukast strip formulation (10mg Unit)

The process for the preparation of the orally dissolving strip formulation of montelukast sodium involves the following steps.

1. About 60 ml of isopropyl alcohol and 20 ml of purified water was taken in a glass beaker, and then montelukast sodium (~10.40 gm) is added to it and stirred for 40 minutes.

2. Sucralose (2.73gm), citric acid (lgm), were added to the contents of step 1 gradually and stepwise and stirred the contents for about 5-20 minutes.

3. Hydroxy Propyl methyl cellulose solution (17.85 gm in 160 gm isopropyl alcohol and 60 gm of purified water) was added to the contents of step 2 and stirred for 5-15 minutes.

4. Glycerol (10 gm), poly ethylene glycol (3 gm), Color (0.02gm) and flavor (2.5 gms) were added stepwise to the contents of step 3 and stirred for 10 minutes

5. The solution was subjected to deaeration.

6. The Step No. 5 composition is subjected to layering on the heat stable polyester sheet and allowed to dry for 10 to 25 minutes at 503C- 602C.

7. Slit the above dried montelukast sodium strip of size equivalent to unit dose containing 10 mg of Montelukast.

Slitted Unit Strip physical parameters:

The above-mentioned examples, which are provided by way of illustration, should not be construed as limiting the scope of the invention with respect to parameter/s, ingredient/s and quantities used in any manner.

CLAIMS
We claim,

1. An orally dissolving strip formulation of montelukast or pharmaceutical acceptable salts thereof comprising montelukast or pharmaceutically acceptable salts, water soluble polymeric component and at least one pharmaceutically acceptable excipient.

2. The orally dissolving strip of montelukast according to claim 1 wherein water soluble polymeric component is present in the range from about 30% to 60% w/w of the total weight of the dosage form.

3. The orally dissolving strip of montelukast or pharmaceutically acceptable salts thereof as per claim 1, wherein the water soluble polymeric component is selected from polyethylene oxide, hydrophilic cellulosic polymer and Maltodextrin or mixture thereof.

4. The orally dissolving strip of montelukast or pharmaceutically acceptable salts thereof as per claim 1, wherein the polyethylene oxide is present in the range from about 2% to 8% by weight of the total strip weight.

5. The orally dissolving strip of montelukast or pharmaceutically acceptable salts thereof as per claim 3, wherein the hydrophilic cellulosic polymer is present in the range from about 15% to 45% by weight of the total strip weight.

6. The orally dissolving strip of montelukast or pharmaceutically acceptable salt thereof as per claim 5, wherein hydrophilic cellulosic polymer is hydroxypropylmethyl cellulose.

7. The orally dissolving strip of montelukast or pharmaceutically acceptable salt thereof as per claim 1, wherein maltodextrin is present in the range from about 8% to 20% by weight of the total strip weight.

8. The Montelukast sodium orally dissolving strip formulation according to claim-1, wherein weight of the strip range from 30 to 70 mg and thickness in the range of 0.04 to 0.11 mm.

9. The Montelukast sodium orally dissolving strip formulation according to claim-8, wherein the surface area of the strip is in the range of 400 to 1100 square mm.

10. A process for preparing Montelukast sodium orally dissolving strip comprising the steps of-

a. preparing an orally dissolving strip composition of Montelukast sodium comprising dissolving Montelukast sodium in water,

b. adding water soluble polymeric component, mannitol and sucralose,

c. stirring the solution at room temperature,

d. adding plasticizer followed by flavoring agent and optionally adding coloring agent,

e. the composition prepared as per the step d.) is subjected to be layered on the heat stable polymer sheet,

f. layered composition on polymer sheet of step e) dried for a time ranging between 5 to 30 minutes at about 70-952C,

g. recovering the dried and cut orally dissolving unit strip of Montelukast sodium.

11. An orally dissolving strips of montelukast or pharmaceutically acceptable salts thereof, comprising montelukast or pharmaceutically acceptable salts thereof, acidic substance, water soluble polymeric component and at least one pharmaceutical acceptable excipient, wherein the water soluble polymeric component is hydroxypropylmethyl cellulose.

12. The orally dissolving strips of montelukast or pharmaceutically acceptable salts thereof, according to claim 1, wherein the acidic substance is citric acid.