The present invention relates to a stable pharmaceutical composition of Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof with pharmaceutically acceptable excipients. In particular, the present invention discloses a stable pharmaceutical composition comprising Ramelteon or a pharmaceutically acceptable salt thereof with pharmaceutically acceptable excipients, wherein the composition is free of copolyvidone and process for preparing the same.
BACKGROUND OF THE INVENTION
Ramelteon is an orally active hypnotic chemically designated as (S)-N-[2-(l, 6, 7, 8-tetrahydro-2H-indeno-[5, 4-b]furan-8-yl)ethyl]propionamide and containing one chiral center. The compound is produced as the (S)-enantiomer with an empirical formula of Ci6H2iN02 is represented by the following formula:
H5C2CONHCH2CH

Ramelteon
Ramelteon tablets are marketed by Takeda as film coated tablets under the brand name Rozerem® in 8 mg strength in US and Japan. Inactive ingredients in the Rozerem® film coated tablets consists of lactose monohydrate, starch, hydroxypropyl cellulose, magnesium stearate, hypromellose, copovidone, titanium dioxide, yellow ferric oxide, polyethylene glycol 8000, and ink containing shellac and synthetic iron oxide black.

Ramelteon is freely soluble in organic solvents, such as methanol, ethanol, and dimethyl sulfoxide; very slightly soluble in water and very slightly soluble in aqueous buffers from pH 3 to pH 11.
Ramelteon is a photosensitive drug and undergoes degradation in presence of light. Light sensitive drugs and their finished products are prone to degradation during manufacturing, storage, and administration, which may result in potency loss, altered efficacy, and adverse biological effects. Therefore, photostability studies of these drugs are required during product development process. These studies should be carried out to ensure quality, efficacy, and safety of the formulated products during manufacture, storage, and use.
Patent publication US6034239 assigned to Takeda discloses Ramelteon as a product.
Patent publication US8821926 assigned to Takeda discloses tablet composition of Ramelteon avoiding dissolution related challenges by using about 3% w/w of Hydroxypropyl cellulose having a viscosity of about 1 to about 4 mPa.s
Patent publication US20040018239 assigned to Takeda discloses a composition of Ramelteon in which the drug is coated and wherein the coating agent containing copolyvidone and is free of polyethylene glycol (PEG). Patent application describes that PEG present in film coating effects the stability of a drug to heat or light, which may lead to an unstable formulation. Therefore inventors used copolyvidone as plasticizer instead of PEG.
Aforementioned publications disclose that PEG in the coating material impairs the stability of Ramelteon in the presence of light and Hydroxypropyl cellulose (HPC) in certain percentage is used to reduce the variability in dissolution. However, due to technical challenges, there is still a need to prepare a cost effective, stable

pharmaceutical composition with desired pharmaceutical technical attributes such as dissolution, disintegration, friability and stability etc.
Accordingly, the inventors of the present invention propose a simple, reproducible and cost-effective process of pharmaceutical compositions of Ramelteon. Further, the pharmaceutical compositions prepared according to the manufacturing process of the present invention is expected to have desirable formulation attributes comparable to the innovator's marketed product.
SUMMARY OF THE INVENTION
In an embodiment of the present invention relates to a stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and one or more excipients, wherein one or more excipients are selected from diluents and/or carriers, binders, disintegrant, antioxidants, lubricants, and the like.
In an embodiment of the present invention relates to the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and at least one or more pharmaceutical excipient, wherein the composition is free of copolyvidone.
Another embodiment of the present invention relates to the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and at least one or more pharmaceutical excipient, wherein the composition is free of Hydroxypropyl cellulose (HPC).
Yet in an embodiment of the present invention, the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs,

enantiomers or mixtures thereof and at least one or more pharmaceutical excipient, wherein the composition is free of copolyvidone and Hydroxypropyl cellulose.
In an embodiment of the present invention, the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and at least one or more pharmaceutical excipient, wherein the one or more excipient is selected from binders, disintegrating agent, diluents, lubricants, glidants and antioxidants.
In an embodiment of the present invention, the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and at least one or more pharmaceutical excipient, wherein the one or more excipient is an antioxidant.
Yet another embodiment of the present invention, the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and one or more excipients, wherein the one or more excipient is antioxidant selected from the group consisting of potassium ascorbate, calcium ascorbate and magnesium ascorbate, vitamin A, vitamin A2, vitamin C (ascorbic acid), natural and synthetic tocopherols (mixed tocopherols concentrate, alpha-tocopherol, beta-tocopherol, synthetic gamma-tocopherol, synthetic delta-tocopherol), vitamin E, ascorbyl palmitate, ascorbyl stearate, propyl gallate, tertiary butyl hydroquinone (TBHQ), dilauryl thiodipropionate, magnesium sulfite or calcium sulfite, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), cysteine, sodium sulfite, sodium metabisulfite, sodium bisulfite, thioglycerol, thioglycollic acid, preferably, used ascorbic acid, citric acid and/or butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT)

Yet in an embodiment of the present invention, the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and at least one or more pharmaceutical excipient, wherein the one or more excipient is an antioxidant and pharmaceutical composition is devoid of coating.
In another embodiment of the present invention, the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and at least one or more pharmaceutical excipient, wherein the composition comprises one or more colorants and dye.
In an embodiment of the present invention, the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and at least one or more pharmaceutical excipient prepared by using direct compression, dry granulation, dry blending or wet granulation process.
Another embodiment of the present invention, the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof with pharmaceutically acceptable excipients, wherein the composition is an immediate release tablet and/or orally disintegrating tablet and/or granules/ capsules.
Yet in another embodiment, the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof of the present invention is expected to be stable for at least about six months at 40°C and 75% relative humidity.
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In further embodiment, the present invention includes method of using the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof, in the treatment of insomnia characterized by difficulty with sleep onset.
In yet another embodiment of the invention, the stable pharmaceutical composition of Ramelteon tablets are packaged in a light protecting amber colored glass bottle, foil, blister, HDPE container, pouch or other suitable package.
DESCRIPTION OF THE INVENTION
The present invention can be more readily understood by reading the following detailed description of the invention and study of the included examples.
As used herein, the term “pharmaceutical composition”is intended to encompass a drug product comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof, and the other inert ingredient(s) (pharmaceutically acceptable excipients). Such pharmaceutical compositions are synonymous with “formulation” and “dosage form”. Pharmaceutical composition of the invention include, but is not limited to, tablets, capsules, oral films, pellets, beads, minitabs, spherules, beadlets, microcapsules, millispheres, microspheres and the like. Preferably, the pharmaceutical composition refers to tablets.
“Ramelteon” as used herein refers to the free acid form, its salts, polymorphs, enantiomers or mixtures thereof. Preferably, Ramelteon used here is Ramelteon free base.
The term "excipient" means a pharmacologically inactive component such as a diluent/ carrier, disintegrant, lubricant, surfactant, or the like. The excipients that are
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useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient. Co-processed excipients are also covered under the scope of present invention. Further, excipient may be in the form of powders or in the form of dispersion. Combination of excipients performing the same function may also be used to achieve desired formulation characteristics.
The term “free of copolyvidone” as used herein refers that the composition is devoid of copolyvidone.
The term “free of Hydroxypropyl cellulose” as used herein refers that the composition is devoid of Hydroxypropyl cellulose.
As used herein, the term "about" means ± approximately 10% of the indicated value. The term “w/w” as used herein refers the total weight of the composition.
The present invention relates to pharmaceutical compositions comprising Ramelteon or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof. Preferably, Ramelteon in the present invention is used in an amount from about 2-80% by weight, more preferably, 2-40%.
In an embodiment of the present invention relates to a stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and at least one or more pharmaceutical excipient, wherein one or more excipients are selected from diluents and/or carriers, binders, disintegrant, antioxidants, lubricants, and co-processed excipients.
8

In an embodiment of the present invention relates to the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and at least one or more pharmaceutical excipient, wherein the composition is free of copolyvidone.
Another embodiment of the present invention relates to the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and at least one or more pharmaceutical excipient, wherein the composition is free of Hydroxypropyl cellulose (HPC).
Yet in an embodiment of the present invention, the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and at least one or more pharmaceutical excipient, wherein the composition is free of copolyvidone and Hydroxypropyl cellulose.
In an embodiment of the present invention, the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and at least one or more pharmaceutical excipient, wherein the one or more excipient is an antioxidant.
Yet another embodiment of the present invention, the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and one or more excipients, wherein the one or more excipient is antioxidant selected from the group consisting of potassium ascorbate, calcium ascorbate and magnesium ascorbate, vitamin A, vitamin A2, vitamin C (ascorbic acid), natural and synthetic tocopherols (mixed tocopherols concentrate, alpha-tocopherol, beta-tocopherol, synthetic gamma-tocopherol, synthetic delta-tocopherol), vitamin E, ascorbyl palmitate, ascorbyl stearate, propyl gallate, tertiary butyl hydroquinone (TBHQ), dilauryl thiodipropionate, magnesium
9

sulfite or calcium sulfite, Butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), cysteine, sodium sulfite, sodium metabisulfite, sodium bisulfite, thioglycerol, thioglycollic acid, preferably, used ascorbic acid, citric acid and/or Butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT)
Yet in an embodiment of the present invention, the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and at least one or more pharmaceutical excipient, and pharmaceutical composition is devoid of coating.
In another embodiment of the present invention, the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and at least one or more pharmaceutical excipient, wherein the composition comprises one or more colorants and dye.
In an embodiment of the present invention, the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and at least one or more pharmaceutical excipient prepared by using direct compression, dry granulation, dry blending or wet granulation process.
Another embodiment of the present invention relates to a process for preparation of a stable pharmaceutical composition comprising Ramelteon and their pharmaceutically acceptable salts and solvates thereof wherein the process comprises of:
a) dry mixing of Ramelteon with pharmaceutical excipients like binder, disintegrant and diluent
b) granulating the resultant blend as obtained in step (a) with aqueous /non-aqueous binder solution
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c) passing the wet mass as obtained in step (b) through suitable size sieve and drying the granulates in a suitable drying equipment,
d) passing the resultant granules through a suitable size mesh and mixing the same with lubricants and glidants,
e) compressing the lubricated granules into tablets
f) optionally, coating the tablets of step (e) using a coating solution
Another embodiment of the present invention, the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof with pharmaceutically acceptable excipients, wherein the composition is an immediate release tablet and/or orally disintegrating tablet and/or granules/ capsules.
Yet in another embodiment, the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof of the present invention is expected to be stable for at least about six months at 40°C and 75% relative humidity.
In further embodiment, the present invention includes method of using the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof, in the treatment of insomnia characterized by difficulty with sleep onset.
In yet another embodiment of the invention, the stable pharmaceutical composition of Ramelteon tablets are packaged in a light protecting amber colored glass bottle, foil, blister, HDPE container, pouch or other suitable package.
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In another embodiment of the present invention the stable pharmaceutical composition comprises Ramelteon or its pharmaceutically acceptable salts, polymorphs, stereoisomers or mixtures thereof, wherein Ramelteon is present in an amount ranging from about 1 mg to about 20 mg.
In another embodiment, the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof exhibited a dissolution profile, which is comparable with ROZEREM® tablets.
In another embodiment of the invention, the stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof, diluent/ carrier in an amount of about 50% w/w to about 90% w/w, disintegrant in an amount of about 5% w/w to about 10% w/w, binder in an amount of about 0% w/w to about 10% w/w, lubricant in an amount of about 0.5% w/w to about 5% w/w and optionally one or more excipients.
Diluents or fillers are substances which usually provide bulk to the composition. Various useful fillers or diluents include, but are not limited to microcrystalline cellulose, silicified microcrystalline cellulose, calcium carbonate, calcium phosphate, dibasic anhydrous, calcium phosphate, dibasic dihydrate, calcium phosphate tribasic, calcium sulphate, cellulose powdered, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, polydextrose, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, trehalose and xylitol, or mixtures thereof. Diluent may constitute from about 10% to about 95% by weight of the composition.
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Binders impart cohesiveness to formulation. Various useful binders include, but are not limited to hypromellose, acacia, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, glucose, guar gum, hydroxypropylcellulose, maltose, methylcellulose, povidone, copovidone, starch, polyvinyl alcohol or polyethylene oxide, or mixtures thereof. The binder may constitute from about 0% to about 20% by weight of the composition.
Glidants improve flowability and accuracy of dosing. Since the present invention relates to an oral pharmaceutical composition, it is imperative to use glidant(s) to achieve desirable flowability of the active. Glidants used in the composition include, but are not limited to, tribasic calcium phosphate, calcium silicate, cellulose, powdered, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, starch and talc or mixtures thereof.
Surfactants or surface-active agents improve wettability of the dosage form and/or enhance its dissolution. Surfactants contemplated in the present invention include but are not limited to anionic surfactants, amphoteric surfactants, non-ionic surfactants and macromolecular surfactants. Suitable examples of anionic surfactants include but are not limited to sodium lauryl sulphate, sodium cetyl stearyl sulphate or sodium dioctyl sulphosuccinate etc. Suitable example of an amphoteric surfactant include but is not limited to lecithin. Suitable examples of non-ionic surfactants include but is not limited to cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, cholesterol, sorbitan fatty acid esters such as sorbitan mono-oleate, polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polysorbate 20, polyoxyethylene fatty acid glycerides such as macrogol 1000 glycerol monostearate, polyoxyethylene fatty acid esters such as polyoxyl 40 stearate, polyoxyethylene fatty alcohol ethers such as polyoxyl 10 oleyl ether, glycerol fatty acid esters such as glycerol monostearate, commercially
available SEPITRAP® 80 or SEPITRAP® 4000 etc.
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Disintegrants selected from the group comprising crospovidone, modified starches, croscarmellose sodium, sodium starch glycolate, low substituted Hydroxypropyl cellulose and carboxymethylcellulose calcium. These disintegrants are also known as superdisintegrants. The disintegrant may constitute from about 5% to about 20% by weight of the composition.
Suitable solvents include aqueous or organic solvents. Preferable solvents include, but are not limited to, water, esters such as ethyl acetate; ketones such as acetone; alcohols such as methanol, ethanol, isopropanol, butanol; dichloromethane, chloroform, dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), ether, diethyl ether and combinations thereof. Preferably, the solvent used during wet granulation preparation is water.
Dry granulation can be performed using roller compactor, slugging and the like; wet granulation can be performed using Rapid mixer granulator, Fluid bed granulator, planetary mixer and the like; dry blending can be performed in V-blender or key blender or by any other method known in the art.
The final formulations may be coated or uncoated. For coating, additional excipients such as film-forming polymers, plasticizers, antiadherents and opacifiers are used.
Various water-soluble polymers are used to form film. Examples include but are not limited to cellulose derivatives such as soluble alkyl- or hydroalkylcellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethylethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, etc., acidic cellulose derivatives, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacrylic acid, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, chitosan and derivatives thereof, shellac and derivatives thereof, waxes and fat substances. If
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desired, the films may contain additional adjuvants for coating such as plasticizers, polishing agents, colorants, pigments, antifoaming agents, opacifiers, antisticking agents, and the like.
Plasticizers used for film coating of tablets to achieve the right film flexibility and avoid cracking and peel-off. Examples include but are not limited to Triethyl citrate (TEC), Tributyl citrate (TBC), Acetyl triethyl citrate (ATEC), Dibutyl sebacate (DBS), Diethyl phthalate (DEP), Dibutyl phthalate (DBP), Triacetin (TA), Vegetable oils, Fractionated coconut oil, Acetylated monoglycerides, preferably, Triethyl citrate (TEC).
In another embodiment the present invention includes particle size of free drug particulate form of Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof, wherein particle diameter at 90% cumulative volume (d90) is less than about 100 µm, preferably less than 50 µm. Particle diameter at X% cumulative Particle size reduction can be performed by techniques including but not limited to fluid energy milling, ball milling, colloid milling, roller milling, hammer milling and the like. Particle size and particle size distribution can be measured by techniques such as Laser light scattering (e.g. Malvern Light Scattering), Coulter counter, microscopy and the like.
Regarding drugs with sensitivity to light, the primary packaging container should have light barrier properties that can be achieved with a colorant to produce a colored (e.g., amber, dark blue) or opaque primary packaging container. Yellow-green blisters/ containers give the best protection in the ultraviolet region; amber colored also blisters/ containers offer desired protection from ultraviolet light, but little protection from infrared light. In an embodiment of the present invention, the stable pharmaceutical composition of Ramelteon tablets are packaged in a light protecting amber colored glass bottle, foil, blister, HDPE container, pouch, capsule or other suitable package.
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The stable pharmaceutical oral dosage form prepared by the above process can be subjected to in vitro dissolution evaluation according to Test 711 "Dissolution" in the United States Pharmacopoeia 37, United States Pharmacopoeial Convention, Inc., Rockville, Md., 2014 ("USP") to determine the rate at which the active substance is released from the dosage form, and the content of the active substance can be determined in solution by high performance liquid chromatography. When comparing the test and reference products (of US and Japan), dissolution profiles should be compared using a similarity factor (f2). The similarity factor is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) of dissolution between the two curves.
f2 = 50 • log {[1 + (1/n)Σt=1n (Rt - Tt)2]-0.5 • 100}
Two dissolution profiles are considered similar when the f2 value is equal to or greater than 50.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail method for the preparation and testing of Ramelteon pharmaceutical composition. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
It is desirable that the pharmaceutical compositions prepared according the present invention are expected to have formulation attributes, like dissolution and photostability comparable to the innovator’s marketed product. Photostability can be measured by exposing the samples to visible light providing an overall illumination of a minimum of 1.2 million lux hours and an integrated near ultraviolet energy of a minimum of 200 watt hours/square meter with spectral distribution of 320-400nm to
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allow direct comparisons to be made between the drug substance and drug product (see ICH Q1B guidance “Photostability Testingof New Drug Substances and Products” in the Code of Federal Regulations).
Following examples are set out to illustrate the invention and do not limit the scope of the present invention
EXAMPLES
The following non-limiting examples are intended to further illustrate certain preferred embodiments of the invention. They are, however not intended to be limiting the scope of the present invention in any way. Stable pharmaceutical composition of Ramelteon may be prepared by using quantitative formula as given in table 1.
TABLE 1

Ingredients %w/w
Examples I II III
1. Ramelteon 6.0 1-60 1-60
2. Lactose 70.0 -- 20-80
3. Corn starch 11.0 10-80 --
4. HPMC 10.0 -- 2-10
5. Povidone -- 0-10 --
6. Citric acid 0.5 -- 0.05-2
7. Ascorbic acid -- 0.05-2 --
8. Croscarmellose Sodium 2.0 0-15 0-10
9. Magnesium Stearate 0.5 1-5 0-3
Optional Film coating
10. HPMC -- 0-20 --
11. Titanium dioxide -- 1-4 --
12. Talc -- 0-3 --
13. Purified Water -- q.s. --
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Preferred method of manufacture: Direct compression/ dry granulation/ wet granulation.

We Claim:

A stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and at least one or more pharmaceutical excipient, wherein the composition is free of copolyvidone and one or more pharmaceutical excipient is selected from the group comprising of binders, disintegrating agents, diluents, lubricants, glidants and antioxidants.
A stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and at least one or more pharmaceutical excipient, wherein the composition is free of Hydroxypropyl cellulose (HPC) and one or more pharmaceutical excipient is selected from the group comprising of binders, disintegrating agents, diluents, lubricants, glidants and antioxidants.
A stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and at least one or more pharmaceutical excipient, wherein the composition is free of copolyvidone and Hydroxypropyl cellulose and the one or more pharmaceutical excipient is selected from the group comprising of binders, disintegrating agents, diluents, lubricants, glidants and antioxidants.
The stable pharmaceutical composition according to claims 1, wherein Ramelteon is present in an amount ranging from about 1 mg to about 20 mg.
The stable pharmaceutical composition according to claim 4 is prepared by processes selected from direct compression, dry granulation, dry blending or wet granulation process.

The stable pharmaceutical composition according to claim 4, wherein antioxidant is selected from the group consisting of potassium ascorbate, calcium ascorbate and magnesium ascorbate, vitamin A, vitamin A2, vitamin C (ascorbic acid), natural and synthetic tocopherols (mixed tocopherols concentrate, alpha-tocopherol, beta-tocopherol, synthetic gamma-tocopherol, synthetic delta-tocopherol), vitamin E, ascorbyl palmitate, ascorbyl stearate, propyl gallate, tertiary butyl hydroquinone (TBHQ), dilauryl thiodipropionate, magnesium sulfite or calcium sulfite, Butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), cysteine, sodium sulfite, sodium metabisulfite, sodium bisulfite, thioglycerol, thioglycollic acid, preferably, used ascorbic acid, citric acid and/or Butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).
The stable pharmaceutical composition according to claim 4, wherein binder is selected from the group comprising of hypromellose, methylcellulose, povidone, starch, polyvinyl alcohol or polyethylene oxide acacia, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, glucose, guar gum, maltose or mixtures thereof.
A stable pharmaceutical composition comprising Ramelteon or its pharmaceutically acceptable salts, polymorphs, enantiomers or mixtures thereof and one or more excipients wherein the pharmaceutical composition is devoid of coating.
A process for preparing a stable pharmaceutical composition comprising Ramelteon and their pharmaceutically acceptable salts and solvates thereof wherein the process comprises of:
a) dry mixing of Ramelteon with pharmaceutical excipients like binder, disintegrant and diluent

b) granulating the resultant blend as obtained in step (a) with aqueous /non-aqueous binder solution
c) passing the wet mass as obtained in step (b) through suitable size sieve and drying the granulates in a suitable drying equipment,
d) passing the resultant granules through a suitable size mesh and mixing the same with lubricants and glidants,
e) compressing the lubricated granules into tablets
f) Coating the tablets of step (e) using a coating solution