FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising apremilast or its pharmaceutical^ acceptable salts, esters, solvates, polymorphs thereof .and a process for preparing the same.
BACKGROUND OF THE INVENTION
Apremilast is a phosphodiesterase-4 (PDE4) inhibitor. Apremilast is chemically known as N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl] acetamide having Formula (I).
Formula I
Apremilast is indicated for the treatment of adult patients with active psoriatic arthritis. It is* available under the trade name of Otezla® tablets supplied in 10, 20 and 30. mg strengths for oral administration. There are several references known in the literature, which describe the different polymorphic forms of apremilast and pharmaceutical composition of the same, which is used in the treatment of various diseases.
U.S. Pat. No. 6,020,358 discloses racemic apremilast and process for
t \ ~
its preparation.
U.S. Pat. No. 6,962,940 discloses methods of using stereomerically pure apremilast the treatment of certain diseases or disorders including, for example, inflammation.

U.S. Pat. No. 7,208,516 discloses methods of using apremilast for the treatment of psoriatic arthritis.
U.S. Pat. No. 7,659^302 discloses methods of using "stereomerically pure" apremilast for the treatment of psoriasis.
U.S. Pat. No. 7,427,638 discloses stereomerically pure (+)-2-[l-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-l,3-dipne, substantially free of its (-) isomer, or a pharmaceutical^ acceptable metabolite, salt, solvate or hydrate, thereof and its pharmaceutical composition.
The stereomerically, pure (+)-2-[l-(3-ethoxy-4^methoxyphenyl)-2-
methylsulfonyl- ethyl]-4-acetylamino- isoindoline-l,3-dione is the (+)-isomer of racemic 2-[l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro -l53--dioxo-lH-isoindol-4-yl]acetamide.
U.S. Pat. No. 8,455,536 discloses methods of using "stereomerically pure" apremilast for the treatment of psoriasis.
U.S.' Pat. No. 8,802,717 discloses methods of using "stereomerically pure" apremilast for the treatment of arthritic conditions. .
U.S. Pat. No. 7,893,101 discloses crystalline form B of apremilast and a solid pharmaceutical composition comprising it.
U.S. Pat. No. 9,018,243 discloses methods of using apremilast Form B, including, for example, the treatment of psoriatic arthritis and/or psoriasis.
U.S. Pat. No. 8,629,173 discloses methods of using apremilast Form A & F, including, for example, the treatment of psoriasis.

U.S. Pat. No. 9,468,605 discloses an immediate-release oral dosage form comprising apremilast, lactose, cellulose, carboxymethyl cellulose, fumed silica
. and magnesium stearate and a coat.
U.S. Pat. No. 9,351,957 discloses an amorphous form of apremilast and pharmaceutical composition comprising amorphous apremilast.
U.S. Pat. No. 9,532,977 discloses"a controlled release oral dosage form comprising apremilast, a swelling excipient; poly (butyl methacylate-co-2-dimethylaminoethyl methacrylate-co-methyl methacrylate) (1 ;2:1); an anionic polymer in acidic pH, and sodium bicarbonate.
U.S. Pub. No. 2016/0045475 discloses a method of treating psoriasis comprising escalating doses of stereomerically pure apremilast, wherein a starting dose is .between about 10 mg per day and about 20 mg per day and a maximum dose is between about 40 mg per day and about 100 mg per day. This seems to covers approved dosage regimen of Otezla for psoriasis.
U.S. Pub. No. 2014/0301980 discloses a method of treating psoriatic arthritis comprising escalating doses of stereomerically pure apremilast, wherein a starting dose is between about 10 mg per day and about 20 mg per day and a maximum dose is between about 40 mg per day and about 100 mg per day. This seems to covers approved dosage regimen of Otezla for psoriatic arthritis.
U.S. Pub. No. 2015/0306226 discloses an immediate release composition comprising a melt of apremilast and excipient.
U.S. Pub. No. 2013/0164376 discloses a pharmaceutical composition comprising apremilast; lactose; microcrystalline cellulose, a disintegrant and a lubricant. The patent further relates to a pharmaceutical composition comprising apremilast, lactose, microcrystalline cellulose, a disintegrant, a lubricant and a filni coating

comprising polyvinyl alcohol as film forming agent.
As pharmaceutical excipients have various functions and contribute to the pharmaceutical formulations in many different ways, e.g^, solubilization, dilution, thickening, stabilization, preservation, coloring and flavoring. The properties that are commonly considered when formulating an active drug substance include bioavailability, ease of manufacture, and ease of administration and stability of the dosage form. Due to the varying properties of the active drug substance to be formulated, dosage forms typically require pharmaceutical excipients that are uniquely tailored to the active drug substance in order to achieve advantageous physical and pharmaceutical properties.
In view of the above, it is therefore, desirable to provide a pharmaceutical
composition of apremilast which provides better/comparable bioavailability and
i
better stability when compared to the. marketed formulation. Further, there-exists need to develop a,process for the development of pharmaceutical composition which provides an efficient and more economical process.
SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising therapeutically effective amount of apremilast or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof and one or more pharmaceutically. , acceptable excipients, wherein the pharmaceutical composition is optionally coated. with one or more polymers.
The present invention further relates to,a pharmaceutical composition comprising
therapeutically effective amount of apremilast or its pharmaceutically acceptable
salts, esters, solvates, polymorphs thereof and one or more pharmaceutically
acceptable excipients, wherein the pharmaceutical composition is substantially free
of lactose. v .
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The present invention further relates to a pharmaceutical composition comprising
therapeutically effective amount of apremilast or its pharmaceutically acceptable
salts, esters, solvates, polymorphs thereof and one or more pharmaceutically
acceptable excipients selected from the group comprising diluents, binders,
disintegrants, glidants, lubricants, surfactants, polymers and/ or combinations
thereof. -
The present invention further relates to a method of treating or preventing a disease or disorder ameliorated by the. inhibition of TNF-[a] production, wherein the method comprises administering a therapeutically or prophylactically effective amount of a pharmaceutical composition comprising apremilast or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof and one or more pharmaceutically acceptable excipients.
The present invention further relates to a process for preparation of a pharmaceutical composition of apremilast or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof, wherein the process comprising the steps of:
(a) blending apremilast or its pharmaceutical acceptable salts, esters, solvates, polymorphs thereof, microcrystalline cellulose and one or more disintegrant in a suitable blender; '
(b) lubricating the blend of step (a) with sodium stearyl fumarate arid/or zinc stearate to get a lubricated blend;

(c) compressing the lubricated blend to get a tablet; and
(d) optionally coating the Tablet with a film forming agent.
DESCRIPTION OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising therapeutically effective amount of apremilast or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is substantially free of lactose.

-The present invention further relates to a pharmaceutical composition comprising therapeutically effective amount of apremilast or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof and-one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is optionally coated with one or more film forming agent, wherein the pharmaceutical composition comprises combination of two or more disintegrants.
Applicant has tried various excipients and combination of excipients to develop ' a pharmaceutical composition of apremilast withjone or more pharmaceutically acceptable excipients, which not only rapidly disintegrates but also provides a stable and bioavailable composition. While working on the present invention inventors have found that the stable and bioavailable pharmaceutical composition can be achieved by using combination of two or more disintegrants. , In another embodiment inventors have develop a stable and bioavailable pharmaceutical composition of apremilast or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof which are substantially free of lactose. The present < invention further relates to a pharmaceutical composition comprising therapeutically effective amount of apremilast or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is optionally coated with one or more film forming agent, wherein the pharmaceutical composition comprises combination of two or more disintegrants and is substantially free of lactose.
Another aspect of the present invention, there is provided a pharmaceutical composition comprising therapeutically, effective amount of apremilast or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition comprising about 5-50% by weight of apremilast or pharmaceutically
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acceptable salts, ester, solvates, polymorphs thereof.
Another aspect of the present invention, there is provided a pharmaceutical composition comprising therapeutically effective amount of apremilast or pharmaceutically acceptable salts, esters, solvates, polymorphs thereof and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition comprising about 5mg to about lOOmg of apremilast or pharmaceutically acceptable salts, ester, solvates, polymorphs thereof.
Another aspect of the present invention, there is provided a pharmaceutical composition comprising therapeutically effective amount of apremilast or pharmaceutically acceptable salts, esters, solvates, polymorphs thereof and one or more pharmaceutically acceptable excipients, wherein the apremilast is present in any known polymorphic form i.e. amorphous or crystalline form:
Another aspect of the present invention, there is provided a pharmaceutical
composition comprising therapeutically effective amount of apremilast1 or its
pharmaceutically acceptable salts, esters,.solvates, polymorphs thereof and one or
more pharmaceutically acceptable excipients, wherein the apremilast is present in s
any one of known polymorphic forms such as, but not limited to, A, B, C, D, E, F,
G, M, stereomerically pure, Form I, Form II, Form S, amorphous form, hydrates
and solvate forms. < ' '
Another aspect of the present invention, there is provided a pharmaceutical
i
composition comprising therapeutically effective amount of apremilast or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof and one or more pharmaceutically acceptable excipients, wherein the apremilast is having the particle size of D90 less than about 200 microns. Preferably, D90 is less than 50 microns and more preferably, D90 is less than 20 microns.
Another aspect of the present invention, there is provided a pharmaceutical

composition comprising apremilast. or its pharmaceutically acceptable salts, ester, solvates, polymorphs thereof and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is in the form of, but
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not limited to, . granules, pellets, beads, spheroids, tablet, minitablet, microtablet, a capsule, granules in a-capsule, pellets in a capsule, microtablets in a capsule and minitablets in a capsule.
Another aspect of the present invention, there is provided a pharmaceutical composition comprising therapeutically effective amount of apremilast or its
pharmaceutically acceptable salts, esters, solvates, polymorphs thereof and one
/
or more . pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients comprising diluents, binders, disintegrants, glidants, lubricants, surfactants, polymers and/ or combination thereof.
Diluents increase the bulk of the composition. Diluents according to the present invention are selected from, but not limited to, sugars such as sucrose, dextrose, niannose, fructose, "galactose; sugar alcohols such as sorbitol, mannitol, erythritol, xylitol, lactitol; organic acids such as malic acid, citric acid; tartaric acid, fumaric acid and the like; inorganic acids such as dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, magnesium carbonate, magnesium oxide, and the like; starlac, starch, modified starches, maltodextrin, calcium sulfate, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, magnesium alumino metasilicate and the like used either alone or in combinations thereof. Preferably, the diluent is microcrystalline cellulose.
The diluent cain be present in an amount of from about 5% to about 95% by
weight of the composition, preferably in the range from about 30% to about
'95% by weight of the composition and more preferably in an amount of about
60% to about 90% by weight of the composition. t > •'

Disintegrants according1 to the present invention are selected from, but not limited to, group comprising, cellulose and its derivatives including low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, sodium starch glycolate, ion-exchange resins, starch and modified starches including, pregelatinized starch, formalin-casein, and the like used either alone or in combinations comprising one or more of the foregoing disintegrants. Preferably the disintegrant is selected from croscarmellose x sodium, Sodium starch glycolate and Crospovidone or combinations thereof.
The combinations of two or more disintegrants are present in the different ratios to get the optimum release profile. Preferably, the composition comprises combination of three disintegrants in the ratio of from 1:1:1 to 2:1:1.
In an embodiment, the disintegrant may be used in the range of about 0.5% to about 60% by weight of the composition. Preferably in the range from about 0.5% to about 20%'by weight of the composition.
An aspect of the present invention, there is provided a pharmaceutical composition a comprising therapeutically effective amount of apremilast. or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof and combination of two or more disintegrants.
An aspect of the present invention, there is provided a pharmaceutical
composition comprising therapeutically effective amount of apremilast or its
pharmaceutically acceptable salts, esters, solvates, polymorphs thereof and
combination of three disintegrants. * ,
As aspect of the present invention, there is provided a pharmaceutical

I
. composition comprising therapeutically effective amount of apremilast or its
pharmaceutically acceptable salts, esters, solvates, polymorphs thereof and
combination of three disintegrants wherein disintegrants are in the ratio from 1:1:
1 to 2:1:1. ' ' *
An aspect of the present invention, there is provided a pharmaceutical composition comprising therapeutically effective amount of apremilast or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof and combination of two or more disintegrants, and one or more pharmaceutically acceptable excipients, wherein the disintegrants are selected from starch, croscarmellose sodium, crospovidone, sodium starch glycolate, and combination thereof.
An aspect of the present invention, there is provided a pharmaceutical composition comprising, therapeutically effective amount of apremilast or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof and combination of two or more disintegrants and one or more pharmaceutically acceptable excipients, wherein the disintegrants are selected from starch, croscarmellose sodium, crospovidone, sodium starch glycolate, and combination thereof and is substantially free of lactose.
Binders hold the ingredients in the composition together. Exemplary binders are selected from, but not limited to group comprising cellulose or its derivatives including microcrystalline cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose and hydroxyethyl cellulose, carboxymethyl cellulose; gelatin, liquid glucose; starch and its derivatives (e.g. corn starch, maize starch, potato starch, pregelatinised starch); hydrocolloids; sugars; polyvinylpyrrolidone, copovidohe, sodium alginate, acacia, alginic acid, tragacanth, xanthan, acacia, and the like used either alone or combination thereof.
Lubricants and(glidants aid in the processing of powder materials, Exemplary
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lubricants are' selected from but not limited to group comprising glycerol behenate, mineral oil, polyethylene glycol, sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, stearic acid1, talc, vegetable oil, and the like used either alone or in combinations comprising one or more of the foregoing lubricants.
Exemplary glidants include but not limited to talc, colloidal silicon dioxide, corn starch, and the like used either alone or in combination thereof.
Surfactants are compounds which are capable of improving the wetting of the drug and/or enhancing the dissolution. The surfactants can be selected from hydrophilic surfactants or lipophilic surfactants or mixtures' thereof. The surfactants can be anionic, nonionic, cationic, and zwitterionic surfactants. Surfactants according to the present invention are selected from but not limited to group comprising polyoxyethylene alkylaryl ethers such as polyoxyethylene , lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether; polyethylene glycol (PEG) fatty acid esters such as PEG monolaurate, PEG dilaurate, PEG distearate, PEG dioleate; polyoxyethylene sorbitan fatty acid ester such as polysorbate 40, polysorbate 60, polysorbate 80; sorbitan fatty acid mono esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene castor'oil derivatives such as polyoxyl castor oil, polyoxyl hydrogenated castor oil, sodium lauryl sulphate and the like used
^T either alone or in combination thereof.
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g which the binder is soluble or dispersible and is selected from, isdpropyl alcohol,

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ethanol, water, acetone, methylene chloride and the like or mixtures thereof.
i In another aspect, the pharmaceutical composition of the present invention is
optionally coated with a coating. The coating can'be a'film coating or a functional

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The film coating includes a film forming agent or combination of a. film forming agents, plasticiser, opacifier,, glidants or colorants or combinations thereof.
Film forming agents include, for example, polyvinylpyrrolidone, natural gums, starches, and cellulosic polymers. A cellulosic polymer may include a molecule comprising at least one cellulose polymer or derivative modified with small amounts of propylene glycol ether groups attached to the cellulose anhydroglucose chain affording binding properties that enhance the reinforcing film properties of film applications. Examples'of cellulosic polymers include, but are not limited to, hydroxypropyl methyl cellulose ("HPMC"), carbbxymethyl cellulose ("CMC") or salts , thereof, hydroxypropyl cellulose ("HPC"), methylcellulose ("MC"), hydroxyethyl cellulose ("HEC")? and the like. In addition, cellulosic polymers may be characterized as ionic or non-ionic. Ionic cellulosic polymers include, for example, sodium CMC. Non-ionic cellulosic polymers include, for example, HPMC, HPC, HEC, and MC. Varieties of commercially available cellulosic polymers exist and may include, for example, Spectracel®. HPMC compositions (available from Sensient Technologies). Further, other commercially available coating materials are available marketed under the brand .name Opadry®. The polymers such as polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate can be used as a film forming agent.
In one aspect, the film forming agent can be used in an amount from 2% to-10%
by weight of the composition. f '
Another aspect of the present invention, there is provided a pharmaceutical composition comprising apremilast or its pharmaceutical^ acceptable salts, ester, solvates, polymorphs thereof and one or more pharmaceutical^ acceptable excipients, wherein the' pharmaceutical composition is suitable for parenteral, transdermal, mucosal, nasal, buccal, sublingual, or oral administration to a patient.

Another aspect of the present invention, there is provided a pharmaceutical composition comprising apremilast or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is in the form of immediate release, delayed releasie, sustained release, extended release, controlled release or modified release form.
Another aspect of the present invention* there is provided a pharmaceutical composition comprising apremilast or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition can be formulated by any suitable granulation methods are known in the art such as wet granulation, direct compression, dry granulation/compaction or melt granulation. More preferably, composition is prepared by direct compression method.

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The present invention further relates to a process for preparation of a pharmaceutical composition of apremilast or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof, wherein the process comprising the steps of:
(a) blending apremilast or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof; microcrystalline cellulose; one or more disintegrant and optionally lubricant or glidant in a suitable blender;
(b) granulating the blend of step (a) using binder solution to obtain granules; (c) lubricating the granules with sodium stearyl fumarate and/or zinc stearate and/or glidant to get a lubricated blend;
(c) compressing the lubricated blend to get a tablet; and
(d) optionally coating the tablet with a film forming agent.
The present invention further relates to a process for preparation of a
pharmaceutical composition of apremilast or its pharmaceutically acceptable
salts, esters, solvates, polymorphs thereof, wherein the process comprising the
steps of: 14
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(a) blending apremilast or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof; microcrystalline cellulose; one or more disintegrant and optionally lubricant or glidant in a suitable blender;
(b) dry granulating/compacting the blend of step (a) to obtain granules;
(c) lubricating the granules with sodium stearyl fumarate and/or zinc stearate and/or glidant to get a lubricated blend; .'

(c) compressing the lubricated blend to get a tablet; and
(d) optionally coating the tablet with a film forming agent. , v
The present invention further relates to a process for preparation of a pharmaceutical composition of apremilast or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof, wherein the process comprising the steps of:
(a) blending apremilast or its pharmaceutically acceptable salts, esters, solvates,
polymorphs thereof; microcrystalline cellulose and one or more disintegrant in.
r
a suitable blender;
(b) lubricating the blend of step (a) with sodium stearyl fumarate and/or zinc stearate to get a lubricated blend;
(c) compressing the lubricated blend to get tablet; and
(d) optionally coating the tablet with a film forming agent.
In another embodiment, the present invention relates to a pharmaceutical composition comprising apremilast or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof in an amount of 5-50%, microcrystalline cellulose in an amount of 60-90%, combination of disintegrants croscarmellose sodium, sodium starch glycolate and crospovidone in a ratio of 2:1:1, colloidal silicon dioxide in an amount of 0-10% and sodium stearyl fumarate in an amount of 0.5-20%. It is further coated with a film'forming agent.
In another embodiment, the present invention relates to a pharmaceutical composition comprising apremilast or its pharmaceutically acceptable salts,

esters, solvates, polymorphs thereof in an amount of 5-50%, microcrystalline cellulose in an amount of 60-90%, combination of disintegrants croscarmellose sodium, sodium starch glycolate and crospovidone in a ratio of 1:1:1, colloidal silicon dioxide in an amount of. 0-10% and sodium stearyl fumarate in an amount of 0.5% -20%. It is further coated with a film forming agent.
i i
The present invention relates to a pharmaceutical composition comprising therapeutically effective amount of apremilast or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof and one or more pharmaceutically acceptable excipients wherein the composition is coated with a film forming agent selected from- hydroxypropyl methyl cellulose, hydroxypropyl cellulose or combinations thereof and wherein the composition is substantially free of lactose.
Another aspect of the present invention, there is provided a pharmaceutical
composition comprising apremilast or its pharmaceutically acceptable salts,
ester, solvates, polymorphs thereof and one or more pharmaceutically acceptable
excipients, wherein the pharmaceutical composition is used for the treatment
of disease or disorder selected from the group consisting of psoriasis,
psoriatic arthritis, rheumatoid arthritis, Behcet's Disease, rheumatoid spondylitis,
an arthritic condition, atopic dermatitis, and ulcerative colitis, treating or
managing obesity or overweight. '
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and don't limit the scope of the invention. Certain modifications and equivalents * will be apparent to tHose skilled in the art and are intended to be included within the scope of the present invention.
Example 1: Pharmaceutical composition of apremilast

Ingredient Quantity %w/w
Apremilast 5-50%
Microcrystalline Cellulose 5-95%
Croscarmellose Sodium 0.5-60%
Sodium starch Glycolate and/ or Crospovidone 0.5-60%
Sodium stearyl fumarate/ Zinc stearate 0.5-20%
Film coating
Hydroxypropyl methyl cellulose q.s
Hydroxyl propyl cellulose q.s
Titanium dioxide q.s
Talc q.s
Process:
(a) Dispense, sift and blend the apremilast, microcrystalline cellulose and other ingredients.
(b) Lubricate the blend obtained from step (a) with sodium stearyl fumarate or zinc stearate.
(c) Compress the lubricated blend using suitable punches and dies.
(d) Coated the compress mixture obtained in step (c) with coating solution.
Example 2: Pharmaceutical composition of apremilast

Ingredient Quantity %w/w
Apremilast 5-50%
Microcrystalline Cellulose 5-95%
Sodium Lauryl sulfate/Pluronic F 68 0-20%
Croscarmellose, Sodium 0.5-60%
Colloidal Silica/ Talc 0-10%
Sodium starch Glycolate and/or Crospovidone 0.5-60%
Sodium stearyl fumarate/ Zinc stearate 0.5-20%
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Film coating
Hydroxypropyl methyl cellulose q.s
Hydroxyl propyl cellulose q.s
Titanium dioxide q.s
Talc q.s
Process:
(a) Dispense, sift and blend apremilast, microcrystalline cellulose and other
ingredients.
(b) Lubricate the blend obtained from step (a) with sodium stearyl fumarate or zinc stearate.
(c) Compress the lubricated blend using suitable punches and dies.
(d) Coated the compress mixture obtained in step (c) with coating solution.
Example 3: Pharmaceutical composition of apremilast

Ingredient Quantity %w/w
Apremilast 10%
Microcrystalline Cellulose 79.8%
Croscarmellose Sodium 4%
Sodium starch Glycolate 2%
Crospovidone 2%
Colloidal Silica 0.2%
Sodium stearyl fumarate 2%
Film coating
Hydroxypropyl methyl cellulose q.s
Hydroxyl propyl cellulose q.s
Titanium dioxide q.s
Talc q.s
Process:

(a) Pispense, sift and blend apremilast, macrocrystalline cellulose and other
ingredients.
(b) Lubricate the blend obtained from step (a) with sodium stearyl fumarate.
(c) Compress the lubricated blend using suitable punches and dies.
(d) Coated the compress mixture obtained in step (c) with coating solution.
The resulting tablets prepared according to Example 3 shows disintegration at 15- 50 sec and have a hardness value of 5-12 kgf.
Dissolution of the six tablets according to Example 3 were conducted at following condition:
• Dissolution Media: pH 6.8 phosphate buffer containing 0.15% sodium * lauryl sulfate
• Volumes: 900ml
• Apparatus: USP type II @ 60rpm.
The dissolution profile is given below in Table-1:
Table 1: Comparative Dissolution profile of tablets prepared according to
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example 3 and marketed formulation in US (Otezla®)

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10 78-81 69-76 '
15 . 82-86 75-80
20 85-89 78-82 '
30 88-92 81-85
45 90-93 83-90
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Tablets prepared according to example 3 shows stability over a period of 6 months. The stability data of tablets is shown in the Table-2 as follows:
Table 2: Stability Data of apremilast tablets (Example 3)
Example 4: Pharmaceutical composition of apremilast

The tablet dosage form is prepared as per the following process:
a) Dispense, shift and blend the apremilast, microcrystalline cellulose and other ingredients.
b) Lubricate the blend obtained from step (a) with sodium stearyl fumarate.
c) Compress the lubricated blend using suitable punches and dies.
d) Coated the compress mixture obtained in step (c) with coating solution.
Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

We Claim:
1. A pharmaceutical composition comprising therapeutically effective amount of apremilast or its pharmacputically acceptable salts, esters, solvates, polymorphs thereof and one or more.pharmaceutical^ acceptable excipients, wherein the composition is substantially free of lactose and the pharmaceutical composition is optionally coated with film forming agents.
2. The pharmaceutical composition as claimed in claim 1, wherein the one or more pharmaceutically acceptable excipients are selected from diluents, binders, disintegrants, glidants, lubricants, surfactants, polymers and/ or combinations
thereof.
i.
3. The pharmaceutical composition ,as claimed in claim, 2, wherein disintegrants are selected form starch, croscarmellose sodium, crospovidone, sodium starch glycolate, and combinations thereof.
4. The pharmaceutical composition as claimed in claim 3, wherein disintegrant is present in an amount from about 0.5 to about 20% by weight of the composition.'

5. The pharmaceutical composition as claimed in claim 3, wherein the disintegrants are a combination of croscarmellose sodium, sodium starch glycolate and crospovidone.
6. The pharmaceutical composition as claimed in claim 5, wherein the ratio of croscarmellose.sodium, sodium starch glycolate and crospovidone is in range from 1:1:1 to 2:1:1.
7. The pharmaceutical composition as claimed in claim 2, wherein diluent is selected from sucrose, dextrose, mannose, fructose, galactose; sugar alcohols such as sorbitol, mannitol, erythritol, xylitol, lactitol, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, magnesium carbonate,

magnesium oxide, starlac, starch, modified starches, maltodextrin, calcium sulfate, ; powdered cellulose, microcrystalline, cellulose, silicified microcrystalline cellulose, magnesium alumino metasilicate or combinations thereof.
8. The pharmaceutical composition as claimed in claim 7, wherein diluent is
microcrystalline cellulose.
9. The pharmaceutical composition as claimed in claim 1, wherein film forming
agent is selected from hydroxypropyl methyl cellulose, hydroxypropyl
cellulose or combinations thereof.
10. A process for preparation of a pharmaceutical composition of apremilast or
its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof,
wherein the process comprises the steps of:
(a) blending apremilast or its pharmaceutically acceptable salts, esters, solvates, polymorphs thereof; microcrystalline cellulose and one or more disintegrant in a suitable blender;
(b) lubricating the blend of step (a) with sodium stearyl fumarate and/or zinc stearate to get a lubricated blend;
(c) compressing the lubricated blend to get tablet; and
(d) optionally coating the tablet with a film forming agent.