DESC:This application claims the benefit of Indian Provisional Applications No. IN2016/21024255 (filed on July 14, 2016), and IN2016/21042640 (filed on December 14, 2016), which are hereby incorporated by reference in entirety.

FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions of apremilast or pharmaceutically acceptable salts thereof. Methods of preparing such compositions are also provided.

BACKGROUND OF THE INVENTION
Apremilast is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels. The specific mechanism(s) by which apremilast exerts its therapeutic action in psoriatic arthritis patients and psoriasis patients is not well defined.

Chemically, Apremilast is N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]acetamide and has the following structure:

Commercially, it is available as Otezla® Tablets marketed by Celgene in 10, 20 & 30 mg strengths.

US6020358 discloses apremilast as product; while US7893101 discloses crystalline Form B of apremilast.

US7427638 discloses stereomerically pure (+) form of apremilast and its composition with pharmaceutically acceptable excipients.

US 2013/0164376A1 discloses pharmaceutical compositions of apremilast.
SUMMARY OF THE INVENTION
The present specification relates to pharmaceutical compositions of apremilast or pharmaceutically acceptable salts thereof and method of preparation of such compositions.

In one aspect, the present specification relates to pharmaceutical compositions comprising apremilast or pharmaceutically acceptable salts thereof and suitable pharmaceutical excipients.

Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments.

DETAILED DESCRIPTION OF THE INVENTION

The present specification relates to pharmaceutical compositions of apremilast or pharmaceutically acceptable salts thereof and method of preparation of such compositions.

In one aspect, the present specification relates to pharmaceutical compositions comprising apremilast or pharmaceutically acceptable salts thereof and suitable pharmaceutical excipients.

The apremilast can be in various forms, such as amorphous, crystalline, and mixtures thereof. Apremilast may be micronized or unmicronized.

The amount of apremilast in the pharmaceutical compositions of the present specification may range from about 5% to 15% by the weight of the composition. e.g. about 10% by the weight of the composition.

Suitable pharmaceutical excipients are selected from fillers, disintegrants, binders, lubricants and glidants.

Suitable fillers according to the present invention include, but are not limited to, dibasic calcium phosphate, microcrystalline cellulose, silicated microcrystalline cellulose, lactose, tricalcium phosphate, magnesium trisilicate, and sugars such as dextrose, maltose, saccharose, glucose, fructose or maltodextrin, sugar alcohols such as mannitol, maltitol, sorbitol, xylitol, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate and starch. Amount of fillers is in the range of about 10% to about 95% by weight of the composition.

Suitable disintegrants according to the present invention include, but are not limited to carboxymethylcellulose sodium, croscarmellose (cross-linked carboxymethylcellulose) sodium, cross-linked polyvinylpyrrolidone, crospovidone (cross-linked povidone, sodium starch glycolate, partially hydrolysed starch, sodium carboxymethyl starch, and starch. Amount of disintegrant is in the range of about 1.0% to about 5.0% by weight of the composition.

Suitable binders according to the present invention include, but are not limited to, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, compressible sugar, polyvinyl pyrrolidone and pregelatinized starch. Amount of total binder is 1% to 5% by weight of the composition.

Suitable glidants include but are not restricted to: silica; colloidal silica, e.g. colloidal silica anhydrous, e.g. Aerosil® 200, magnesium trisilicate, powdered cellulose, starch and talc. Preferably, colloidal silicon dioxide is used. Amount of glidants is in the range of 0.1% to 1% by weight of the composition.

Suitable lubricants include but are not restricted to: Mg-, Al- or Ca-stearate, glyceryl mono fatty acid. e.g. glyceryl monostearate, glyceryl dibehenate (e.g. Compritol™, Gattefossé), glyceryl palmito-stearic ester (e.g. Precirol™, Gattefossé), hydrogenated cotton seed oil (Lubitrab™, Edward Mendell), castor seed oil (Cutina™, Henkel). In one embodiment, magnesium stearate is used. Amount of lubricants is in the range of 0.1% to 5% by weight of the composition.

The pharmaceutical compositions of the present specification may be prepared by conventional methods such as wet granulation, dry granulation or direct compression.

Further, the pharmaceutical compositions of the present specification may be coated or uncoated.

Suitable plasticizers in the coating composition include but are not restricted to: Polyols such as PEG 400, Organic esters such as dibutyl sebacate, diethyl phthalate, triethyl citrate, triacetin and Oils/glycerides such as medium chain triglycerides, castor oil etc.

The following experiments are provided to exemplarily illustrate various aspects of the inventive subject matter presented herein. However, it should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein.
Table 1

Sr. No. Ingredients Example 1 Example 2 Example 3 Example 4
%w/w %w/w %w/w %w/w
1 Apremilast 10 10 10 10
2 Mannitol < 20 - - 50-70
3 Microcrystalline cellulose PH 102 > 60 > 60 > 60 20-40
4 Lactose monohydrate - < 20 - -
5 Lactose anhydrous - - < 20 -
6 Croscarmellose sodium 1-5 1-5 1-5 1-5
7 Magnesium stearate 0.1-5 0.1-5 0.1-5 0.1-5
Total 100 100 100 100
The above test composition of Example 1-4 are prepared by following method:
Apremilast is mixed with mannitol/lactose, microcrystalline cellulose and croscarmellose sodium in geometric proportion. The blend is either granulated by dry or wet granulation or the lubricated blend is directly compressed. Compressed tablets are optionally coated with coating composition as follows:
Table 2
Sr. No Coating composition %w/w
1 Hypromellose 35-45
2 Lactose Monohydrate 25-35
3 Titanium Dioxide 20-30
4 Triacetine/Medium chain triglycerides 5-10
5 Colour Pigments 0-3
Total 100

,CLAIMS:1. A pharmaceutical composition comprising apremilast or pharmaceutically acceptable salts thereof and suitable pharmaceutical excipients.
2. The pharmaceutical composition of claim 1, wherein the suitable pharmaceutical excipients comprise filler, disintegrant & lubricant.
3. The pharmaceutical composition of claim 2, wherein the filler is selected from dibasic calcium phosphate, lactose, microcrystalline cellulose, sugars, sugar alcohols, powdered cellulose, starch and mixtures thereof.
4. The pharmaceutical composition of claim 3, wherein the filler is present at an amount of about 10% to about 95% by weight of the total composition.
5. The pharmaceutical composition of claim 2, wherein the disintegrant is selected from carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone ,alginic acid, sodium alginate, sodium starch glycolate.
6. The pharmaceutical composition of claim 2, wherein the lubricant is selected from Mg-, Al- or Ca-stearate, glyceryl mono fatty acid, hydrogenated cotton seed oil castor seed oil.
7. The pharmaceutical composition of claim 1 may be prepared by direct compression or by dry granulation or wet granulation.
8. The pharmaceutical composition of claim 1 may be optionally coated.