Claims:1. A pharmaceutical composition comprising Apremilast in an amorphous form, ethyl cellulose and one or more pharmaceutically acceptable excipients(s).

2. The pharmaceutical composition according to claim 1, which provides dissolution of not more than 85% in 30 minutes as measured using Apparatus-IV (Flow through cell- Turbulent flow) with flow rate of 12 ml /min in 1000ml of medium constituted by phosphate Buffer (pH 5.0) + 0.2 % SLS.

3. The pharmaceutical composition according to claim 1, which provides dissolution of not more than 55% in 10 minutes, not more than 65% in 15 minutes, not more than 75% in 20 minutes and not more than 85% in 30 minutes, as measured using Apparatus-IV (Flow through cell- Turbulent flow) with flow rate of 12 ml /min in 1000ml of medium constituted by phosphate Buffer (pH 5.0) + 0.2 % SLS.

4. The pharmaceutical composition according to claim 1, comprising 5-15 % w/w Apremilast in an amorphous form, 0.5-5 % w/w ethyl cellulose and one or more pharmaceutically acceptable excipients(s).

5. The pharmaceutical composition according to claim 1, comprising Apremilast in an amorphous form, ethyl cellulose and one or more pharmaceutically acceptable excipients(s) selected from diluent, disintegrant and/or lubricant.

6. A process for preparation of pharmaceutical composition comprising:
a) Mixing and blending Apremilast in an amorphous form with one or more pharmaceutically acceptable excipients;
b) Preparing a solution by dissolving ethyl cellulose in a suitable solvent;
c) Granulating the dry mix prepared in step a) using solution prepared in step b);
d) Optionally mixing the granules prepared in step c) with one or more pharmaceutically acceptable excipients;
e) Preparing pharmaceutical composition from granules prepared in step c) or step d) in the form of tablet or capsule; and
f) Optionally coating the tablets prepared in step e).

7. A pharmaceutical composition comprising Apremilast in an amorphous form, ethyl cellulose and one or more pharmaceutically acceptable excipients(s) as described with reference to the examples provided in the specification.
, Description:FIELD OF INVENTION
Present invention relates to a pharmaceutical composition comprising Apremilast in an amorphous form, ethyl cellulose and one or more pharmaceutically acceptable excipient(s). Invention also relates to process for preparation of said pharmaceutical composition and its use in the treatment of severe plaque psoriasis and psoriatic arthritis.

BACKGROUND OF INVENTION:
Apremilast which is chemically known as N-{2-[(1S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl} acetamide is shown as Formula-I given below.

Formula-I

Apremilast is a selective inhibitor of enzyme Phosphodiesterase (PDE-4) specific for cyclic adenosine monophosphate (cAMP) and indicated for treatment of adults with active psoriatic arthritis and for the treatment of moderate to severe plaque psoriasis.

US7427638 discloses phenethylsulfones as PDE IV inhibitors including Apremilast.

Apremilast is known to exist in various polymorphic forms having different physicochemical properties viz. Form A, B, C, D, E, F, G and amorphous form, as reported in WO 2009120167. The marketed formulation of Apremilast (Otezla®) comprises form B of Apremilast.

It was observed that Amorphous form of Apremilast has more solubility as compared to other known crystalline polymorphs of Apremilast, particularly form B, which may result into faster dissolution of drug. Several prior arts also ascertain the fact, for example, US2015306226, CN104523574, US9351957, WO2015173792 and WO2016135755 disclose Amorphous Apremilast and/or composition of Apremilast in an amorphous form providing faster dissolution and thereby enhanced bioavailability.

Hence, it is challenging to develop pharmaceutical formulations comprising amorphous form of Apremilast having desired dissolution profile and release rate which is comparable and bioequivalent to the marketed formulation Otezla®.

Present application provides a composition comprising amorphous form of Apremilast, wherein dissolution profile of the composition is similar to Otezla®.

SUMMARY OF THE INVENTION
One aspect of the present invention is to provide a pharmaceutical composition comprising Apremilast in an amorphous form, ethyl cellulose and one or more pharmaceutically acceptable excipients(s).

Another aspect of the present invention is to provide a pharmaceutical composition comprising Apremilast in an amorphous form, ethyl cellulose and one or more pharmaceutically acceptable excipients(s), wherein said composition provides dissolution of not more than 85% in 30 minutes as measured using Apparatus-IV (Flow through cell- Turbulent flow) with flow rate of 12 ml /min in 1000ml of medium constituted by phosphate Buffer (pH 5.0) + 0.2 % SLS.

Another aspect of present invention is to provide process of preparation of a pharmaceutical composition comprising Apremilast in an amorphous form, ethyl cellulose and one or more pharmaceutically acceptable excipients(s).

DETAILED DESCRIPTION OF THE INVENTION
The following paragraphs detail various embodiments of the invention. For the avoidance of doubt, it is specifically intended that any particular feature(s) described individually in any one of these paragraphs (or part thereof) may be combined with one or more other features described in one or more of the remaining paragraphs (or part thereof). In other words, it is explicitly intended that the features described below individually in each paragraph (or part thereof) represent important aspects of the invention that may be taken in isolation and combined with other important aspects of the invention described elsewhere within this specification as a whole, and including the examples and figures. The skilled person will appreciate that the invention extends to such combinations of features and that these have not been recited in detail here in the interests of brevity.

The use of the terms “a” and "an” and "the” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have” and "include" and variations such as "comprises", "comprising", “having”, "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.

The term “adding” “added” “mixing” “mixed” “blended” and “blending” as used herein are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply mixing, adding or blending one or more excipient(s) with each other or with granules to form mixture or blend.

The term “Apremilast” as used herein means Apremilast, its isomers and enantiomers and its pharmaceutically acceptable salts. Preferably, Apremilast is in an amorphous form.

The term “Amorphous Apremilast” or “Apremilast in an amorphous form” refers to a solid form of Apremilast that lacks the long-range order characteristic of a crystal, containing less than 20%, less than 10%, less than 5%, less than 1%, less than 0.5% or less than 0.1% of the one or more crystalline forms of Apremilast, based on the total volume or weight of the amorphous Apremilast and the one or more other crystalline forms of Apremilast.

The term “w/w” as used herein means weight of component by total weight of composition, unless specified otherwise.

One embodiment of present invention is to provide a pharmaceutical composition comprising Apremilast in an amorphous form, ethyl cellulose and one or more pharmaceutically acceptable excipients(s).

It was observed that Amorphous form of Apremilast is highly soluble and composition prepared using amorphous Apremilast exhibits very fast dissolution. Surprisingly, it was observed that composition prepared according to present invention solves above problem by providing dissolution profile which is equivalent to marketed formulation of Apremilast Otezla®.

Another embodiment of the present invention is to provide a pharmaceutical composition comprising Apremilast in an amorphous form, ethyl cellulose and one or more pharmaceutically acceptable excipients(s), wherein said composition provides dissolution of not more than 85% in 30 minutes as measured using Apparatus-IV (Flow through cell- Turbulent flow) with flow rate of 12 ml /min in 1000ml of medium constituted by phosphate Buffer (pH 5.0) + 0.2 % SLS.

In a preferred embodiment, the present invention provides a pharmaceutical composition comprising Apremilast in an amorphous form, ethyl cellulose and one or more pharmaceutically acceptable excipients(s), wherein said composition provides dissolution of not more than 55% in 10 minutes, not more than 65% in 15 minutes, not more than 75% in 20 minutes and not more than 85% in 30 minutes, as measured using Apparatus-IV (Flow through cell- Turbulent flow) with flow rate of 12 ml /min in 1000ml of medium constituted by phosphate Buffer (pH 5.0) + 0.2 % SLS.

Another embodiment of present invention provides a pharmaceutical composition comprising Apremilast in an amorphous form, ethyl cellulose, one or more diluent(s), one or more disintegrant, and/or one or more lubricant.

A preferred embodiment of present invention provides a pharmaceutical composition comprising 5-15 % w/w Apremilast in an amorphous form, 0.5-5 % w/w ethyl cellulose, 50-90 % w/w diluent(s), 0.2-10 % w/w disintegrant(s), and/or 0.1-2 % w/w lubricant(s).

Structure of ethyl cellulose or cellulose ethyl ether is known from Handbook of pharmaceutical excipients (sixth edition, 2009), which is partially ethoxylated and can have suitable degree of substitution. Suitable ethyl cellulose preferably has a viscosity between 5 and 300 cP at a concentration of 5 % in toluene/ethanol 80:20, more preferably between 100 and 300 cP at these conditions.

Another embodiment of present invention provides a pharmaceutical composition comprising Apremilast in an amorphous form, ethyl cellulose, Lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and/or magnesium stearate.

Another embodiment of present invention provides a pharmaceutical composition comprising 5-15 % w/w Apremilast in an amorphous form, 0.5-5 % w/w ethyl cellulose, 50-90 % w/w Lactose monohydrate, 2-20 % w/w microcrystalline cellulose, 1-5 % w/w croscarmellose sodium, and/or 0.1-2 % w/w magnesium stearate.

A preferred embodiment of present invention provides a pharmaceutical composition comprising about 10 % w/w Apremilast in an amorphous form, about 3 % w/w ethyl cellulose, about 78 % w/w Lactose monohydrate, about 4 % w/w microcrystalline cellulose, about 3 % w/w croscarmellose sodium, and/or about 1 % w/w magnesium stearate.

The pharmaceutical composition may be prepared by any of the conventional methods known in the art such as Dry granulation, Wet granulation or Direct compression. Preferably, wet granulation method has been used to prepare the composition of present invention.

Another embodiment of the present invention is to provide a process for preparation of pharmaceutical composition, comprising:
a) Mixing and blending Apremilast in an amorphous form with one or more pharmaceutically acceptable excipients;
b) Preparing a solution by dissolving ethyl cellulose in a suitable solvent;
c) Granulating the dry mix prepared in step a) using solution prepared in step b);
d) Optionally mixing the granules prepared in step c) with one or more pharmaceutically acceptable excipients;
e) Preparing pharmaceutical composition from granules prepared in step c) or step d) in the form of tablet or capsule; and
f) Optionally coating the tablets prepared in step e).

Another aspect of the present invention is to provide a process for preparation of pharmaceutical composition, comprising:
a) Mixing and blending Apremilast in an amorphous form with lactose monohydrate, microcrystalline cellulose and croscarmellose sodium;
b) Preparing a solution by dissolving ethyl cellulose in isopropyl alcohol;
c) Granulating the dry mix prepared in step a) using solution prepared in step b);
d) Mixing the granules prepared in step c) with lactose monohydrate and magnesium stearate;
e) Preparing pharmaceutical composition from granules prepared in step d) in the form of tablet; and
f) Coating the tablets prepared in step e).

Pharmaceutical excipient according to present invention comprises diluent, binder, disintegrant, lubricant, glidant and the like.

Compositions according to present invention may optionally further comprise one or more stabilizer, anti oxidant, coloring agent and the like. Example and suitable amount of said optional excipient is known to a skilled person or as given in Handbook of pharmaceutical excipients (sixth edition, 2009).

Diluent according to present invention includes but not limited to powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, Pregelatinised starch, dibasic calcium phosphate, tribasic calcium phosphate, dibasic sodium phosphate, tribasic sodium phosphate, calcium carbonate, magnesium carbonate, calcium bicarbonate, magnesium bicarbonate magnesium oxide, calcium sulfate; sugars such as dextrose, lactose (monohydrate or anhydrous), fructose or sucrose, maltose maltodextrin; sugar alcohols such as mannitol, sorbitol, xylitol, lactitol, maltitol or erythritol; dextrin, kaolin and mixtures thereof. Preferably, lactose anhydrous and microcrystalline cellulose are used. The diluents(s) may be present in an amount ranging from 50 % to 90 % by weight of the composition. Preferably, the diluents are present in an amount ranging from 75-85 % w/w of the total weight of the composition.

Disintegrant according to present invention includes but not limited to carboxymethyl cellulose and its salt including sodium or calcium salt, cross-linked carboxymethyl cellulose (croscarmellose) sodium, cross-linked carboxymethyl cellulose calcium, cross-linked polyvinylpyrrolidone (crospovidone), microcrystalline or microfine or powdered cellulose, silicified microcrystalline cellulose, sodium alginate; starch derivatives such as maize starch, rice starch, pregelatinized starch; cross-linked N-vinyl-2-pyrrolidone ("CLPVP") (marketed under the trade names Polyplasdone® XL and Polyplasdone® XL-10), sodium starch glycollate, low substituted hydroxypropyl cellulose and mixtures thereof. Preferably, cross-linked carboxymethyl cellulose (croscarmellose) sodium is used. Pharmaceutical composition comprises disintegrant in the amount of 0.2 % to 10 % by weight of the total composition. Preferably, the disintegrants are present in an amount ranging from 1-5 % w/w of the total weight of the composition.

Binder according to present invention include polyvinyl alcohol, polyvinyl acetate, starch, pregelatinised starch; cellulose derivatives such as cellulose powder, microcrystalline cellulose, hydroxypropyl methylcellulose, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium; carbomers, dextrin, gelatin, zein, shellac, polymethacrylates, povidone, copovidone, sodium alginate, alginic acid; gums such as xanthan gum, guar gum, locust bean gum, carrageenan, acacia, tragacanth, synthetic resins or mixtures thereof. The binder may be present in an amount ranging from 0.1 % to 20 % by weight of the composition.

Granulating solvent may be selected from water, isopropyl alcohol, ethanol, methanol, acetone, methylene chloride or mixtures thereof. Preferably, isopropyl alcohol is used. Granulating solution according to the present invention is a mixture of ethyl cellulose in the granulating solvent. Preferably, ethyl cellulose is dissolved in isopropyl alcohol to form a granulating solution.

Lubricant according to present invention includes but not limited to metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, sodium stearyl fumerate hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc and mixture thereof. Preferably, magnesium stearate is used. The lubricant may be present in an amount ranging from about 0.2 % to about 10 % by weight of the composition. Preferably, it is present in an amount of 1 % by weight of the composition.

Glidant according to present invention includes but not limited to talc, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, tribasic calcium phosphate or mixture thereof. Preferably, colloidal silicon dioxide is used. The glidant may be present in an amount ranging from about 0.2 % to about 10 % by weight of the composition.

Coating agent according to the present invention includes cellulose derivatives such as hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, ethyl cellulose, methyl cellulose; polyvinyl compounds such as polyvinyl alcohol, polyvinyl pyrrolidone (povidone), polyvinyl acetal diethylaminoacetate, polyvinyl acetate; acrylate derivatives such as aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer; saccharides such as sucrose, Mannitol and the mixture thereof. Preferably, hydroxypropyl methylcellulose (hypromellose) based coating is used.

The coating material may further include plasticizers such as polyethylene glycols, propylene glycol, dibutyl phthalate, dibutyl sebacate, glycerin fatty acid esters, sucrose fatty acid esters, castor oil, triethyl citrate, triacetin; a lubricant/glidant such as stearic acid, magnesium or calcium stearate, talc; coloring agent such as iron (II) oxide, iron (III) oxide or titanium oxide.

Another embodiment of present invention provides use of the prepared pharmaceutical composition according to present invention for treatment of severe plaque psoriasis and psoriatic arthritis.

The invention will be further illustrated by the following examples, however, without restricting its scope to these embodiments.

Example 1

Sr. No. Ingredients % w/w

Core tablet
1. Apremilast 10
2. Lactose monohydrate 71.66
3. Microcrystalline cellulose 4.66
4. Croscarmellose sodium 3
5. Ethyl cellulose 3
6. Isopropyl alcohol q.s
Extragranular material
7. Lactose monohydrate 6.66
8. Magnesium stearate 1
Total 100
Coating
9. Opadry (HPMC based) 4 % of total weight of core tablet

Apremilast, Lactose monohydrate, Microcrystalline cellulose and Croscarmellose sodium were sifted through a 40# sieve and mixed in high shear mixer for sufficient time. The mixture of excipients was granulated in Rapid Mixer Granulating bowl using granulating solution containing ethyl cellulose in isopropyl alcohol to obtain granules. The granules were then dried in rapid dryer and sized. The granules were blended with extragranular material Lactose monohydrate and Magnesium stearate for sufficient time to obtain the blended material. The final blend material was compressed using rotary machine to obtain tablets. The tablets prepared were further film coated with OPADRY® (HPMC based) coating material containing HPMC, Polyethylene glycol, Hydroxypropyl cellulose, titanium dioxide, red iron oxide, black iron oxide and yellow iron oxide to obtain film coated tablets.

In vitro dissolution profile of formulation prepared according to Example 1 and marketed formulation Otezla® was measured using Apparatus-IV (Flow through cell- Turbulent flow) with flow rate of 12 ml /min in 1000ml of medium constituted by phosphate Buffer (pH 5.0) + 0.2 % SLS The results of dissolution profile of Apremilast for marketed formulation and formulation according to Example 1 is as shown in the Table 1.
It was observed that dissolution profile of formulation prepared according to Example 1 was similar to that of marketed formulation.
Hence, it was observed that composition comprising Apremilast in an amorphous form and ethyl cellulose yields desired dissolution profile comparable to the marketed formulation.

Table 1. Dissolution profile
Sr. No. Time (Mins) % Drug release
Marketed formulation: (SPGF-4) Formulation prepared according to Example 1
1 10 49.7 46.2
2 15 62.5 60.3
3 20 70.8 69.7
4 30 77.7 80.7
5 45 82.3 88.9