DESC:INTRODUCTION
The present invention relates to a pharmaceutical composition of apremilast, comprising apremilast and one or more pharmaceutically acceptable excipients and process of preparation thereof.
BACKGROUND OF THE INVENTION
Apremilast is a phosphodiesterase 4 (PDE4) inhibitor. Apremilast is known chemically as N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide.
Class of compounds covering apremilast and use thereof has been disclosed in US Patent No. 6,020,358. Further, US Patent No 7,427,638 discloses a pharmaceutical composition comprising stereomerically pure apremilast, or a pharmaceutically acceptable salt, solvate or hydrate, thereof; and a pharmaceutically acceptable carrier, excipient or diluent.
US Patent No 9,468,605 discloses an immediate-release oral dosage form comprising apremilast, and pharmaceutically acceptable excipients such as lactose, carboxymethyl cellulose, fumed silica, and magnesium stearate.
In spite of the work done in the art, there remains a need of an alternative pharmaceutical composition of apremilast.

SUMMARY OF THE INVENTION
A first aspect of the present invention relates to a pharmaceutical composition of apremilast comprising apremilast and one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION OF THE INVENTION
A first aspect of the present invention relates to a pharmaceutical composition of apremilast comprising apremilast and one or more pharmaceutically acceptable excipients.
According to a first embodiment of above aspect, the apremilast is present in an amount of from 8 % by weight to 15% by weight of the unit composition weight.
According to a second embodiment of above aspect, the composition comprises apremilast having a particle size distribution D50 value of about 3 µm to about 30 µm, D90 value of about 10 µm to about 60 µm.
According to a third embodiment of above aspect, the composition comprises apremilast having a particle size distribution D50 value of about 5 µm to about 17 µm, D90 value of about 20 µm to about 40 µm.
According to a fourth embodiment of above aspect, the apremilast is either in amorphous form or in crystalline form.
According to a fifth embodiment of above aspect, the pharmaceutically acceptable excipients are selected from diluent, release modifier, binder, disintegrant, film forming polymer, glidant and lubricant.
According to a sixth embodiment of above aspect, the pharmaceutical composition of apremilast comprising apremilast in an amount of from 8 % by weight to 15% by weight, diluent in an amount of from 55 % by weight to 90 % by weight, a release modifier in an amount of from 1 % by weight to 20 % by weight, binder in an amount of from 1 % by weight to 10 % by weight, and disintegrant in an amount of from 1 % by weight to 10 % by weight of the unit composition weight.
According to a seventh embodiment of above aspect, the pharmaceutical composition is prepared by a process selected from direct compression, dry granulation, and wet granulation.
The term “pharmaceutical composition,” as used herein may include solid dosage forms suitable for oral administration such as tablets, capsules, pills, caplets and the like. In particular the pharmaceutical composition is a tablet. Tablet may be an immediate release tablet, a delayed release tablet, a modified release tablet, a chewable tablet, a confectionary tablet, an oral disintegrating tablet. Core of the may be coated with film coating or sugar coating with the aim of, for example, preventing abrasion wear, masking bitterness, improving stability, and the like.
The term “apremilast” as used herein may include apremilast free base or pharmaceutically acceptable salt, stereoisomer, prodrug, solvate, hydrate, clathrate, thereof. The pharmaceutically acceptable salts may include salts of apremilast base formed with organic acids or inorganic acids.
Suitable organic acids include maleic, fumaric, ascorbic, benzoic, succinic, acetic, formic, oxalic, propionic, tartaric, salicylic, methanesulfonic acids and the like. Suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric nitric acid and the like.
The apremilast may be either in amorphous form or in crystalline form. The crystalline form of apremilast is polymorphic form B.
The term “particle size distribution” as used herein is defined by D50 value and D90 value.
D50 value, also known as median particle size, is defined as the particle diameter at which 50% of the particles have a diameter less than the diameter which corresponds to that D50 value. The D50 value of apremilast particles in the present invention may be from about 3 µm to about 30 µm. Further, the D50 value of apremilast particles may be from about 5 µm to about 17 µm.
D90 value is defined as the particle diameter at which 90% of the particles have a diameter less than the diameter which corresponds to that D90 value. The D90 value of apremilast particles in the present invention may be from about 10 µm to about 60 µm. Further, the D90 value of apremilast particles may be from about 20 µm to about 40 µm.
The term “amorphous” as used herein relates to a substance, component or product lacking long range crystalline order.
The term “polymorphic form” as used herein relates to two or more crystal forms that consist essentially the same molecule, molecules, and/or ions. Different polymorphs may have different physical properties such as melting temperature, heat of fusion, solubility, dissolution properties and the like.
The term “pharmaceutically acceptable excipients” as used herein relates to any physiologically inert additives that are routinely used in pharmaceutical dosage forms. Pharmaceutically acceptable excipients are selected from the group comprising diluent, release modifier, binder, disintegrant, glidant and lubricant.
Suitable diluents are selected from the group comprising microcrystalline cellulose, e.g., microcrystalline cellulose PH 112, microcrystalline cellulose PH 101, and microcrystalline cellulose PH 102; lactose e.g., lactose monohydrate, directly compressible lactose, lactose anhydrous, and spray dried lactose; Sugars e.g., dextrose, sucrose, emdex, maltodextrin, maltose, and isomaltose; invert sugar e.g., levulose (fructose); Sugar alcohols e.g., xylitol, sorbitol, erythritol, mannitol, maltitol, and Isomalt starch, e.g., pregelatinized starch; Polyethylene Glycol; dicalcium phosphate; calcium sulfate; calcium carbonate and combinations thereof. In particular the diluents are lactose monohydrate, directly compressible lactose, microcrystalline cellulose, and combinations thereof. The diluents may be present in amount of 55 % by weight to 90 % by weight of the core weight.
Suitable release modifiers are selected from the group comprising hydrogenated castor oil, glyceryl behenate, ethylcellulose, cetyl alcohol, povidone and combinations thereof. The release modifiers may be present in an amount of 1 % by weight to 20 % by weight of the core weight.
Suitable binders are selected from the group comprising povidone; copovidone; acacia; tragacanth; xanthan gum; sodium alginate; corn syrup; sugar syrup; gelatin; polyvinylpyrrolidone; celluloses, e.g., hydroxypropyl methylcellulose, hydroxy ethylcellulose, hydroxypropyl cellulose, methylcellulose, and ethylcellulose; starch, e.g., pregelatinized starch and low density starch; microcrystalline cellulose; propylene glycol; polyvinyl alcohol; methacrylates; carboxyvinyl polymers, e.g., carbomers and combinations thereof. Binders may be present in an amount of 1 % by weight to 10 % by weight of the core weight.
Suitable disintegrants are selected from the group comprising croscarmellose sodium, sodium starch glycolate, hydroxypropyl cellulose, crospovidone, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, gums, alginic acid or alginates, pregelatinized starch, corn starch, modified starch, carboxymethyl starch, polyacrylates, and combinations thereof. Disintegrants may be present in an amount of 1 % by weight to 10 % by weight of the core weight.
Suitable glidants are selected from the group comprising talc, magnesium stearate, stearic acid, calcium stearate, colloidal silicon dioxide, starch, and combinations thereof.
Suitable lubricants are selected from the group comprising magnesium stearate, talc, and silica.
The core of the tablet may be coated with film coating using suitable film forming polymers.
Suitable film forming polymers are selected from the group comprising cellulose ethers e.g., methylcellulose, Hydroxyethyl cellulose, hydroxypropyl cellulose; acrylic polymers and copolymers; polyethylene glycols; polyvinyl pyrrolidone; polyvinyl alcohol; and OPADRY,
The term “direct compression” as used herein relates to a process generally described in the art, by which powder blends of the active ingredient and suitable excipients are compressed directly in a die cavity and form into a firm compact.
The term “dry granulation” as used herein relates to a process generally described in the art, which involves the step of compressing premixed powders and reducing the compressed material to the proper size for tablet granulation purposes. Examples of dry granulations include but not limited to compaction granulation and slugging. In slugging slugs or large tablets are compressed and are subsequently grounded to the desired granulation characteristics. The dry granulation may be carried out twin screw granulator.
The term “wet granulation” as used herein relates to a process generally described in the art, in which a liquid is added to the powder in a vessel equipped with any type of agitation that will produce agglomeration or granules. The liquid may be aqueous liquid or non-aqueous liquid. The wet granulation may be carried out in granulation instruments e.g., fluid bed granulator, rapid mixer granulator, and the like.

HYPOTHETICAL EXAMPLES
Example I: Direct Compression
Unit Composition 1
Ingredients Quantity (mg/Tab)
Apremilast 30.000
Microcrystalline Cellulose 117.500
Lactose Monohydrate 136.000
Croscarmellose Sodium 15.000
Magnesium Stearate 1.500
Core Tablet Weight 300.000
Opadry II White 9.000
Purified water Q.S.
Coated Tablet Weight 309.000

Unit Compositions 2 and 3
Ingredients Quantity (mg/Tab)
Composition 2 Composition 3
Apremilast 30.000 30.000
Microcrystalline Cellulose 117.500 117.500
Lactose Monohydrate 131.000-111.000 131.000-111.000
Croscarmellose Sodium 20.000-40.00 mg 0.00
Sodium starch glycolate 0.00 20.000-40.00
Magnesium Stearate 1.500 1.500
Core Tablet Weight 300.000 300.000
Opadry II White 9.000 9.000
Purified water Q.S. Q.S.
Coated Tablet Weight 309.000 309.000

Unit Compositions 4 to 9
Ingredients Quantity (mg/Tab)
Composition 4 Composition 5 Composition 6 Composition 7 Composition 8 Composition 9
Apremilast 30.00 30.00 30.00 30.00 30.00 30.00
Lactose Monohydrate 136.00 -- 136.00 -- 136.00
Hypromellose 6.00 18.00 -- -- -- --
Hydroxy Propyl Cellulose -- -- 6.00 18.00 -- --
Ethyl cellulose -- -- -- -- 6.00 18.00
Microcrystalline Cellulose 243.5 117.5 243.5 117.5 243.5 117.5
Croscarmellose Sodium 15.00 15.00 15.00 15.00 15.00 15.00
Magnesium Stearate 1.50 1.50 1.50 1.50 1.50 1.50
Core Tablet Weight 296.00 318.00 296.00 318.00 296.00 318.00

Example II: Compaction granulation using twin screw granulator
Unit Compositions 10 to 13
Ingredients Quantity (mg/Tab)
Composition 10 Composition 11 Composition 12 Composition 13
Apremilast 30.00 30.00 30.00 30.00
Stearic Acid 15.00 40.00 -- --
Hydrogenated castor oil -- -- 15.00 40.00
Microcrystalline cellulose 207.50 207.50 207.50 207.50
Croscarmellose sodium 10.00 10.00 10.00 10.00
Magnesium Stearate 1.50 1.50 1.50 1.50
Tablet weight 264.00 279.00 264.00 289.00

Example III: Wet granulation with top spray
Unit Compositions 14 to 17
Ingredients Quantity (mg/Tab)
Composition 14 Composition 15 Composition 16 Composition 17
Apremilast 30.00 30.00 30.00 30.00
Microcrystalline cellulose 170.00 170.00 170.00 170.00
Stearic Acid 15.00 40.00 -- --
Hydrogenated castor oil -- -- 15.00 40.00
Acetone QS QS QS QS
Microcrystalline cellulose 44.5 44.5 63.50 63.50
Croscarmellose sodium 10.00 10.00 15.00 15.00
Magnesium Stearate 1.50 1.50 1.50 1.50
Tablet weight 276.00 301.00 300.00 325.00

Unit Composition 18
Ingredients Qty (mg/Tab)
Apremilast 30.000
Microcrystalline Cellulose 117.500
Lactose Monohydrate 120.000
Croscarmellose Sodium 15.000
Hypromellose/ PVP/ Hydroxypropyl cellulose 16.00
Purified water Q.S.
Magnesium Stearate 1.500
Core Tablet Weight 300.000
Opadry II White 9.000
Purified water Q.S.
Coated Tablet Weight 309.000
,CLAIMS:We Claim:
Claim 1: A pharmaceutical composition of apremilast comprising apremilast and one or more pharmaceutically acceptable excipients.

Claim 2: The pharmaceutical composition according to claim 1, wherein the apremilast is present in an amount of from 8 % by weight to 15% by weight of the unit composition weight.

Claim 3: The pharmaceutical composition according to claim 1, wherein the composition comprises apremilast having a particle size distribution D50 value of about 3 µm to about 30 µm, D90 value of about 10 µm to about 60 µm.

Claim 4: The pharmaceutical composition according to claim 1, wherein the composition comprises apremilast having a particle size distribution D50 value of about 5 µm to about 17 µm, D90 value of about 20 µm to about 40 µm.

Claim 5: The pharmaceutical composition according to claim 1, wherein the apremilast is either in amorphous form or in crystalline form.

Claim 6: The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipients are selected from diluent, release modifier, binder, disintegrant, film forming polymer, glidant and lubricant.

Claim 7: The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition of apremilast comprising apremilast in an amount of from 8 % by weight to 15% by weight, diluent in an amount of from 55 % by weight to 90 % by weight, a release modifier in an amount of from 1 % by weight to 20 % by weight, binder in an amount of from 1 % by weight to 10 % by weight, and disintegrant in an amount of from 1 % by weight to 10 % by weight of the unit composition weight.

Claim 8: The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is prepared by a process selected from direct compression, dry granulation, and wet granulation.