DESC:The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION
The present invention relates to a pharmaceutical composition of eliglustat and one or more pharmaceutically acceptable excipients and process of preparation thereof.
BACKGROUND OF INVENTION
Eliglustat hemitartrate (GENXZ-112638) is a specific inhibitor of glucosylceramide synthase and is marketed in United States under the trade name CERDELGA by Genzyme for treatment of gaucher’s disease. The approved product is a hard gelatin capsule having a strength of 84mg. Chemically CERDELGA is named as N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)octanamide (2R,3R)-2,3-dihydroxysuccinate and has the structural formula as shown in Formula 1.

Formula 1
In Gaucher’s disease, there is diminished activity of the lysosomal enzyme called acid ß-glucosidase which leads to accumulation of glucosylceramides and related substrates, primarily in the spleen, liver, and bone marrow. Eliglustat is a selective, potent inhibitor of glucosylceramide synthase, the enzyme responsible for biosynthesis of glucosylceramides which accumulate in Gaucher’s disease.
WO2003/008399 discloses synthesis of amino ceramide-like compounds. It also discloses a process for the preparation of eliglustat or a pharmaceutically acceptable salt thereof.
WO2011/066352 discloses hemitartrate salt of eliglustat as inhibitor of glucosylceramide synthase for treatment of gaucher’s disease.
There remains a need of pharmaceutical composition of eliglustat which provides uniform drug release from the dosage form.
SUMMARY OF INVENTION
The present specification relates to a composition of eliglustat with pharmaceutically acceptable excipients.
In one aspect, the present invention relates to a pharmaceutical composition comprising:
(i) eliglustat,
(ii) binder; and
wherein the ratio of eliglustat to binder is in the range from 1:0.25 to 1:3 respectively.

In another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) eliglustat,
(ii) cellulose binder; and
wherein the ratio of eliglustat to cellulose binder is in the range from 1:0.25 to 1:3 respectively.

In another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) eliglustat,
(ii) hydroxypropyl methyl cellulose; and
wherein the ratio of eliglustat to hydroxypropyl methyl cellulose is 1:0.25 to 1:3 respectively.

In yet another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) eliglustat,
(ii) hydroxypropyl methyl cellulose; and
wherein the ratio of eliglustat to hydroxypropyl methyl cellulose is 1:1 respectively.

In one aspect, the present invention relates to a pharmaceutical composition comprising:
(i) eliglustat,
(ii) hydroxypropyl methyl cellulose; and
(iii) pharmaceutically acceptable excipients.

In another aspect, the pharmaceutical composition is prepared by a conventional process selected from direct compression, dry granulation, wet granulation and fluidized bed process.

In yet another aspect, the process for preparing the pharmaceutical composition of the present invention comprises the steps of:
(i) preparing the drug solution with binder,
(ii) spraying the drug solution on the sugar spheres; and
(iii) drying, lubricating and filling the drug loaded sugar spheres in capsule.

DESCRIPTION OF INVENTION
In one aspect, the present invention relates to a pharmaceutical composition comprising:
(i) eliglustat,
(ii) binder; and
wherein the ratio of eliglustat to binder is in the range from 1:0.25 to 1:3 respectively.

In another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) eliglustat,
(ii) cellulose binder; and
wherein the ratio of eliglustat to cellulose binder is in the range from 1:0.25 to 1:3 respectively.

In another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) eliglustat,
(ii) hydroxypropyl methyl cellulose; and
wherein the ratio of eliglustat to hydroxypropyl methyl cellulose is 1:0.25 to 1:3 respectively.

In yet another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) eliglustat,
(ii) hydroxypropyl methyl cellulose; and
wherein the ratio of eliglustat to hydroxypropyl methyl cellulose is 1:1 respectively.

In one aspect, the present invention relates to a pharmaceutical composition comprising:
(i) eliglustat,
(ii) hydroxypropyl methyl cellulose; and
(iii) pharmaceutically acceptable excipients.

In another aspect, the pharmaceutical composition is prepared by a conventional process selected from direct compression, dry granulation, wet granulation and fluidized bed process.

In yet another aspect, the process for preparing the pharmaceutical composition of the present invention comprises the steps of:
(i) preparing the drug solution with binder,
(ii) spraying the drug solution on the sugar spheres; and
(iii) drying, lubricating and filling the drug loaded sugar spheres in capsule.

The term “pharmaceutical composition,” as used herein may include solid dosage forms suitable for oral administration such as tablets, capsules, pills, granules, caplets and the like. In particular the pharmaceutical composition is a capsule.
The term “eliglustat” as used herein refers to eliglustat free base or pharmaceutically acceptable salt, stereoisomer, prodrug, solvate, clathrate, thereof.
Eliglustat may be either in amorphous form or in crystalline form.
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, binder, disintegrant, glidant and lubricant.
Eliglustat can be used directly in composition or can be processed to form a premix with carrier. Suitable carriers are selected from copovidone, hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl pyrrolidone, povidone and colloidal silicon dioxide.
The present invention may contain one or more diluents selected from, but are not limited to 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, dextrates hydrated, 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 microcrystalline cellulose, lactose, mannitol and combinations thereof.
The present invention may contain one or more binders selected from but are not limited to acacia; tragacanth; xanthan gum; sodium alginate; corn syrup; sugar syrup; gelatin; celluloses, e.g., hydroxypropyl methylcellulose, hydroxy ethylcellulose, hydroxypropyl cellulose, methylcellulose, and ethylcellulose; starch, e.g., pregelatinized starch and low density starch; microcrystalline cellulose; copovidone; povidone; propylene glycol; polyvinyl alcohol; methacrylates; carboxyvinyl polymers, e.g., carbomers and combinations thereof. In particular the binders are hydroxypropyl methylcellulose, hydroxy ethylcellulose, hydroxypropyl cellulose, copovidone, povidone and combinations thereof.
The present invention may contain one or more lubricants selected from, but are not limited to magnesium stearate; stearic acid; silica; talc; glyceryl behenate; sodium steryl fumarate and combinations thereof.

The specification will now be described in more detail by reference to the following non-limiting examples.
EXAMPLES
Example-1.
Name of the Ingredient mg/cap (mg)
Eliglustat 100
Sugar Spheres #30/35 150
HPMC 3 cps 100
Glyceryl behenate 2
Sub Coating
Opadry AMB _II Clear 10.5
Lubrication
Glyceryl Behenate 3.5
Total fill volume 366
Hard gelatin capsule size 1 70
Gross weight with capsule 436
Manufacturing Process
(i) Sifting: sugar spheres were passed through #30 Mesh (ASTM) and retrained through #35 Mesh, the obtained fraction were taken in the FBP.
(ii) Preparation of binder solution (20%w/w Aq. Solution): Added hypromellose to purified water until a clear binder solution was formed then eliglustat was added to solvent & stirred for 45 min to one hour to get clear solution, glyceryl behenate was dispersed in the binder solution until a homogenous mixture was obtained .
(iii) Bottom Spray: Fluidised the sugar spheres in the FBP and loaded the drug on to the pellets by spraying the binder solution.
(iv) Dispersion for seal coating: (7%w/w Aq. Dispersion): Dispersed Opadry AMB-II clear in the purified water until a homogenous dispersion was obtained.
(v) Seal Coating: Sprayed the dispersion obtained in step (iv) on to the drug loaded sugar spheres until they are 3.5%w/w seal coated.
(vi) Sifting of extra granular ingredients: Sifted glyceryl behenate through #80 (ASTM) mesh.
(vii) Lubrication: Lubricated the seal coated spheres with glyceryl behenate for 4 Min @ 20 rpm.
(viii) Capsule filling: The lubricated blend was filled in capsules of suitable size (Size 01) using suitable automatic capsule filling machine.
Example 2.
Name of the Ingredient mg/cap (mg) mg/cap (mg) mg/cap (mg)
Eliglustat 100 100 100
Sugar Spheres #30/35 135 135 135
HPMC 3 cps 100 100 100
Glyceryl behenate 2 2 2
Lubrication
Talc 3.37 - -
Glyceryl behenate - 3.37 -
Sodium steryl fumarate - - 3.37
Total fill volume 340.37 340.37 340.37
Hard gelatin capsule size 1 75 75 75
Gross weight with capsule 416.37 416.37 416.37
Manufacturing Process
(i) Sifting: Sugar spheres were passed through #30 Mesh and #35.
(ii) Drug solution preparation: Dissolved 100 gm of eliglustat in purified water and added HPMC 3 cps followed by glyceryl behenate and stirred for about 45 min and allowed to dissipate the foam.
(iii) Bottom spray: Loaded the sugar spheres in to the fluid bed processor and sprayed the drug solution on spheres with the following parameters: spray rate, atomization, fluidization, wruster height, product temperature, exhaust temperature.
(iv) Drying: Dried the spheres until the LOD was achieved below 1.5%w/w.
(v) Lubrication: Lubricated the spheres for 5 min at 20 rpm
(vi) Filling: Filled the spheres into size 1 capsules and packed.
Example 3.
Name of the Ingredient mg/cap (mg) mg/cap (mg)
Eliglustat 100 100
Sugar Spheres #30/35 183 145
HPMC 3 cps 50 80
Glyceryl behenate 2 2
Lubrication
Talc 3.0 3.00
Total fill volume 338 330
Hard gelatin capsule size 1 75 75
Gross weight with capsule 413 405
Manufacturing Process
(i) Sifting: Sugar spheres were passed through #30 Mesh and #35.
(ii) Drug solution preparation: Dissolved 100 gm of eliglustat in purified water and added HPMC 3 cps followed by glyceryl behenate and stirred for about 45 min and allow to dissipate the foam.
(iii) Bottom spray: Loaded the sugar spheres in to the fluid bed processor and sprayed the drug solution on spheres with the following parameters: spray rate, atomization, fluidization, wruster height, product temperature, exhaust temperature.
(iv) Drying: Dried the spheres until the LOD was achieved below 1.5%w/w.
(v) Lubrication: Lubricated the spheres for 5 min at 20 rpm
(vi) Filling: Filled the spheres into size 1 capsules and packed.
Example 4.
Name of the Ingredient mg/cap (mg)
Eliglustat 100
Hypromellose ( methocel 3cps) 100
Microcrystalline cellulose (Avicel PH 112) 35
Lactose Anhydrous (Super tab 21 AN) 52.3
Purified Water q.s
Glyceryl Behenate (Compritol 888 ) 2.7
Total fill volume 290
Hard gelatin capsule 65
Gross weight with capsule 355
Manufacturing Process
(i) Sifting: Eliglustat was sifted through #30mesh. Lactose anhydrous & microcrystalline cellulose were sifted through #30mesh separately.
(ii) Preparation of binder solution: Slowly added hypromellose followed by eliglustat to solvent & stirred to get a clear solution.
(iii) Granulation & Drying: Sprayed the prepared binder solution on to bed of excipients (lactose anhydrous & microcrystalline cellulose) with optimal process parameters of spray rate, atomization pressure & CFM. Dried the wet mass using suitable temperature conditions.
(iv) Milling: Milled the dried granules using Quadro-co mill fitted with #50G screen.
(v) Sifting of extra granular ingredients: Glyceryl Behenate was sifted through #60 mesh.
(vi) Lubrication: Milled granules and sifted extra granular material were mixed in double cone blender for 4min at 20rpm.
(vii) Capsule filling: The lubricated blend to be filled in capsules of suitable size.

Example 5.
Name of the Ingredient mg/cap (mg)
Eliglustat 100
Copovidone (Kollidon VA 64) 100
Microcrystalline cellulose (Avicel PH 112) 35
Lactose Anhydrous (Super tab 21 AN) 52.3
Purified Water q.s
Glyceryl Behenate (Compritol 888 ) 2.7
Total fill volume 290
Hard gelatin capsule 65
Gross weight with capsule 355
Manufacturing process
(i) Sifting: Eliglustat was sifted through #30mesh.
Lactose anhydrous & microcrystalline cellulose were sifted through #30mesh separately.
(ii) Preparation of binder solution: Slowly added hypromellose followed by eliglustat to solvent & stirred to get a clear solution.
(iii) Granulation & Drying: Sprayed the prepared binder solution on to bed of excipients (lactose anhydrous & microcrystalline cellulose) with optimal process parameters of spray rate, atomization pressure & CFM. Dried the wet mass using suitable temperature conditions.
(iv) Milling: Milled the dried granules using Quadro-co mill fitted with #50G screen.
(v) Sifting of extra granular ingredients: Glyceryl behenate was sifted through #60 mesh.
(vi) Lubrication: Milled granules and sifted extra granular material were mixed in double cone blender for 4min at 20rpm.
(vii) Capsule filling: The lubricated blend to be filled in capsules of suitable size.
Example 6.
Name of the Ingredient mg/cap (mg)
Eliglustat Copovidone Premix 200
Microcrystalline cellulose (Avicel PH 112) 35
Lactose Anhydrous (Super tab 21 AN) 52.3
Extragranular
Glyceryl Behenate (Compritol 888 ) 2.7
Total fill volume 290
Hard gelatin capsule 65
Gross weight with capsule 355
Manufacturing Process
(i) Sifting: Eliglustat copovidone premix, lactose anhydrous & microcrystalline cellulose were sifted through #30mesh.
(ii) Premixing: Sifted ingredients were mixed in double cone blender for 10 min at 20 rpm.
(iii) Dry Granulation: Premix blend was added slowly in roller compactor to obtain milled granules with parameters like Roller gap; Roller pressure; Roller speed; Screw feeder.
(iv) Sifting of extra granular ingredients: Glyceryl behenate was sifted through #60 mesh.
(v) Lubrication: Milled granules and sifted extra granular material was mixed in double cone blender for 4min at 20rpm.
(vi) Capsule filling: Lubricated blend was filled in capsules of suitable size.
Example 7.
Name of the Ingredient mg/cap (mg)
Eliglustat Copovidone Premix 125
Microcrystalline cellulose (Avicel PH 112) 70
Lactose Anhydrous (Super tab 21 AN) 56
Extragranular
Lactose monohydrate 36
Glyceryl Behenate (Compritol 888 ) 2.7
Total fill volume 290
Hard gelatin capsule 65
Gross weight with capsule 355
Manufacturing Process
(i) Sifting: Eliglustat copovidone premix, lactose anhydrous & microcrystalline cellulose were sifted through #30mesh.
(ii) Premixing: Sifted ingredients were mixed in double cone blender for 10min at 20rpm.
(iii) Dry Granulation: Premix blend was added slowly in roller compactor to get final milled granules with parameters like Roller gap; Roller pressure; Roller speed; Screw feeder.
(iv) Sifting of extra granular ingredients: Glyceryl Behenate was sifted through #60 mesh.
(v) Mixing: Lactose monohydrate was added to the above milled granules and blend for 5 min at 20 rpm.
(vi) Lubrication: The blend of step (v) and the sifted extra granular material obtained in step (iv) were mixed in double cone blender for 4min at 20rpm.
(vii) Capsule filling: The lubricated blend was filled in capsules of suitable size.

Example 8.
Name of the Ingredient mg/cap (mg)
Eliglustat HPMC Premix 200
Microcrystalline cellulose (Avicel PH 112) 35
Lactose Anhydrous (Super tab 21 AN) 52.3
Extragranular
Glyceryl Behenate (Compritol 888 ) 2.7
Total fill volume 290
Hard gelatin capsule 65
Gross weight with capsule 355
Manufacturing Process
(i) Sifting: Eliglustat HPMC premix, lactose anhydrous & microcrystalline cellulose were sifted through #30mesh.
(ii) Premixing: Sifted ingredients were mixed in double cone blender for 10min at 20rpm.
(iii) Dry Granulation: Premix blend was added slowly in roller compactor to get final milled granules with parameters like Roller gap; Roller pressure; Roller speed; Screw feeder.
(iv) Sifting of extra granular ingredients: Glyceryl behenate was sifted through #60 mesh.
(v) Lubrication: Milled granules and sifted extra granular material were mixed in double cone blender for 4min at 20rpm.
(vi) Capsule filling: The lubricated blend was filled in capsules of suitable size.
Example 9.
Name of the Ingredient mg/cap (mg)
Eliglustat HPMC Premix 125
Microcrystalline cellulose (Avicel PH 112) 70
Lactose Anhydrous (Super tab 21 AN) 56
Extragranular
Lactose monohydrate 36
Glyceryl Behenate (Compritol 888 ) 2.7
Total fill volume 290
Hard gelatin capsule 65
Gross weight with capsule 355
Manufacturing Process
(i) Sifting: Eliglustat HPMC Premix, lactose anhydrous & microcrystalline cellulose were sifted through #30mesh.
(ii) Premixing: Sifted ingredients were mixed in double cone blender for 10min at 20 rpm.
(iii) Dry Granulation: Premix blend was added slowly in roller compactor to get final milled granules with parameters like Roller gap; Roller pressure; Roller speed; Screw feeder.
(iv) Sifting of extra granular ingredients: Glyceryl Behenate was sifted through #60 mesh.
(v) Mixing: Lactose monohydrate was added to the above milled granules and blend for 5 min at 20 rpm.
(vi) Lubrication: The above blend and the sifted extra granular material were mixed in double cone blender for 4min at 20rpm.
(vii) Capsule filling: The lubricated blend was filled in capsules of suitable size.
,CLAIMS:We Claim:
Claim 1: A pharmaceutical composition comprising:
(i) eliglustat,
(ii) binder; and
wherein the ratio of eliglustat to binder is in the range from 1:0.25 to 1:3 respectively.

Claim 2: The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises:
(i) eliglustat,
(ii) cellulose binder; and
wherein the ratio of eliglustat to cellulose binder is in the range from 1:0.25 to 1:3 respectively.

Claim 3: The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises:
(i) eliglustat,
(ii) hydroxypropyl methyl cellulose; and
wherein the ratio of eliglustat to hydroxypropyl methyl cellulose is 1:0.25 to 1:3 respectively.

Claim 4: The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises:
(i) eliglustat,
(ii) hydroxypropyl methyl cellulose; and
wherein the ratio of eliglustat to hydroxypropyl methyl cellulose is 1:1 respectively.

Claim 5: A pharmaceutical composition comprising:
(i) eliglustat,
(ii) hydroxypropyl methyl cellulose; and
(iii) pharmaceutically acceptable excipients.

Claim 6: The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition is prepared by a conventional process selected from direct compression, dry granulation, wet granulation and fluidized bed process.

Claim 7: The process for preparing the pharmaceutical composition according to claim 6, wherein the process comprises the steps of:
(i) preparing the drug solution with binder,
(ii) spraying the drug solution on the sugar spheres; and
(iii) drying, lubricating and filling the drug loaded sugar spheres in capsule.

Claim 8: A pharmaceutical composition comprising eliglustat as hereinbefore described with reference to any one of the examples and embodiment.