Field of invention

The invention relates to the pharmaceutical field. Specifically it relates to process for preparing pharmaceutical compositions comprising aprepitant, graft copolymer of polyethylene glycol, polyvinylcaprolactam and polyvinyl acetate (Soluplus®) and optionally one or more pharmaceutically acceptable excipients.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ARTS

Aprepitant is a substance P/neurokinin 1 (NK1) receptor antagonist, also referred to as tris (1-aziridinyl) phosphine sulfide. It is indicated for the prevention of chemotherapy induced nausea and vomiting (CINV) and for the prevention of postoperative nausea and vomiting (PONV).

Aprepitant is chemically, 5-[[(2R, 3S)-2-[(lR)-l-[3,5-bis (trifluoromethyl) phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-l,2dihydro-3H-l,2,4-triazol-3-one. Its empirical formula is C23H21F7N4O3, and its molecular weight is 534.43. It is practically insoluble in water. Aprepitant is sparingly soluble in ethanol and isopropyl acetate and slightly soluble in acetonitrile.

In the U.S., aprepitant was introduced by Merck & Co. under the brand name Emend® as an oral capsule containing either 40 mg, 80 mg, or 125 mg of aprepitant and the following inactive ingredients: sucrose, microcrystalline cellulose, hydroxypropyl cellulose and sodium lauryl sulfate. The capsule shell excipients are gelatin, titanium dioxide, and may contain sodium lauryl sulfate and silicon dioxide. The 40-mg capsule shell also contains yellow ferric oxide, and the 125-mg capsule also contains red ferric oxide and yellow ferric oxide.

Aprepitant has poor solubility and poor permeability characteristics i.e. BCS class IV molecule. The rate of dissolution of poorly water-soluble drug is a rate-limiting factor in its bioavailability. Currently marketed formulation Emend® is a nanoparticle based formulation of aprepitant developed to overcome its poor solubility/permeability characteristics.

U.S. Patent No. 5,145,684 discloses platform technology for preparing stable, dispersible drug nanoparticles by wet milling in the presence of grinding media in conjunction with a surface modifier; the same platform technology is used for formulating marketed aprepitant formulation Emend , with improved dissolution and bioavailability of aprepitant.

U.S. Patent Application No. 2011/009362 discloses a solid state nanoparticulate solubility-enhanced form of aprepitant comprising aprepitant as a co-precipitate, premix, or a solid dispersion in the form of an inclusion complex with at least one cyclodextrin or cyclodextrin derivative.

U.S. Patent Application No. 2010/151035 discloses a process for preparing solid dispersion comprising aprepitant to improve its dissolution and bioavailability, wherein the process comprising the steps of: a) dissolving the drug, or a pharmaceutically acceptable salt thereof, and at least one polymer in a suitable solvent, to form a solution; b) spraying the solution onto inert pellets; and c) drying the inert pellets to remove the solvent.

PCT Application No. 2011/158053 discloses a process for preparing nanostructured aprepitant having average diameter of less than about 200 nm. The nanostructured aprepitant is prepared by controlled nano-precipitation in a continuous flow reactor, preferably in microfluidic continuous flow reactor, using pharmaceutically acceptable carrier(s), and preferably stabilizer(s), wherein the stabilizer is preferably selected from the group of cellulose and its derivatives, polyvinylpyrrolidone, graft copolymer comprised of polyethylene glycol, polyvinylcaprolactam and polyvinylacetate (e.g. Soluplus®), and sodium lauryl sulfate.

In the above mentioned prior arts several attempt have been made to improve the dissolution and bioavailability of aprepitant. Thus the poor solubility and permeability characteristic of aprepitant poses a challenge to the formulation scientist to formulate aprepitant oral solid dosage form with acceptable dissolution and bioavailability characteristics.

Thus, there is constant need in the art for preparing pharmaceutical composition comprising aprepitant and one or more pharmaceutically acceptable excipient with improved dissolution and bioavailability characteristics by overcoming its poor solubility and permeability problems.

The present inventors surprisingly found that pharmaceutical compositions comprising aprepitant, Soluplus® and optionally one or more pharmaceutically acceptable excipients, when prepared using melt-extrusion process, improves the solubility characteristic of aprepitant and also enhances the dosage form characteristics in terms of drug release and bioequivalence parameters, thus making it comparable or "same as" to the commercially available Emend .

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to process for preparing pharmaceutical composition comprising aprepitant and optionally one or more pharmaceutically acceptable excipient with improved dissolution and bioavailability. More specifically, it relates to melt-extrusion process for preparing pharmaceutical composition comprising aprepitant, Soluplus® and one or more pharmaceutically acceptable excipients.

An objective of the invention is to prepare solid oral pharmaceutical composition comprising aprepitant, Soluplus® and optionally one or more pharmaceutically acceptable excipients, wherein the process involves melt-extrusion.

Another objective of the invention is to prepare pharmaceutical composition in the form of capsule comprising aprepitant, Soluplus® and optionally one or more pharmaceutically acceptable excipients, wherein the process involves melt-extrusion.

Yet another objective of the invention is to prepare pharmaceutical composition in the form of capsule comprising aprepitant, Soluplus® and

optionally one or more pharmaceutically acceptable excipients, having comparable in-vitro dissolution profile and in-vivo pharmacokinetic parameters with that of the marketed Emend® capsules, wherein the process involves melt-extrusion.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

As discussed in the background, poor solubility and permeability characteristic of aprepitant possess a challenge to the formulation scientist to formulate aprepitant oral solid dosage form with acceptable dissolution and bioavailability characteristics.

The present inventors surprisingly found that pharmaceutical compositions comprising aprepitant, Soluplus® and optionally one or more pharmaceutically acceptable excipients, when prepared by using melt-extrusion process, improves the solubility characteristic of aprepitant and also enhances the dosage form characteristics in terms of drug release and bioequivalence parameters, thus making it comparable or "same as" to the commercially available Emend®.

Specifically, the invention relates to a solid oral pharmaceutical composition comprising:
a. aprepitant;

b. graft copolymer of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (Soluplus®) and
c. optionally one or more pharmaceutically acceptable excipients, whereby the pharmaceutical composition is prepared by melt-extrusion process.

The solid oral pharmaceutical composition is preferably a tablet, hard gelatin capsule, or a soft gelatin capsule. More preferably it is hard gelatin capsule.

Melt-extrusion process involves mixing two or more components using high shear mixing and controlled temperature in an extruder. The granular or powder material is generally fed into the extruder feeding port at controlled rate while the extruder screws are rotating. The mixture is processed at elevated temperature and force, which disperses the drug in the matrix at a molecular level through the formation of a solid solution. Extruded material can be further processed into a variety of dosage forms like tablets and capsules.

Specifically, the process to prepare aprepitant capsules comprising graft copolymer of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (Soluplus®) and optionally one or more pharmaceutically acceptable excipients, involves the steps of:

a. mixing aprepitant, Soluplus® and optionally other pharmaceutically acceptable excipients in a blender, to get an uniform blend;

b. introducing said blend of step a) into a melt-extruder maintained at a suitable temperature below 250°C to get extrudes;

c. milling and sifting said extrudes of step b) to get granules or powder;

d. filling said granules or powder of step c) into empty capsule shells.

More specifically, according to an embodiment of the invention, the melt-extrusion process for preparing capsule formulation comprising aprepitant, polyvinyl caprolactam and polyvinyl acetate (Soluplus®) and optionally one or more pharmaceutically acceptable excipient involves the steps of:

a. Sifting aprepitant through suitable size sieve;

b. Separately sifting Soluplus® and one or more pharmaceutically acceptable excipient(s) through suitable size sieve;

c. Loading the sifted material of step (a) and step (b) into the blender and mixing well to get uniform blend;

d. Passing the blend of step (c) through melt-extruder at a temperature preferably below 250°C to get extrudes, and allowing the extrudes to air cool;

e. Milling of the extrudes obtained in step (d) using suitable mill such as Quadro® Comil®;

f. Sifting of the milled extrudes obtained in step (e) using suitable size sieve to get granules and/or powder;

g. Optionally; mixing of sifted granules and/or powder obtained in step (f) with glidant and/or with lubricant;

h. Filling of the granules and/or powder blend obtained in step (g) into appropriate size empty capsule shells.

According to the invention, aprepitant may be present in an amorphous or crystalline form. As used herein, the term "aprepitant" is intended to include the active agent itself, as well as its pharmaceutically acceptable salts or derivatives thereof.

According to the invention, Soluplus® is preferably used as polymer matrix for melt-extrusion process for preparing aprepitant pharmaceutical oral solid composition.

According to the invention, the solid oral pharmaceutical composition comprising aprepitant and Soluplus®, optionally further comprises of one or more pharmaceutically acceptable excipient(s) selected from a group comprising of surfactant(s), glidant and/or lubricant(s), adsorbent(s) and etc.

Suitable adsorbent(s) according to the invention include, but are not limited to, mannitol, xylitol, sorbitol, lactose, microcrystalline cellulose (Avicel®), colloidal silicon dioxide (Aerosil®), carboxymethylcellulose calcium, carboxymethylcellulose sodium, calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate, calcium phosphate tribasic, calcium trisilicate, magnesium trisilicate, cellulose acetate, or combinations thereof.

Suitable surfactants according to the invention include, but are not limited to, anionic surfactants such as
potassium laurate, triethanolamine stearate, sodium lauryl sulphate, cationic surfactants include quaternary ammonium compounds, benzalkonium chloride, cetyltrimethylammonium bromide; nonionic surfactants include glycerol monostearate (GMS), cetyl alcohol, cetostearyl alcohol, and. polyoxyethylene glycol sorbitan alkyl esters (polysorbate), sorbitan alkyl esters (span), poloxamer or combinations thereof.
Suitable glidants and/or lubricants according to the invention include, but are not limited to, colloidal silicon dioxide, talc, magnesium and combinations thereof.

According to the invention, Soluplus® along with one or more polymers such as polyethylene glycol (PEG), copovidone (Kollidon®), and polyvinylpyrrolidone (PVP) can be used as polymer matrix for preparing aprepitant oral solid formulation using melt-extrusion process.

According to the invention, Soluplus® along with one or more surfactant(s) such as Poloxamer (Lutrol®) and glyceryl monostearate (GMS) can be used as polymer matrix for preparing aprepitant oral solid composition using melt-extrusion process.

In an embodiment of the invention the pharmaceutical composition comprising aprepitant comprises Soluplus®, and polyethylene glycol (PEG) as polymer matrix for melt-extrusion process.
In an embodiment of the invention, the pharmaceutical composition comprising aprepitant comprises Soluplus®, polyethylene glycol (PEG), and Poloxamer (Lutrol®) as polymer matrix for melt-extrusion process.

In an embodiment of the invention, the pharmaceutical composition comprising aprepitant comprises Soluplus®, polyethylene glycol (PEG), and copovidone (Kollidon®) as polymer matrix for melt-extrusion process.

In an embodiment of the invention, the pharmaceutical composition comprising aprepitant comprises Soluplus®, polyethylene glycol (PEG), and polyvinylpyrrolidone (PVP) as polymer matrix for melt-extrusion process.

In an embodiment of the invention, the pharmaceutical composition comprising aprepitant comprises Soluplus®, polyethylene glycol (PEG), and sodium lauryl sulphate (SLS) as polymer matrix for melt-extrusion process.

In an embodiment of the invention, the pharmaceutical composition comprising aprepitant comprises Soluplus®, polyethylene glycol (PEG), and glyceryl monostearate (GMS) as polymer matrix for melt-extrusion process.

In an embodiment of the invention, the pharmaceutical composition comprising aprepitant comprises Soluplus®, microcrystalline cellulose (Avicel®), and copovidone (Kollidon®) and colloidal silicon dioxide (Aerosil®) as matrix material for melt-extrusion process.

EXAMPLES;
Following examples are illustrative and do not limit the scope of this invention.

Example -1
Unit Composition:

Ingredients % w/w
Aprepitant 25.0
Soluplus* 71.7
Polyethylene glycol 4000 3.3
Total 100

Brief manufacturing process:
1. Sift aprepitant through # 30 sieve.
2. Separately sift Soluplus® and polyethylene glycol through # 30 sieve.
3. Load the sifted material of step 1 and step 2 into the blender and mix well to get uniform blend.
4. Pass the blend obtained in step 3 through melt-extruder maintained at suitable temperature below 250°C to get extrudes and allow the extrudes to air cool.
5. Mill the extrudes obtained in step 4 using suitable mill such as Quadro® Comil®.
6. Sift the milled extrudes obtained in step 5 through # 40 sieve to get granules and/or powder.
7. Fill the granules and/or powder blend obtained in step 6 into appropriate size capsule shells.

Example - 2
Unit Composition:

Ingredients % w/w
Aprepitant 25.0
Soluplus® 62.5
Poloxamer 188 9.2
Polyethylene glycol 4000 3.3
Total 100
10

Brief manufacturing process:
1. Sift aprepitant through # 30 sieve.
2. Separately sift Soluplus®, poloxamer 188 and polyethylene glycol through #30 sieve.
3. Load the sifted material of step 1 and step 2 into the blender and mix well to get uniform blend.
4. Pass the blend obtained in step 3 through melt-extruder maintained at suitable temperature below 250°C to get extrudes and allow the extrudes to air cool.
5. Mill the extrudes obtained in step 4 using suitable mill such as Quadro® Comil®.
6. Sift the milled extrudes obtained in step 5 through # 40 sieve to get granules and/or powder.
7. Fill the granules and/or powder blend obtained in step 6 into appropriate size capsule shells.

Example - 3
Unit Composition:
Ingredients % w/w
Aprepitant 26.0
Aerosil® (first part) 0.3
Soluplus® 34.4
Microcrystalline cellulose 29.0
Kollidon CL 10.0
Aerosil® (second part) 0.3
Total 100

Brief manufacturing process:
1. Sift aprepitant through # 30 sieve.
2. Separately sift Soluplus®, Aerosil through # 30 sieve.
3. Separately sift microcrystalline cellulose, Kollidon CL, and Aerosol (second part) through #30 sieve.
4. Load the sifted material of step 1, and step 2 into the blender and mix well to get uniform blend.
5. Pass the blend obtained in step 4 through melt-extruder maintained at suitable temperature below 250°C to get extrudes and allowing the extrudes to air cool.
6. Mill the extrudes obtained in step 5 using suitable mill such as Quadro® Comil®.
7. Sift of the milled extrudes obtained in step 6 through # 40 sieve to get granules and/or powder.
8. Load the sifted material of step 3, and step 7 into the blender and mix well to get uniform blend.
9. Fill the granules and/or powder blend obtained in step 8 into appropriate size capsule shells.

Example - 4
Unit Composition:

Ingredients % w/w
Aprepitant 22.7
Soluplus* 56.1
Polyvinylpyrrolidone (PVP) 18.2
Polyethylene glycol 4000 3.0
Total 100

Brief manufacturing process:
1. Sift aprepitant through # 30 sieve.
2. Separately sift Soluplus®, PVP and polyethylene glycol through #30 sieve.
3. Load the sifted material of step 1 and step 2 into the blender and mix well to get uniform blend.
4. Pass the blend obtained in step 3 through melt-extruder maintained at suitable temperature below 250°C to get extrudes and allow the extrudes to air cool.
12

5. Mill the extrudes obtained in step 4 using suitable mill such as Quadro Comil®.
6. Sift the milled extrudes obtained in step 5 through # 40 sieve to get granules and/or powder.
7. Fill the granules and/or powder blend obtained in step 6 into appropriate size capsule shells.
Example - 5

Unit Composition:

Ingredients % w/w
Aprepitant 46.8
Soluplus® 38.2
Glyceryl monostearate 7.5
Polyethylene glycol 1500 7.5
Total 100

Brief manufacturing process:
1. Sift aprepitant through # 30 sieve.
2. Separately sift Soluplus®, glyceryl monostearate and polyethylene glycol through #30 sieve.
3. Load the sifted material of step 1 and step 2 into the blender and mix well to get uniform blend.
4. Pass the blend obtained in step 3 through melt-extruder maintained at suitable temperature below 250°C to get extrudes and allow the extrudes to air cool.
5. Mill the extrudes obtained in step 4 using suitable mill such as Quadro® Comil®.
6. Sift the milled extrudes obtained in step 5 through # 40 sieve to get granules and/or powder.
7. Fill the granules and/or powder blend obtained in step 6 into appropriate size capsule shells.

13

Example - 6
Unit Composition:

Ingredients % w/w
Aprepitant 24.0
Soluplus® 68.9
Sodium Lauryl Sulphate 3.8
Polyethylene glycol 1500 3.2
Total 100.00

Brief manufacturing process:
1. Sift aprepitant through # 30 sieve.
2. Separately sift Soluplus® and polyethylene glycol through #30 sieve.
3. Sift sodium lauryl sulfate through # 40 sieve.
4. Load the sifted material of step 1 and step 2 into the blender and mix well to get uniform blend.
5. Pass the blend obtained in step 4 through melt-extruder maintained at suitable temperature below 250°C to get extrudes and allow the extrudes to cool.
6. Mill of the extrudes obtained in step 5 using suitable mill such as Quadro® Comil®.
7. Sift the milled extrudes obtained in step 6 through # 40 sieve to get granules and/or powder.
8. Blend granules and/or powder blend obtained in step 7 with sifted sodium lauryl sulphate of step 3.
9. Fill the granules and/or powder blend obtained in step 8 into appropriate size capsule shells.

Example - 7
Unit Composition:
Ingredients % w/w
Aprepitant 22.7
Soluplus® 56.0
Polyvinylpyrrolidone (PVP) 18.2
Polyethylene glycol 4000 3.1
Total 100

Brief manufacturing process:

1. Sift aprepitant through # 30 sieve.
2. Separately sift Soluplus®, PVP and polyethylene glycol through # 30 sieve.
3. Load the sifted material of step 1 and step 2 into the blender and mix well to get uniform blend.
4. Pass the blend obtained in step 3 through melt-extruder maintained at suitable temperature below 250°C to get extrudes and allow the extrudes to air cool.
5. Mill the extrudes obtained in step 4 using suitable mill such as Quadro® Comil®.
6. Sift the milled extrudes obtained in step 5 through # 40 sieve to get granules and/or powder.
7. Fill the granules and/or powder blend obtained in step 6 into appropriate size capsule shells.

Example - 8
Unit Composition:
Ingredients % w/w
Aprepitant 24.0
Soluplus® 68.9
Sodium Lauryl Sulphate 3.8
Polyethylene glycol 4000 3.2
Total 100.00

Brief manufacturing process:
1. Sift aprepitant through # 30 sieve.
2. Separately sift Soluplus® and polyethylene glycol through # 30 sieve.
3. Sift sodium lauryl sulfate through # 40 sieve.
4. Load the sifted material of step 1 and step 2 into the blender and mix well to get uniform blend.
5. Pass the blend obtained in step 4 through melt-extruder maintained at suitable temperature below 250°C to get extrudes and allow the extrudes to cool.
6. Mill the extrudes obtained in step 5 using suitable mill such as Quadro® Comil®.
7. Sift the milled extrudes obtained in step 6 through # 40 sieve to get granules and/or powder.
8. Blend granules and/or powder blend obtained in step 7 with sifted sodium lauryl sulphate of step 3.
9. Fill the granules and/or powder blend obtained in step 8 into appropriate size capsule shells.

Example - 9
Unit Composition:
Ingredients mg/unit % w/w
Aprepitant 125.000 25.00
Soluplus® 358.340 71.67
Polyethylene glycol 4000 16.660 3.33
Total 500.000 100.00

Brief manufacturing process:
1. Aprepitant was sifted through #30 mesh.
2. Soluplus® and Polyethylene glycol were sifted separately through # 30 mesh.
3. Material of step no 1 and 2 were blended properly to get uniform mixture.
4. Step no.3 material was added slowly in the oil bath under continuous stirring for 20min.
5. The blend obtained from step no 4 allow to cool in the room temperature for 35 min.
6. Milled the mass of Step no.5 were milled by using Quadro mill with 40G screen and sifted through sieve # 40 mesh to get granules and/or powder.
7. Granules/ powder of step no 5 were filled into appropriate size capsule shells.
Comparative dissolution data:

Aprepitant capsule prepared according to example 9 and marketed 125mg Emend® capsule were subjected in-vitro dissolution test by using USP type II dissolution apparatus using 900ml of 2.2% sodium lauryl sulfate solution in purified water at 100 rpm and the resultant data is compiled in Table 1.

Table -1

Time (Minutes) Emend® Capsules - 125mg Example - 9
45 96 100

Bio-equivalence Data:
Aprepitant capsules prepared according to example 9 (test product) and Emend® 125mg capsules (reference product) were subjected to the in-vivo bioequivalence study in healthy human volunteers (n=16) under fasting condition and the resultant data is compiled in Table 2.

Above in-vivo bioequivalence data shows the aprepitant capsules prepared according to the Example 9 showed comparative in-vivo bioequivalence profile with that of marketed Emend® 125mg capsules.
Stability Data:
Aprepitant capsule prepared according to example 8 were subjected to stability test by analyzing the formation of impurities and related substances (RS) at initial and after 4 weeks at 40°C and 75% RH, the resultant data is compiled in Table 3.

Table - 3

Pack HDPE container
Storage Condition Initial 40°C / 75% RH 4 weeks Physical Data

Description white opaque cap and body hard gelatin capsule filled with white to off white granules powder white opaque cap and body hard gelatin capsule filled with white to off white granules powder
Disintegration 4min 10 Sec 4 min 20sec

Related substances (% w/w)
Known Impurity 0.036 0.074
Any Individual Unknown Impurity 0.114 0.167
Total Impurities 0.381 0.87

WE CLAIM

1. A solid oral pharmaceutical composition comprising:

a. aprepitant;
b. graft copolymer of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (Soluplus®) and
c. optionally one or more pharmaceutically acceptable excipients,

wherein said pharmaceutical composition is prepared by melt-extrusion process.

2. The solid oral pharmaceutical composition according to claim 1, wherein said composition is a tablet, hard gelatin capsule, or a soft gelatin capsule.

3. The solid oral pharmaceutical composition according to claim 1, wherein said one or more pharmaceutically acceptable excipients are selected from a group consisting of surfactant(s), glidant and/or lubricant(s), adsorbent(s).

4. The solid oral pharmaceutical composition according to claim 1, wherein said composition further comprises polymers selected from polyethylene glycol, copovidone, and polyvinylpyrrolidone.

5. A solid oral pharmaceutical composition according to claim 1, wherein said composition further comprises surfactants selected from poloxamer, sodium lauryl sulphate and glyceryl monostearate.

6. A melt-extrusion process to prepare aprepitant capsules comprising graft copolymer of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (Soluplus®) and optionally one or more pharmaceutically acceptable excipients, wherein said process involves the steps of:

a. mixing aprepitant, Soluplus and optionally other pharmaceutically acceptable excipients in a blender, to get an uniform blend;

b. introducing said blend of step a) into a melt-extruder maintained at a suitable temperature below 250°C to get extrudes;

c. milling and sifting said extrudes of step b) to get granules or powder;

d. filling said granules or powder of step c) into empty capsule shells.

7. A capsule having the unit composition:

wherein said composition is prepared by melt-extrusion process.