FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
COMPLETE SPECIFICATION
(SECTION 10)
'PHARMACEUTICAL COMPOSITION OF APREP1TANT"
Glenmark Generics Limited
an Indian Company, registered under the Indian company's Act 1957
and having its registered office at
B/2, Mahalaxmi Chambers, 22 Bhulabhai Desai Road,
Mumbai-400 026
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF INVENTION
[0001] The present invention relates to the pharmaceutical composition comprising a solid solution of aprepitant or pharmaceutically acceptable salts thereof and water insoluble inert pharmaceutical carrier. More particularly, the invention relates to the composition of aprepitant, wherein aprepitant is present in the form of solid solution and to the process of preparation thereof.
BACKGROUND OF THE INVENTION
[002] Aprepitant is a substance P/Neurokinin 1 receptor antagonist, which is chemically 5-[{(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-- , morpbolinyl]methyl]-1,2dihydro-3H-l,2,4-triazol-3-one. It is represented by the following chemical structure (I)

[0003] Aprepitant is available as an oral capsule, under the brand name EMEND® by Merck for the prevention of chemotherapy-induced nausea and vomiting and post-operative nausea and vomiting.
[0004] U.S. Patent No. 5719147 discloses aprepitant. U.S. Patent No. 6096742 and 6583142 disclose two polymorphic forms of aprepitant viz. form I and form II. U.S. Publication No. 20040214746 discloses a nanoparticulate composition of aprepitant that adopts the Nanocrystal® technology of Elan.
[0005] Aprepitant is a poorly soluble drug and belongs to BCS Class IV. Developing a bioavailable pharmaceutical composition of a poorly soluble drug is indeed a challenging task. There are ample ways to improve the bioavailability of a poorly soluble drug and developing nanoparticulate dosage form is one of the preferred ways for the same. The

commercial Emend® formulation of aprepitanl is probably based on Nanocrystal technology which is especially devised for poorly soluble drugs like aprepitant. This technology basically increases the dissolution of the drug from the dosage form due to its reduced particle size (nanosize) and large surface area, thereby making the drug available for absorption. A dispersion of the drug in a suitable liquid medium is subjected to milling. One or more surface stabilizers are added during or after milling due to which the milled drug particles adsorb on its surface one or more surface stabilizer so as to maintain a particle size of less than about 1000nm. The nanodispersion is then formulated in to an amenable dosage form by spray coating the dispersion on to microcrystalline spheres.
[0006] Nanocrystal technology is a cumbersome and highly skilled technology with specific ' requirements of machinery and other infrastructure. It also demands specific process parameters like achieving a specific narrow range of particle size.
[0007] The inventors of the present invention have devised a pharmaceutical composition of aprepitant which is less tedious as compared to the one known in the art.
SUMMARY OF INVENTION
[0008] One aspect of the present invention relates to an oral pharmaceutical composition of
aprepitant comprising a solid solution of aprepitant and water insoluble inert
pharmaceutical carrier. [0009] Jn a preferred embodiment, the pharmaceutical composition of aprepitant comprises a
solid solution of aprepitant. water insoluble inert pharmaceutical carrier and optionally
disintegrant. [0010] In another preferred embodiment, the pharmaceutical composition of aprepitant
comprises a solid solution of arrcpitant, water insoluble inert pharmaceutical carrier,
optionally disintegrant and optionally anionic surfactant. [0011] In yet another preferred embodiment, the pharmaceutical composition of aprepitant
comprises a solid solution of aprepitant. water insoluble inert pharmaceutical carrier,

wherein the mean particle size of the water insoluble inert pharmaceutical carrier is not more than 200 microns.
[0012] Second aspect of the present invention relates to the process for the preparation of an oral pharmaceutical composition comprising solid solution of aprepitant and pharmaceutically acceptable excipienls.
DETAILED DESCRIPTION OF INVENTION
[0013] One aspect of the present invention relates to an oral pharmaceutical composition of aprepitant comprising a solid solution of aprepitant and water insoluble inert pharmaceutical carrier.
[0014] According to this invention, the pharmaceutical composition of aprepitant comprising a solid solution of aprepitant and water insoluble inert pharmaceutical carrier is to be envisaged in any of these possible manner viz. a coating of aprepitant solid solution on the water insoluble inert pharmaceutical carrier or a mere deposition of aprepitant solid solution on the water insoluble inert pharmaceutical carrier or granulation of the solid solution of aprepitant and the watt; insoluble inert pharmaceutical carrier or a mere aggregation or admixture or association of solid solution of aprepitant and the water insoluble inert pharmaceutical carrier or a direct compression of the solid solution of aprepitant and the water insoluble inert pharmaceutical carrier.
[0015] In a preferred embodiment the pharmaceutical composition of aprepitant comprises a
solid solution of aprepitant, water insoluble inert pharmaceutical carrier and optionally
disintegrant. [0016] In another preferred embodiment, the pharmaceutical composition of aprepitant
comprises a solid solution of aprepitant, water insoluble inert pharmaceutical carrier,
optionally disintegrant and optionally anionic surfactant. [0017] According to this invention, solid solution of aprepitant is a homogenous mixture of
aprepitant and atleast one hydrophilic polymer. [0018] In one of the preferred embodiment, this homogenous mixture is an absolute solution of
aprepitant or its pharmaceutically acceptable salt and atleast one hydrophilic polymer.

[0019] The solvent for preparing this solution should be capable of completely dissolving aprepitant as well as the hydrophilic polymer. In no case, the solution containing aprepitant and the hydrophilic polymer will contain aprepitant particles. Since aprepitant is a poorly soluble compound and the invention demands its complete solubility in a suitable solvent, it is preferred to use an organic solvent for this purpose.
[0020] Suitable solvents that can be used for preparing solid solution of aprepitant include, but are not limited to methanol, ethanol, isopropyl alcohol, n-propanol, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, acetone, ethyl methyl ketone, methyl isobutyl ketone, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, diethyl ether, dimethyl ether, diisopropyl ether, toluene, xylene, n-heptane, cyclohexane, n-hexane, acetonitrile, propionitrile or mixtures thereof. Preferably the solvent selected is a blend of dichloromelhane and methanol. The quantity of solvent used should be just sufficient to dissolve completely both aprepitant and the hydrophilic polymer.
[0021] Accordingly, in one of the preferred embodiment, the solid solution of aprepitant is prepared by dissolving aprepaant and atleast one hydrophilic polymer in a solvent blend of dichloromethane and methanol.
[0022] Unless and otherwise specified, "Aprepitant" includes without any limitation all its salts, solvates, hydrates, polymorphs and enantiomers thereof. Further, aprepitant may be in a crystalline or amorphous form. Though it is not necessary for the success of this invention, it is desired that the particle size of aprepitant to be used in the. prescrt invention should not be more than 200 microns.
[0023] The hydrophilic polymer used in the solid solution of aprepitant can be selected from but not limited to povidone, crospovidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene oxide, gelatin, carbomer, carboxymethylcellulose. croscarmellose, methylcellulose, methacrylic acid copolymer, methacrylate copolymer, ana vvater soluble salts such as sodium and ammonium salts of methacrylic acid and methacrylate copolymers, cellulose acetate phthalate,

hydroxypropylmethyl cellulose phthalate and propylene glycol alginate. Preferably the hydrophilic polymer is polyvinylpyrrolidone, hydroxypropylmethyl cellulose.
[0024] Accordingly, in one of the preferred embodiment solid solution of aprepitant is made by dissolving aprepitant and polyvinylpyrrolidone in a solvent dichloromethane and methanol.
[0025] The ratio of aprepitant to the hydrophilic polymer used in the pharmaceutical composition is about 1:0.5 to about 1:3. Preferably, the ratio is 1:1.
[0026] In the context of the present invention, the phrase "inert pharmaceutical carrier" means a pharmaceutical excipient that does not adversely react with aprepitant to the extent as to cause degradation of more than 10% of aprepitant during the course of its shelf life or al accelerated stability conditions.
[0027] According to the invention, the water insoluble inert pharmaceutical carrier may be any pharmaceutical material that could serve as a bed for either coating or depositing or granulating solid solution of aprepitant upon it. The water insoluble inert pharmaceutical carrier is essentially a particulate matter having no well-defined size or shape, essentially non-spherical but should be of an irregular shape.
[0028] Suitable water insoluble inert pharmaceutical carrier that can be used for the purpose of this invention can be selected from macrocrystalline cellulose available under the brand name Avicel PH-102, Avicel PH-112, Avicel PH-302, Celex 101, Emocel 90M, Vivapur 102 or dibasic calcium phosphate dihydrate or mixture thereof. Preferably microcrystalline cellulose available under the brand name Avicel PH-302 from FMC Biopolymer is used. According to this invention, the mean particle size of the water insoluble inert pharmaceutical earner is not more than 200 microns, preferably not more than 100 microns. The particle size specification is in line with those mentioned in the "The Handbook of Pharmaceutical Excipients"

[0029] More particularly, the water insoluble inert pharmaceutical carrier used for the purpose of this invention being essentially a non-spherical but an irregular particulate matter, there is a wide distribution of particle size amongst it. Preferably, the particle size distribution of the water insoluble inert pharmaceutical carrier is such that not more than 10% of particles are above 250 microns and not less than 45% of particles are between 50 microns and 250 microns. Further, the mean particle size is about 80 to 100 microns.
[0030] In a preferred embodiment, Avicel PH-302 (microcrystalline cellulose) is used as the water insoluble inert pharmaceutical carrier and the preferred particle size distribution is such that not more than 8% by weight of its population is above 250 microns and not less than 45% by weight of its population is between 75 microns and 250 microns.
[0031] In a specific embodiment, the pharmaceutical composition of the present invention comprises about 50-70%w/w of solid solution of aprepitant, about 10-30%w/w of water insoluble inert pharmaceutical carrier and about 4-10%w/w of disintegrant.
[0032] In another specific embodiment, the pharmaceutical composition of the present invention comprises about 50-70%w/w of solid solution of aprepitant, about 10-30%w/w of water insoluble inert pharmaceutical carrier, about 4-10%w/w of disintegrant and about 10-15%w/w of anionic surfactant.
[0033] In yet another specific embodiment, the pharmaceutical composition of the present invention comprises about 60% of solid solution of aprepitant. comprising aprepitant and polyvinylpyrrolidone in the ratio of about 1:1, about 20%w/w of microcrystailine Cellulose (Avicel PH 302). about 7%w/w of crosscaramellose sodium and 13%w/w of sodium lauryl sulfate.
[0034] Second aspect of the present invention relates to the process for the preparation of an oral pharmaceutical composition 'omprising solid solution of aprepitant and pharmaceutically acceptable excipients.

[0035] According to the invention, the process for preparing the pharmaceutical composition of aprepitant involves the following steps:
1) Preparing a solid solution of aprepitant
2) Preparing granules of the solid solution of aprepitant that comprises essentially water insoluble inert pharmaceutical carrier
3) Incorporating the aprepitant granules formed in step 2 and other pharmaceutically acceptable excipients in to a suitable dosage form like tablet or capsule
1. Preparing a solid solution of aprepitant
[0036] In one embodiment, the process of preparing solid solution of aprepitant is carried out by dissolving aprepitant and atleast one hydrophilic polymer in a solvent that completely solubilizes both the aprepitant and the hydrophilic polymer.
[0037] In one of the preferred embodiment, solid solution of aprepitant is made by dissolving aprepitant and polyvinylpyrrolidone in a solvent dichloromethane and methanol.
2. Preparing granules of the solid solution of aprepitant
[0038] In one of the preferred embodiment, the granulation of solid solution of aprepitant is conveniently carried out in a fluidized bed granulator. In this process, the solid solution of aprepitant is either coated or deposited or granulated with the particulate matter in the fluidized bed with appropriate operation parameters. Parameters such as spraying rate, atomizing air pressure, fluidizing air volume, temperature of the bed, inlet air temperature should be optimized for achieving the promising pharmaceutical composition of aprepitant.
[0039] Fluidized bed in the context of present invention is a bed of particulate maner having no well-defined size or shape, essenially non-spherical but should be of an irregular shape, which serves as a bed on which solid solution of aprepitant is either coated or deprived or granulated in a fluidized bed granulator.
[0040] In one of the preferred embodiment, the particulate matter of the fluidized bed essentially comprises of water insoluble inert pharmaceutically earner. The fluidized bed may additionally comprise disintegrant, anionic surfactant optionally.

[0041] In yet another preferred embodiment, the mean particle size of the water insoluble inert pharmaceutical carrier is not more than 200 microns, preferably not more than 100 microns.
[0042] Disinlegranls can be selected from carboxymethyl cellulose sodium, crosspovidone sodium starch glycolate or mixture thereof. Preferably, carboxymethyl cellulose sodium is used as the disintegrant.
[0043] Anionic surfactants can be selected from sodium lauryl sulfate, docussate sodium, preferably, sodium lauryl sulfate is used as the surfactant.
[0044] In one of preferred embodiment, the fluidized bed comprises of a blend of microcrystalline cellulose, carboxymethyl cellulose sodium and sodium lauryl sulfate.
3. Incorporating the aprepilant granules in to a solid dosage form
[0045] The granules containing solid solution of aprepitant obtained from the fluidized bed granulator is further blended with other pharmaceutically acceptable excipients known in the art like fillers, binders, lubricants, disintegrants, sweetners, flavours etc.
[0046] Common diluents that can be used in pharmaceutical composition include but are not limited to microcrystalline cellulose, lactose, starch, pregelatinized starch, sugar mannitol. sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like.
[0047] Common disintegrants that can be used in the pharmaceutical compositions include but are not limited to methyl cellulose, microcrystalline cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, povidone K-30, guar gum, magnesium aluminum silicate, colloidal silicon dioxide, polacrilin potassium, starch, pregelatinized starch, sodium starch glycolate and sodium alginate.
[0048] The pharmaceutical composition may be eventually in the form of free flowing granules encapsulated in to a capsule shell or compressed in to tablet.

[0049] In one of the preferred embodiment, the pharmaceutical composition is in the form of capsule containing the solid solution of aprepitant granules.
[0050] The following examples describe compositions of the present invention containing aprepitant, but they are not to be interpreted as limiting the scope of the claims.

Tabic 1
Sr. No. Ingredients mg/Cap
A. Solid solution of aprepitant
1 Aprepitant 125.00
2 PVP K-30 120.00
3 Methanol q.s.
4 Dichloromethane q.s.
B. Granulation of Aprepitant s olid solution
5 Microcrystalline Cellulose (Avicel PH 302) 77.0
6 Crosscaramellose sodium (Ac-Di-Sol) 16.00
7 Sodium laury] sulfate 25.00
C Extragranular
8 Crosscaramellose sodium CAc-Di-Sol) 12.00
9 Sodium Iauryl sulfate 25.00
Total Weight 400.00

Process:
1. Microcrystalline cellulose (Avicel pH 302), croscarmellose sodium (Ac-di-sol) and sodium lauryl sulfate were co-sifted through #40 mesh.
2. Aprepitant was dissolved in a mixture of methanol and dichloromethane and then polyvinyl pyrrolidone (PVP K-30) was dissolved in the same mixture to get a clear solution.
3. The blend from step 1 was placed in Fluidised Bed Granulator.

4. The solution from step 2 was sprayed on the material of step 3.
5. The material obtained as a result of step 4 was collected and passed through #40 mesh.
6. The material of step 5 was blended at 10 rprn for 10 min.
7. Extragranular materia! like cro'.-carmellose sodium (Ac-di-sol) and sodium lauryl sulfate were sifted through #4;! mesh and blended with the material of step 6 at 10 rprn for 10 min.
8. The blend of step 7 was filled in a hard gelatin capsule.

CLAIM S:
1. A pharmaceutical composition comprising solid soltion of aprepitant or pharmaceutically acceptable salts thereof and water insoluble inert pharmaceutical carrier.
2. The pharmaceutical composition according to claim 1, which further comprises disintegrant and anionic surfactant.
3. The pharmaceutical composition according to claim 2. wherein the disintegrant is carboxymethyl cellulose sodium and the anionic surfactant is sodium lauryl sulfate
4. A pharmaceutical composition comprising
a) a solid solution consisting of
a, aprepitant and
b. hydrophilic polymer
b) water insoluble inert pharmaceutical carrier.
5. The pharmaceutical composition according to claim 3. wherein the solid solution is
obtained by
a. completely dissolving aprepitant in an organic solvent and
b. adding hydrophilic polymer to the aprepitant solution obtained from step (a).
6. The pharmaceutical composition according to claim 3, wherein the hydrophilic polymer is polyvinylpyrrolidone.
7. Pharmaceutical composition according to claim 3, wherein the water insoluble inert pharmaceutical carrier comprises microcrystalline cellulose, carboxymethyl cellulose sodium and sodium lauryl sulfate.