DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

Title: NANOPARTICULATE PHARMACEUTICAL COMPOSITIONS OF APREPITANT

GLENMARK PHARMACEUTICALS LIMITED,
An Indian Company registered under The Companies Act, 1956, India
and having its office at
Glenmark House, HDO – Corporate Bldg,
Wing A, B. D. Sawant Marg,
Chakala, Andheri (East),
MUMBAI – 400 099

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

NANOPARTICULATE PHARMACEUTICAL COMPOSITIONS OF APREPITANT

FIELD OF INVENTION
The present invention relates to a nanoparticulate pharmaceutical composition comprising aprepitant or its pharmaceutically acceptable salt and at least one surface stabilizer; a method for preparing the same; and; use of the same in the treatment or prevention of nausea and vomiting.

BACKGROUND OF THE INVENTION
Aprepitant, chemically known as 2-(R)- (1-(R)-(3, 5- bis (trifluoromethyl) phenyl) ethoxy)-3-(S)- (4-fluoro) phenyl-4-(3- (5-oxo-1H, 4H-1, 2, 4-triazolo) methylmorpholine is an antagonist of substance P/neurokinin 1 (NK1) receptor antagonist useful as an antiemetic agent. It is commercially available in the United States as EMEND® capsules in the strengths of 40 mg, 80 mg or 125 mg of aprepitant for oral administration. It is indicated in combination with other antiemetic agents for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin, prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) and for the prevention of postoperative nausea and vomiting.

Aprepitant is practically insoluble in water, sparingly soluble in ethanol and isopropyl acetate and slightly soluble in acetonitrile. Aprepitant has poor solubility and poor permeability characteristics. The poor solubility of aprepitant in aqueous media and poor delivery characteristics pose a tremendous challenge to develop its pharmaceutical composition having adequate bioavailability when administered orally.

International Patent Application Publication No.WO2003/049718 discloses a nanoparticulate composition comprising the compound 2-(R)- (1-(R)-(3, 5- bis (trifluoromethyl) phenyl) ethoxy)-3-(S)- (4-fluoro) phenyl-4-(3- (5-oxo-1H, 4H-1, 2, 4-triazolo) methylmorpholine (aprepitant) or a pharmaceutically acceptable salt thereof, the compound having adsorbed on its surface at least one surface stabilizer in an amount sufficient to maintain an effective average particle size of less than about 1000 nm.

International Patent Application Publication No. WO 2007/016582 describes co-precipitates comprising amorphous aprepitant and pharmaceutically acceptable carriers.

International Patent Application Publication No. WO 2008/110534 discloses a solid dispersion of aprepitant which is prepared by dissolving aprepitant or its salt thereof and at lease one polymer in a suitable solvent, spraying the solution onto inert pellet; and drying the inert pelts to remove the solvent.

There is still a need for the development of an alternative pharmaceutical composition comprising aprepitant and at least one surface stabilizer.

SUMMARY OF THE INVENTION
The present invention relates to a nanoparticulate pharmaceutical composition comprises aprepitant or its pharmaceutically acceptable salt and at least one surface stabilizer, wherein the surface stabilizer is adsorbed to the surface of the aprepitant.

In an embodiment the present invention provides a nanoparticulate pharmaceutical composition comprising aprepitant or its pharmaceutically acceptable salt, at least one surface stabilizer adsorbed on the surface of the aprepitant in an amount sufficient to maintain an effective average particle size of less than about 1000 nm, preferably, less than about 500 nm, more preferably, less than about 250 nm.

In an embodiment, the present invention relates to a pharmaceutical dosage form comprising a nanoparticulate pharmaceutical composition of aprepitant or its pharmaceutically acceptable salt; a surface stabilizer adsorbed on the surface of aprepitant; and; optionally a pharmaceutically acceptable excipient.

In one embodiment, the present invention relates to a pharmaceutical dosage form comprising a nanoparticulate pharmaceutical composition comprising 15% - 60% by weight of aprepitant or its pharmaceutically acceptable salt; 10% -65% by weight of a surface stabilizer; and 0% - 50% by weight of pharmaceutical excipients, to the total weight of the pharmaceutical dosage form.

In one embodiment, a pharmaceutical dosage form comprising the nanoparticulate pharmaceutical composition comprising aprepitant or its pharmaceutically acceptable salt having a particle size of less than 250 nm, a surface stabilizer, a carrier and other pharmaceutical excipients.

In another embodiment, the present invention relates to a pharmaceutical dosage form comprising a nanoparticulate pharmaceutical composition comprising about 25-45% by weight of aprepitant having a particle size of less than 250 nm; about 20-45% by weight of a surface stabilizer; about 0-20% by weight of a carrier; and about 0-20% by weight of a other pharmaceutical excipients, to the total weight of the pharmaceutical dosage form.

In another embodiment, the present invention relates to a pharmaceutical dosage form comprising a nanoparticulate pharmaceutical composition comprising about 30-40% by weight of aprepitant having a particle size of less than 250 nm; about 22-40% by weight of a surface stabilizer; about 5-20% by weight of a carrier; and about 5-15% by weight of a other pharmaceutical excipients, to the total weight of the dosage form.

In one embodiment, the present invention relates to a pharmaceutical dosage form comprising a nanoparticulate pharmaceutical composition comprising 30%-40% by weight of aprepitant, 4%-6% by weight of hydroxyl ethyl cellulose, 6%-9% by weight of poloxamer 14%-18% by weight of povidone, 12%-17% by weight of mannitol, 3%-5% of vitamin E polyethylene glycol succinate, 5%-8% by weight of microcrystalline cellulose, 0.1%-1% by weight of colloidal silicon dioxide, 0.1%-1% by weight of sodium steryl fumarate, to the total weight of the dosage form.

In one of the embodiment, the present invention relates to a process of preparing the nanoparticulate pharmaceutical composition comprising the steps of: a) dispersing aprepitant or its pharmaceutically acceptable salt and at least one surface stabilizer in a liquid dispersion medium; (b) wet grinding the mixture a) in the presence of rigid grinding media to form a nanosuspension having a desired particle size; and; (c) isolating the resultant nanoparticulate composition of step b) from the grinding media.

In one of the embodiment, the present invention relates to a process of preparing the pharmaceutical dosage form comprising the steps of: a) preparing a nanosuspension of aprepitant or its pharmaceutically acceptable salt and at least one surface stabilizer ; b) spray drying the suspension to form granules; c) optionally lubricating the spray dried granules; and; d) optionally encapsulating the resultant product into hard gelatin capsules.

In one of the embodiment, the present invention relates to a process of preparing the pharmaceutical dosage form comprising the steps of: a) preparing a nanosuspension of aprepitant or its pharmaceutically acceptable salt and at least one surface stabilizer; b) spray drying the suspension to form granules; c) optionally compacting the spray dried granules by using roller compactor at suitable parameters d) lubricating the spray dried granules; and; d) optionally encapsulating the resultant product into hard gelatin capsules.

In one of the embodiment, the present invention relates to a process of preparing the pharmaceutical dosage form comprising the steps of: a) preparing a nanosuspension of aprepitant or its pharmaceutically acceptable salt and at least one surface stabilizer; b) spray coating the nanosuspension onto solid support; c) optionally lubricating the coated spheres; and; d) optionally encapsulating the resultant product into hard gelatin capsules.

The present invention also relates to a method of treating or preventing nausea and vomiting comprising administering to a patient in need of a therapeutically effective amount of a pharmaceutical composition according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a nanoparticulate pharmaceutical composition comprises aprepitant or its pharmaceutically acceptable salt and at least one surface stabilizer, wherein the surface stabilizer is adsorbed to the surface of the aprepitant.

The present invention provides a nanoparticulate pharmaceutical composition (i.e. Nanoparticles) comprising aprepitant or its pharmaceutically acceptable salt, at least one surface stabilizer adsorbed on the surface of the aprepitant in an amount sufficient to maintain an effective average particle size of less than about 1000 nm, preferably, less than about 500 nm, more preferably, less than about 250 nm.

The inventors have discovered that a nanoparticulate pharmaceutical composition or pharmaceutical dosage form of aprepitant having particle size of less than about 1000 nm, preferably less than about 500 nm, more preferably less than about 250 nm and surface stabilizer (for example hydroxyethyl cellulose) increases the oral bioavailability of aprepitant.

Aprepitant having the surface stabilizer adsorbed on the surface thereof to maintain an effective average particle size of less than about 1000 nm, preferably, less than about 500 nm, more preferably, less than about 250 nm is also referred to herein as active ingredient “Nanoparticles”or “Nanoparticulate drug particles”.

In an embodiment, nanoparticulate pharmaceutical composition has at least one additional surface stabilizer adsorbed onto the surface of aprepitant. The additional surface stabilizer is selected from povidone, poloxamer and Vitamin E TPGS. Two or more surface stabilizers can also be employed in the compositions and methods of the invention. Preferred additional surface stabilizers include non-ionic or anionic surfactant.
The nanoparticulate pharmaceutical composition of the present invention may be further formulated into a suitable pharmaceutical dosage form for oral administration which includes, but not limited to suspension, syrup, tablets, capsules, powder, granules, pellets. The nanoparticulate pharmaceutical composition is formulated in the form of tablet or capsule.

The present invention provides a pharmaceutical dosage form comprising a nanoparticulate pharmaceutical composition of aprepitant or its pharmaceutically acceptable salt; a surface stabilizer adsorbed on the surface of aprepitant; and; optionally a pharmaceutically acceptable excipient.

In an embodiment, the present invention relates to a pharmaceutical dosage form comprising the nanoparticulate pharmaceutical composition comprising aprepitant or its pharmaceutically acceptable salt having a particle size of less than 250 nm, a surface stabilizer, a carrier and other pharmaceutical excipients.

The present invention further provides a process for preparing a nanoparticulate pharmaceutical composition of aprepitant of the present invention. Such process comprises contacting aprepitant with at least one surface stabilizer under conditions sufficient to provide a nanoparticulate surface stabilized composition; and; further reducing the particle size of the composition to get a desired particle size. The surface stabilizers can be contacted with aprepitant either before, during, or after size reduction of the composition.

The present invention also relates to a method of treating or preventing nausea and vomiting comprising administering to a patient in need of a therapeutically effective amount of a pharmaceutical composition according to the present invention.

The terms used herein are defined as follows.

By “salt” or “pharmaceutically acceptable salt”, it is meant those salts and esters which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with reasonable benefit to risk ratio, and effective for their intended use. Representative acid additions salts include the hydrochloride, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and lauryl sulphate salts. Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts. Preferably, the salt of Compound I includes sodium salt or potassium salt.

The term “surface stabilizer” as used herein includes the agents which associate with the surface of particles of the aprepitant, but do not chemically bond to or interact with it. Surface stabilizer generally provides steric and ionic barrier to prevent agglomeration of the particles.

The surface stabilizer as contemplated herein includes polymer and surfactant. In the context of present invention, the polymer includes, but is not limited to one or more of, cellulose derivatives, such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose sodium or calcium salt, hydroxyl ethyl cellulose, polyvinyl pyrrolidone, copovidone, carbopols, copolymers of polyvinyl pyrrolidone, polyoxyethylene alkyl ether, polyethylene glycol, co-block polymers of ethylene oxide and propylene oxide (Poloxamer®, Pluronic®), poly methacrylate derivatives, polyvinyl alcohol, polyvinyl alcohol derivatives and polyethylene glycol derivatives, such as macrogol glycerol stearate, natural gums like xanthan gum, locust bean gum, alginic acid, carrageenan, sodium alginate and the like.
Surfactants are wetting agents that lower the surface tension of a liquid allowing easier spreading and lower the interfacial tension between two liquids. Surfactants are usually organic compounds that are amphiphilic, therefore, they are soluble in both organic solvents and water. Surfactants reduce the surface tension of water by adsorbing at the liquid-gas interface. They also reduce the interfacial tension between oil and water by adsorbing at the liquid-liquid interface.
Surfactants are classified into two primary groups: ionic (anionic, cationic and zwitterionic) (dual charge) and non-ionic. Typically, the surfactant includes, but is not limited to one or more of poloxamer, polyoxyethylene sorbitan esters (known as Polysorbate® or Tween®), polyethoxylated castor oil (Cremophor®), methyl glucose sesquistearate, PEG-20 methyl glucoside sesquistearate, caprylocaproyl macrogol-8 glycerides, lauroyl macrogol-32- glycerides Steareth-21, polyethylene glycol 20 sorbitan monostearate, polyethylene glycol 60 sorbitan monostearate, polyethylene glycol 80 sorbitan monostearate, Steareth-20, Ceteth-20, PEG- 100 stearate, sodium stearoyl sarcosinate, hydrogenated lecithin, sodium cocoylglyceryl sulfate, sodium stearyl sulfate, sodium stearoyl lactylate, PEG-20 glyceryl monostearate, sucrose monostearate, sucrose polystearates, polyglyceryl 10 stearate, polyglyceryl 10 myristate, steareth 10, DEA oleth 3 phosphate, DEA oleth 10 phosphate, PPG-5 Ceteth 10 phosphate sodium salt, PPG-5 Ceteth 10 phosphate potassium salt, steareth-2, PEG-5 soya sterol oil, PEG- 10 soya sterol oil, diethanolamine cetyl phosphate, sorbitan monostearate, diethylenglycol monostearate, glyceryl monostearate, sodium stearyl sulfate, benzalkonium chloride, docusate sodium, triethanolamine, phospholipids and the like. Preferably, the surfactant includes polyoxyethylene sorbitan esters (known as Polysorbate® or Tween®), polyethoxylated castor oil (known as Cremophor®), glycerol monostearate, phospholipids, benzalkonium chloride, triethanolamine, sodium lauryl sulfate, docusate sodium, Vitamin E TPGS, soya lecithin, and the like. Preferrably the surfactant includes, but is not limited to, poloxamer, polyoxyethylene sorbitan esters (known as Polysorbate® or Tween®), polyethoxylated castor oil (known as Cremophor®), glycerol monostearate, phospholipids, benzalkonium chloride, triethanolamine, monoethanolamine, sodium lauryl sulfate, docusate sodium, Vitamin E TPGS, soya lecithin, and the like.
Most of these surface stabilizers are known and described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association, specifically incorporated by reference. The surface stabilizers are commercially available and/or can be prepared by techniques known in the art. The surface stabilizers physically adhere to the surface of aprepitant or its salt, but it does not form chemical bond to or chemically react with the aprepitant. Such chemical bonding or interaction would be undesirable as it could result in altering the function of the drug. The surface stabilizer is adsorbed on the surface of the active ingredient in an amount sufficient to maintain an effective average particle size of less than about 1000 nm, and more preferably, less than about 500 nm, and most preferably, less than about 250 nm. Individually adsorbed molecules of the surface stabilizer are essentially free of intermolecular cross-linkages.

In one embodiment, the surface stabilizer includes hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, polyethylene glycol, vitamin E-TPGS, poloxamer, Labrasol, magnesium aluminum silicate, povidone copovidone and natural gums. Preferably, hydroxyethyl cellulose, poloxamer, povidone and vitamin E-TPGS are used as a surface stabilizer.

By “pharmaceutically acceptable excipient” it is meant any of the components of a formulation or pharmaceutical composition other than the active ingredient, and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.

Pharmaceutically acceptable excipient, which includes, but not limited to one or more of carrier, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, opacifiers, colorants, gelling agents, antioxidants and solvents.

Non limiting carrier that can be employed in the spray drying for pharmaceutical compositions include, but are not limited to, saccharides, such as sugars and sugar alcohols (for example, lactose or sucrose, mannitol, or sorbitol), starches, flour, cellulose preparations and/or salts such as carbonates, bicarbonates and phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate. In one embodiment, the carrier excipient is mannitol or sucrose.

Non-limiting examples of diluents includes one or more of microcrystalline cellulose, silicified microcrystalline cellulose (e.g., Prosolv®), microfine cellulose, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like; cores/beads comprising insoluble inert materials like glass particles/beads or silicon dioxide, calcium phosphate dihydrate, dicalcium phosphate, calcium sulfate dihydrate, cellulose derivatives; soluble cores such as sugar spheres of sugars like dextrose, mannitol, sorbitol, or sucrose; insoluble inert plastic materials such as spherical or nearly spherical core beads of polyvinyl chloride, polystyrene or any other pharmaceutically acceptable insoluble synthetic polymeric material, acacia, guar gum, alginic acid, dextrin, maltodextrin, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel®), low substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose (e.g., Methocel®), carboxymethyl cellulose sodium, povidone (various grades of Kollidon®, Plasdone®), carboxymethyl cellulose calcium, croscarmellose sodium, (e.g., Ac-Di-Sol®, Primellose®), crospovidone (e.g., Kollidon®, Polyplasdone®), povidone K-30, polacrilin potassium, sodium starch glycolate (e.g., Primogel, Explotab®).

Non-limiting examples of glidants and lubricants includes one or more of stearic acid, magnesium stearate, talc, colloidal silicon dioxide, and sodium stearyl fumarate.

Non-limiting examples of preservatives includes one or more of phenoxyethanol, parabens such as methyl paraben and propyl paraben and their sodium salts, propylene glycols, sorbates, urea derivatives such as diazolindinyl urea, and the like and mixtures thereof. Non-limiting examples of buffering agents include sodium hydroxide, potassium hydroxide, ammonium hydroxide and the like and mixtures thereof. Non-limiting examples of chelating agents include ethylene diamine tetraacetic acid (“EDTA”), disodium edetate and EDTA derivatives, and the like.
Non-limiting examples of polymers includes one or more of gum arabic, sodium based lignosulfonate, methyl methacrylate, methacrylate copolymers, isobutyl methacrylate, ethylene glycol dimethacrylate, and the like.

Non-limiting examples of gelling agents/viscosifying agents includes one or more of carbomers (carbopol), modified cellulose derivatives, naturally-occurring, synthetic or semi-synthetic gums such as xanthan gum, acacia and tragacanth, sodium alginate, gelatin, modified starches, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose; co-polymers such as those formed between maleic anhydride and methyl vinyl ether, colloidal silica and methacrylate derivatives, polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, polyvinyl alcohol and the like.

Non-limiting examples of co-solvents includes one or more of propylene glycol, polyol esters of fatty acids, trialkyl citrate esters, propylene carbonate, dimethylisosorbide, ethyl lactate, N-methylpyrrolidones, transcutol, glycofurol, decaglycerol mono-, dioleate (Caprol PGE-860), triglycerol monooleate (Caprol 3GO), polyglycerol oleate (Caprol MPGO), mixed diesters of Caprylic/Capric acid and propylene glycol (Captex 200) , glyceryl mono- and di-caprate (Capmul MCM), isostearyl isostearate, oleic acid, peppermint oil, oleic acid, soybean oil, safflower oil, corn oil, olive oil, cottonseed oil, arachis oil, sunflower seed oil, palm oil, rapeseed oil, ethyl oleate, glyceryl monooleate, Vitamin E TPGS and the like.

Non-limiting examples of solvents includes one or more of water; tetrahydrofuran; propylene glycol; liquid petrolatum; ether; petroleum ether; alcohols, e.g., methanol, ethanol, isopropyl alcohol and higher alcohols; alkanes, e.g., pentane, hexane and heptane; ketones, e.g., acetone and methyl ethyl ketone; chlorinated hydrocarbons, e.g., chloroform, carbon tetrachloride, methylene chloride and ethylene dichloride; acetates, e.g., ethyl acetate; lipids, e.g., isopropyl myristate, diisopropyl adipate and mineral oil and the like.

The “nanoparticulate pharmaceutical composition” in the context of present invention refers to a pharmaceutical dispersion wherein drug particles are dispersed in a solvent, and having an effective average particle size of less than about 1000 nm.

The terms "dispersion" and "suspension" are synonymous and used interchangeably herein and refer to a formulation where the ingredient particles remain suspended undissolved in a fluid such as water.

The term "patient" or "subject" as used herein refers to an animal, preferably a mammal, most preferably a human (such as an adult, including an elderly adult such as an elderly man or an elderly woman), who has been the object of treatment, observation or experiment.

The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.

As used herein, the term "effective average particle size" (or synonymously, "mean particle size") refers to the distribution of particles, wherein about 50 volume percent of all the particles measured have a size less than the defined average particle size value. This can be identified by the term "D50" or “d (0.5)”.

As used herein, the term "D10" refers to the distribution of particles; wherein about 10 volume percent of all the particles measured have a size less than the defined particle size value. This can be identified by the term “d (0.1)” as well. Similarly, as used herein, the term "D80" refers to the distribution of particles; wherein about 80 volume percent of all the particles measured have a size less than the defined particle size value. This can be identified by the term or “d (0.8)” as well. On similar lines, as used herein, the term "D90" refers to the distribution of particles; wherein about 90 volume percent of all the particles measured have a size less than the defined particle size value. This can be identified by the term or “d (0.9)” as well.

The particle size can be measured using various techniques like laser diffraction, photon correlation spectroscopy (PCS) and Coulter’s principle. When PCS is used as the method of determining particle size, the average particle size is the Z-average particle diameter known to those skilled in the art. Typically, instruments like ZETASIZER® 3000 HS (Malvern® Instruments Ltd., Malvern, United Kingdom), NICOMP 388TM ZLS system (PSS-Nicomp Particle Sizing Systems, Santa Barbara, CA, USA), or Coulter Counter are generally used to determine the mean particle size. Preferably, Mastersizer 2000 (Malvern® Instruments Ltd., Malvern, United Kingdom) is used to determine the particle size of the particles.

The nanoparticles of the invention comprises aprepitant which can exists as a an amorphous form or in a crystalline form such as Form I, Form II, Form III, Form IV or a mixture thereof. Preferably, aprepitant used herein is a mixture of crystalline Form I and Form II.

The relative amount of aprepitant and one or more surface stabilizer can vary depending upon hydrophilic-lipophilic balance (HLB), melting point, and water solubility of the surface stabilizer, and the surface tension of water solutions of the stabilizer etc.

In one embodiment the present invention relates to a process for preparation of a nanoparticulate composition. The typical processes involved in the preparation of the nanoparticulate composition (or pharmaceutical dosage form containing the nanoparticulate composition) include various unit operations such as milling, micronization, mixing, homogenizing, sifting, spraying, solubilizing, dispersing, granulating, lubricating, compressing, coating, filling, and the like. These processes, as contemplated by a person skilled in the formulation art, have been incorporated herein for preparing the nanoparticulate pharmaceutical composition of the present invention. The reduction of the particle size may be achieved using various techniques like dry/wet milling, micronization, high pressure homogenization, controlled precipitation using antisolvent, micoprecipitation techniques, microfluidization and supercritical fluid technology. Exemplary methods of making nanoparticulate compositions are described in U.S. Pat nos. 5,145,684 and 5,862,999.

The process for preparing a pharmaceutical dosage form comprising a nanoparticulate pharmaceutical composition of aprepitant generally comprises steps of nanosupension preparation of aprepitant, premilling, media milling, spray drying, coating dispersion preparation, Wurster column coating, sieving, blending, and encapsulation.

In one of the embodiment, the present invention relates to a process of preparing the nanoparticulate pharmaceutical composition comprising the steps of: a) dispersing aprepitant or its pharmaceutically acceptable salt and at least one surface stabilizer in a liquid dispersion medium; (b) wet grinding the mixture a) in the presence of rigid grinding media to form a nanosuspension having a desired particle size; and; (c) isolating the resultant nanoparticulate composition of step b) from the grinding media.

In one of the embodiment, the present invention relates to a process of preparing the pharmaceutical dosage form comprising the steps of: a) preparing a nanosuspension of aprepitant or its pharmaceutically acceptable salt and at least one surface stabilizer ; b) spray drying the suspension to form granules; c) optionally lubricating the spray dried granules; and; d) optionally encapsulating the resultant product into hard gelatin capsules.
In an embodiment, the present invention relates to a process of preparing pharmaceutical dosage form comprises the nanoparticulate pharmaceutical composition of the present invention which includes, but not limited to suspension, syrup, tablets, capsules, powder, granules, pellets. The nanoparticulate pharmaceutical composition is formulated in the form of tablet or capsule. In case of tablet dosage form, nanoparticulate pharmaceutical composition can be compressed into tablet. While in case of capsule dosage form, nanoparticulate composition can be encapsulated in hard gelatin capsule. Mini-tablet can also be enclosed with hard gelatin capsule shell. The tablet or capsule dosage form generally comprises at least one pharmaceutical excipient.

In an embodiment, the present invention relates to a pharmaceutical dosage form comprising the nanoparticulate pharmaceutical composition comprising aprepitant or its pharmaceutically acceptable salt having a particle size of less than 250 nm, a surface stabilizer, a carrier and other pharmaceutical excipients.

In another of the embodiment, the pharmaceutical dosage form can be prepared by spray drying or spray coating of dispersion of nanoparticulate composition of aprepitant onto solid support such as microcrystalline cellulose spheres or sugar pellets and lubricating the coated spheres or spray dried granules; and; formulating into desired dosage form i.e. tablet or capsule. The preferred pharmaceutical dosage form is capsule.

Pharmaceutical compositions according to the invention may also comprise one or more binding agents, filling agents, lubricating agents, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, and other excipients. Such excipients are known in the art.

Milling of aprepitant to obtain a nanoparticulate drug particles comprise dispersing particles of aprepitant in a liquid dispersion medium, followed by applying mechanical means in the presence of grinding media to reduce the particle size of aprepitant to the desired effective average particle size. The particles of aprepitant can be reduced in size in the presence of at least one surface stabilizer. Alternatively, the particles of the aprepitant can be contacted with one or more surface stabilizers after attrition. Other pharmaceutical acceptable excipients, such as a carrier, diluent, can be added to aprepitant /surface stabilizer composition during the size reduction process. Dispersions can be manufactured continuously or in a batch mode. The resultant nanoparticulate dispersion can be utilized in solid or liquid dosage formulations, such as controlled release dosage formulations, solid dose fast melt formulations, aerosol formulations, tablets, capsules, etc.

The mechanical means applied to reduce the particle size of the active ingredient can be a dispersion mill. Suitable dispersion mills include, but are not limited to, a ball mill, an attritor mill, a vibratory mill, and media mills such as a sand mill or a bead mill. A media mill is preferred due to the relatively shorter milling time required to provide the desired reduction in particle size.

In a preferred grinding process, the particles are made continuously. In such a continuous method, the slurry of active ingredient/surface stabilizer and optionally an additional surface stablizer is continuously introduced into a milling chamber, the active ingredient is continuously contacted with grinding media while in the chamber to reduce the particle size of the active ingredient, and the active ingredient is continuously removed from the milling chamber. The surface stabilizer, either alone or in conjunction with one or more additional surface stabilizers, can also be continuously added to the media chamber along with the active ingredient, or it can be added to the active ingredient which is removed from the chamber following grinding.

The resulting dispersion of the present invention is stable and comprises the liquid dispersion medium described above. The dispersion of surface stabilizer and nanoparticulate active ingredient can be spray dried, spray coated onto a solid support such as cellulose spheres or sugar spheres or other pharmaceutical excipients using techniques well known in the art.

The grinding media for the particle size reduction step can be selected from rigid media which is preferably spherical or particulate in form and which has an average size of less than about 3 mm and, more preferably, less than about 1 mm. Such media can provide the desired drug particles of the invention with shorter processing times and impart less wear to the milling equipment. The selection of material for the grinding media is not believed to be critical. Zirconium oxide, such as 95% ZrO stabilized with yttrium and 95% ZrO stabilized with magnesia, zirconium silicate, and glass grinding media have been found to provide particles having acceptable minimal levels of contamination for the preparation of pharmaceutical compositions. Other media, such as stainless steel, titania, and alumina can also be used. Preferred grinding media have a density greater than about 3 g/cm3.

The grinding media can comprise particles, preferably spherical in shape, such as beads, consisting of essentially polymeric resin. Alternatively, the grinding media can comprise particles having a core with a coating of the polymeric resin adhered thereto. The media can range in size from about 0.1 to about 3 mm. For fine grinding, the particles preferably are from about 0.2 to about 2 mm, and more preferably, from about 0.25 to about 1 mm in size.

The polymeric resin can have a density from about 0.8 to about 3.0 g/cm3. Higher density resins are preferred as such resins can provide more efficient particle size reduction.

In general, polymeric resins suitable for use in the present invention are chemically and physically inert, substantially free of metals, solvent, and monomers, and of sufficient hardness and friability to enable them to avoid being chipped or crushed during grinding. Suitable polymeric resins include, but are not limited to, cross-linked polystyrenes, such as polystyrene cross-linked with divinylbenzene, styrene copolymers, polycarbonates, polyacetals such as Delrin.RTM., vinyl chloride polymers and copolymers, polyurethanes, polyamides, poly(tetrafluoroethylenes), such as Teflon.RTM. and other fluoropolymers, high density polyethylenes, polypropylenes, cellulose ethers and esters such as cellulose acetate, polyhydroxymethacrylate, polyhydroxyethyl acrylate, silicone containing polymers such as polysiloxanes, and the like. The polymer can also be biodegradable. Exemplary biodegradabe polymers include, but are not limited to, poly(lactides), poly(glycolide) copolymers of lactides and glycolide, polyanhydrides, poly(hydroxy-ethyl methacylate), poly(imino carbonates), poly(N-acylhydroxyproline)esters, poly(N-palmitoyl hydroxyproline)esters, ethylene-vinyl acetate copolymers, poly(orthoesters), poly(caprolactones), and poly(phoshazenes). For biodegradable polymers, contamination of the resultant composition from the media itself can advantageously metabolize in vivo into biologically acceptable products that can be eliminated from the body.

The grinding media is separated from the milled particulate active ingredient using conventional separation techniques in a secondary process, such as by filtration, sieving through a mesh filter or screen, and the like. Other separation techniques such as centrifugation may also be employed. The surface stabilizer can be added to the milled particulate product either before or after the milled product is separated from the grinding media.

In one embodiment, the present invention relates to a pharmaceutical dosage form comprising a nanoparticulate pharmaceutical composition comprising 15% - 60% by weight of aprepitant or its pharmaceutically acceptable salt; 10% -65% by weight of a surface stabilizer; and 0% - 50% by weight of pharmaceutical excipients, to the total weight of the pharmaceutical dosage form.

In another embodiment, the present invention relates to a pharmaceutical dosage form comprising a nanoparticulate pharmaceutical composition comprising about 25-45% by weight of aprepitant having a particle size of less than 250 nm; about 20-45% by weight of a surface stabilizer; about 0-20% by weight of a carrier; and about 0-20% by weight of a other pharmaceutical excipients, to the total weight of the pharmaceutical dosage form.

In another embodiment, the present invention relates to a pharmaceutical dosage form comprising a nanoparticulate pharmaceutical composition comprising about 30-40% by weight of aprepitant having a particle size of less than 250 nm; about 22-40% by weight of a surface stabilizer; about 5-20% by weight of a carrier; and about 5-15% by weight of a other pharmaceutical excipients, to the total weight of the dosage form.

In one embodiment, the present invention relates to a pharmaceutical dosage form comprising a nanoparticulate pharmaceutical composition comprising 30%-40% by weight of aprepitant, 4%-6% by weight of hydroxyl ethyl cellulose, 6%-9% by weight of poloxamer 14%-18% by weight of povidone, 12%-17% by weight of mannitol, 3%-5% of vitamin E polyethylene glycol succinate, 5%-8% by weight of microcrystalline cellulose, 0.1%-1% by weight of colloidal silicon dioxide, 0.1%-1% by weight of sodium steryl fumarate, to the total weight of the dosage form.

In one of the embodiment, the present invention relates to a process of preparing the nanoparticulate pharmaceutical composition comprising the steps of: a) dispersing aprepitant or its pharmaceutically acceptable salt and at least one surface stabilizer in a liquid dispersion medium; (b) wet grinding the mixture a) in the presence of rigid grinding media to form a nanosuspension having a desired particle size; and; (c) isolating the resultant nanoparticulate composition of step b) from the grinding media.

In one of the embodiment, the present invention relates to a process of preparing the pharmaceutical dosage form comprising the steps of: a) preparing a nanosuspension of aprepitant or its pharmaceutically acceptable salt and at least one surface stabilizer ; b) spray drying the suspension to form granules; c) optionally lubricating the spray dried granules; and; d) optionally encapsulating the resultant product into hard gelatin capsules.

In one of the embodiment, the present invention relates to a process of preparing the pharmaceutical dosage form comprising the steps of: a) preparing a nanosuspension of aprepitant or its pharmaceutically acceptable salt and a surface stabilizer; b) spray drying the suspension to form granules; c) optionally compacting the spray dried granules by using roller compactor at suitable parameters d) lubricating the spray dried granules; and; d) optionally encapsulating the resultant product into hard gelatin capsules.
In one of the embodiment, the present invention relates to a process of preparing the pharmaceutical dosage form comprising the steps of: a) preparing a nanosuspension of aprepitant or its pharmaceutically acceptable salt and at least one surface stabilizer; b) spray coating the nanosuspension onto solid support; c) optionally lubricating the coated spheres; and; d) optionally encapsulating the resultant product into hard gelatin capsules.

In another embodiment, the present invention relates to a process for preparing a pharmaceutical dosage form is as follows: (a) making a slurry preparation by dispersing aprepitant, surface stabilizers such as Vitamin E TPGS, hydroxy ethyl cellulose, poloxamer and/or povidone and carrier such as mannitol in water, (b) media milling using zirconium beads to obtained desired nanosuspension, (d) filtration of nanosuspension, (e) spray drying, (f) sieving, (g) compaction of spray dried granules, (h) blending of granules with suitable lubricant, and (i) encapsulation in capsules.

The present invention also relates to a method of treating or preventing nausea and vomiting comprising administering to a patient in need of a therapeutically effective amount of a pharmaceutical composition according to the present invention.

The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.

EXAMPLES

EXAMPLE 1: Nanoparticulate pharmaceutical composition of aprepitant
Ingredient Quantity (mg/unit)
1A 1B 1C
Aprepitant 125 125 125
Hydroxyethyl Cellulose 250L 15 15 15
Vitamin E TPGS 25 25 25
Poloxamer 407 5 30 5
Polyvinyl Pyrrolidone K30 - 100 100
Mannitol - 40 -
Caprylocaproyl macrogol-8 glyceride (Labrasol®) - 10 -
PEG 1500 100 - -
Purified water q.s. q.s. q.s.
Total weight (mg) 270 340 260

Manufacturing process

1. Aprepitant, hydroxyethyl cellulose, vitamin E TPGS, polaxamer, PVP K30, Mannitol, Labrasol® or PEG 1500 were dispersed in weighed quantity of water to make a slurry.
2. The slurry of step 1 was charged into media mill containing either 0.2 or 0.1 mm zirconium beads.
3. The slurry of step 2 was milled till the particle size of d(0.9) less than 0.4µ was obtained.
4. The suspension of step 3 was filtered using nylon filter.
5. The nanosuspension of step 4 was further processed to either spray drying or spray coating on a solid support.
Particle size data: Particle size of nanoparticulate composition 1B

Parameter (volume % undersize) Particle size (nm)
D10 140 nm
D50 192 nm
D90 280 nm

EXAMPLE 2: Pharmaceutical dosage form containing nanosuspension pharmaceutical composition of aprepitant
Ingredients Quantity (mg/unit)
2A 2B 2C 2D 2E
Nanosuspension of Example 1 270 270 270 340 260
Mannitol 125 125 125 45 90
PVP K30 143 43 43 20 20
Monoethanolmine 1 1 1 1 1
Caprylocaproyl macrogol-8 glyceride (Labrasol®) 10 10 10 - 10
Purified Water q.s. q.s. q.s. q.s. q.s.
Microcrystalline Cellulose 25 25 35 35 -
Colloidal Silicon Dioxide 4 4 4 4 -
Sodium stearyl fumarate 5 5 5 5 4
Total weight (mg) 583 483 493 450 385

Procedure for spray drying of the nano-suspension by using spray dryer
1. Nanosuspension of Example 1 along with Mannitol, PVPK30, labrasol, monoethanolamine was dispersed in water to make a slurry.
2. The dispersion of step 1 was Spray dried at outlet temperature of 50° C -60° C and inlet temp 100° C to 140° C.
3. The spray dried granules of step 2 were passed through ASTM # 40 sieve.
4. Microcrystalline cellulose and Colloidal silicon dioxide were sifted through ASTM # 40 and sodium stearyl fumarate was sifted through ASTM # 60.
5. The spray dried granules of step 3 were blended with blend of step 4.
6. The powder blend of step 5 was encapsulated in hard gelatin capsules of suitable size using a suitable capsule filling machine.

EXAMPLE 3: Pharmaceutical dosage form containing nanoparticulate pharmaceutical composition of aprepitant
Ingredients Quantity (mg/unit)
3A 3B 3C 3D 3E
Nanosuspension of Example 1 270 270 270 340 260
Mannitol 125 125 125 45 90
PVP K30 143 43 43 20 20
Aerosil 200 1 1 1 - -
Monoethanolmine 1 1 1 1 1
Caprylocaproyl macrogol-8 glyceride (Labrasol®) 10 10 10 - 10
Purified Water q.s. q.s. q.s. q.s. q.s.
Microcrystalline beads 100 100 100 100 100
Total weight (mg) 650 550 570 506 481

Procedure for loading of the nanosuspension on MCC beads
1. Nanosuspension of Example 1 along with Mannitol, PVP K30, Labrasol, monoethanolamine were dispered in in water to make a slurry.
2. The slurry of step 1 was coated on to microcrystalline cellulose spheres using a Wurster coater at inlet temperature of 40°C -60°C. Aerosil may be optionally added during coating.
3. The coated beads of step 2 were sifted through ASTM # 18 sieve.
4. The beads of step 3 were encapsulated in suitable size hard gelatin capsules.

EXAMPLE 4: Pharmaceutical composition containing spray dried granules of Aprepitant
Ingredient Quantity (mg/unit)
4A 4B 4C
Aprepitant 125 80 40
Hydroxyethyl Cellulose 250L 20 12.8 6.4
Vitamin E polyethylene glycon succinate 15 9.6 4.8
Polaxamer 407 30 19.2 9.6
Polyvinyl Pyrrolidone K30 (PVPK30) 60 38.4 19.2
Mannitol 50 32 16
Purified Water q.s. q.s. q.s.
Total weight of nanosuspension (mg) 300 192 96
Roller compaction
Spray dries granules 300 192 96
Lubrication
Spray dries granules 300 192 96
Microcrystalline cellulose 24 15.36 7.68
Colloidal silicon dioxide 3 1.92 0.96
Sodium stearyl fumarate 3 1.92 0.96
Total weight (mg) 330 211.2 105.6
Hard gelatin capsule shell 76 61 38
Final weight (mg) 406 272.2 143.6

A. Procedure for nanosuspension preparation for aprepitant
1. Aprepitant, vitamin E PGS, polaxamer, PVPK30, Mannitol, were dispersed in weighed quantity of water to make a slurry.
2. The slurry of step 1 was charged into media mill containing either 0.2 or 0.1 mm zirconium beads.
3. The slurry of step 2 was milled till the particle size of d(0.9) less than 0.32µ was obtained.
4. Hydroxyethyl cellulose was added to the milled slurry of step 3 and milling was continued to obtain the desired particle size of the nanosuspension.
5. The milled nanosuspension of step 4 was filtered.
B. Procedure for spray drying of the nanosuspension by using spray dryer
6. The nanosuspension of step 5 was spray dried at outlet temperature of 50° C -60° C and inlet temp 100° C to 140° C to obtain spray dried granules.
7. The spray dried granules of step 6 were sifted through ASTM # 24.
C. Roller compaction and Lubrication of Spray Dried Granules
8. The spray dried granules obtained in step7 were compacted using roller compactor and were sifted through ASTM # 24.
9. The oversized granules from the compacts of step 8 were milled and sifted through ASTM # 24.
10. Microcrystalline cellulose and Colloidal silicon dioxide were sifted through ASTM # 40 and Sodium stearyl fumarate was sifted through ASTM # 60.
11. The sifted spray dried granules of steps 7 to 9 were blended with blend of step 10.
12. The lubricated blend of step 11 was filled in suitable size hard gelatin capsules.
Particle size data: Particle size data of Aprepitant nanosuspension and compacted powder
Parameter (volume % undersize) Particle size (nm)
Aprepitant Nanosuspension 4A 4B 4C
D10 137 136 136
D50 187 185 186
D90 268 265 266
Aprepitant compacted powder
D10 145 144 145
D50 202 201 203
D90 321 313 323

EXAMPLE 5: Stability data of Aprepitant composition as per Example 4A (125mg Capsule), 4B (80mg Capsule) and 4C (40mg Capsule)
Storage Condition: 25ºC/60% ± 5% Relative Humidity
Pack Details:
Example 4A (125mg Capsule) – 4 capsules packed in Alu-Alu Blister pack
Example 4B (80mg Capsule) – 6 capsules packed in Alu-Alu Blister pack
Example 4C (40mg Capsule) - 6 capsules packed in Alu-Alu Blister pack
Tests 125mg Capsule 80mg Capsule 40mg Capsule
3M 6M 9M 3M 6M 9M 3M 6M 9M
Dissolution (Mean%) 95 102 97 100 101 98 104 102 100
Water content (%w/w) 4.2 3.4 3.0 2.8 3.4 3.1
Related Substance (w/w)
Any other impurity (%w/w)