PHARMACEUTICAL COMPOSITIONS COMPRISING APREPITANT

INTRODUCTION

Aspects of the present application relate to pharmaceutical compositions comprising aprepitant and processes for preparation thereof. In embodiments, the application relates to pharmaceutical compositions comprising solubility-enhanced aprepitant compositions, wherein aprepitant along with one or more miscible polymers is the form of a melt extrudate.

The drug compound having the adopted name "aprepitant" has a chemical name 5-
[[(2R,3S)-2-[(lR)-l-[3,5-bis (trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-
morpholinyl]methyl]-l,2-dihydro-3H-l,2,4-triazol-3-one. It has structural Formula I.
Formula I

Aprepitant is a neurokinin-1 (NK-1) receptor antagonist, useful as an antiemetic agent. It is approved for the treatment of emesis associated with chemotherapy and is commercially available in products sold as EMEND® in capsules containing 40 mg, 80 mg, or 125 mg of aprepitant for oral administration.

Aprepitant is practically insoluble in water, sparingly soluble in ethanol and isopropyl alcohol, and slightly soluble in acetonitrile. Aprepitant is a molecule having poor solubility and poor permeability characteristics. Additionally, the delivery of aprepitant is also associated with high inter-patient variability when delivered by a solid dosage form. The poor solubility of aprepitant in aqueous media and poor delivery characteristics pose a tremendous challenge to the pharmaceutical composition scientist in providing for its delivery in adequate concentrations into the systemic circulation. Some of the generally known approaches to improve drug solubility characteristics include salt formation, particle size reduction, pH adjustment, use of surfactants, inclusion complexes with cyclodextrins, use of oily compositions, use of self-emulsifying drug delivery with cyclodextrins, use of oily compositions, use of self-emulsifying drug delivery systems, formation of co-precipitates with hydrophilic polymers, and co-milling with hydrophilic excipients, to name a few.

The rate of dissolution of poorly water-soluble drug is a rate-limiting factor in its absorption by the body. It is generally known that a reduction in the particle sizes of an active ingredient can result in an increase in the dissolution rate of such compounds through an increase in the surface area of the solid phase that comes in contact with the aqueous medium. There is no way to predict the extent to which the dissolution rate of an active will be enhanced through particle size reduction or what is the desirable particle size for achieving desired bioavailability characteristics. Particle size reduction beyond certain values may many times result in other material handling and processing issues, such as generation of static charges on new exposed surfaces and agglomeration, thereby resulting in unpredictable variation in solubility, dissolution, and hence bioavailability.

The use of cyclodextrins to enhance stability, aqueous solubility and bioavailability of poorly soluble drugs has been described. U.S. Patent Nos. 5,070,081, 5,942,501, 6,071,964, and 6,828,334 describe methods to enhance stability and/or solubility, and bioavailability, of poorly soluble drugs with cyclodextrins.
U.S. Patent No. 5,145,684 describes nanoparticles of pharmaceutical actives that are stabilized with a surface stabilizer, and processes to make these particles. U.S. Patent Application Publication No. 2004/0214746 and International Application Publication No. WO 03/049718 describe nanoparticulate compositions of aprepitant and their use in the treatment of disease conditions.

In spite of a product being commercially available as a nanoparticulate composition (EMEND®) with an average particle size less than about 1000 nm, the bioavailability of the compound when given orally is only about 60-65%. Additionally, the preparation of a nanoparticulate composition with an average particle size less than 2000 nm is difficult and involves processing over extended periods of time using specialized equipment, making the product uneconomical to manufacture on a large scale. Also, nanoparticulate products are subject to agglomeration and have surface changes requiring special precautions such as addition of surface stabilizers during the processing and layering directly onto substrates to overcome these problems. Such nanonization processes can also result in physical and chemical instability of aprepitant, which is undesirable.

Conversion of a less soluble polymorphic form of an active agent to a polymorphic form having improved solubility is another approach to achieve desired release profile of active agent. International Application Publication No. WO 2007/088483 describes a preparation of amorphous aprepitant. International Application Publication No. WO 2007/112457 discloses a mixture of two crystalline forms, viz., Form I and Form II, and pharmaceutical compositions thereof. International Application Publication No. WO 2007/147160 describes compositions of amorphous aprepitant in the form of a co-precipitate that has enhanced solubility of aprepitant and a composition comprising the solubility enhanced form in the form of an inclusion complex. International Application Publication No. WO2007/016582 discloses a co-precipitate comprising amorphous aprepitant and a pharmaceutically acceptable carrier. International Application Publication No. WO2009/108828 discloses solubility-enhanced forms of aprepitant that also possess stability against solid state conversions. Certain solubility-enhanced forms of aprepitant comprise a cyclodextrin or any of its derivatives. Other solubility-enhanced forms of aprepitant comprise fine particle preparations of aprepitant. The application further provides non-nanoparticulate pharmaceutical compositions prepared using solubility-enhanced forms of aprepitant.

Solid dispersion is an approach to disperse a poorly soluble drug in a polymer matrix in the solid state. Several techniques have been developed to prepare solid dispersions, including co-precipitation (see, e.g., U.S. Patent Nos. 5,985,326 and 6,350,786), fusion, spray-drying (see, e.g., U.S. Patent No. 7,008,640), and hot-melt extrusion (see, e.g., U.S. Patent No. 7,081,255). These techniques provide a highly dispersed drug molecule in a polymer matrix, usually at the molecular level or in a microcrystalline phase. The amorphous or the microcrystalline drug in solid dispersions can be more stable than its pure form in the same physical state. However, the solid dispersions prepared from different methods can differ in properties, such as porosity, surface area, density, stability, hygroscopicity, dissolution, and therefore bioavailability. There is no evidence in the literature suggesting the superiority of one method over another to achieve a desired pharmacokinetic profile, or better dose proportionality.

U.S. Patent No. 6,548,555 describes the use of ionic polymers, including hydroxypropyl methylcellulose acetate succinate (HPMCAS), to prepare solid dispersions for improved solubility and better bioavailability.

U.S. Application Publication No. 2008/0293787 discloses solid dispersions prepared by co-precipitation and hot melt extrusion having sustained drug release profiles. U.S. Application Publication No.

2010/0015225 discloses solid dispersions of a neurokinin antagonist that can be prepared by melt extrusion of the drug with a carrier.

The publication further states that solid dispersions prepared by other methods have better bioavailability than the one prepared by melt extrusion. International Application Publication No. WO2009/048606 discloses a nonaqueous, extrudable composition comprising at least one thermoplastic polymer in an amount more than 20 wt % of the whole composition and a bioactive agent. U.S. Application Publication Nos. 2006/0034937 and 2007/0178152 disclose a pharmaceutical composition in the form of a solid carrier comprising an admixture of: an active pharmaceutical ingredient, and at least one hydrophilic surfactant.

International Application Publication No. WO2010/149183 describes solid solutions of aprepitant wherein aprepitant is molecularly dispersed in the matrix and there are no more aprepitant particles.
However, there remains a need for developing pharmaceutical compositions of aprepitant that have appreciable solubility and storage stability, are easy to manufacture, are cost-effective, and can be bioequivalent to a commercial product.

SUMMARY
In certain aspects, the present application relates to pharmaceutical compositions comprising melt extruded aprepitant compositions and processes for preparation thereof. In embodiments, the present application relates to compositions containing solubility-enhanced aprepitant compositions.
In embodiments, solubility-enhanced aprepitant compositions of the present application comprise aprepitant together with one or more miscible polymer, in the form of melt extrudates, and optionally at least one other pharmaceutically acceptable excipient.

In embodiments, solubility-enhanced aprepitant compositions of the present application comprise aprepitant together with one or more miscible polymers and at least one dispersing agent, in the form of melt extrudates, and optionally at least one other pharmaceutically acceptable excipient.

In embodiments, solubility-enhanced compositions of the present application comprise aprepitant in the form of melt extrudates together with one or more miscible polymers, wherein a miscible polymer is an ionic or non-ionic polymer such as a polymethylmethacrylate, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone-polyvinylalcohol, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, or methylcellulose acetate phthalate, and a polymeric surfactant such as a poloxamer.

In embodiments, solubility-enhanced compositions of the present application comprise aprepitant in the form of melt extrudates together with one or more miscible polymers and at least one dispersing agent, such as a polyethoxylated castor oil (e.g., Cremophor® RH 40), diacetylated monoglyceride, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, triethyl citrate, or poloxamer (e.g., Lutrol® F 68).

In embodiments, solubility-enhanced compositions of the present application comprise aprepitant in the form of melt extrudates together with one or more miscible polymers, wherein a miscible polymer is a polyvinylpyrrolidone.

In embodiments, solubility-enhanced compositions of the present application comprise aprepitant in the form of melt extrudates together with one or more miscible polymers, wherein weight ratios of aprepitant
to miscible polymer are in the range of 1:0.5 to 1:15.

In embodiments, solubility-enhanced compositions of the present application comprise aprepitant in the form of melt extrudates together with one or more dispersing agents, wherein weight ratios of aprepitant to dispersing agent are in the range of 1:10 to 10:1.

In embodiments, pharmaceutical compositions comprising melt extruded aprepitant possess improved drug solubility, as compared to other pharmaceutical compositions of aprepitant.

In embodiments, pharmaceutical compositions comprising melt extruded aprepitant of the present application exhibit in vitro dissolution profiles that are comparable to commercially available EMEND® capsules.

In embodiments, pharmaceutical compositions comprising melt extruded aprepitant of the present application possess excellent storage stability.

In an aspect, the present application relates to processes for preparing pharmaceutical compositions comprising melt extruded aprepitant, embodiments comprising:

(i) Combining aprepitant and a miscible polymer.
(ii) Extruding the mixture of (i).
(iii) Milling the extrudates to produce desired particle sizes.
(iv) Blending the milled extrudate with other excipients.

In embodiments, pharmaceutical compositions of the present application comprising aprepitant in the form of melt extrudates provide in vitro dissolution of aprepitant such that more than about 80% of the drug is dissolved within about 60 minutes after immersion into 900 mL of a 0.5% w/v sodium lauryl sulphate aqueous solution, wherein the dissolution is conducted using USP type 2 (paddle type) apparatus with shakers, with 75 RPM stirring.

An aspect of the application includes pharmaceutical compositions comprising aprepitant in the form of melt extrudates, providing in vitro dissolution of aprepitant such that about 25% to about 90% of the aprepitant is dissolved within about 30 minutes, and about 40% to about 99% of the aprepitant is dissolved within about 60 minutes, after immersion into 900 mL of fed state simulated intestinal fluid pH 5.8 dissolution medium, when tested in USP apparatus 2 with 75 rpm stirring.

An aspect of the application also provides methods of using pharmaceutical compositions comprising melt extruded aprepitant, such as in the treatment of chemotherapy-induced nausea and vomiting.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows Initial comparative X-ray powder diffraction (XRPD) patterns of Aprepitant crystalline form (A), Aprepitant composition of example 1A (B) and placebo composition prepared using formula of example 1A except the active ingredient (C).

Fig. 2 shows comparative X-ray powder diffraction (XRPD) patterns of XRPD of Aprepitant crystalline form (A), placebo composition prepared using formula of example 1A except the active ingredient (B), Aprepitant composition of example 1A (C) on storage of 1 month at temperature of 25°C and relative humidity (RH) of 60% and Aprepitant composition of example 1A (D) as initial composition.

Fig. 3 shows comparative X-ray powder diffraction (XRPD) patterns of XRPD of Aprepitant crystalline form (A), placebo composition prepared using formula of example 1A except the active ingredient (B), Aprepitant composition of example 1A (C) on storage of 1 month at temperature of 40°C and relative humidity (RH) of 75% and Aprepitant composition of example 1A (D) as initial composition.

DETAILED DESCRIPTION

Unless mentioned otherwise, all embodiments of the application can be used for the delivery of aprepitant or any of its pharmaceutically acceptable salts, solvates, enantiomers, or mixtures thereof, without limitation.

The term "aprepitant" includes an amorphous form, alone or in combination with any other polymorphic form, crystalline Forms I or II, or includes a combination of crystalline Forms I and II, solid dispersions, and the like.

The term "crystalline aprepitant" includes crystalline Form I or Form II, or a mixture of crystalline Forms I and II in a ratio ranging from about 5:95 to about 95:5.

"Substantially particulate form" provides for aprepitant in particulate form wherein not less than about 10% of the aprepitant is present as crystalline particles.

"Solubility-enhanced aprepitant composition" or "melt extruded aprepitant composition" or "aprepitant melt extrudate" "melt extrudate" or "aprepitant composition" means compositions wherein aprepitant, together with one or more miscible polymers and optionally at least one dispersing agent is present as a melt extruded composition.

The term "composition" as used herein refers to pharmaceutical dosage forms comprising solubility-enhanced aprepitant compositions and one or more pharmaceutically acceptable excipients as desired for the effective delivery of aprepitant.

In embodiments, the application relates to pharmaceutical compositions of aprepitant having improved solubility characteristics that have improved dissolution profiles of aprepitant.

For a poorly water soluble drug, one effective formulating approach is solid solution formation with the
drug and a hydrophilic excipient to increase solubility and bioavailability. In a solid solution, the drug is molecularly dissolved and has a lower thermodynamic barrier for dissolution. Hot melt extrusion processes yield what are called solid solutions, enabling poorly soluble drugs with otherwise limited bioavailability. Hot melt extrusion technology shows numerous benefits over other methods, including shorter processing times, few processing steps, the ability for continuous operation, environmental advantages due to the elimination of solvents, and efficient delivery of drugs to patients through formation of solid dispersions and improved bioavailability.

Aprepitant has a very high melting point of about 255°C and has a high glass transition temperature (Tg) of about 91°C. It is thermally stable up to 220°C and degrades with melting beyond 250°C. These characteristics of aprepitant confirm the feasibility of utilizing melt extrusion technology for extrusion of aprepitant-containing mixtures.

Aspects of the present application relate to pharmaceutical compositions comprising melt extruded aprepitant compositions and other pharmaceutically acceptable excipients, and processes for preparation thereof.

In embodiments, the present application relate to pharmaceutical compositions comprising melt extruded aprepitant compositions and other pharmaceutically acceptable excipients, and processes for preparation thereof wherein aprepitant is present in substantially particulate form.

In embodiments, the present application relate to pharmaceutical compositions comprising melt extruded aprepitant compositions and other pharmaceutically acceptable excipients, wherein the aprepitant compositions is in the form of physically stable solid dispersions and wherein aprepitant is present in substantially particulate form.

In embodiments, a miscible polymer useful to prepare melt extrudates should be capable of having a strong interaction with the drug, resulting in depression of the melting point of aprepitant in the polymer blend and a single high Tg for polymer-drug systems, which indicates a potential for physically stable solid dispersions.

In embodiments, the present application relates to pharmaceutical compositions comprising aprepitant melt extrudates wherein a miscible polymer is an ionic or non-ionic polymer, such as a polymethylmethacrylate, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone-polyvinylalcohol, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, or methylcellulose acetate phthalate, and a polymeric surfactant such as a poloxamer.

In embodiments, the present application relates to pharmaceutical compositions comprising aprepitant melt extrudates wherein a miscible polymer is a polyvinylpyrrolidone.

In embodiments, the present application relates to pharmaceutical compositions comprising aprepitant melt extrudates wherein weight ratios of aprepitant to miscible polymer are in the range of 1:0.5 to 1:15.
In embodiments, the present application relates to pharmaceutical compositions comprising aprepitant melt extrudates wherein weight ratios of aprepitant to dispersing agent are in the range of 1:10 to 10:1.
In embodiments, pharmaceutical compositions comprising aprepitant melt extrudates possess improved solubility, as compared to other compositions of aprepitant.

In embodiments, pharmaceutical compositions comprising aprepitant melt extrudates of the present application exhibit in vitro dissolution profiles that are comparable to commercially available EMEND® capsules.

In embodiments, pharmaceutical compositions comprising aprepitant melt extrudates possess excellent storage stability for commercially relevant times.

In aspects, the present application relates to processes for preparing pharmaceutical compositions comprising aprepitant melt extrudates and other pharmaceutically acceptable excipients, embodiments comprising:

(i) Combining aprepitant and a miscible polymer.
(ii) Extruding a melted mixture of (i).
(iii) Milling the extrudate to produce desired particle sizes.
(iv) Blending milled extrudate with other excipients.

In embodiments, pharmaceutical compositions comprising aprepitant melt extrudates provide in vitro dissolution of aprepitant such that more than about 90% of the drug is dissolved within 60 minutes after immersion into 900 mL of a 0.5% w/v sodium lauryl sulphate (SLS) aqueous solution, wherein the dissolution is conducted using USP type 2 (paddle type) apparatus with 75 RPM stirring.

In embodiments, pharmaceutical compositions comprising aprepitant melt extrudates provide in vitro dissolution of aprepitant such that about 25% to about 90% of the aprepitant is dissolved within about 30 minutes, and about 40% to about 99% of the aprepitant is dissolved within about 60 minutes, after immersion into 900 mL of fed state simulated intestinal fluid pH 5.8 dissolution medium, when tested in USP apparatus 2 at 75 rpm stirring.

Aspects of the application also provide methods of using pharmaceutical compositions comprising aprepitant melt extrudates, such as in the treatment of chemotherapy induced nausea and vomiting.
The particle size distribution of a material can be described in terms of D10, D50, D90, and D[4,3] values, used routinely to describe the particle sizes and size distributions. They are expressed as volume, weight, or surface area percentages. Dx as used herein is defined as a size value for particles, where x percent of the particles have sizes less than the value given. D[4,3] is the volume mean diameter of the particles. D90 for example means that 90% of the particles are below the specified particle size value. Similarly, a particle size distribution where 50 percent of the particles have sizes less than a specified size is referred to as "D50" and a distribution where 10 percent of particles have sizes less than a specified size is referred to as "D10." Particle sizes or particle size distributions of pharmaceutical compositions of aprepitant of the present application can be determined using any techniques that are known to a person skilled in the art, including, but not limited to, sieve analysis, optical microscopy, size analysis by laser light scattering such as using a Malvern particle size analyzer (Malvern Instruments Ltd., Malvern, Worcestershire, United Kingdom), and the like.

According to embodiments of the application particle size distributions of aprepitant which is used for hot melt extrusion have D10 less than about 10 um, D50 less than about 30 urn, and D90 less than about 50 um.

In embodiments, pharmaceutical compositions comprising aprepitant melt extrudates are subjected to storage stability testing at 25°C and 60% RH, and 40°C and 75% RH, for a commercially relevant time and analyzed for drug-related impurities. The total impurities are found to be less than about 5%, or less than about 2%, of the label aprepitant content at the end of one month of storage at both 25°C and 60% RH, and 40°C and 75% RH.

In embodiments, pharmaceutical compositions comprising aprepitant melt extrudates are characterized for solubility, bulk density, tapped density, Hausner ratio, moisture content, Carr index, angle of repose, blend particle sizes, and other parameters useful in the characterization of pharmaceutical compositions.
In embodiments, pharmaceutical compositions comprising aprepitant melt extrudates have drug solubility of more than about 200 |ig/mL in 0.5% sodium lauryl sulphate in water.

In embodiments, pharmaceutical compositions comprising aprepitant melt extrudates have bulk density and tapped density less than about 1 g/cm3 and Carr's index values less than about 40%, or less than about 20%, thus representing good flow properties.

In embodiments, pharmaceutical compositions comprising aprepitant melt extrudates have moisture contents less than about 8%, or less than about 5%, by weight.

In embodiments, pharmaceutical compositions comprising aprepitant melt extrudates have blend particle sizes such that more than about 60% of the particles are smaller than 1000 um, more than about 15% of the particles are smaller than 500 um, and less than about 5% of the particles are smaller than 250 um.
In embodiments, pharmaceutical compositions of the present application are solid dosage forms such as tablets, capsules, granules, pellets, beads, particles, mini-tablets, or orally disintegrating tablets, or are liquid dosage forms such as solutions, suspensions, syrups, and the like. The pharmaceutical compositions of the application may be prepared using any process operations, such as one or more of wet granulation, dry granulation, direct compression, compaction, spheronization, etc.

In embodiments, aprepitant compositions of the present application comprise one or more miscible polymers that are ionic and/or non-ionic polymers. Non-limiting examples of ionic and nonionic polymers useful in the present application are polymethylmethacrylates, polyvinylpyrrolidones, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, polyvinylpyrrolidone-polyvinylalcohols, hydroxypropyl methylcellulose acetate succinates, hydroxypropyl methylcellulose phthalates, polyvinyl acetate phthalates, cellulose acetate phthalates, hydroxypropyl cellulose acetate phthalates, and methylcellulose acetate phthalates. Compositions can also contain polymeric surfactants such as poloxamers.

In embodiments, pharmaceutical compositions of the present application comprise at least one dispersing agent, such as a polyethoxylated castor oil (e.g., Cremophor® RH 40), diacetylated monoglyceride, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, triethyl citrate, or poloxamer (e.g., Lutrol® F 68).

In embodiments, pharmaceutical compositions of the present application include any desired number of additional excipients, such as one or more of surfactants, emulsifiers. pH modulators, fillers, binders, diluents, disintegrants, glidants, lubricants, flavors, colorants, and the like.

Examples of suitable disintegrants include natural starches such as maize starch and potato starch; directly compressible starches such as starch 1500, modified starches such as carboxymethyl starch and sodium starch glycolate, starch derivatives such as amylase, various grades of crospovidones, croscarmellose sodium, alginic acid and sodium alginate, microcrystalline celluloses, crosslinked polymers, crosslinked starches, cationic and anionic ion exchange resins, and the like.

Surfactants improve the wettability of the active agent. Various useful surfactants include, but are not limited to, sodium lauryl sulfate, cetrimide, polysorbates such as polysorbate 80, poloxamers such as poloxamer 188 and poloxamer 407, sodium carboxymethylcelluloses, hydrogenated oils, polyoxyethylene glycols, polyoxypropylene glycols, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyglycolized glycerides, such as are available commercially as GELUCIRE® 40/14, GELUCIRE 42/12, and GELUCIRE 50/13, vitamin E TGPS, TWEEN® surfactants, SPAN® surfactants, and mixtures thereof.

Emulsifying agents can include any of a wide variety of cationic, anionic, zwitterionic, and amphoteric surfactants known in the art. Nonlimiting examples of anionic emulsifying agents include the alkoyl isothionates, alkyl and alkyl ether sulfates and salts thereof, alkyl and alkyl ether phosphates and salts thereof, alkyl methyl taurates, and alkali metal salts including sodium or potassium salts of long chain fatty acids.

Examples of amphoteric and zwitterionic emulsifying agents include, but are not limited to, carboxy, sulfonate, sulfate, phosphate, or phosphonate compounds. Examples include alkylimino acetates and iminodialkanoates and aminoalkanoates, imidazolinium and ammonium derivatives betaines, sultaines, hydroxysultaines, alkyl sarcosinates and alkanoyl sarcosinates, and the like.

Examples of suitable emulsifying agents include disodium cocoampho diacetate, oxyethylenated glyceryl cocoate (7 EO), PEG-20 hexadecenyl succinate, PEG-15 stearyl ether, the ricinoleic monoethanolamide monosulfosuccinate salts, oxyethylenated hydrogenated ricinoleic triglyceride, poloxamers, non-solid fatty substances such as sesame oil, almond oil, apricot stone oil, sunflower oil, octoxyglyceryl palmitate (or 2-ethylhexyl glyceryl ether palmitate), octoxyglyceryl behenate (or 2-ethylhexyl glyceryl ether behenate), dioctyl adipate, tartrates of branched dialcohols, and the like. Other useful non-ionic emulsifying agents include alkylene oxide esters of fatty acids, alkylene oxide diesters of fatty acids, alkylene oxide ethers of fatty alcohols, alkylene oxide esters, and the like.

Various useful diluents include, but are not limited to, different varieties and grades of starches like pregelatinized starches and maize starch, sugars such as lactose and sucrose, cellulose derivatives such as microcrystalline celluloses, and the like. Other useful diluents include but are not limited to carmelloses, sugar alcohols such as mannitol, sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.

Various useful binders include, but are not limited to, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, polyvinylpyrrolidones, copovidones, powdered acacia, gelatin, guar gum, carbomers (e.g., Carbopol™ products), methylcelluloses, polymethacrylates, and starches.

Various useful glidants or anti-adherents include, but are not limited to, talc, silica derivatives, colloidal silicon dioxide, and the like.

Various lubricants that can be used include, but are not limited to, stearic acid and stearic acid derivatives such as magnesium stearate, calcium stearate, zinc stearate, sucrose esters of fatty acids, polyethylene glycols, talc, sodium stearyl fumarate, castor oils, and waxes.

In aspects, the present application includes processes for preparing pharmaceutical compositions containing melt extruded aprepitant compositions, embodiments comprising:

a) Blending drug, miscible polymer and surfactant.
b) Melt extruding the blend of step a).
c) Milling the extrudate of step b).
d) Blending the extrudate of step c) with a disintegrant and glidant. Optionally, the blend of step d)
can be filled into capsules, or compressed into tablets. Alternatively the step d) blend may be blended with other sifted excipients and compressed into tablets or can be filled into capsules or may be compacted and milled, then further blended with other excipients and compressed into tablets or filled into capsules.

Pharmaceutical compositions of the present application can be subjected to in vitro dissolution evaluations according to Test 711 "Dissolution" in United States Pharmacopoeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2005 ("USP"), to determine the release of drug from the dosage forms into aqueous media, and drug content can conveniently be determined in solutions by high performance liquid chromatography. The dissolution testing frequently is carried out using USP type 2 apparatus. In specific embodiments, in vitro dissolution studies are carried out using USP type 2 apparatus and 0.5% of sodium lauryl sulphate (SLS) in water, and/or in fed state simulated intestinal fluid (FeSSIF) pH 5.0, as the dissolution media, with 75 rpm stirring.

In aspects, pharmaceutical compositions of the present application provide in vitro dissolution of aprepitant such that more than about 80% of the drug is dissolved within 60 minutes after immersion into 900 mL of a 0.5% w/v SLS aqueous solution.

The composition and preparation for FeSSIF biorelevant medium for dissolution testing comprises:
Sodium taurocholate, 15 mM.

Lecithin, 3.75 mM.
NaOH (pellets), 4.04 g.
Glacial acetic acid, 8.65 g.
NaCl, 11.874 g.

Water, q.s. to 1000 mL. The fluid has a pH of 5.8 and an osmolality of about 670 mOsmol/kg.

Preparation of blank FeSSIF: Dissolve 20.2 g of NaOH (pellets), 43.25 g of glacial acetic acid, and 59.37 g of NaCl in water and dilute to 5 L. Adjust the pH to exactly 5.0 using IN NaOH or 1NHC1.

Preparation of FeSSIF: Dissolve 16.5 g of sodium taurocholate in 500 mL of blank FeSSIF. Add 59.08 mL of a solution containing 100 mg/mL lecithin in methylene chloride, forming an emulsion. The methylene chloride is eliminated under vacuum at about 40°C, by applying a vacuum for fifteen minutes at 250 mbar, followed by 15 minutes at 100 mbar. This results in a clear to slightly hazy, micellar solution having no perceptible odor of methylene chloride. After cooling to room temperature, adjust the volume to 2 L with blank FeSSIF. The recommended volume for simulating conditions in the upper small intestine after a meal is one liter.

In aspects, pharmaceutical compositions of the present application provide in vitro dissolution of aprepitant such that about 25% to about 90% of the aprepitant is dissolved within about 30 minutes, and about 40% to about 99% of the aprepitant is dissolved within about 60 minutes, after immersion into 900 mL of fed state simulated intestinal fluid pH 5.0 dissolution medium.

In aspects, pharmaceutical compositions of the present application exhibit a comparable dissolution profiles to that of a commercial aprepitant composition (EMEND®) having a similar drug content. Bioequivalent compositions may be prepared using solubility-enhanced melt extruded pharmaceutical compositions of the present application.

In embodiments, pharmaceutical compositions of the present application are appreciably stable for commercially relevant periods and easy to manufacture using conventional processing steps, as compared to the currently marketed nanoparticulate compositions of aprepitant (EMEND®) that are prepared using difficult manufacturing steps and specialized machinery, but still provides in vitro and in vivo release profiles of aprepitant that are comparable to those of EMEND® capsules.

The present application also provides methods of use of pharmaceutical compositions comprising melt extruded aprepitant in the management (e.g., prophylaxis, amelioration and/or treatment) of chemotherapy induced nausea and vomiting, comprising administering to a subject in need thereof an effective amount of aprepitant.

In an aspect, the application includes use of product packaging materials for pharmaceutical compositions such as containers and closures made from high-density polyethylene (HDPE), low-density polyethylene (LDPE), polypropylene, and/or glass, and blisters or strips composed of aluminum, high-density polypropylene, polyvinyl chloride, and/or polyvinylidene dichloride. The described packaging materials are only representative, as many other materials will be suitable.

Certain specific aspects and embodiments of the application will be further described in the following examples, which are provided solely for purposes of illustration and are not intended to limit the scope of the disclosure in any manner.

EXAMPLE 1; Aprepitant compositions. Melt extrusion.
Manufacturing procedure:

1. Sift together the aprepitant, polyvinylpyrrolidone, and poloxamer through a 40 mesh sieve and blend thoroughly.

2. Extrude the blend as thin strips using a 12 mm co-rotating twin screw extruder. The parameters for hot melt extrusion are as follows:

3. Mill the extrudate of step 2 and sift the milled extrudate through a mesh # 24 sieve.

Extrusion is carried out using various temperature zones having temperatures about 40°C to about 200°C at a vacuum of 160-180 mm Hg, in a twin screw extruder model Omicronl2P from STEER Engineering Pvt. Limited, Bangalore, India. The extruder has barrels enclosing two 12 mm diameter screws, which transport and subsequently force a melt through a die, giving it a particular shape. The barrel is heated to the desired temperatures for plasticizing the polymer in the fed material. A mixture of drug, polymer, and the other excipients is fed from an inlet and passes through various segments including melting, mixing, and shaping segments. At the end of the barrels, the attached die dictates the shape of the extrudate. The extruded material is collected from the outlet.

Composition.
Manufacturing procedure:

1. Sift crospovidone through a 24 mesh sieve and talc through a 40 mesh sieve and blend.
2. Blend the appropriate aprepitant extrudate with the mixture of step 1.
3. Fill the blend of step 2 into capsules.

An in-vitro dissolution study is conducted using the compositions of Examples 1A and IB and commercial Emend 125 mg capsules, giving the results as shown in Table 1. The following conditions are used:
Apparatus: USP type 2 (paddle) with sinkers.

Paddle speed: 75 rpm.
Medium: 900 mL of 0.5% SLS in water.
Temperature : 37±0.5°C.

Table 1
A similar in vitro dissolution study is conducted using Emend 125 mg capsules, Example 1A capsules, and crystalline aprepitant (25:75 mixture of Form I and Form II) that was used to make the extrudate in the capsules, with the dissolution medium 900 mL of fed state simulated intestinal fluid, and the results are as shown in Table 2.

Table 2

Samples of the Example 1A capsules and the placebo composition were stored in closed HDPE bottles for one month at 25°C and 60% relative humidity (RH), and at 40°C and 75% RH, and are analyzed by X-ray powder diffraction (XRPD) to determine the drug polymorphic stability.

Figure 1 shows XRPD patterns of: the crystalline aprepitant that is used to make extrudate (A); the composition of Example 1A (B) as prepared; and a similarly prepared placebo composition, except omitting the active ingredient (C).

Figure 2 shows XRPD patterns of: the crystalline aprepitant (A); a placebo composition prepared as in Example 1A, except omitting the active ingredient (B); the composition of Example 1A (C) after storage for one month at 25°C and 60% RH (C); and the composition of Example 1A as prepared (D).

Figure 3 shows XRPD patterns of: the crystalline aprepitant (A); a placebo composition prepared as in Example 1A, except omitting the active ingredient (B); the composition of Example 1A (C) after storage for one month at 40°C and 75% RH (C); and the composition of Example 1A as prepared (D).
EXAMPLE 2: Aprepitant compositions. Melt extrusion.

* EUDRAGIT E PO is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, from Evonic Industries, Germany.

** Soluplus is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, from BASF, Germany.

Manufacturing procedure:

1. Sift together aprepitant and Eudragit EPO (for Example 2A), aprepitant, hydroxypropyl cellulose and poloxamer (for Example 2B), or aprepitant, hydroxypropyl cellulose and Soluplus (for Example 2C) through a 40 mesh sieve and blend.

2. Extrude the blend of step 1 as thin strips using a 12 mm co-rotating twin screw extruder. The parameters for hot melt extrusion are as follows:

3. Mill the extrudate of step 2 and sift the milled extrudate through a sieve. Composition.

Manufacturing procedure:

1. Sift crospovidone and talc through a 40 mesh sieve and blend.

2. Blend the appropriate aprepitant extrudate with the mixture of step 1.

3. Fill the blend of step 2 into capsules.

EXAMPLE 3: Aprepitant compositions. Melt extrusion.

Manufacturing procedure:

1. Sift together aprepitant, polyvinylpyrrolidone, and poloxamer (for Example 3A), or aprepitant, polyvinylpyrrolidone, and Soluplus (for Example 3B) through a 40 mesh sieve and blend.

2. Extrude the blend of step 1 as thin strips using a 12 mm co-rotating twin screw extruder. The parameters for hot melt extrusion are as follows:

3. Mill the extrudate of step 2 and sift the milled extrudate through a sieve. Composition.

Manufacturing procedure:

1. Sift crospovidone and talc through a 40 mesh sieve and blend.
2. Blend the appropriate extrudate with the mixture of step 1.
3. Fill the blend of step 2 into capsules.

EXAMPLE 4: Aprepitant compositions.
Manufacturing procedure for Example 4A:

1. Sift together aprepitant and Kollidon VA64 through a 40 mesh sieve and blend.

2. Extrude the blend of step 1 as thin strips using a 12 mm co-rotating twin screw extruder, using the parameters for hot melt extrusion as described for Example 3.

3. Mill the extrudate of step 2 and sift the milled extrudate through a sieve.

4. Sift crospovidone and talc through a 40 mesh sieve and blend.

5. Blend the extrudate of step 3 with the mixture of step 4.

6. Fill the blend of step 5 into capsules.

Manufacturing procedure for a Comparative Example 4B:

1. Sift together aprepitant and Kollidon VA64 through a 40 mesh sieve and blend.

2. Sift crospovidone and talc through a 40 mesh sieve and blend.

3. Blend the mixtures of steps 1 and 2.

4. Fill the blend of step 3 into capsules.

The aprepitant solubilities of compositions of Example 4 at 24 hours of contact with different media are shown in Table 3. Values are in ug/mL.

EXAMPLE 5: Aprepitant compositions.

Manufacturing procedure:
1. Sift aprepitant extrudate through a 40 mesh sieve.
2. Sift microcrystalline cellulose, lactose anhydrous, and crospovidone XL or croscarmellose sodium through a 24 mesh sieve.
3. Blend the mixtures of steps 1 and 2.
4. Sift colloidal silicon dioxide through a 20 mesh sieve and sift talc through a 60 mesh sieve, and blend with the mixture of step 3.
5. Sift stearic acid through a 20 mesh sieve and blend with the mixture of step 4.
6. Compress the blend of step 5 into tablets. EXAMPLE 6; Aprepitant compositions.

* MicroceLac 100 is a spray-dried composition containing 75% a-lactose monohydrate and 25% microcrystalline cellulose, by weight. Manufacturing procedure:

1. Sift aprepitant extrudate through a 40 mesh sieve.

2. Sift MicroceLac 100, dibasic calcium phosphate, pregelatinized starch, croscarmellose sodium, and sodium starch glycolate through a 24 mesh sieve.

3. Blend materials from steps 1 and 2 and sift through a 20 mesh sieve.

4. B lend half the quantity of magnesium stearate with the mixture of step 3.

5. Roller-compact the blend of step 4.

6. Sift the compacted material of step 5 through an oscillating granulator having a 30 mesh screen.

7. Sift the remaining quantity of magnesium stearate through a 60 mesh sieve and blend with the
granules of step 6.

8. Compress the blend of step 7 into tablets.

We claim:

1. A pharmaceutical composition of aprepitant comprising aprepitant and one or more miscible polymers and optionally at least one pharmaceutically acceptable excipient.

2. The pharmaceutical composition as claimed in claim 1 wherein aprepitant and one or more miscible polymers are in the form of melt extrudates.

3. The pharmaceutical composition as claimed in claim 1 wherein the pharmaceutical composition is in the form of tablet or capsule.

4. The pharmaceutical composition as claimed in claim 1 wherein the polymer is ionic polymer, non-ionic polymer or combination thereof.

5. The pharmaceutical composition as claimed in claim 4 wherein the ionic polymer and non-ionic polymers are selected from the group comprising of polymethyl methacrylate, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone-polyvinylalcohol, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, or methylcellulose acetate phthalate.

6. A pharmaceutical composition comprising solubility-enhanced aprepitant compositions comprising aprepitant, one or more miscible polymers, dispersing agent and optionally at least one pharmaceutically acceptable excipient.

7. The pharmaceutical composition as claimed in claim 6 wherein the dispersing agent is selected from a group comprising of polyethoxylated castor oil, diacetylated monoglyceride, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, triethyl citrate, or poloxamer.

8. A process for preparing pharmaceutical composition of aprepitant comprising:

(i) Combining aprepitant, one or more miscible polymers and optionally at least one pharmaceutically acceptable excipient (ii) Extruding the mixture of (i).

(iii) Milling the extrudates to produce desired particle sizes, (iv) Blending the milled extrudate with other excipients and filled in capsules or compressed into tablets.

9. A pharmaceutical composition as claimed in claim lor 6 wherein composition provides an in-vitro release of aprepitant from the dosage of more than 80% within 60 minutes after immersion into 900 mL of a 0.5% w/v sodium lauryl sulphate aqueous solution, wherein the dissolution is conducted using USP type 2 (paddle type) apparatus with shakers, with 75 RPM stirring.

10. A pharmaceutical composition of aprepitant and process of preparation thereof, as described and illustrated in the examples herein.