The present invention relates to a solid dispersion containing crystalline aprepitant particles and aprepitant in molecular ly dispersed form as well as to a pharmaceutical composition containing the solid dispersion.

Aprepitant is an antagonist of neurokinin 1 (NK 1) receptor. The dominating natural ligand of this receptor is Substance P, a neuropeptide from the family of tachykinins. Substance P is abundantly and widely distributed in the mammalian central nervous system and other tissues. Substance P is able to induce emesis by binding to NK 1 receptors that are located in the regions of the brain involved in the regulation of emesis.

Aprepitant is marketed under the tradename Emend ⁴ " in the form of a capsule or powder for oral suspension. Emend ^® is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy including high-dose cisplatin and of moderately emetogenic cancer chemotherapy as well as for the prevention of postoperative nausea and vomiting in adults. The recommended regimen of aprepitant is 125 mg orally 1 hour prior to chemotherapy treatment on day 1 and 80 mg orally 1 hour prior to chemotherapy on days 2 and 3. If no chemotherapy is given on days 2 and 3, Emend ^® should be administered in the morning. Aprepitant is a crystalline solid and practically insoluble in water. Two crystalline forms of aprepitant exist, whereby Form I is the therraodynamically stable polymorph. As stated in the Scientific Discussion for the approval of Emend ^® (EMEA 2004), Emend* contains Form I, and no conversion to the thermodynamically less stable polymorph (Form II) during the manufacture and storage of Emend ^® was observed. Crystalline Forms I and II are described in WO 99/01444.

In order to enhance the bioavailability of aprepitant, Emend ^® contains aprepitant in a nanoparticulate form. As stated in the Scientific Discussion, the manufacture of Emend ^® contains the following method steps:

(1) production of a slurry of water, hydroxypropyl cellulose and aprepitant,

(2) pre-milling,

(3) addition of an aqueous sodium lauryl sulfate dispersion,

(4) media-milling to form a colloidal dispersion,

(5) addition of an aqueous sucrose dispersion,

(6) spray-coating of microcrystalline cellulose beads with the colloidal dispersion,

(7) sieving of the coated beads,

(8) blending of coated beads with micronized sodium lauryl sulfate and finally (9) encapsulation of the blended beads.

A detailed description of the manufacturing method is reported in WO 2003/049718. This application relates to aprepitant nanoparticles having a surface stabilizer adsorbed on the surface of the particles in order to maintain an effective average particle size of less than about 1000 run. As stated in the description of the application, an effective average particle size of less than about 1000 nm means that at least 50 % of the aprepitant particles are smaller than 1000 nm when measured, e.g., by photon correlation spectroscopy. In Emend ^® , sodium lauryl sulfate is used as surface stabilizer and in order to prevent agglomeration of the beads, which allows the aprepitant particles to re-disperse from the beads in vivo with maintained small size.

WO 2011/158053 discloses a process for preparing aprepitant nanoparticles by using a microfluidic based continuous flow reactor; the aprepitant nanoparticles are prepared by controlled precipitation. In the exemplified process, aprepitant, sodium dodecyl sulfate and polyvinylcaprolactam/polyvinyl acetate/polyethylene glycol graft copolymer (Soluplus ^® ) were dissolved in ethanol. The solution was mixed with water in the microfluidic continuous flow reactor in order to precipitate aprepitant The obtained colloidal solution contained nanoparticles having an average diameter of less man 200 run, meaning that at least 50 % of aprepitant particles are smaller than 200 run, when measured by, e.g., photon correlation spectroscopy. Finally, the colloidal dispersion is converted to a solid by using rotary evaporation and freeze drying.

WO 2007/016582, WO 2007/147160 and WO 2009/108828 disclose solid dispersions and solid solutions containing aprepitant within a matrix of a pharmaceutical excipient. Co-precipitation of aprepitant and polyethylene glycol from a solution by evaporation of the solvent gave a solid dispersion, whereas co- precipitation from a solution containing polyvinylpyrrolidone by evaporation of the solvent resulted in a solid solution. In addition, an inclusion complex of aprepitant with cyclodextrin or a cyclodextrin derivative is described in order to enhance aprepitant's aqueous solubility. WO 2010/149183 relates to a solid solution of aprepitant within a pharmaceutical excipient prepared by hot-melt extrusion. Preferred pharmaceutical excipients constituting the matrix of the extrudes include polyvinylpyrrolidone, poly(vinylpyrrolidone/vinyl acetate), hydroxypropylmethyl cellulose, micro- crystalline cellulose and polyacrylate. WO 2015/104047 relates to a solid solution of aprepitant within a matrix made from glycol graft copolymer (Soluplus ^® ). Preferably, the matrix also contains an auxiliary agent, e.g. poloxamer or a low viscosity grade hydroxypropylmcthyl cellulose. The weight ratio of aprepitant to Soluplus* is 1 :4 to 3:7, while the weight ratio of drug to auxiliary agent is 1:1 to 7:1. It is stated in WO 2015/104047 that spray-drying and hot-melt extrusion are common methods known in the art for the preparation of solid solutions. However, these methods have disadvantages as the use of high temperatures or high solvent consumption, which increases the operation costs. The application suggests as an alternative process the preparation of a solid solution by continuous drum- drying.

A hot-melt extrusion process for preparing extrudes containing aprepitant and Soluplus* is disclosed in Research Disclosure June 2013, RD 590079. The extrudes were milled, subsequently mixed with microcrystalline cellulose and crospovidone, and finally filled into capsules. In addition, a granulation process is disclosed, in which microcrystalline cellulose is granulated in a fluid bed granulator with a solution of Soluplus* sodium lauryl sulfate and aprepitant in ethanol/water. The granules are dried, sieved, mixed with colloidal anhydrous silica and finally filled into capsules.

A solid dispersion containing aprepitant particles in the crystalline Form I and aprepitant in molecularly dispersed form within a mixture of hydroxypropyl cellulose (HPC-SL) and D-a-tocopheryl polyethylene glycol succinate (vitamin-E.TPGS) prepared by hot-melt extrusion is disclosed in Research Journal of Pharmaceutical, Biological and Chemical Sciences 2014, 5(3), 1469-1485. As observed by scanning electron microscopy (SEM), the crystalline aprepitant particles appeared as fine needles partially agglomerated in bundles. A solid solution prepared from aprepitant in the crystalline Form I and Soluplus ^® by hot-melt extrusion is disclosed in Molecules 2015, 20, 11345-11356. The absence of crystalline drug in the final product was confirmed by DSC, powder X-ray diffraction (PXRD) and SEM. The Tmax of the solid solution was markedly shorter than that of Emend* but Emend ^® had a better oral bioavailability; the relative bioavailability was 93.12 %. In this regard, WO 2015/104047 discloses for the solid solution of aprepitant within Soluplus ^® that a fast onset of the dissolution of aprepitant solid solution is fundamental for reaching the bioavailability of the aprepitant, as the kinetic of absorption of the dissolved amount of aprepitant is very fast in the human body. On the other hand, in vitro dissolution tests show that a supersaturated solution is reached very quickly (after 20 min), so that dissolved aprepitant may precipitate in the gastrointestinal tract (WO 2015/104047, example 2 and figure 1). Hence, the prior art teaches that the aqueous solubility of aprepitant may be enhanced by decreasing the particle size of the drug. Emend ^® contains aprepitant nanoparticles, and other prior art documents suggest solid dispersions or solid solutions as alternative formulations. In solid solutions, aprepitant is present in molecularly dispersed form, and it is generally believed that such formulations will result in the best bioavailability due to the fast onset of dissolution; the drug is already dissolved in a matrix, so that no energy is required for breaking the crystal lattice of aprepitant On the hand, the fast release of aprepitant from a solid solution could be detrimental to bioavailability if the drug concentration becomes too high in the gastrointestinal tract, so that the drug may precipitate.

In view of the above described state of the art, the objective underlying the present invention was the provision of a pharmaceutical composition containing aprepitant, whereby the bioavailability of aprepitant provided by the composition can easily be made to match that provided by Emend ^® . This objective is attained by the subject matter as defined in the claims. It has been found that the bioavailability of a pharmaceutical composition containing a solid dispersion of aprepitant depends on the amount of crystalline aprepitant particles present in the dispersion. The optimum bioavailability, which matches that provided by Emend ^® , is achieved if the weight ratio of molecularly dispersed aprepitant to crystalline aprepitant in the solid solution is adjusted to 98:2 to 80:20, preferably 93:7 to 84:16. Hence, the present invention relates to a solid dispersion consisting of crystalline aprepitant particles, aprepitant in molecularly dispersed form and an amorphous, non-enteric polymer that forms the matrix of the solid dispersion, wherein the weight ratio of molecularly dispersed aprepitant to crystalline aprepitant is adjusted to 98:2 to 80:20, preferably 93:7 to 84:16. According to a preferred embodiment of the present invention, the weight ratio of aprepitant to amorphous, non-enteric polymer is 2:3 to 1:4, preferably 1 :2 to 1 :3. The crystalline aprepitant particles have a length-wise diameter in the range of 1-50 μιη, preferably 2-30 μπι and more preferred 2.5-20 μιη, as determined by scanning electron microscopy (SEM). SEM provides information on the area projection particle size and particle shape. Alternatively, the particle size may be determined by SEM-EDX, which is a combination of scanning electron microscopy and energy-dispersive X-ray spectroscopy. SEM-EDX allows the determination of the increased fluorine concentration in the aprepitant crystals compared to the solid solution.

The weight ratio of molecularly dispersed aprepitant to crystalline aprepitant can be determined by measuring the crystallinity of the solid dispersion. The crystallinity is determined by PXRD. The %-ciystallinity is the ratio of sum of areas of crystalline peaks to total area (crystalline and amorphous area) x 100. Since the solid dispersion contains no other crystalline material than the crystalline aprepitant particles, the crystallinity is directly proportional to the content of crystalline aprepitant particles in the solid dispersion. For example, if the solid dispersion consists of 1 part by weight of aprepitant and 2.5 parts by weight of amorphous, non-enteric polymer and the crystallinity is 2.5 %, 8.75 % by weight (2.5 * 3.5) of the total weight of aprepitant is in crystalline form. Since the bioavailability of aprepitant depends on the weight ratio of molecularly dispersed aprepitant to crystalline aprepitant (the higher the amorphous content the higher the bioavailability), the determined %-crystallinity is directly proportional to Gnu and AUC. It has to be noted that such a direct correlation of crystallinity and bioavailability is not possible with a nanocrystalline material, because such a material will give broad signals in the powder XRD as the amorphous material.

The amorphous, non-enteric polymer contained in the solid dispersion is preferably selected from polyvinylpyrrolidone, hydroxypropyl cellulose, poly(vinylpyrrolidone/ vinyl acetate), polyvmylcaprolactam/polyvinyl acetate/polyethylene glycol graft copolymer, polyethylene glycol/polyvinyl alcohol graft copolymer, poly(ethylene oxide/propylene oxide), macrogolglycerol hydroxystearate, polyethylene glycol, and D-a-tocopheryl polyethylene glycol succinate, and is preferably polyvinyl- caprolactam/polyvinyl acetate/polyethylene glycol graft copolymer.

The solid dispersion of the present invention is preferably prepared by hot-melt extrusion, whereby the crystallinity of the solid dispersion may be adjusted by choosing an appropriate screw configuration and temperature profile. It appears that for aprepitant 2-3 kneading elements are required, which provide a specific mechanical energy consumption of 0.160-0.210 kWh/kg. The maximum temperature applied in the hot-melt extrusion was 200-240 °C. The present invention further relates to a pharmaceutical composition containing above solid dispersion and a pharmaceutical excipient. The pharmaceutical composition may be prepared by a process comprising the steps of: i) subjecting a mixture of crystalline aprepitant and an amorphous, non-enteric polymer to hot-melt extrusion to obtain extrudes in the form of a solid dispersion, which consist of crystalline aprepitant particles, aprepitant in molecularly dispersed form and the amorphous, non-enteric polymer, wherein the weight ratio of molecularly dispersed aprepitant to crystalline aprepitant is 98:2 to 80:20, preferably 93:7 to 84:16,

ii) milling the extrudes to obtain granules,

iii) preparing a mixture of the granules and a pharmaceutical excipient, iv) compressing the mixture obtained in step (iii) into a tablet or filling the mixture obtained in step (iii) into a capsule or a pouch.

The crystalline aprepitant used for the preparation of the solid dispersion is typically in non-micronized form. The particle size distribution of the crystalline aprepitant starting material as determined by laser diffraction spectroscopy (Malvern) is typically as follows: D _v 10 = 6-12 urn, D _v 50 = 20-35 um and Dv90 = 30-100 um.0

The weight ratio of solid dispersion to pharmaceutical excipient in the pharmaceutical composition of the present invention is usually 20:1 to 5:1, preferably 15:1 to 8:1 and more preferred 11:1 to 9:1. The pharmaceutical excipient is selected from diluents, disintegrants, glidants and optionally lubricants. Examples of diluents include microcrystalline cellulose, calcium hydrogen phosphate, lactose (anhydrous or monohydrate) and calcium carbonate. Examples of disintegrants include croscarmellose sodium, sodium starch glycolate, polyvinylpolypyrrolidone (crospovidone) and low-substituted hydroxy-0 propyl cellulose (L-HPC). As glidants silicon dioxide, talc and the like may be used, while magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate and glycerol dibehenate are examples of suitable lubricants.

The preferred pharmaceutical composition of the present invention contains besides aprepitant, acetate/polyethylene glycol graft copolymer, microcrystalline cellulose, crospovidone and silicon dioxide.

The following examples are intended to further illustrate the present invention. Examples

Hot-melt extrusion was performed with a Pharma 11 or 16 Twin-screw hot melt extruder form Thermo Fischer Scientific Inc. The manufacturing process of the exemplified capsule formulations is described below.

1. Sifting:

1.1 Sift Aprepitant through # 25 mesh

1.2 Sift Polyvinylcaprolactani/polyvinyl acetate/polyethylene glycol graft copolymer (Sohiplus ^® ) through # 25 mesh

2. Blending for extrusion:

2.1 Load the material of 1 in Blender and mix for 7 minutes. Collect the samples from 10 different locations and shall be analyzed for the uniformity of content 3. Hot Melt Extrusion:

3.1 Set the hot melt extruder Screw design as per the drawing mentioned below.

-

Note: EXT means extension, D means diameter, FS means feeding screw, F means forward direction and A means alternative

3.2 Load the blended material of 2 in the hopper of the hot melt extruder feeder.

3.3 Set the zone temperatures as per the following table

3.3 Set the screw rpm as 300 ± 25 Feed rate as 0.4 ± 0.05 kg/h and record the following machine parameters.

Torque (Ncm and %)

Product Melt Temperature (°C)

Die Pressure (bar)

4. Sizing of Extrudes:

4.1 Mill extrudes using co mill with first through 32C screen at 5500 rpm followed by 24R screen at 5500 rpm. Follow this steps intermittently when required.

5. Mixing of Extrudes:

5.1 Finally load the milled extrudes of 4,1 in Blender and mix for 5 minutes. Collect the samples from 10 different locations and shall be analyzed for the uniformity of content. 5.2 Submit the milled extrudes for analysis. Follow this steps intermittently when required but uniformity of content shall be tested only on final sample.

6. Sifting of extra-granular materials for blending:

6.1 Sift Cellulose, Microcrystalline through # 35 mesh.

6.2 Sift Crospovidone (Type-A) through # 35 mesh.

6.3 Sift Silica, Colloidal Anhydrous through # 35 mesh.

7. Blending:

7.1 Load the milled extruded powder into the blender.

7.2 Add sifted materials of step 6.

7.3 Mix for 5 minutes. Collect the sample from 10 different locations and analyze for uniformity of content

7.4 Store the blend in airtight container (with double poly bag with a desiccant between two bags).

8. Encapsulation:

8.1 Fill the empty hard gelatin capsules using appropriate capsule shells and process parameters.

The crystalline aprepitant starting material was the crystalline Form II as described in WO 99/01444 and had a particle size distribution (Malvern):

Examples 1, 2 and 3

The crystallinity of the milled extrudes was 3.5 %, which corresponds to a ratio of molecularly dispersed aprepitant to crystalline aprepitant of 87.75:12.25. The formulations were bioequivalent to Emend ^® .