CA2679028A1 - Pharmaceutical formulation - Google Patents

Abstract

Dispersions of a compound of formula I and a polymer such as HPMCAS and/or PVP are described, including compositions comprising the dispersions, meth ods of making the dispersions and methods of using the dispersions.

Description

PHARMACEUTICAL FORMULATION

CLAIM OF PRIORITY
This application claims priority to U.S. Provisional Application No.
60/891,272, filed February 23, 2007, the entire contents of which are hereby incoiporated by refei-ence.
FIELD OF THE INVENTION

The present invention relates to fol-ms of (2R,4S)-Quinoline-4-carboxylic acid [I-(3,5-bis-trifluar-omethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] anlide, or an active metabolite thereof, or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] aniide and methods of making and using the same.

BACKGROUND OF THE INVENTION
Water-insoluble di-ugs present manv challenging aspects to the forinulation scientist in the development of a suitable dosage form for oral administration. The solubility, dissolution, and per-ineability of a conzpound all contribute to the bioavailability of a drug. Although incozporation of cet-tain excipients into fozxnulations for permeability enhancement has been stuciied, results are inconciusive and not widely accepted as a mcans to improve bioavailability of watcr-insoluble drug candidatcs.
Micronization of drug substanee is an established technology platfoi-in which improves dissolution, and thus potentially bioavailability, through reduction of particle size and an associated increase in surface area. Processing and physical stability, e.g.
cxcessive flocculation or agglomeration, are challenges that exist for the inicronization platform.
Other techniques such as complexation with cyclodextrins and lipid-based formulations are typically limited to lower drug loadings. Solid dispersions of insoluble drugs dissolved in a polynzcr carrier or caz-riers provide a means of improving oral bioavailability. The drug substance typically exists in its amorphous forzn, and if dispersed at the molecular level, provides the ultimate in particle size reduction and improved dissolution and solubility, i.e. the surface area is at its greatest and there is no crystal packing energy to overcozne. Several methods exist for the generation of solid I

dispersions including spray drying and hot melt extrusion, both with some xnanufacturing challenges. Somc of the challenges in the use of solid dispersions for the delively of water-insoluble dl-ug candidates are the difficulty in processing the solid dispersions into suitable Dt-ug Product and the lack of suitable physical stability associated with the amotphous drug required for a Drug Product which is at least 2 years at room temperature and humidity. Therefore, there is a need for additional solid dispersions of water-insoluble di-ugs with improved physical stability and processing.

BRIEF SUMMARY OF THE INVENTION
Applicants have discovered that certain solid forms, e.g., solid dispersions of (2R.4S)-Quinoline-4-carboxylic acid []-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloi-obenzyl)-piper-idin-4-yl] amide, or an active metabolite ther-eof;
(2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide provide desirable qualities, including solubility, bioavailability, and stability (e.g., physical and chernical stability).

In one aspect, the invention features a solid dispersion comprising a compound of fozznula 1, pt-efel-ably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide, or an active metabolite thereof, or (2R,4S)-Quinazoline-4-carboxylic acid [1-Q,5-bis-triz`luoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] aznide and HPMCAS.

In some embodiments, the active metabolite is (2kZ.,4S)--Quinoline-N-oxide-4-carboxylic acid [1-(3,5.-bis-trifluoromethyl-benzoyl)-2-(4--chlorobenzyl)-piperidin-4-yl]
amide or (2R,4S)-2-Hydroxy-quinoline-4-carbox.ylic acid [1-(3,5-bismtrifluoromethyl-benzoyl)--2-(d.-chlorobenzyl)-piperid'zn-4--yl] aznide.

In some eznbodiznents, the ratio of the compound of forznula 1, preferably (2R,4S)-Quinoline--4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)--2-(4-chlorobenzyl)-piperidin-4-yl] amide,, or active metabolite th.ereof, or (2R,4S) -Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide to HPMCAS is from about 1:5 to about 5:1, for example, from about 1:3 to about 3: 1, exemplary ratios include about 1:1 or about 3:1.

In sonie embodiments, the dispersion is substantially hornogencous. In some einbodimcnts, the dispersion has a single T~. In some embodiments, the dispersion maintains a single "h,, at 25 C, 60% relative humidity for at least two weeks. In somc embodiments, the dispersion maintains a single T. at 40 C, 75% relative humidity for at least two weeks. In some embodiments, the dispersion maintains a single Tg at 25 C, 90% relative humidity for at least two weeks.

In some embodiments, the T. is at least about 50K greater than 25 C at from about 50% to about 90% relativc humidity. In some embodiments, the Te is at least about 50K gi-catei- than 25 C at fi-om about 60% to about 75% relative humidity. In some embodiments, the T, is from about 98 C to about 102 C at 25 C, 60% relative humidity.
In some cmbodiments, the dispei-sion comprises at least one non-homogeneous region enriched with the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide, or active metabolite thei-eof, ot- (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-vl] amide.

In some embodiments, the dispersion comprises at least one non-homogeneous region enriched tivith (2R,4S)-Quinoline-4-carboxylic acid [I-(3,5-bis-trifluoromcthyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.

In some embodiments, at least about 50% of the conipound of formula I, preferably (2I2.,4S)-Quinoline-4-carboxylic acid [I-(3,5.-bis-tz-if7.uoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or active inetabolite thereof, or (2R,4S)--Quinazoline-4-carboxylic acid [l.-(3,5-bis-trifluoron-lethyl-benzoyl)-2-(4-chlorobenzyl).-piperidin-4-yl] amide within the solid dispersion is amorphous, for exainple, at least about %5% of the compound of formula I, preferably (2R,4S)-Quinoline--4carboxylic acid [I-(3,5-bis-trifhioromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin. 4~y1]
amide or active metabolite thereof or (21Z,4S)-Quinazoline.-4~-carboxyhc acid [l-(3,5-bis-tritluoroznethyl-benzoyl)-2.-(4-chlorobenzyl)--piperidin-4-yl] ainide within the solid dispersion is amorphous or substantially all of the compound of formula 1, preferably (2R,4S)-Quinoline-4-caz=boxylic acid [1-(3,5-bis-trifluoromethyl-bei.-izoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] ainide or active metabolite thereof or (2FZ,4S)-Quinazoline.-4-carboxyhc acid [1-(3,5-bis-trifluar-on-iethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide within the solid dispersion is amorphous.
In soim embodiinents, the HPMCAS dissolves at pH > 5.5, e.g.. at pH > 6.0, or at pI-I > 6.5. In some embodiments, the HPMCAS is HPMCAS-LF.

In some embodiments, the dispersion further comprises a surfactant. In some embodiments, the surfactant is an anionic sur factant. In some embodiments, the surfactant is present in the dispersion from an amount of fi-om about 0.1 % to about 20%, for example, from about 1% to about 10%. In some embodiments, the surfactant is selected from sodium lauryl sulfate and docusate sodium.
In some embodiments, the dispersion further comprises a plurality of surfactants.
In some embodiments. the dispei-sion eompr-ises an additional polyiner, for example, a water soluble polymer such as PVP. In some embodiments, the ratio of HPMCAS to PVP is from about 5:1 to about 1:5, fot- example about from about 3:1 to 1:3, or 1:1.

In some embodiments, the dispersion comprises (2IZ,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoroznethyl-benzoyl)-2-(4--chlorobenzyl)-piperidin-4-yl]
amide.

In some embodiments, the dispersion is substantially free of active metabolite of (2IZ,4 s)-Quin.olizie-4--carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4.-clalorobenzyl)-pipericiin-4-y1] amide.
In some embodiments, the AUC of the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or active metabolite thereof or (2I2,4S)-Ouinazoline 4--carboxylic acid [1-(3,5--bis-trizluoromethyl..benzoyl).-2.-(4--chlorobenzyl)--piperidin-4-y1] ami.de when dosed in a subject is at least about 1.25 times the AUC of compound of formula 1, preferably (2R,4S)--Quinoline-.4-carboxylic acid [1-(3,5-bis-trifluorometh.yl-benzoyl)_.2-(4-chlorobenzyl)-.piperidin-4-yl] amide or active metabolite thercof or (2R,45)-Otilinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide in an undispersed preparation, for example, at least about 1.5 times, at least about 2 times, at least about 2.5 tirnes, at least about 3 times, at least about 4 times, at least about 5 tinaes, or at least about 10 times.

In sonle embodiments, the compound of forlnula I, preferably (2R,4S)--Quinoline- 4-carboxylic acid [1-(3,5-bis-trifluoroznethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]

amide or active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluor-omethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide is substantially amorphous and remains substantially amorphous for 2 weeks at 40 C/75%
relative humidity for 2 weeks. In some embodiments, the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or active metabolite thereof or (2R,4S)-Quinazoline--4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide is substantially amoiphous and remains substantially amoiphous for 2 weeks at 25 C/90% relative humidity for 2 weeks.
In one aspect, the invention features a solid dispersion comprising a compound of fol-mula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoroinethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R.4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloi-obenzyl)-piperidin-4-yl] amide and PVP, wherein the weight percent of the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)-Quinazoiine-4-carboxylic acid [1-(3,5-bis-triz`luoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide within the solid dispersion is at lcast about 50% by weight, for example at least about 55% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 85% by weight, or 90% by weight.
In some embodiments, the active metabolite is (2R,4S)-Quinoline-N -oxide-4-carboxyli.c acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin--4.-y1]
amide or (2R,4S)--2--I-Iydroxy-guinoline-4--carboxylic acid [1-(3,5-bis-trif7uoromethyl-benzoyl)-2-(4-chlorobenzyi)--piperidin-4--yl] amide.
In some embodiments, the ratio of the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1.-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide to PVP is from about 1:1 to about 5:1, e.g., from about 2:1 to about 4: 1, exemplary ratios include about 1:1 or about 3.5: 1.

In some enibodiments, the dispersion is substantially homogcneous.
In some eanbodiinents, the Tn is at least about 50K greater than 25 C at from about 50% to about 90% relative humidity, for example, the T. is at least about 50K
greater than 25 C at fi-om about 60% to about '75% relative humidity.
In some embodiments, the TQ is at least about 100 C at 25 C and 60% relative huinidity, for example. the T, is from about 115 C to about 155 C.
In some embodiments, the dispersion has a single To. In some embodiments, the dispersion maintains a single T~ at 25 C, 60% relative humidity for at least two weeks.
In soine embodiments, the dispei-sion maintains a single T, at 40 C, 75%
relative humidity for at least two weeks. In soine embodiments, the dispersion maintains a single T. at 25 C_ 90% relative humidity for at least two weeks.
In some embodiments, the dispersion comprises at least one non-homogeneous region enriched with the compound of fot-mula 1, prefel-ably (2R,4S)-Quinoline-carboxylic acid [1-(3,5-bis-trif7uoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide or an active metabolite tllercof or (2R.4S)-Quinazoline-4-carboxylic acid [ 1-(3,5-bis-trifluoromthyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] ainide.
In soine embodiincnts, the dispersion comprises at least one non-homogeneous region enriched with the (2R,4S)-Quinoline-4-carboxylic acid [1--(3,5-bis-trifluorolnethyl benzoyi)2 (4 chiorobenzyl) piperidin 4 y1] arnide.
In some embodiinents, at least about 50% of the compound of formula 1, preferably (2R,4 s)-Quinolinea4-carboxyl.ic acid [1.-(3,5~-bis-trifluoz omethyl-benzoyl)-2-(4 -chlorobenzyl)--piperidin--4-yl] amide or active metabolite thereof or (2R,4S)-.
Qi.ainazoline-4-carboxyhc acid [1 .-(3,5--bis-trifluoroniethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amid.e within the solid dispersion is amorphous, for example, at least about 75% of the cornpound of formula I, pi-eferably (2R,4S)-Quinoline-4--carboxyhc acid [1 -(3,5--bis-trifluoroznethyl-benzoyl)-2-(4--chlorobenzyl)-piperidin 4 -yl] amide or active metabolite thereof or (2Re4S)-Quinazoline-4--carboxylic acid [I -(3,5-bis-(rifluoroznethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide within the solid dispersion is amorphous or substantially all of the cornpound of foramla I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5--bis-trilluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or active metabolite thereof or (2R,4S)-(Zuinazoline--4-cai-boxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2.-(4-chlorobenzyl)-piperidin-4-yl]
amide within the solid dispersion is amot-phous.

In some embodiments, the PVP is K29/32. In some embodiments. the PVP has a molecular weight of fi-om about 30,000 to about 100,000 daltons.

In some embodiments, the dispersion further comprises a surfactant, for exaniple, an anionic sut-factant. In some embodiments, the surfactant is present in the dispersion from an amount of ft-oin about 0.1 % to about 20% by weight, e.g., fi om an amount of from about 1% to about 10% by weight. In some embodiments, the surfactant is selected from sodium laui-yl sulfate and docusate sodiuni. In some embodiments, the dispersion comprises a plurality of sur-factants.

In solne einbodiments, the dispersion fui-ther compi-ises an additional polymer_ for example, a water soluble polymer such as HPMCAS.
In soine embodiments, the dispersion compi-ises (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluorarnethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide.
In some embodinaents, the dispersion is substantially fi-ee of active metabolite of (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobcnzyl)-piperidin-4-y1] amide.

In some embodiments, the AUC of the compound of formula 1, preferably (2R,4S)-Quinoline-4carboxylic acid [ 1-(3,5-bis-trizl.uoromethyl-benzoyl)-2-(4-chtorobenzyl)-piperidin-4-yl] amide or active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [I-(3,5-bi.s-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)mpiperidin-4-yl]
arnidc when dosed in a subject is at least about 1 .25 times i.he.AIJC of compound of formu.la I, preferably (2R,4S)-Quinoline_4._carboxylic acid [1._(3,5--bis-trifluorornethyl-benzoyl) 2-(4--chlorobenzyl)-piperidin-.4--y1] amide or active metabolite thereof or (2p..,4S).-(3uinazoline 4--carboxylic acid [1-(3,5-bis-trilluoromethyl-benzoyl).-2-(4~
chlorobenzyl)-piperidin-4-yl] amide in an undispersed preparation, for exaxnple, at Icast about 1.5 times, at least about 2 times, at least about 2.5 tijnes, at least about 3 tijnes, at least about 4 tiznes, at least about 5 tiznes, or at least about 10 times.

In some embodiments, the compound of fornjula I, preferably (2R,4S)-Ouinoline-4-carboxylic acid [1-(3,5-bis-trifluorometh.yl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
anlide or active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [I-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide is substantially amorphous and remains substantially amor-phous at 40 C/75% relative humidity for 2 weeks. In soine embodiments, the coanpound of foi-mula I. prefcrably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-tY-ifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide is substantially amolphous and remains substantially amorphous for 2 weeks at 25 C/90%
relative humidity for 2 weeks.
In one aspect, the invention features a solid dispei-sion of eompound of foi-tnula I, preferably (2R,4S)-Quinoline-N-oxide-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzvl)-piperidin-4-vl] amide or (2R,4S)-2-Hydroxy-quinoline-4-carboxylic acid [1-(3,5-bis-trifluoi-omethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide and a polymer.
In some embodiments, the dispersion comprises (2R,4S)-Quinoline-N-oxide-4-carboxylic acid [1-(3,5-bis-trifluoromedlyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide. In some embodiments, the dispersion comprises (2R,4S)-2-I-Iydroxy-quinoline-4-carboxylic acid [1-(3,5-b1 s-trifluoromethyl-benzoyl)-2-(4-chloi obenzyl)-piperidin-4-yl]
amide.
in some embodiments, the polymer is a water soluble polymer, for example, HPMCAS or PVI'.
In some embodiments, the dispersion is substantially homogeneous.
In some embodiments, the T, is at least about 50N. greater than 25 C at from about 50% to about 90% relative humidity. In some embodiments, the 'f g is at least about 50K greater than 25 C at from about 60% to about 75% relati.ve humidity.

In some embodiments, the dispersion has a single Tg. In some embodiments, the dispersion maintains a single T. at 25 C, 60% relative humidity for at least two weeks.
In somc embodiments, the dispersion maintains a single 'he at 40 C, 75%
relative humidity for at least two weeks. In some embodiznents, the dispersion maintains a single T. at 25 C, 90% relative humidity for at least two weeks.

In some embodiments, the dispersion comprises at least one non-homogeneous region em-iched with (2R,4S)-Quinoline-N-oxide-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide. In somc embodiments, the dispersion comprises at least one non-homogcneous region cnriched with (2R,4S)-2-Hydroxy-quinoline-4-carboxylic acid [1-(3,5-bis-trilluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piper-idin-4-yl] amide.

In some ernbodiments, at least about 50% of the (2R,4S)-Quinoline-N-oxide-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide within the solid dispersion is amorphous, e.g., at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or substantially all of the (2R,4S)-Quinoline-N-oxide-4-carboxylic acid [I-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide within the solid dispersion is amor-phous.
In some embodirnents, at least about 50% of the (2R,4S)-2-Hydroxy-quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlar-obenzyl)-piperidin-4-yl]
amide within the solid dispersion is amorphous, e.g., at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or substantially all of the (2R,4S)-2-Hydroxy-quinoline-4-carboxylic acid [1-(3,5-bis-trifluorornethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide within the solid dispersion is amorphous. In some embodiments, the dispersion fur-iher comprises a surfactant, for exanlple, 20 an anionic surfactant such as sodium lauryl sulfate or docusate sodium. In some embodiments, the surfactant is present in the dispersion fi-orn an amount of from about Oe 1% to about 20%, for example, fi om about 1% to about 10%.

In some embodirnents, the dispersion comprises a plurality of surfactants. In some embodiments, the dispersion further cornprises an additional polymer-, for example, a water soluble polymer.

In some embodiments, the AUC of the (2R,4S)--Quin.oline N-oxide-4-carboxylic acid [I-(3,5-bis-trifYuoromethyl--benzoyl)-2-(4-chlorobenzyl)-pipcridin-4-y1]
amide when dosed in a subject is at least about 1.25 tin-les the AUC of (2R,4S)-Quinoline-N-oxide-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)--piperidin-4-yl]
amide in an undispersed preparation, for example, at least about 1.5 times, at least about 2 times, at least about 2.5 tilnes, at least about 3 times, at least about 4 times, at least about 5 times, or at least about 10 times.
In sonle embodiments, the AUC of the (2R,4S)-2-Hydroxy-quinoline-4-carboxylic acid [1-(3,5-bis-trifluoronaethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide when dosed in a subject is at least about 1.25 times the AUC of (2R,4S)-Hydroxy-quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide in an undispersed preparation, for example, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 4 times, at least about 5 times, or at least about 10 times.
In some embodiments, the (2R,4S)-Quinoline-N-oxide-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide is substantially amorphous and remains substantially amoiphous for 2 weeks at 40 C/75%
relative humidity for 2 weeks. In some embodinlents, the (2R,4S)-2-Hydroxy-quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-pipcridin-4-yl]

amide is substantially amorphous and remains substantially amorphous for- 2 weeks at 40 C/75% relative humidity for 2 weeks.

In one aspect, the invention features a solid dosage form of a dispersion described herein, for example a dispersion of a compound of formula I.

In one aspect, the invention features a particle coated with a compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-y1] amide or active metabolite thereof or (2R,4S)-Quinazohne.4-carboxylic acid [1-(3,5-bi.s-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl) piperidinm4myl] amide and a polymer.
In sozne einbodiments, the particle is a non-pariel, a lactose prill, microcrystaltine cellulose, or starch.
In some embodiments, the active metabolite is (2R,4S)-Quinoline-N-oxide-4-carboxylic acid [1-(3,5-bis-trifluoroznethyl-benzoyl)-2._(4-chlorobenzyl)-piperidin-4-yl]
aznide. hn some embodiments, the active metabolite is (2R,4S)-2-Hydroxy-quinohne.-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4--chlorobenzyl).-piperidin-4-yl]
amide.

In some cnibodilnents, at least a portion of the coXnpound of formula 1, prefer-ably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or active metabolite thereof is dispersed in a polyiner.
In some embodiments, the dispersion is substantially homogeneous. In some embodiments, the Tg of the dispersion is at least about 40K greater than RT at from about 60% to about 75% relative humidity. In some embodiments, the Tg of the dispersion is from about 65 C to about 155 C. In some embodiments, the dispersion has a single Tg.
In some embodiments, the compound of foi-mula I, preferably (2R,4S)-Quinoline-carboxylic acid [1-(3,5-bis-trifluorolnethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide or active metabolite thereof is substantially amorphous and the dispersion has a single T" at 25 C 60% relative huniidity foi- at least 15 months. In some embodiments, the dispersion comprises at least one non-homogeneous region enriched with the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or active inetabolite thereof. or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide In some embodiments, the dispersion comprises at least one non-homogeneous region enriched with (2R,4S)-Quinoline-carboxylic acid [I-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)--piperidin-4-yl]
amide. In some embodiments, at least about 50% of the compound of formula 1, preferably (2R,4S)-Quinoline--4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl).-2-(4-chlor.obenzyl)._ piperidin-4-y1] amide within the dispersion is amorphous e.g., at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or substantially all of the compound of formula I, preferably (2R,4S)-Quinolinc-4-carboxylic acid [1-(3,5-bis-trifluoron-iethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or activc metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [I-(3,5--bis-trifluoromethyl-benzoyl)-2--(4-chlorobenzyl)-piperidin-4-yl] amide within the dispersion is amorphous. In some embodiments, the dispersion fur-ther- comprises a surfactant, for example, an anionic surfactant such as sodiuzn lauryl sulfate and docusate sodium. In some embodiments, the 11 surfactant is present in the di.spersion fi-om an amount of from about 0. 1%
to about 20%, for example, fi-om about I% to about 10%. In some embodiments, the dispersion compriscs a plurality of surfactants.
In some embodiments, the AUC of the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [l -(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide when dosed in a subject is at least about 1.25 times the AUC of conlpound of forinula I, prefei-ably (2R,45)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluol-omethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or active metabolite thereof or (2R,45)-Quinazoline-4-carboxylic acid [1-(3.5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide in an undispersed preparation, for example, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 tiines, at least about 4 times, at least about 5 times, or at least about 10 times.
In some embodinlents, the polymer is a water soluble polymer.

In some embodiments, the polymer is HPMCAS. In some embodiments, the ratio of the compound of fozsnula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5--b1 s-trilluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or active metabolite thereof to Hp iVIC.A.S within the dispersion is I`rom about 1:5 to about 5:1, e.g., from about 1:3 to about 3:1; exemplary ratios include about 1:1, o,r about 3:1. In some embodiments, the HPMCAS dissolves at pH > 5.5, for example, at pH >6.0, or at pH >
6.5. In some embodiments, the HPMCAS is HpMCAS-f,p`.
hn some eznbodiments, the particle is further coated by an addi.tional polynier, such as a water soluble polym-er.
In somc embodiments, the polymer is pVf. bn sorn-e embodiments, the ratio of the compound of formula I, preferably (2R,4S)-Quinoline4-carboxylic acid [I-(3,5-bis-trifluoromethyl-benzoyl)-2-(d-chlorobenzyl)-pipcridin-4.-yl] ami.de or active inetabohte thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-ti.-illuoromethyl-benzoyl)-2-(4-chlorobenzyl)--piperid'zn-4--yl] amide to PVP within the dispersion is from about 1:5 to about 5:1, e.g., from about 1:3 to about 3:1; exeinplary ratios include about 1: 1, or about 3: 1. In some embodiments, the weight percent of coinpound of forznula 1, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trif7uoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide within the solid dispersion is at least about 50%, e.g., at least about 55%, at least about 60%, at least about 65%, at least about 70%, or at least about 75%. In some embodiments, the ratio of the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide to PVP is from about 1:1 to about 5:1, e.g., fi-om about 2:1 to about 4:1; exemplai-y ratios include about 1:1 or about 3.5:1. In some embodiments, the PVP is K29/32.
In sonle embodiments. the pai-ticle comprises (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-pipei-idin-4-yl]
amide.
In some embodiments, the particle is substantially free of active metabolitc of (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoroi n ethyl -b enzoyl) -2 - (4-chlorobenzyl)-piperidin-4-yl] amide.
In some embodiments, the compound of formula 1, preferably (2R,4S)-Quinoline-4-carboxyhc acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide or active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl benzoyl) 2(4 chlorobenzyl) piperidin-4-y1] amide is substantially amoiphous and remains substantially amorphous for 2 weclcs at 40 C/75%
relative humidity for 2 weeks. In some embodiments, the compound of formula 1, preferably (2R,4S)-Quinoline.-4-carboxylic acid [lw(3,5-bis-ti-ifluoromethyl-benzoyl)-.2-(4.-chlorobenzyl)--piperidin...4.-yl] amide or active metabolite thereof or (2R,4S).-Quinazolinc;
4--carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperi.din-4-yl]

amide is substantially amorphous and remains substantially ainoxphous for 2 weeks at 25 C/90% relative humidity for 2 weeks.
In one aspect, the invention features a solid dosage fornlulation comprising a particle described herein a dispersion described herein.
In some embodiments, the formulation further comprises one or more of an excipient, a diluent, a binder, a disintegrant, a glidant, a lubricant, and/or a surfactant.

In some enabodiments, the dosage formulation is a tablet. In some embodiments, the dosagc formulation is a capsule.
In some embodimcnts, the dosage formulation furthei- comprises a coating, for examplc, an enteric polymer such as a cellulosic polymer.

In some embodiments, solid dosage fonnulation comprises about 20 mg of the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide. In some embodiments, solid dosage foar-mulation comprises about 40 mg of the coinpound of for-inula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] arnide. In some embodiments, solid dosage forinulation comprises about 160 n1g of the compound of fonnula I, preferably (2R,4S)-Quinoline-4-cal-boxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide. In some embodiments, solid dosage formulation comprises about 320 mg of the compound of fonnula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.
In some embodiments, solid dosage formulation comprises (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide;

PVP;
DOSS;
microcrystalline cellulose;
croscarmellose;
SL,S; and niagnesium stc:arate.
In some embodiments, the (2R,4S)-Quinolin.e-4._carboxylic acid [1-(3,s-bis-trifluoromethyl--benzoyl)-2-(4-chlorobenzyl)--piperidin-4--yl] amide and PVP Conn a solid dispersion.
In some embodiments, solid dosage formulation coinprises from about 20 to about 30 % by weight (2R,4S)-Quinoline-4-carboxyhc acid [1-(3,5--bis trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide;
from about 20 to about 30 % by weight PVP;

from about 0.2 to about 1.0 % by weight DOSS;
from about 30 to about 50 % by weight microcrystallinc cellulose;
from about 5 to about 10 % by weight croscarmellose;
from about 0.5 to about 3 % by weight SLS; and from about I to about 2 % by weight magnesitun stearate.
In some embodiments, solid dosage formulation comprises about 25 % by weight (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2--(4-chlorobenzyl)-piperidin-4-y1] amide;
about 25 % by weight PVP;
about 0.6 % by weight DOSS;

about 40 % by weight microcystalline cellulose;
about 7.5 % by weight croscarmellose;
about 1% by weight SLS; and about 1.5 % by weight magnesium stearate.
In some embodiments, solid dosage formulation comprises (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide;
HPMCAS;
microcrystalline cellulose;
dicalcium phosphate croscarmellose;
SLS;
silicon dioxide; and inagnesium stearate.

In some embodiments, the (2R,4S).-Quinoline-4-carboxylic acid [1-(3,5-bis--trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-y1] amide and HPMCAS fozin a solid dispersion.

In some embodiments, solid dosage foi-inulation comprises from about 20 to about 30 % by weight (2IZ,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)--2-(4-chlorobenzyl)-piperidin-4-yl] anlide;
from about 20 to about 30 % by weight HPMCAS;

fi-om about 15 to about 25 % by weight inicrocrystalline ccllulose;
from about 15 to about 25 % by weight dicalcium phosphate fi-om about 2 to about 8 % by -eight croscarmellose~
fi-om about 0.2 to about 0.8 % by weight SLS;

from about 0.2 to about 0.8 % by weight silicon dioxide; and fi=om about I to about 2 % by weight magnesiuxn stearate.
In some embodiments, solid dosage formulation comprises about 25 % by weight (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide;
about 25 % by weight HPMCAS;
about 21 % by weight microcrystalline cellulose;
about 21 % by weight dicalcium phosphate about 5 % by weight croscarmellose;
about 0.5 % by weight SLS;
about 0.5 % by weight silicon dioxide; and about 1.5 % by weight magnesium stearate.
In some embodiments, solid dosage fornzulation comprises (2F{.,4S)-Quinoline-.4..carboxylic acid [1-(3,5--bis-tril7uoromethyl-benzoyl)-2-(d-cniorobenzyl)-piperidin-4-yl] amide;
t'Vp;
DOSS;
microcrystalline cellulose; and SLS.

In sonae embodimcnts, the (2R,4.S)-Quinoline-4-carboxylic acid [1-(3,5-bis-txifluoromethyl-benzoyl)._2 -(4._chlorobenzyl)-pi.peridin-d-y1] amide and p'VP
are coated onto the microcrystalline cellulose.
In some embodimen'r.s, the (21Z,4S)-Quinoline-4-carboxylic acid [1--(3,5-bis-trilluoromethyl-benzoyl)-2-(4-chlorobenzyl)-.piperidin-d-yl] anlide and PVP
fol-in a solid dispersion.
In some embodiments, solid dosage foi-inulation comprises frojn about 20% to about 30% by weight (2R,4S)-Quiiioline-4-carboxylic acid [1-(3,5-bis-tz-ifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] aznide;
fi-oTn about 7% to about 10% by weight PVP;
from about 0.1 % to about 0.5% by weight DOSS;
from about 60% to about 70% by weight microcrystalline cellulose; and from about 0.2% to about 0.8% by weight SLS.

In some embodiments, solid dosage formulation comprises about 27% by weight (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoroznethyl-benzovl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide;
about 8% by weight PVP;
about 0.3 ,o by weight DOSS;

about 64% by weight microcrystalline cellulose; and about 0.5% by weigl-rt SLS.

In some enibodiments, solid dosage formulation cornprises (2R.4S)-Quinoline-4-carboxylic acid [1-(3.5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide;

DOSS;
SLS;
PVP;
croscaz-znellose;
lactose;
crospovidone; and rnagneszurz3 stearate.

In soine embodiments, wherein. (2R,4S)-Quirioline-4-carboxylic acid [1.-(3,5-bi_s-75 trifluorometh.yl .benzoyl) )-(4-cb.lorobenzyl)-piperidin-4-yl] amidc and PVP are coated onto the lactose, ln soine cinbodimeirts9 whcrein (2R,4S).-Qtainoline-4-carboxylic acid [1-(3,5-bis-tri~luorozmthyl-benzoyt)-2-(4-chlorobenzyl)-piperidin-4-yl] amide and PVP form a solid dispersion.

In some embodiments, solid dosage formulation comprises from about 25% to about 35% by weight (2R,4S)-Quinoline-4-carboxylic acid [l-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-pipcridin-4-yl] ainide;
fi-om about 3% to about 5% by weight DOSS;
from about 1% to about 3% by weight SLS;
from about 7% to about 1 1% by weight PVP;
from about 8% to about 12% by weight croscarmellose;
from about 25% to about 45% by weight lactose;
from about 5% to about 9% by weight crospovidone; and from about 0.2% to about 0.8% by weight magnesium stearate.
In some embodiments, solid dosage formulation comprises about 29% by weight (2R,4S)-Quinoline-4-carboxylic acid [1-(3.5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide;
about 4% by weight DOSS;
about 2% by weight SLS;
about 9% by weight PVP;
about 10% by weight croscarmellose;
about 38% by weight lactose;
about 7% by weight crospovidone; and about 0.5% by weight magnesium stearate.
In one aspect, the invention features a method of making a carrier coated with a compound of forrnula 1, preferably (2R,4S)-Quinoline-4-carboxylic acid [I-(3,5.-bi.s..
trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-pipezidin-4-yl] amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxyhc acid [l--(3,5-bis-firifluoromethyl-benzoyl)-2-(4--chlorobenzyl)-piperidin-4-yl] amide, the inetbod comprising providing particles comprising the compound of foianula 1, preferably (2R,4S)--Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof oz- (2R,4S)-Quinazoline-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide suspending the particles in an aqueous solution comprising a water soluble polymer; and spray coating the particles onto a carrier to provide a cai-i-ier coated with the compound of formula 1, prcfcrably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [I-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide and a water soluble polymer.

In some embodiments, the compound of formula I, prefer-ably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide is substantially amorphous.

In some embodiments. the solvent is methanol.

In some embodiments, the water soluble polytner is PVP. In some embodiments, the water soluble polymer is HPMCAS.

In some embodiments, the carrier comprises lactose particles. In some embodiments, the car7=ier comprises microcrystalline cellulose.

In one aspect, the invention features a method of making particles comprising the compound of formula 1, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-pipelidin-4-yl] amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluorozmthyl- benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide, the method comprising dissolving the compound of foirnula I, preferably ('/-R,4'3)-Quinoline-4-carboxylic acid 20 [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] ainide in a solvent and a polymer to provide a solution of the compound of fonn-aula 1, preferably (2R,4S).-Quinoline-4-carboxylic acid [1 ,-(3,5 -bis-tri.fluoroni ethyl-benzoyl)-2-(4-chlorobenzyl)-pipeYidin-4--yl] amide or an active metabolite thereof or (2R,4S)-Quinazoline-.4-carboxylic acid [1-(3,5-bis-tri:fluoromethyl-benzoyl)-2-(4--chlorobenzyl)-piperidi-n-4-yl]
an-iide and polymere spray drying the solution to provide a dispersion comprising the compound of formula 1, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-.
(4-chlorobenzyl)-piperidin-4-y1] amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-pipci-idin-4-yl] amide and polylner.
In some embodinaents, the polymer in the dispersion is PVP. In some embodiments, the polymer in the dispersion is HPMCAS.
In some embodiments, the solvent dissolving the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-pipcridin-4-yl] amide and polymet- is selected from the group consisting of ethyl acetate, mcthanol, acetone, and ethanol.
In some embodinlents, the solvent dissolving the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [I-(3,5-bis-trifluoroimthyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active inetabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-1 S piperidin-4-yl] amide and polymer is a methanol or ethanol.
In some embodiments, the solvent dissolving the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-.2,-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-caz-boxylic acid [1-(3,5-bis-trizluoromethyl.-benzoyl)-2-(4-chlorobenzyl)m piperidin-4-yl] amide and polymer is a mixture of organic solvents.
In some embodiments, the resulting particles have a bulk density of f_rom about 0.20 g/ml to about 0.30 g/ml.
In some embodiments, the resulting particles have a I.~,0 of less than about I
p.m.
In some embodiments, the Ta,, of thc spray dryer is frozn about 70 C to about C.
In some embodiments, the solids load of the compound of Corinula I, preferably (2R,4S)--Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin--4-y1] ainide or an active metabolite thereof or (2R,4S)-.
Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)- 30 piperidin-4-yl] amide and polylmr in solution is from about 1% to about 20% by weight, for example, about 5% by weight.

In one aspect, the invention features a method of treating an NK-1 1-elated disorder, the method comprising administering to a subject a pai-ticle or dispersion described hcrein.
In solne embodiments, the coinpound of foi-mula 1, prefel-ably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide is administered to a subject who has eaten.

In some embodiments, the invention features a the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide is administered to a subject who has not eaten at least 1 hour before or two hours after administration.

In some embodiments, the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide is adnlinistered to a subject who has eaten within 60 zninutes prior to administration or eats witbin 120 minutes after administration.

In some embodiments, the method comprises administering a dose coznprising from about I to about 1000 mg of the compound of forzn.ula 1, preferably (2R,4S)--Quinoline-4--carboxylic acid [1-(3;5-bis--trifluoromethyl-benzoyl)-2-(4achlorobenzyl)-piperidirz-4-yl] amide or an active metabolite thereof. or (2R,4S)-Quinazoline-carboxyli.c acid [1-(3,5-bis-trifluoroimthyl-benzoyl)-.2_(4_-chlorobenzyl)-piperidin--4-y1]
amide.

In some embodiznents, the method coi-rrprises administering a dose comprising about 40 mg of the compound of formula 1, preferabl-y (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide or an active metabolite thereof. or (2R,4S)-Quinazoline-4-carboxylic acid [I-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin--4-y1] amide.

In some enibodiments, the method comprises adininistering a dose comprising about 320 n1g of the compound of formula 1, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-y1]
amidc or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-.(4-chlorobenzyl)-piperidin-4-yl] amide.
In some embodiments, the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide is administered once daily.
In some einbodiments, the compound of fonnula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [I-(3,5-bis-trifluorometlryl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide is administered twice daily.
In some embodiments, the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-y1]
arnide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxyli.c acid [1--(3,5-bis-tril`luoromethyi-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide is administered tlu-ee times daily.
In some embodiments, the compound of formula I, preferably (2R,4S)-Quinohne.-4-carboxylic acid [1 (3,5-bis.-tri.Iluoromethyl.-benzoyl) 2..,(4-chlorobenzyl)-piperidin.a4--yl]
at-riide or an active r.-netabohte thereof or (2R;4S)-Qui-n.azol.inee4 carboxylic acid [1-(3,5--bis-t:rifluoroinethyl benzoyQ.-2.._(4--chlorobenzyl)-piperidin-4my1] azn.ide is administered wit:h, an additional the_rapeutic agent.
In soxne embodiments, the compound of fonnaula I, preferably (2R,4S)-Quinoline-4--carboxylic acid [1-Q,5-bis-trifluoroxnethyl-benzoyQ-2-(4-chlorobenzyl)-piperidin--4--y1]
ainide or an active inetabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bi-s-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide and the additional therapeutic agent are administered in a combined dosage form.

In some embodimcnts, the compound of formula 1, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-henzoyl)-2-(4-ehlorobenzyl)-piperidin-4-yl]
amide or an active nietabolite thel-eof or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoramethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide is administered orally.
In some embodiments, the compound of foi-nnula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-pipei-idin-4-yl] amide is administered topically.

An amorphous form of a drug may exhibit different propei-ties than the crystalline form. To improve the stability of an amorphous solid (which is generally less stable than a crystal form), a polymer or polymeric mixture can be used to form an alnoiphous solid dispersion system together with the drug. In some embodiments, a "solid solution", 15 whicb is a system wbieh will not phase separate over time, or a solid dispersion can be formulated in which the recrystallization of the drug is limited or slowed during a pharmaceutically significantly long period (e.g., two years) at ambient temperature.
Solid dispeisions of the compound of formula I, preferably (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-irifluoromethyl-benzoyl)-2-(4--chlorobenzyl)-piperidin-4-yl]
amide can provide improved bioavailability orally adininistered relative to the administration of undispered compound of formula I, preferably (2R,4S)-Quinohne-_4-carboxylic acid [1-(3,5-bis-trilluoromethyl-benzoyl)-2-.(4-chlorobenzyl)-piperidin--4-y1]
amide, e.g., crystalline compouzid of formula I, preferably (2R,4S)-Quinoline-caxboxylic acid [1-(3o5-bis--trifluoroinethyl-betizoyl)-2,-(4-chlot obenzyl)-piperidin-4-yI]

amide. In some embodiments, these solid dispersions are i.n a solid state that can be conveniently stored and admini_stered. The manufacture of the solid dispersions can be conducted and scaled up successfully by selecting an organic solvent or solvent mixture (for example, methanol, acetone, ctc.). In some embodiments, solid dispersions can have improved chemical and physical stability. For example, in some instances the solid dispersions can be chemically and/or physically stable for at least a year, e.g., at least 15 months, 18 months, two years, or longer at conventional storage conditions (room tempcrature).
The details of one or nlore eznbodiments of the invention are set forth in the accompanying description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.
DETAILED DESCRIPTION OF THE INVENTION
It is the discovery of the present invention that various factors and components are important to the stability and bioavailability of a pharmaceutical composition, especially foarmulations comprising solid dispersions of a water-insoluble drug.
Accordingly the present invention provides fol-mulations of solid dispersions and methods of making these formulations.

COmpOur-ds of f rmula I
The solid dispersions herein include a compound of for-mula I, or pharmaceutically acceptable salts oar solvates thereof X
HNO
~ ~.
N~
..
O

I
wherein X is CH, N, or N-09 Y is CH, N, or N-O, Z is halogen, preferably chloro; and R
is H or OH. In some preferred embodiments, X is CH or N (e.g., CH); Y is N or NnO and R is H. In some preferred eanbodiznents, X is CH, N; Y is CH, N, or N--O; Z is halogen;, preferably chloro and R OFI. Formula I includes coii-ipounds whieh can be formed in the body via a metabolic pathway, and are also included herein as components of the solid dispersions described herein. Exemplary active metabolites include (2R,4S)-Quinoline-N-oxide-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-pipci-idin-4-yl] amide and (2R,4S)-2-Hydroxy-quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.

Preferred compounds of foiinula I include the following: (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-tl-ifluoi-omethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]

amide; (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide, (2R,4S)-Quinoline-N-oxide-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
arnide(2R,4S)-Quinoline-N-oxide-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide; or (2R,4S)-2-Hydroxy-quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or salts or solvates thereof. (2R_4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide, having the following for~nula:

HNe- , l ~~:11 ~;~: - - ` - -'---~--'~

is a highly preferred embodiinent of the compound of formula I.

The compounds described herein include various solid forrns thereof, including polyinorphic forms, solvates and salts thereof. 'I'he compounds described herein also include tautoniezic foz ins drereof.

Rispersi ns of tht C mp und of I+' rmu&a I

Described herein are dispersions including a coznpound of Formula 1, or an active metabolite thereof, and a polymer, such as a water soluble polymer. Preferred polymers include HPMCAS and PVP.
As used herein, "dispersion' refers to a disperse system in which one substance, the dispersed phase, is distributed, in discrete units, throughout a second substance (the continuous phase or vehicle). The size of the discrete units of the dispersed phase can vary considerably (e.g. a single molecule, to colloidal particles of nanometer dimension, to multiple inicrons in size). In general, the dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solids. In pharmaceutical applications, a solid dispersion can include a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase), or alternatively, an amorphous drug (dispersed phase) in an amoiphous polymer (continuous phase).
In some embodiments an amorphous solid dispersion includes the polyiner constituting the dispersed phase, and the drug constitute the continuous phase.
The telm "amorphous solid dispersion" generally refei-s to a solid dispersion of two or more components, usually a drug and polymer or combination of polymers, but possibly containing other components sucb as surfactants or other pharmaceutical excipients, where the drug is in the alnorphous phase (e.g., wherein substantially all of the drug is in the amoxphous phase), and the physical stability and/or dissolution and/or solubility of the aznorphous drug is enhanced by the other components.
An exemplary solid dispersion is a co-precipitate or a co-a.nelt of (2tZ,4S)-Quinoline-4-carboxylic acid [1 -(3,5 -bis-trifluorolnethylnbenzoyl)--2-(4-chlorobenzyl)-piperidin-4-yl.] amide with HPMCAS or PVP. A "Co.-precipitate" is a product after dissolving a dz-Lig and a polymer in a solvent or solvent inixturc followed by the removal of the solvent or solvent mixture, Son-ictimes the polymer can be suspended in the solvent or solvent inixture. The solvent or solvent xnixture includes organic solvents and supercritical fluids. tn some cases, the solid dispersions arc prepared by adding a solution of a drug and a solid polymer followed by mixing and removal of the solvent.
To remove the solvent, vacuum drying, spray drying, tray drying, lyophilization, and other drying procedures may be applied. Applying any of these methods using appropriate processing parameters, according to this invention, would provide (2I2,4S)-Quinoline-4-caT-boxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide in an amorphous state in the final solid dispersion product.
Dispersions inchiding HPMCAS and/or PVP
A solid dispersion can have any form suitable for pharmaceutical use. For example, the solid dispersions can be in the form of a powder, or a coating on a substrate (e.g., the solid dispersion can be spray coated onto a particle such as lactose or microcrystalline cellulose).
The ratio of polymer to the compound of formula I affects the properties of the solid dispersion. For example, if the ratio of polymer to the compound of formula I is relatively high, the compound of formula I will tend to form a molecular dispersion or a dispersion having very small doarnains of the water-insoluble drug dispersed in the water-soluble polymer phase. However, if the ratio of polymer to the compound of formula I is higher, the concentration of water-insoluble drug in the solid dispersion will be low, tbereby requiring large amounts of the solid dispei-sion in pharmaceutical compositions comprising the solid dispersion. In addition, the low concentration of the compound of forinula I can reduce the rate of absorption of the compound of formula I in a patient.
If the ratio of polyiner to the compound of formula I is relatively low, the compound of formula I will tend to form dispersions of domains of the compound of foi-rnuia I in the polymer phase, rather than the molecular dispersions of the coznpound of formula I in polymer. However, if the ratio polymer to compound of formula I
is too low, the dispersed domains of the compound of formula I will be so large that dissolution and absorption of the drug in a patient will be reduced, thereby reducing the bioavailability of the compound of formula 1. The appropriate ratio of polymer to compound of formula 1 will depend on the compound, the polymer, the intended use, An exemplary solid dispersion includes a compound of formula I, such as (2IZ,4S)-Ouinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethylm-benzoyl)-2-(4-chlorobenzyl)-piperidin-4.-yl] amide or an active metabolite thereof or (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis--trifluoromethylmbenzoyl)-2-(4-chlorobenzyl)-piperidin-4--yl] amide, and HPMCAS.

The alnount of compound of formula I to HPMCAS can vary. For example, the dispersion can be pl-edomiizantly compound of fota.nula I, predominantly HPMCAS, or a relatively even balance of compound of formula I and HPMCAS. The ratio of compound of foi~nula I to polymer can be varied to alter the characteristics of the solid dispersion.
For example, in some embodiments, it is preferred to have a ratio of compound of formula I to polymer to provide a homogeneous dispersion, whereas in some embodiments the ratio of compound of formula I to polymer to provide regions enriched for the compound of forinula I. Exemplary ratios of the compound of formula I
to HPMCAS include fi-om about 1:20 to about 5:1, for example, fi-om about 1:4 to about 4:1, fi-om about 1:2 to about 3:1, e.g., about 1:1.

In another embodiment, the coinposition of the solid dispersion lnay include the compound of formula I and a combination or polymers such as HPMCAS and PVP.
Exemplary ratios of HPMCAS:PVP include about 5:1, 4:1, 3:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:3, 1:4, or 1:5. The polymer ratio may be adjusted to optimize the physical stability and/or the manufacturability (i.e. flow, compaction, etc) of the solid dispersion.
Another exemplary solid dispersion includes a compound of formula I, such as (2IZ.,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide or an active metabolite thereof or (2tZ,4S) Quinazoline-4-carboxylic acid [1-(3,5-bis-triiiuoromethyl-benzoyl)-,2-(4-chlorobenzyl).-piperidin-4-yl] amide, and PVP, wherein the amount of compound of formula I
within the dispersion is at least about 25%, e.g., at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or greater. Exemplary ratios of the compound of formula I to PVP include froin about 1:2 to about 5:I, e.g., from about 1:1 to about 4:1, 11-1 some prefez~-ed embodi.inents the compound of forsnula I and PVP are present in a ratio of about I: I or about 3.5:1.
Dispersions of the compound of foranula I and apol mex Dispersions including a compound of formula I and a polymer, such as a water soluble polymer are included here. For example, a dispersion of (2R,4S)-Quinoline-Iai-oxide-4-carboxylic acid [1-(3,5-bis-trifluorarnethyl-benzoyl)-2-(4-chlorobenzyl)- 28 piperidin-4-yl] amide and a polyner or a dispcz-sion of (21Z,4S)--2-Hydroxy-quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
aznide and a polymcr al-c disclosed herein.
Exemplary polymet-s include a watcr soluble polymer. The term "water-soluble polymer" refers to any polymer, natural or synthetic, which has an apparent viscosity of less than 100 mPs-s measured for a 2% aqueous solution of the water-soluble polymer at 20 C. Non-limiting examples of suitable water-soluble polymers include cellulose ethers such as methylcellulose, hydroxyrnethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, and earboxymethylethylcellulose; cellulose esters such as hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydi-oxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP); starches; pectines such as sodiun-i carboxymethylamylopectine; chitin derivates such as chitosan; polysaccharides such as alginic acid, and alkali metal and amrnoniun7 salts thereof; carrageenans; galactomannans; tragacanth; agar-agar;
gummi arabicuzn; guar gummi; xanthan gummi; polyacrylic and polymethacrylic acids and salts thereof; acrylate and methacrylate copolymers; polyvinylalcohol;
polyvinylpyrrolidone;

copolymers of polyvinylpyrrohdone with vinyl acetate; and polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide.
Ratios of compound for fortnula I and polymer include those ratios described above, for example the dispet;sions above including HPMCAS and/or PVPe Aclditiortal cozxtpom nts Other pharz-naccutically acceptable ingredients can also be included %n the dispersions described herein such as a surfactant or an additional polyaaer, for example a water-soluble polymer.

SuYfactc~nt The surfactant is generally present in the dispersion in an amount from about 0.1 to about 20% by weight, for example, from about 1 to about 15% by weight (e.g., about 9%), e.g., from about 0.5 to about 10%, from about 0.5 to about 5%, or from about 1 to about 2%. The weight ratio of compound of formula I to surfactant ranges from about 300:1 to about 1:1. for example, about 50:1 to about 20:1, e.g., about 25:1 or about 4:1.
Suitable surfactants include anionic surfactants, cationic surfactants, and non-ionic surfactants. Anionic surfactants are amphiphilic molecules having a negative charge. Non-limiting examples of suitable anionic surfactants include alkyl, aryl, or aryl alkyl carboxylates, sulfonates, sulfates, phosphates, or acylated protein hydrolysates.
Suitable carboxylated surfactants include, for example, soaps (i.e., fatty acid salts), bile salts, polyalkoxycarboxylates and N-acylsarcosinates. Suitable sulfonated surfactants include, for example alkylsulfonates, alkylbenzenesulfonates, alkylarenesulfonates, short-chain lignosulfates, naphthalenesulfonates, a.-olefinsulfonates, petroleum sulfonates, and sulfonates with estel-, amide, or ether linkages. Suitable sulfated surfactants include, foi-example sulfate esters of fatty alcohols, sulfated alkylphenols, sulfated acids, amides, and esters, and sulfated natural oils and fats. Suitable phosphonated surfactants include fatty alcohol mono- and diesters of orthophosphoric acid.

In some embodiments, an anionic surfactant is preferred. Bxemplary anionic surfactants include, for example, fatty acid salts such as sodium caproate, sodiuin caprylate, sodium caprate, sodium laurate, sodium myristate, sodium myristolate, sodium palmitate, sodiurn palmitoleate, sodiuin oleate, sodium ricinoleate, sodiuln linoleate, sodium linolenate, sodium stearate, sodium lauryl sulfate (SLS), sodium tetradecyl sulfate, sodium lauryl sarcosinate, sodium dioctylsulfosuccinate, etc.; bile salts such as sodium cholate, sodium tarocholate, sodium glycocholate, sodium deoxycholate, sodium taurodeoxycholate, sodium glycodeoxycholate, sodium ursodeoxycholate, sodium chemodeoxycholate, sodium glycochemodeoxycholate, sodium cholylsarcosinate, sodium N-methyl taurocholate, sodium hth.ocholate, etc.; phosphoric acid esters such as esterification products of fatty alcohols or fatty alcohol ethoxylates with phosphoric acid or anhydride, ete.; carboxylates such as ether alkyl carboxylates formed by the oxidation of terzninal -O14 groups of fatty alcohol ethoxylates, suceinylated monoglycerides, sodium stearyl filmarate, stearoyl propyleneglycol hydrogen succinate, Mono/diacetylated tartaric acid esters of mono- and diglycerides, citrie acid esters of inono- and diglycerides, glyceryl-lacto esters of fatty acids, lactylic esters of fatty acids, calciumisodium stearoyl-2-lactylate, calciuin/sodium stearoyl lactylatc, alginate salts, propyleneglycol alginates, etc.; sulfates and sulfonates such as ethoxylated alkyl sulfates, alkyl benzene sulfonates, a-olefin sulfonates, acyl isethionates, acyl taurates, acyl glycei-yl ether sulfonates, octyl sulfosuceinate disodium (i.e., dioctyl sodium sulfosuccinate (DOSS) or sodium docusate), disodium undecylenamido-ME.A.-sulfosuccinate, etc.
Preferred surfactants include sodium lauryl sulfate and sodium docusate, which can be used alone, or in combination. For example, a mixture of sodium lauryl sulfate and sodium docusate.
In some embodiments, two oi- more surfactants are used in combination. If the colnpositioils of the present invention include a mixture of two or more surfactants, the two or moi-e surfactants can be selected from the same class of surfactant (e.g., the two or-more surfactants can each be anionic surfactants), or can be selected from different classes of surfactant (e.g., one of the two or more surfactants can be any non-ionic surfactant, and at least one other surfactant can be an anionic surfactant).
When a mixture of surfactants is present in the composition of the present invention, for example, two surfactants, the weight ratio of the two surfactants can range from about 5:1 to about 1:1. For example, the weight ratio of the two surfactants can be about 5:1, 4:1, 3:1, 2:1, or 1:1.
Additional polyinei-s In some embodiments a dispersion described herein includes a compound of formula I and two oi- more polyiners. For example, the dispersion e.g., the dispersion of the compound of formula I and HPMCAS or the dispersion of the compound of formula I
and PVP, can include an second polymer, such as a water soluble polymcl , to provide a of a compound of formula I dispersed in two polymers, e.g., HPMCAS and a second polymer or PVP and a second polymer. In some instances, the two polymers are chosen for theif- complementary properties, such as solubility, compressability, flowability ease of handling, cost, etc. The ratio of the first polyzner:second polymer can vary and generally ranges from about 1:4 to about 4:1, e.g., from about 1:3 to about 3:1, from about 1 : 2 to about 2 : 1 , e.g., about 1 : J. .

Characteristics of dispersions As described above, the dispersiolr can be hoinogeneous or can be non-homogeneous, for example having a region rich in the compound of formula I.
The size distribution of the domains of the enriched region (c.g, discontinuous phase) distributed within the dispersion phase can be unimodal, or bimodal. In one enibodiment, inorc than 90% of domains of the compound of foT-mula I dispersed in the polymer (i.e., HPMCAS
or PVP) have a size ranging from 10 mn to 1000 nm, or 100 nm to 800 nm, or 100 nrn to 500 nm.
In some embodiments, the compound of formula I, within the dispersion is substantially amoarphous (e.g., at least about 50% of compound of formula I is amotphous, at least about 55% of compound of formula I is amorphous, at least about 60%
of compound of formula I is amorphous, at least about 65% of compound of formula I is amorphous, at least about 70% of compound of formula I is aniorphous, at least about 75% of compound of foi-rnula I is amotphous, at least about 80% of compound of formula I is amorphous, at least about 85% of compound of formula I is amorphous, at least about 90% of compound of formula I is amoiphous, at least about 95% of compound of formula I is amorphous, at least about 98% of compound of formula I is amorphous, at least about 99% of compound of foz-rn.ula I is amorphous, or substantially all of compound of formula I is amorphous.
As used herein, the term "amoiphous" refers to a solid znaterial having no long range order in the position of its atoms. Amorphous solids are generally supercooled liquids in which the molecules az-e arranged in ai andom manner so that there is no well-defined azrangement and no long range order. Amorphous solids are generally isotropic, i.e. exhibit similar properties in all directions and do not have definite melting points. For example, an amozphous material is a solid material having no sharp characteristic crystallirze peak(s) in its Y-x ay power diffraction (XRPD) patterrl (i.e., is not crystalline as detcr~~.ined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an aznorphous solid. See, US
2004/0006237 for a compai-ison of XRPDs of an amoi-phous material and crystalline material.
As used herein "crystalline solids" refei-s to colnpounds or compositions where the str-uctural units are arranged in fixed geometric patterns or lattices, so that crystalline solids have rigid long range order. The units that constitute the crystal structure can be atoms, molecules, or ions. Crystalline solids show definite melting points.
In some embodiments, the dispersion has a single glass ti-ansition temperature ("T.'"). The To is a characteristies temperature where a glassy material, upon heating, undergoes a rapid physical change from a glassy state to a zubbery state. The Tg can be determined by several commonly accepted techniques such as differential scanning calorimetry (DSC) or by a dynamic mechanical analyzer (DMA). It is preferable that the T. of the dispersion is generally at least about 50K greater than the storage conditions at room temperatur-e and relative humidity conditions (e.g., 25 C, 60% RH). For example, in solid dispersions including the compound of formula I and HPMCAS in an equivalent ratio, the Tg of the dispersion at room temperattiu-e/humidity conditions is generally from about 98 C to about 102 C (e.g., about 100 C or 101 C). In solid dispersions including the compound of formula I and PVP in an equivalent ratio, the Tg of the dispersion at room temperature/humidity conditions is generally from about 130 C to about 135 C. It is well understood that the Tg of a dispersion is dependent upon many factors such as the components (i.e. their st1-uctures, interactions, etc.) their weight fraction of the dispersion, and the equilibrium solvent and/or moisture content of the dispersion to name a few.
Further, the Tg of a homogeneous blend of amorphous coinponents (i.e. the polymer and compound) can be estimated in many cases by the C-ordon--Taylor Equation in which the weight fractions of each component and their respective Tg's are used to estimate the T9 of the dispersion. It is preferable that the ratio of forinula I to polyzner in the dispersion is such that a sufficient therapeutic amount of formula I can be manufactured into a conventional dosage form of conventional size (i.e. 650 mg preferable to 1300 mg), using cojnmon techniques (e.g. roller compaction, wet granulation, etc) and that the dispersion has a single Ti of at least 50K greater than tb.e anticipated storage conditions.
Solid dispersions described herein are generally stable, e.g. chemically and physically stable. for example, in some preferred embodiments, the solid dispersion is both chelnically and physically stable under accelerated storage conditions such as 40 C/75% and/or 25 C/90% for at least 2 weeks. The physical stability of the dispersion can be evaluated for content of amorphous forin of coznpound of formula I via XRPD, DSC, and/or microscope observations. For example, in a solid dispersion including the compound of formula I and PVP in an equivalent ratio, the Tg at room teznperature/humidity conditions is gcnerally fl-oin about 130 C to about 135 C, the T.
of the same dispet-sion at 40 C!75% storage for two weeks reinains at about 130 C to about 135 C, finally, the Te of the same dispersion at 25 C/90% storage for at least two weeks is about 130 C to about 135 C. In another embodiment, a dispersion of PVP and the compound in foi-inula I coated onto lactose and subsequently blended with common excipients and filled into a gelatin capsules is stable for at least 15 months at room temperature and relative humidity conditions (e.g., 25 C, 60% RH).

The solid dispersions described herein, can be used as a component in a phar-maceutical composition, for example as a component as a powder for oral suspension, tablet, capsule, etc. In general, the solid dispersions described herein have a bulk density of from about 0.20 g/ml to about 0.30 g/ml, and a tap density of from about 0.34 ghnl to about 0.40 g/ml. The solid dispersions generally have a D50 of less than about I m.
In another embodiment, a composition of compound formula I consists of solid dispersion that is present in sufficient amount such that following an administration of the composition containing a solid dispersion to an animal, the level of compound of formula I in the blood of the animal is at least about 20% higher than seen with an administration of compound of formula I which does not include a solid dispersion, for example, at least about 25% higher, at least about 50% higher, at least about 100% higher, at least about 200% higber, at least about 300% higher or at least about 400% higher. In another embodinient, the composition of the present %nvention provides an increased bioavailabi.hty of at least 1.25 fold, fold, 1.50 fold, or at least 2.0 fold over the bioavailability of non-formulated water-i.nsoluble drug.

Particles incluclinR the campound of formula I

Particles of the compound of forznula I ai-e described herein. Fox- example, particles comprising amorphous coznpound of forznula I are described herein, e.g., particles containing substantially amot-phous compound of formula I are described herein.
Amorphous compound of fo7-inula I can be made, for example, by spray drying the compound of fo1 inula I to providc particles of compound of formula I suitable for formulation into a pharmaceutical composition such as an oral dosage foi znulation.

As described above, the conlpound of formula I and dispersions including the coinpound of formula I dcscribed herein can be used as a componcnt in a pharmaceutical composition. In soine embodinient the dispersion is formulatcd directly into the composition. In some embodiments, the compound of formula I, e.g.. a dispersion including a compound of formula I as described herein, is coated onto a par-ticle, which particle is formulated onto the pharinaceutical composition.

The compound of formula 1, e.g., amorphous compound of formula I, can be coated onto a particle, for example with a water soluble polymer. In some embodiments a dispersion described herein is coated onto the surface of a particle.
Exemplary particles useful fbr coating with a dispersion described herein include non-pariels such as lactose or microcrystalline cellulose or starch.

A compound of formula I or a dispersion described herein can be coated onto the surface of the particle in a spray coating process, for example, by providing a suspension or slurry of the compound of formula I, for example amot-phous compound of fol~nula I
or a dispersion described herein, and par-ticle and spraying the suspension or slurry to provide a pai-ticle coated with the compound of formula I. In some embodiments the surface of the particle can also be coated with additional ingredients, for example an enteric coating.

The coated par-ticles can then be forrned into a suitable dosage forin, for example by encapsulation. Alternatively, the coated substrate can be mixed with one or znore additional ingredients as disclosed herein, using processes known in the phaxinaceutical field, such as wet or dry granulation, milling, etc. and then formed into a suitable dosage fot-in, for example by encapsulation, tabletting, or pelletization.

Methods of makiiag dispersions including a compound of formula I
Any method for obtaining solid dispersions could be used in connection with this the dispersions described herein. In general, methods that could be used include those that involve rapid removal of solvent from a mixture or cooling a molten sample. Such methods include, but are not limited to, rotational evaporation, fi-eeze-drying (i.e., lyophilization), vacuum drying, melt congealing, and melt extrusion. However, a prefezTed embodiment of this invention involves amorphous solid dispersion obtained by spi-ay-drying. Accordingly, in anodler embodiinent, this invention provides diying the product obtained by spi-ay drying to remove the solvent.
Pl-eparations disclosed herein, c.g., a pharmaccutical composition, can be obtained by spray-drying a mixture comprising a compound of formula 1, HPMCAS and/oi-PVP, and an appropriate solvent (e.g., acetone). Spray drying is a method that involves atomization of a liquid nlixture containing, e.g., a solid and a solvent, and removal of the solvent. Atomization may be done, for example, through a nozzle or on a rotating disk.
Spray drying is a process that conver-ts a liquid feed to a dried particulate forrn.

Optionally, a secondary drying process such as fluidized bed drying or- vacuum dlying, may be used to reduce residual solvents to phai-inaceutically acceptable levels. Typically, spi-ay-drying involves contacting a highly dispersed liquid suspension or solution, and a sufficient volume of hot ai1- to produce evaporation and drying of the liquid droplets. The preparation to be spray dried can be any solution, coarse suspension, slurry, colloidal dispersion, or paste that may be atomized using the selected spray-drying apparatus. In a standard procedure, the preparation is sprayed into a cui7ent of wal-m filtered air that evaporates the solvent and conveys the dried product to a collector (e.g., a cyclone). The spent air is then exhausted with the solvent, or altematively the spent air is sent to a condenser to capture and potentially recycle the solvent.
Commercially available types of apparatus may be used to conduct the spray-drying. For example, commercial spray dryers are znanufactured by Buchi Ltd. and Niro (e.g., the PSD line of spray driers manufactured by Niro) (see, US 2004/0105820, US 2003/0144257).
Spray-drying typically employs solids loads of material frozn, about 2% to about 25%, (i.e., compound of forznula I and excipients) preferably at least about 4% or 5%. In general, the upper limit of solids loads is governed by the viscosity of (e.g., the ability to pump) the resulting solution and the solubility of the components in the solution.
Techniques and methods for spray-drying may be found in Perry's Chemical Engineering Handbook, 6th Ed., R.H. PelTy, D.W C7reen & J.O. Maloney, cds.), McGraw-Hill book co. (1984); and Marshall "Atomization and Spray--Drying" 50, Chem.
Eng. Prog. Monogr. Series 2 (1954).
In general, the spray-drying is conducted with an inlet tein.perature of from about 60 C to about 200 C, for example, from about 130 C to about 180 C. The spray-drying is generally conducted with an outlet tcmperature of from about 70 C
to about 150 C, for example from about 80 C to about 110 C.

Pl-eferred solvents are those solvents NN7 here the compound of for7nula I has a solubility of at least about 10 mg/ml (e.g., at least about 15 ing/ml, 20 mg/ml, 25 mg/ml, 30 mg/mI, 35 mg/ml, 40 mg/ml, 45 mg/ml, 50 mg/ml, 75 mghnl, 100 mg/ml, 125 mg/hnl, 150 mg/ml, 175 mg/ml, 200 mg/ml, or greater).
Suitable solvents include esters, ketones, and alcohols. Exemplary solvents that could be used include ethyl acetate, methanol, acetone, and ethanol. Some prefer-red embodiments include ethyl acetate. In some embodiments, a mixture of solvents is used.

In a preferred embodiment a common dissolves both the compound of for-znula I
and the polylner (i.e., HPMCAS and/or PVP).
Removal of the solvent may require a subsequent drying step, such as tray drying, fluid bed drying (e.g., from about room temperature to about 100 C), vacuum drying, microwave drying, rotary druln drying or biconical vacuum drying (e.g., from about room temperature to about 200 C).
The resulting dispersed particles (e.g., after spray drying) generally have an average pai-ticle size of less than I m, for example average particle sizes ranging from about 100 nin to about 900 nm, including average particle sizes of about 8 50 nm, about 800 nm, about 750 nm, about 700 nm, about 650 nm, about 600 nm, about 550 nm, about 500 nm, about 450 nm, about 400 nm, about 350 nm, about 300 nm, about 250 nm, about 200 nm, and about 150 nm, including all ranges and subranges therebetween. The pai-ticle size distribution of the dispersed particles can be essentially un.imodal or bimodal.
If the pal'cicle size distribution is essentially unimodal, at least 50% of the particles have a particle size of less than 1 m. for example, at least 50% of the particles have a particle size of less than 900 nm, 800 x)an, 700 nrn, 600 nm, 500 nrri, 400 nm, 300 nm, or 200 nm, including all ranges and subranges therebetween.

Particle coatirzg In some embodiments a compound of forinula (1) or a dispersion comprising a compound of formula (I) and a polymer is coated onto a carrier such as a solid particle, e.g., a particle such as lactose or microcrystalline cellulose or starch. A.
compound of fonnula I, or a dispersion of the compound of formula I and a polymei- as described herein is suspended in a solution of watet- and a water-soluble polymer (e-g., PVP). The suspension is layered onto a carrier such as solid par-ticle such as lactose or a sphere of microcrystalline cellulose (e.g. Celsphere).
In some embodiments the water soluble polymer is the same polymer as the polymer in the solid dispersion (or a polymer in the solid dispersion in exaniples of dispersions including more than one polymer).
In general the solids load of the water-soluble polymer in the coating process is from about 10 to about 60 % by weight.

Corrap siti ,is comprising a dispersion of a c rrep und of formula I
The solid dispersions described herein and particles coated with the solid dispersions described herein can be formulated with additional pharmaceutically acceptable excipients to provide dosage fonnulations for administration to a subject.
The weight percentage of the compound of for mula I in the compositions described herein can range from about 99 wt.% to about 15 wt.%. For example, the weight percentage of water-insoluble drug can be about 99, about 95, about 90, about 85, about 80, about 75, about 70, about 65, about 60, about 55, about 50, about 45, about 40, about 35, about 30, about 25, about 20, and about 15 wt io.
The unit dosage employed may be varied depending upon the requirements of the patient and the condition being treated. For convenience, the total daily dosage may be divided and administered in poi-tions during the day as requir.ed. The cluantity of water-insoluble dr ug i.n the compositions of the present invention ranges frorrr about 1 rng to about 500 mg per unit dose. For example, the quantity of water-insoluble drug per unit dose of the compositions of the present inventioza can be about 1 m_g, 5 mg, 10 r.ng, 15 mg, 20 mg, 25 mg, 30 rng, 35 rng, 40 r rg, 45 mg, 50 rng, 60 mg, 70 rn.g, 80 rng, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mge 150 mg, 160 ing, 170 rng, 180 u-ig, 190 rng, 200 rng, 250 mg, 300 mg, 320 mg, 350 nag, 400 mg, 450 rng, 480 mg, 500 rng, 640 nig, 750 mg, 1000 mg, etc.
The weight percentage of water-soluble polymer in the compositions of the present invention can range from about 90 to about 5 wt.%. For example, the weight percent of water-insoluble polymer in the composition can be about 90, about 85, about 80, about 75, about 70, about 65, about 60, about 55, about 50, about 45, about 40, about 35, about 30, about 25, about 20, about 15, about 10, and about 5 wt.%.
When prescnt, the weigbt percentage of the total amount of the one or more additional ingredients in the composition of the present invention can range from about 90 to about 5 wt.%. For example, the weight percent of the total amount of one or more additional ingredients in the composition can be about 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, and 20 wt.%.
Exemplary pharmaceutically acceptable excipients include diluents or fillers, drug complexing agents or solubilizers, disintegrants, binders, lubricants, glidants, pH
modifiers, and surfactants. Examples of suitable diluents ol- fillers include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and starch. Examples of drug complexing agents or solubilizers include polyethylene glycols, caffeine, xanthene, gentisic acid, and cyclodextrins. Examples of disintegrants include sodium starch glycolate, sodium alginate, carboxymethylcellulose sodium, methylcellulose, croscarmellose sodium, and crospovidone, preferably croscarmellose sodium and/or crospovidone. Examples of binders include methylcellulose, povidone, microcrystallinc cellulose, starch, hydroxypropyl cellulose, hydroxymethyl propyl cellulose, and gums such as guar and tragacanth, preferably povidone. Examples of lubricants include 20 magnesium stearate, steai-ic acid, sodium stearyl fumurate.. An cxample of a ghdant is silicon dioxide. Examples of pH modifiers include acid such as citric acid, acetic acid, ascorbic acid, lactic acid, aspat-tic acid, succinic acid, phosphoric acid, and buffers corriprising mixtures of any of the abovemnoted ac%ds and their salts.
Examples of surfactants are provided above. Preferred sui-factant excipicnts include DOSS and SLS. The weigbt percentage of surfactant in the compositions of the present invention can range from about 0.1 wt.% to about 20 wt.%. For example, the weight percent of surfactant in the composition can be about 20, about 19, about 18, about 17, about 16, about 15, about 14, about 13, about 12, about 11, about 10, about 9, about 8, about 7, about 6, about 5.5, about 5.0, about 4.5, about 4.0, about 3.5, about 3.0, about 2.5, about 2.0, about 1.5, about 1.0, about 0.9, about 0.8, about 0.7, about 0.6, about 0.5, about 0.4, about 0.3, about 0.2, about 0.1 wt.%,.

.Additional ingredients can independently include one, or two or more individual components selected from each of the classes of phalinaccutically acceptable excipients described herein. That is, compositions included herein can include e.g., one or more diluents or fillers and a disintegt-ant, a single diluent or filler and two or more disintegrants, a filler, a disintegrants, a binder, a lubricant, etc.
In some embodiments, the compositions described herein include an additional therapeutic agent, for example to provide co-administration of the compound of formula I
with a second therapeutic agent. The tei-rn "therapeutic agent", as used herein is used in its conventional sense, denoting a compound or any synthetic or naturally existing entity having beneficial prophylactic and/or therapeutic propei-ties when administered to a mammal, especially a human. Non-limiting examples of suitable water-insoluble drugs include, for example, drugs from a variety of lcnown classes of dr-ugs, including proteins, peptides, nucleotides, anti-obesity drugs, nutraceuticals, corticosteroids, elastase inhibitors, analgesics, anti-fungals, oncology therapies, anti-emetics, cardiovascular agents, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antinauscarinic agents, antiinycobacterial agents, antineoplastic agents, irnmunosuppressants, antithyroid agents, antiviral agents, anxiolyties, sedatives, astringents, (3-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, cholinesterase inhibitors, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, imznunological agents, lipid regulating agents, modulators of intestinal motility, muscle relaxants, parasyznpathornimetics, parathyroid calcitonin and hiphosphonates, prostaglandins, radio-phaz-inaceuticals, sex horznones, anti-allergic agents, stimulants and ax2oretics, sympathomimetics, thyroid agents, vasodilators, and xanthines.
The particles of the solid dispersion can then be formed into a suitable dosage form, for example by encapsulation. Alternatively, the particles of solid dispersion can be mixed with one or more additional ingredients as disclosed herein, using unit processes known in the pharmaceutical field, such as wet or dry granulation, milling, etc., and then forlned into a suitable dosage forna, for example by encapsulation, pelletization, or tabletting.

The compositions of the present invention can be pi-ovidcd in any dosage form suitable fol- delivery of a therapeutically effective dose of the water-insoluble drug to a patient. Non-limiting examples of suitable dosage foz7ns include a mini capsule, a capsule, a tablet, and implant, a troche, a lozenge, a suspension, an ovule, a suppository, a wafer, a chewable tablet, a quick or fast dissolving tablet, an effervescent tablet, a buccal or sublingual solid, a granule, a film, a pellet, a bead, a pill, a powder, a strip, or a sachet.
The compositions of the present invention can be fonnulated for oral, sub-lingual, 10 buccal, nasal, ocular, pulmonary, uretl-iral, transmucosal, vaginal, topical, or rectal delivery. In one embodilnent, the conipositions of the present invention are formulated so that it is suitable to be administered to a subject orally and taken into the subject system through, e.g., gastric/intestinal tract. In some preferred embodiments, a composition described herein is for-mulated for oral administration, for example as a tablet, a capsule, or a powder for oral suspension, preferably a tablet or a capsule. When forrnulated as a mini capsule or capsule, the capsule can be a hard or soft gelatin capsule, starch capsule, or cellulosic capsule.
The composi_tions of the present invention can also be coated with one or more coatings in order to control the rate of disintegration, e.g. in the digestive tract, in order to provide immediate release, pulsatile release, controlled release, extended release, delayed release, targeted release, synchronized release, or targeted delayed release properties.
Such coatings can include an enteric coatings, film coatings, barrier coatings, compress coatings, fast disintegrating coatings, enzyme degradable coatings, etc.

Methods of using dispersions including a compound of formula I
The compounds and solid dispersions, particles including the solid dispersions and compositions including the compounds and solid dispersions described herein can be used in therapy, for example to treat an NK-1 related disorder. A.
therapeutically effective amount of a solid dispersion including a compound of formula I as described herein (and/or a particle including a solid dispersion and/or a composition including a solid dispersion) can be adzninistcred to a subject, for exainple a subject in need of such treatment, to treat an NK-1 related disorder.
'I'he tenn "therapeutically effectivc aznount" is an afnount of water-insoluble drug which provides a clinically useful effect, e.g. reducing or alleviating symptoms, or preventing or ameliorating a disease or condition. Exelnplary NK-1 related disorders include disorders such as depression, anxiety, cognitive and memory deficits, acute and chronic pain, allergic disorders, asthzna, chronic obstructive pulmonary disease, derniatological disorders, incontinence, inflammation, en-iesis, irritable bowl syndrome, sleep disorders, substance withdrawal, immune system disorder, inflammatory disorders such as osteoarthritis, rheumatoid arthritis, and other arthritides, inflammatory bowel disease scleritis, visceral disorders such as pelvic inflammatory disorder, vesicultis and dyspareunia. In some preferred embodiments a compound or dispersion described herein or a composition including a compound or dispersion described herein is administered to a subject for the treatment of social anxiety disorder, incontinence, and/or irritable bowl syndrome.
The colnpounds and dispersions described herein can be administered with or witbout food. In some embodiments, a dispersion described herein is administered to a subject who has eaten within 2 hours of administration of the solid dispersion or will eat within an hour after administration of the solid dispersion. The frequency of dosing can vary depending on a number of factors, including the disorder being treated, the dosage foi-inulation, the dosage amount, and the patient. Accordingly, a compound or dispersion d.escribed berein can be administered once daily, twice daily, three times daily, or four tiines daily.

Exampl~~s `f'he following examples are intended to illustrate but not to limit the invention in any manner, shape, or forin, either explicitly or implicitly. While they are typical of those that rnight be used, other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used.

Exaa~ple ~ ~ Ild das~ers~ a~s incl~~iln~ PVF ~ ~IP1~CAS

Various drug/polymer and drug/polymer/surfactant combinations were dissolved in various solvents and then spray dried to form solid dispersion particles The polymer, solvent, surfactant concentration (% docusate sodiuln), % solids and diug/polynzer ratio are shown in Table 1., below:

Table I.
LOT Solvent Polymer I)rug*oPolymer DOSS-" % Solids (%) A001 Ethyl Acetate NA NA 5.00 A002 Ethanol 200 PVP (K29/32) 1:3 NA 5.00 A003 Ethanol 200 PVP (K29/32) 1:1 NA 5.00 A004 Ethanol 200 PVP (K29/32) 3:1 NA 3.33 A005 Ethanol 200 PVP (K29/32) 1:1 1.50 4.76 A006 Ethano1200 PVP (K29/32) 1:1 2.00 4.76 A007 Ethano1200 PVP (K29/32) 1:1 9.00 4.76 A008 Ethano1200 NA * NA 2.50 A009 Methanol NA Y NA 5.00 A010 Methanol PVP (K29/32) 1:1 1.00 5.00 A011 Methanol PVP (K29/32) 1:1 NA 5.00 A012 Acetone I-IPIVICAS-L,F 1:1 1.00 5.00 A013 Acetone 1-IPMCASmI,F 1:1 NA 5.00 D007 Ethyl Acetate NA 12.20 5.00 ~ (2IZ,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2a(4-chlorobenzyl)-piperidin-4-yl] alnide ** docusate sodium Physical analyses of the solid dispersions frol-n "I'able I. were perforrned to evaluate the foz zn (i.e. amorphous or ci-ystalline) of the drug within the dispersions and to deterln.ine the glass transition temperatures of the solid dispersions as presented in Table 2.
The methods used to deteriuine the forn:r. and TQ were XRPl.~ and modulated DSC, respectively.

Table 2.
LOT Polymer Drug*:Polymer DOSS** Form Tg( C') (%) 25 "C/60%
XRPD > 2 weeks mDSC
A001 NA NA amorphous 91 A002 PVP (K29/32) 1:3 NA amorphous 152 A003 PVP (K29/32) 1:1 NA amorphous 135 A004 PVP (K29/32) 3:1 NA amorphous 115 A005 PVP (K29/32) 1:1 1.50 amorphous 133 A006 PVP (K29/32) 1:1 2.00 amoiphous 130 A007 PVP (K29/32) 1:1 9.00 amoiphous 119 A008 NA ~ NA amorphous 94 A009 NA = NA amorphous 94 A012 HPMCAS-LF 1:1 1.00 amoiphous 100 A013 HPMCAS-LF 1:1 NA amoiphous 101 D007 NA * 12.20 amorphous 66 * (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide ** docusate sodium Exa~nple 2 o St~~ss~d ~t~b~lah f ~ ~~d d~~p~~ s~ r~s ~~cludlaa~ PVP r HPMCAS
Exemplary solid dispersions from Table J. were subjected to accelerated stability conditions, including 25 C/90% RH for 2 weeks and 40 C/75% RH for 2 weeks with the results presented in Table 3, The Tg`s were determined with mI?SC. Further evaluation of the foz zn of drug in the dispersions was performed by microscope assessment.
Table 3.
LOT Polymer Drug*to DOSS-` 1<9 i-m Tg( C) 4'g( C) T~(",) P lymr 25 C/60% 40 075% -25 090%
- - - - - - ---Microscope > 2 weeks 2 weeks 2 weeks --- --- - - - -- ---- -- --- -- ---observations mDSC niDSC MOSC
--- --------- - -- --- -- - -- ---- - -A003 PVP 1:1 NA Not 135 125 135 (K29/32) birefringent -- --- - -- - -- ---A004 PVP 3:1 NA Not 115 116 117 _ (K29/32) birefringent _ A007 PVP 1:1 9.00 Not 119 119 (K29/32) birefringent A008 NA AV608 NA Not 94 92 94 birefringent ~ (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-triftuoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] alnide ** docusate sodiuin Ia,xample 3: F rrnulated ral d sa e forms The dispersions described herein can be prepared and further formulated into an oral dosage form such as a tablet or capsule. Alternatively, the solid dispersion may be formulated into a dosage for-in by coating onto lactose or an acceptable carrier first and subsequently processed into a capsule or tablet.
The compositions of Table 4. were prepared by dissolving dissolving (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide and the chosen polymer (PVP or HPMCAS) in a common organic solvent. The resulting solution was spray-dried to provide nano-sized solid dispersion particles of which approximately 50% had a diameter of about 0.8 um or less.
The solid dispersions were fur-thcr processed into tablet dosage forms by blending with diluents, a glidant, and a portion of a lubricant which was densified by slugging and subsequently n-iilled. A disintegrant and the balance of the lubricant were added to the milled granulation and blended. The lubricated gi anulation was compressed into tablets, The tablcts can also be coated with a functional or non--functional film coat.

I'able 4e LOT X608OCT'A 00 it X6O8OCT A002 - - -Dosage S&reng&.h 160 mg Tablet 1 60 mg 'l,able'r.
---Coznponent (~/ ) (~/~) ---- -- -(2R,4S)-Quinoline 4-carboxyl.ic acid [1 -(3,5 bxs- 24,7 25.0 trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-y1] amide _ - --Povidone (PVP) 24.7 0.0 HPMCAS 0.0 25.0 Docusate Sodium 0.6 0.0 Croscaranellose Sodium 7.5 5.0 Silicon Dioxide 0.0 0.5 Sodium Lauryl Sulfate 1.0 0.5 -----Mici-ocrystalline cellulose 40.0 21.25 Dicalcium Phosphate 0.0 21.25 Magnesium Stearate 1.5 1.5 Total 100 100 The GMP#3 composition of Table 5 was prepared by dissolving (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide and docusate sodium in ethyl acetate. The resulting solution was spi-ay-di-ied to provide nano-sized particles of (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide and docusate sodium. Approxiinately 50% of the nano-sized par-ticles had a diameter of about 0.8 in or less. The nano-sized particles were then added to an aqueous solution of povidone and the 1-esulting suspension was spray coated onto lactose prills. The dried, coated lactose prills were then dry blended with croscarmellose sodium, crospovidone, and sodium lauryl sulfate. Magnesium stearate was added to the mixture and blended and then subsequently en.capsulated.
In another exemplary dosage form, X608PF'CA003 was prepared in the same fashion as GMP#3 with the exceptions of the PVP:drug suspension being layered onto a rn.icrocrystalline cellulose (Celsphere) prior to encapsulation.

'fable S.
LOT GMP#3 X608PFCAO03 Unit Dose ----- - 160 mg Capsule 160 mg Tablet Component - ------ ---- -------- ~~~ ) - ------~~~~~ -------- ----(2R,4S)-Quinoline-4-carboxylic acid 29.0 27.3 [ 1-(3,5--bisatrifluoromethyl-ben-zoyl)-2-(4-chlorobenzyl),-piperidin-4-yl] amide Docusate Sodium 4.1 0.3 Sodiuzn Lauryl Sulfate 2.3 0.5 Povidone (PVP) 9.2 7.7 Croscai-nlellose Sodium 10.0 0.0 Lactose 37.9 0.0 Ci-ospovidone 7.0 0.0 Microcrystalline Cellulose (Celsphere) 0.0 64.20 Magnesium Stearate 0.5 0.0 Total 100 100 Exapple 4 o Stressed stability of formulated oral dosage forms Exemplary solid dispei-sions foinlulated into Drug Product (Tables 4. and 5.) were subjected to accelerated stability conditions, including 25 C/90% RH for 2 weeks and 40 C/75% RH for 2 weeks, 5 weeks, 3 months and 6 months. Table 6 illustrates the Tg's that were determined with mDSC for the 2 week timepoint analysis. Further evaluation of the form of drug in the dispersions was perforined by microscope assessmcnt. 10 'f'able 6.
LOT Polymer Drug*: Form '1'g( C) Tg( C) Pol nier 40 C/75% 25 C/90 '/
Mici oseope 2 weeks 2weeks ------------ ------ ----------- obse~ vata ns mDSC
rnUSC -- - - - -X608OCTA001 PVP 1:1 Not 138 ---birefringet-~t - - ------- - --- --- --------- -- - -- ---- ------X608OCTA.002 HPMCAS 1:1 Not 102 102 birefringezat X608PFCA003 PVP 3,5:1 Not 94 93 birefringent -----* (2R,4S)-Quizioline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloz-obenzyl)-piperidin-4-y1] amide "I'ables 7., 8., and 9., show the appearance, assay, related substance, and dissolution results for formulations Y608OCTA0 1, X608OCT,4.002, and X604PFCA003, respectively, stored for various times at 40 C/75%. The assay and impurity results demonstrate chemical stability for the foi-mulations and the dissolution results, which when significantly depressed from initial are a suitable surrogate for the crystallization of the dr-ug form, show minimal change.

Table 7. Formulation X608OCTA 1 stored at conditions 40 C/75 /a TEST Initial 5 weeks 3 months 6 months Appearance white white white, Off-white mottled Assay (%) 95.5 96.5 96.7 94.6 Total Related Substances (%) <0.05 <0.05 <0.05 0.05 Dissolution (% released) minutes 2 3 3 4 30 minutes 3 5 5 6 45 minutes 5 8 7 8 60 minutes 7 10 10 11 120 minutes 14 22 20 21 Table 8. Formulation X608OCTA002 stored at conditions 40 C/75 /0 TEST Initial 5 weeks 3 months 6months Appearance -- - - white white white white ---Assay (%)-------------- ------ 94.9 ---96.9~- 97.2 94.8 ------------ Total Related Substances (%) <0.05 <-0.05 <0.05 0.07 Dissolution (% released) ---.~.---------_------- ----------- ----- ----- ---_----- ------ 15 minutes 26 30 minutes ------ --- 33 ---- 34 28 31---- 45 lninutes 39 40 35 39 60 minutes --- ----- 45 46 40 45 120 minutes 59 61 55 57 10 Table 9. Formulation X608PF'CA003 stored at conditions 40 C/75 /

TEST Initial 5 weeks 3 months 6 months Appearance * * *
-- -- -- -- - -- - -Assay (%) 95.3 100.2 99.6 101.7 Total Related Substances (%) 0.05 <0.05 <0.05 0.05 Dissolution (% released) 15 minutes 17 16 14 13 30 minutes 26 25 27 25 45 minutes 36 36 36 36 60 minutes 43 49 44 45 120 minutes 71 79 73 76 ~ Free flowing pellets in an off-white `00" HPMC capsule Example 5: Improved dissolution of select solid dispersions A notable disadvantage of solid dispersion tablets is their extremely long disintegration and dissolution tin-ies. These prolonged tinies may lead to rate limited absorption in both humans and dogs. Since many of the water-soluble polymers are also used as binders, e.g. PVP, HPMC, HPC, etc., the slow disintegration and dissolution times are not unexpected. However, solid dispersion tablets comprised of HPMCAS or solid dispersion layered pellets comprised of PVP offer substantial improvements in dissolution tixne when compared to a solid dispersion tablet of PVP. This is apparent when examining the dissolution times listed in Tables 7.-9. for formulations listed in Tables 4. and 5.

Example 60 BioavailabIllnty of selected oral dosage foi mulation.s in d gsa Nunierous formulations have been tested in dogs. The results fi oin the dog studics are predictive of the exposure trends seen in the huzinan studies. The AUC of (2R,4S)--Quinoline-4-carboxylic acid [1-.(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide, including two active metabolites, (_I~,4S)-Quinoline--N-oxidea4-carboxylic acid [1-(3,5-bis-trifluorom.ethylbenzoyl)-2-(4-chlorobenzyl)-piperidinn4-y1]
amide and (2tZ,4S)-2-Hydroxy-quinoline--4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide, for the bioavailability studies in dogs are provided in Table 10.. Therc appears to be nauch larger AUC benefit for solid dispersion based formulations of the active ingredient (and two active metabolites) relative to the non-dispersed formulations of the active drug ingredient.
Results are from two separate dog studies separated by the table division after the 9th row.
Table 10, Formulation Dose (mg/kg) AUC-Drug and metabolites (0-72 br r-g/rr-I.) 101 10 23,630 WG#2 10 21,304 WG#3 10 22,894 GMP#3 10 72,380 101 80 92,390 WG#2 80 86,870 WG#3 80 77,950 GMP#3 80 427,410 X608OCTA001 80 392,830 X608OCTA002 80 545,077 X608PFCA003 80 482,335 GMP#3 80 524,774 The compositions of the last four formulations were presently previously in Tables 4. and 5. The compositions of the other three formulations (i.e. `101', WG#2 and WG#3) are presented in Table 11. Note that the PVP in formulations WG#2 and WG#3 was admixed and was not present as a dispersion.

Table 11.
-- - - - - - - -FormtAlali n 101 WC,q2* WC#3~, Dosage S1reiigtb 160 nzg Tablet 160 mg Tablet 160 mg Tablet -- ---- ---------- ---- -----Component ( / ) M) %
(2R,4S)-Quinoline-4mcarboxylic acid 47.0 35.Q - -- 35.0 [ 1-(3, 5 -bis-trifluoromethyl--benzoyl)=-2-(4-chlorobenzyl)-piperidin-4-yl]
amide Povidone (PVP) 0.0 ---2.0 ` ---- 2.0 Cros-povidone 0.0 6.9 6.9 Docusate Sodium 0.0 4.9 4.9 Lactose Monohydrate 53.0 0 0 Sodium Lauryl Sulfate 0.0 2.3 2.3 Microcrystalline cellulose 0.0 38.6 38.6 Croscai-mellose Sodium 0.0 9.8 9.8 Magnesium Stearate 0.0 0.5 0.5 Total 100 100 100 *WG#2 was spray dried from a 1:3 znethanol:acetone solvent; WG#3 was spray dried from methylene chloride.

Example 7: Bioavailability of selected oral dosage formulations in humans.
Several formulations have been tested in human clinical studies. The composition of GMP#3, an exemplary solid dispersion of (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoroznethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide and PVP
along with a non-solid dispersion Control, GMP#2, are listed in Table 12. The AUC and Cmax values of (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide, including two active metabolites, (2R,4S)-Quinoline-N-oxide-4-carboxylic acid [1-(3,5-bis-trifluoroxnethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide and (2R,4S)-2...1-iydroxy-quinoline-4-carboxylic acid [1.-(3,5...bis-trifluoromethyl-benzoyl)-2-(4,-chlorobenzyl)-piperidin-4-yl]
amide are also provided in Table 13.. The AUC of the parent molecule, (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoroznethyl--benzoyl)-2.-(4-chlorobenzyl)-piperidin~-4-yl] amide, and the AUC values of the two metabolites, (2R,4S)-Quinoline-N-oxide,-4-carboxylic acid [1 (3, 5-.bis-trifluorornethyl-benzoyl)-2.-(4-chlorobenzyl)--piper-idin-4-yl]
amide and (2R,4S).-2-Hydroxy-quinoline--4-carboxylic acid [1-(3,5.-bis-trifluoromethyl-benzoyl)-2-(4.-chlorobenzyl)-piperidin-4-yl] amide, are significantly higher for the exemplary solid dispersion formulation GMP#3 in coznparison to the AUC values for the Control formulation, GMP#2. In addition, the Cmax values of the parent, (2R,4S)-Quinol1ne-4carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
arnide, and the Cn1ax values of the two metabolites, (21Z,4S)-Quinoline-N-oxidc-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]
amide and (2R,4S)-2-1-lydroxy-quinoline-4-carboxylic acid [1-(3,5-bis.-trifluoroznethyl-benzoyl)-2-(4-chlorobenzyl)-pipez-idin-4-yl] amide, az-e significantly higher foa- the excinplary solid dispersion formulation GMP93 in coznparison to the Cmax values for the Contr-ol formulation, GMP#2.

Table 12.
LOT GNIP#2 GMP#3 Unit Dose 160 mg Capsule 160 mg Capsule -- - - - -- -- -Component (2R,4S)-Quinoline-4-carboxylic acid 38.0 29.0 [1-(3,5-bis-tzifluoromethyl-benzoyl)-2-(4-chlorobenzyl)_piperidin-4-yl] amide Docusate Sodium 0.0 4.1 Sodium Lauryl Sulfate 2.5 2.3 Povidone (PVP) 0.0 9.2 Crosearmellose Sodiuin 10.0 10.0 Lactose 42.0 37.9 Crospovidone 7.0 7.0 Magnesium Stearate 0.5 0.0 Total 100 100 Table 13a ---Fo~l-riulation GMP#2" G1`/fP#3"
-----------..-,------------AUC (0-24 hr ng/mL) AUC (0-24 hr ng/mL) AUC (0-24 hr ng/mL) ~~ ,-~~ -~.ra~d,~:,,~.,~, .,,~,~.~.~~~. ~------ -- --- ------_ _- - --------- ------ -_---._.__._.
/a.V608- '723. I 3340 AV609** 3198 12467 AV810` * 5439 171195 Cmax (ng/mi) Cniax (ng/ml) Ci-ni ax (ng/rrnl) AV608* 87.4 -- --- - 360.3 - - -- -- - ------ -- --- --- --- AV609** 209.0 722.1 - - - - ---A..V810*=Y 343.9 955.6 *(2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4--chlorobenzyl)-piperidin-4-y1] amide **(2R,4S)-2-Hydroxy-quinoline-4-carboxylic acid [1-(3,5-bis-trifluoronaethyl-benzoyl)-2-(4-chlar-obenzyl)-piperidin-4-yl] ainide ***(2R,4S)-Quinoline-N-oxide-4-carboxylic acid [1-(3,5-bis-trifluoroimthyl-benzoyl)-2-(4-chlar-obenzyl)-piperidin-4-y1] ainide 'Two unit dose capsules of compositions described in Table 11. were administered OAUC and Cmax values are from Day 1 dosing at 24 hours.
Thosc skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims:

Claims (54)

1. A solid dispersion comprising a compound of formula I, wherein X is CH, N, or N-O;
Y is CH, N, or N-O;
Z is halogen; and R is H or OH
and PVP, wherein the weight percent of the compound of formula I within the solid dispersion is at least about 50% by weight.

2. The solid dispersion of claim 1, wherein the weight percent of the compound of formula I is at least about 70% by weight.

3. The solid dispersion of claim 1, wherein the compound of formula I is (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl) piperidin-4-yl] amide.

4. The solid dispersion of claim 1, wherein the compound of formula I is (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.

5. The solid dispersion of claim 1, wherein the compound of formula I is (2R,4S)-Quinoline-N-oxide-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.

6. The solid dispersion of claim 1, wherein the compound of formula I is (2R,4S)-2-Hydroxy-quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.

7. The solid dispersion of claim 1, wherein the ratio of the compound of formula I, to PVP is from about 1:1 to about 5:1.

8. The solid dispersion of claim 7, wherein the ratio of the compound of formula I, to PVP is about 3.5:1.

9. The solid dispersion of claim 1, wherein the dispersion is substantially homogeneous.

10. The solid dispersion of claim 1, wherein the T g is at least about 50K
greater than 298K at from about 50% to about 90% relative humidity.

11. The solid dispersion of claim 10, wherein the T g is at least about 50K
greater than 298K at from about 60% to about 75% relative humidity.

12. The solid dispersion of claim 1, wherein the dispersion has a single T g.

13. The solid dispersion of claim 1, wherein the dispersion comprises at least one non-homogeneous region enriched with the compound of formula I.

14. The solid dispersion of claim 1, wherein at least about 50% of the compound of formula I, is amorphous.

15. The solid dispersion of claim 1, wherein substantially all of the compound of formula I, is amorphous.

16. The solid dispersion of claim 1, wherein the PVP is K29/32.

17. The solid dispersion of claim 1, wherein the PVP has a molecular weight of from about 30,000 to about 100,000 daltons.

18. The solid dispersion of claim 1, further comprising a surfactant.

19. The solid dispersion of claim 18, wherein the surfactant is present in the dispersion from an amount of from about 0.1% to about 20% by weight.

20. The solid dispersion of claim 18, wherein the surfactant is selected from sodium lauryl sulfate and docusate sodium.

21. The solid dispersion of claim 1, wherein dispersion is substantially free of active metabolite of (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.

22. The solid dispersion of claim 1, wherein AUC of the compound of formula I, when dosed in a subject is at least about 1.25 times the AUC of compound of formula I, in an undispersed preparation.

23. The solid dispersion of claim 22, wherein AUC of the compound of formula I, when dosed in a subject is at least about 3 times the AUC of compound of formula I, in an undispersed preparation.

24. A particle coated with a compound of formula I, wherein X is CH, N, or N-O;

Y is CH, N, or N-O;
Z is halogen; and R is H or OH and a polymer.

25. The particle of claim 24, wherein the particle is a non-pariel, a lactose prill, microcrystalline cellulose, or starch.

26. The solid dispersion of claim 24, wherein the compound of formula I is (2R,4S)-Quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl benzoyl)-2--(4-chlorobenzyl)-piperidin-4-yl] amide.

27. The solid dispersion of claim 24, wherein the compound of formula I is (2R,4S)-Quinazoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.

28. The solid dispersion of claim 24, wherein the compound of formula I is (2R,4S)-Quinoline-N-oxide-4 carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4 chlorobenzyl)-piperidin-4-yl] amide.

29. The solid dispersion of claim 24, wherein the compound of formula I is (2R,4S)-2-Hydroxy-quinoline-4-carboxylic acid [1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl] amide.

30. The particle of claim 24, wherein at least a portion of the compound of formula I, is dispersed in a polymer

31 The particle of claim 30, wherein substantially all of the compound of formula I is dispersed in a polymer

32. The particle of claim 30, wherein the dispersion is substantially homogeneous

33. The particle of claim 30, wherein the T g of the dispersion is at least about 50K
greater than 298K at from about 60% to about 75% relative humidity

34 The particle of claim 30, wherein the dispersion has a single T g.

35 The particle of claim 30, wherein the dispersion comprises at least one non-homogeneous region enriched with the compound of formula I

36. The particle of claim 24, wherein at least about 50% of the compound of formula I, is amorphous.

37. The particle of claim 36, wherein the at least a portion of the compound of formula I
is dispersed in a polymer.

38 The particle of claim 37, wherein substantially all of the compound of formula I is dispersed in a polymer.

39 The particle of claim 37, wherein substantially all of the compound of formula I is amorphous.

40. The particle of claim 30, wherein the PVP is K29/32.

41. The particle of claim 40, wherein the PVP has a molecular weight of from about 30,000 to about 100,000 daltons.

42. The particle of claim 30, further comprising a surfactant.

43. The particle of claim 42, wherein the surfactant is selected from sodium lauryl sulfate and docusate sodium.

44. The particle of claim 42, wherein the surfactant is present in the dispersion from an amount of from about 0.1% to about 20%.

45. The particle of claim 30, wherein the AUC of the compound of formula I, when dosed in a subject is at least about 1.25 times the AUC of compound of formula I, in an undispersed preparation.

46. The particle of claim 45, wherein the AUC of the compound of formula I, when dosed in a subject is at least about 3 times the AUC of compound of formula I, in an undispersed preparation.

47. The particle of claim 30, wherein the polymer is PVP and the ratio of the compound of formula I, to PVP within the dispersion is from about 1: 5 to about 5:1.

48. The particle of claim 30, wherein the polymer is PVP and the ratio of the compound of formula I, to PVP within the dispersion is about 3.5:1

49. The particle of claim 30, wherein the polymer is PVP and the weight percent of compound of formula I is at least about 50%.

50. The particle of claim 30, wherein the polymer is PVP and the weight percent of compound of formula I is at least about 70%.

51. The particle of claim 30, wherein the compound of formula I is substantially amorphous and remains substantially amorphous for at least 2 weeks at 40 °C/75% relative humidity.

52. The particle of claim 30, wherein the compound of formula I has an accelerated dissolution profile of at least 3 fold at 30 minutes relative to the dissolution profile of the same dispersion of the compound of formula I wherein the dispersion is formulated into a tablet.

53. The particle of claim 52, wherein the compound of formula I has an accelerated dissolution profile of at least 3 fold at 60 minutes relative to the dissolution profile of the same dispersion of the compound of formula I wherein the dispersion is formulated into a tablet.

54. The particle of claim 53, wherein the compound of formula I has an accelerated dissolution profile of at least 3 fold at 120 minutes relative to the dissolution profile of the same dispersion of the compound of formula I wherein the dispersion is formulated into a tablet.