JP2010519312A - Pharmaceutical formulation - Google Patents

Abstract

Also described are dispersions of compounds of formula I and polymers, such as HPMCAS and / or PVP, and compositions comprising the dispersion, methods of making the dispersion, and methods of using the dispersion. In one embodiment, the invention provides a compound of formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -piperidin-4-yl] amide, or an active metabolite thereof, or (2R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- Features a solid dispersion containing (4-chlorobenzyl) -piperidin-4-yl] amide and HPMCAS.

Description

This application is a priority to US Provisional Application No. 60 / 891,272, filed Feb. 23, 2007, the entire contents of which are incorporated herein by reference. Insist.

The present invention relates to (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] Amides, or active metabolites thereof, or (2R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine- It relates to forms of 4-yl] amide and methods of making and using them.

  Water-insoluble drugs present many difficulties for formulation engineers in developing suitable dosage forms for oral administration. The solubility, solubility, and permeability of the compound all contribute to the bioavailability of the drug. Incorporating certain excipients into the formulation to enhance permeability has been studied, but the results are not definitive, and as a means to improve the bioavailability of water-insoluble drug candidates It is not widely allowed. The miniaturization of drug substances is an established technology platform that improves solubility and consequently potential bioavailability through particle size reduction and concomitant increase in surface area. Processing and physical stability, such as excessive wool agglomeration or agglomeration, is a difficulty that exists with respect to micronized platforms. Other approaches such as complex formation with cyclodextrins and lipid-based formulations are typically limited to lower drug loadings. Solid dispersions of insoluble drugs dissolved in a polymer carrier provide a means to improve oral bioavailability. The drug substance typically exists in its amorphous form and, if dispersed at the molecular level, ultimately results in reduced particle size and improved solubility and solubility, i.e., the surface area is at its maximum. Thus, there is no longer crystal filling energy to be overcome. There are several methods for forming solid dispersions, including spray drying and hot melt extrusion, both of which have some manufacturing difficulties. Some of the difficulties in using solid dispersions for the delivery of water-insoluble drug candidates are the difficulty of processing the solid dispersion into a suitable drug product, and at least two years at room temperature and humidity. The lack of adequate physical stability associated with the amorphous drug required to become a drug product.

  Accordingly, there is a need for another solid dispersion of a water-insoluble drug that has advanced physical stability and processability.

  Applicant has (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide, or Its active metabolite, (2R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] It has been discovered that certain solid forms of amides, such as solid dispersions, provide desirable properties including solubility, bioavailability, and stability (eg, physical and chemical stability).

  In one embodiment, the invention provides a compound of formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -piperidin-4-yl] amide, or an active metabolite thereof, or (2R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- Features a solid dispersion containing (4-chlorobenzyl) -piperidin-4-yl] amide and HPMCAS.

  In some embodiments, the active metabolite is (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.

  In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -piperidin-4-yl] amide, or an active metabolite thereof, or (2R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- The ratio of (4-chlorobenzyl) -piperidin-4-yl] amide to HPMCAS is from about 1: 5 to about 5: 1, such as from about 1: 3 to about 3: 1; : 1 or about 3: 1.

In some embodiments, the dispersion is substantially uniform. In some embodiments, the dispersion has a single T _g. In some embodiments, the dispersion of at least 2 weeks, 25 ° C., maintaining a single T _g of at 60% relative humidity. In some embodiments, the dispersion of at least 2 weeks, 40 ° C., maintaining a single T _g of at 75% relative humidity. In some embodiments, the dispersion of at least 2 weeks, 25 ° C., maintaining a single T _g of at 90% relative humidity.

In some embodiments, the T _g is at least about 50K higher than 25 ° C. at about 50% to about 90% relative humidity. In some embodiments, the T _g is at least about 50K higher than 25 ° C. at about 60% to about 75% relative humidity. In some embodiments, T _g is from about 98 ° C. to about 102 ° C. at 25 ° C. and 60% relative humidity.

  In some embodiments, the dispersion is a 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) At least one heterogeneous region enriched with -2- (4-chlorobenzyl) -piperidin-4-yl] amide.

  In some embodiments, the dispersion is (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine. It includes at least one heterogeneous region enriched with -4-yl] amide.

  In some embodiments, a compound of formula I in a solid dispersion, 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- At least about 50% of the (benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide is amorphous, for example a compound of formula I in a solid dispersion, 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 ( At least about 75% of R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide A compound of formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2, which is amorphous or in a solid dispersion -(4-Chlorobenzyl) -piperidin-4-yl] amide, or an active metabolite thereof, or (2R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl- Substantially all of the benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide is amorphous.

  In some embodiments, HPMCAS dissolves at pH ≧ 5.5, such as at pH ≧ 6.0, or at pH ≧ 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 surfactant. In some embodiments, the surfactant is present in the dispersion in an amount from about 0.1% to about 20%, such as 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 dispersion includes an additional polymer, eg, a water soluble polymer such as PVP. In some embodiments, the ratio of HPMCAS to PVP is about 5: 1 to about 1: 5, such as about 3: 1 to 1: 3, or 1: 1.

  In some embodiments, the dispersion is (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine. -4-yl] amide.

  In some embodiments, the dispersion is (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine. It is substantially free of active metabolites of -4-yl] amide.

  In some embodiments, a compound of formula I when administered to a subject, 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 AUC is a compound of formula I in an undispersed preparation, 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 At least about 1.25 times the AUC of 4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide, such as 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, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -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 substantially amorphous and remains substantially amorphous for 2 weeks at 40 ° C./75% relative humidity. In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -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 substantially amorphous and remains substantially amorphous for 2 weeks at 25 ° C./90% relative humidity.

  In one embodiment, the invention provides a compound of formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -piperidin-4-yl] amide, or an active metabolite thereof, or (2R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- Features a solid dispersion comprising (4-chlorobenzyl) -piperidin-4-yl] amide and PVP, wherein the compound of formula I in the solid dispersion, 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, The weight percent of S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide is at least about 50 wt. %, Such as at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% by weight.

  In some embodiments, the active metabolite is (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.

  In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro The ratio of (benzyl) -piperidin-4-yl] amide to PVP is from about 1: 1 to about 5: 1, such as from about 2: 1 to about 4: 1, and the exemplified ratio is about 1: 1 or about 3 .5: 1 included.

  In some embodiments, the dispersion is substantially homogeneous.

In some embodiments, T _g is at least about 50K higher than 25 ° C. at about 50% to about 90% relative humidity, eg, T _g is at least about 25 ° C. at about 60% to about 75% relative humidity. It is 50K high.

In some embodiments, T _g is at least about 100 ° C. at 25 ° C. and 60% relative humidity, for example, T _g is from about 115 ° C. to about 155 ° C.

In some embodiments, the dispersion has a single T _g. In some embodiments, the dispersion maintains a single T _g at 25 ° C. and 60% relative humidity for at least 2 weeks. In some embodiments, the dispersion maintains a single T _g at 40 ° C. and 75% relative humidity for at least 2 weeks. In some embodiments, the dispersion maintains a single T _g at 25 ° C. and 90% relative humidity for at least 2 weeks.

  In some embodiments, the dispersion is a 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 enriched with at least one heterogeneous region.

  In some embodiments, the dispersion is (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl)- At least one heterogeneous region enriched with piperidin-4-yl] amide.

  In some embodiments, a compound of formula I in a solid dispersion, 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- At least about 50% of the (benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide is amorphous, for example a compound of formula I in a solid dispersion, 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 ( At least about 75% of R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide A compound of formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2, which is amorphous or in a solid dispersion -(4-Chlorobenzyl) -piperidin-4-yl] amide, or an active metabolite thereof, or (2R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl- Substantially all of the benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide is amorphous.

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

  In some embodiments, the dispersion further comprises a surfactant, such as an anionic surfactant. In some embodiments, the surfactant is present in the dispersion in an amount of about 0.1 to about 20% by weight, such as about 1 to about 10% by weight. In some embodiments, the surfactant is selected from sodium lauryl sulfate and docusate sodium. In some embodiments, the dispersion includes a plurality of surfactants.

  In some embodiments, the dispersion further comprises an additional polymer, eg, a water soluble polymer such as HPMCAS.

  In some embodiments, the dispersion is (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine. -4-yl] amide.

  In some embodiments, the dispersion is (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine. It is substantially free of active metabolites of -4-yl] amide.

  In some embodiments, a compound of formula I when administered to a subject, 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 AUC is a compound of formula I in an undispersed preparation, 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 At least about 1.25 times the AUC of 4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide, such as 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, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -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 substantially amorphous and remains substantially amorphous at 40 ° C./75% relative humidity for 2 weeks. In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -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 substantially amorphous and remains substantially amorphous for 2 weeks at 25 ° C./90% relative humidity.

  In one embodiment, the invention provides a compound of formula I, preferably (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 Features a solid dispersion of-(4-chlorobenzyl) -piperidin-4-yl] amide and polymer.

  In some embodiments, the dispersion is (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -piperidin-4-yl] amide. In some embodiments, the dispersion is (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -piperidin-4-yl] amide.

  In some embodiments, the polymer is a water soluble polymer, such as HPMCAS or PVP.

  In some embodiments, the dispersion is substantially homogeneous.

In some embodiments, the T _g is at least about 50K higher than 25 ° C. at about 50% to about 90% relative humidity. In some embodiments, the T _g is at least about 50K higher than 25 ° C. at about 60% to about 75% relative humidity.

In some embodiments, the dispersion has a single T _g. In some embodiments, the dispersion of at least 2 weeks, 25 ° C., maintaining a single T _g of at 60% relative humidity. In some embodiments, the dispersion of at least 2 weeks, 40 ° C., maintaining a single T _g of at 75% relative humidity. In some embodiments, the dispersion of at least 2 weeks, 25 ° C., maintaining a single T _g of at 90% relative humidity.

  In some embodiments, the dispersion is (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4- At least one heterogeneous region enriched with (chlorobenzyl) -piperidin-4-yl] amide. In some embodiments, the dispersion is (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro Benzyl) -piperidin-4-yl] amide enriched with at least one heterogeneous region.

  In some embodiments, (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4 -Chlorobenzyl) -piperidin-4-yl] amide is at least about 50% amorphous, for example (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- At least about 55%, at least about 60%, at least about 65%, at least about 70% of (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide , At least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or substantially all amorphous.

  In some embodiments, (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4 -Chlorobenzyl) -piperidin-4-yl] amide is at least about 50% amorphous, for example, (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- At least about 55%, at least about 60%, at least about 65%, at least about 70% of (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide , At least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or substantially all amorphous.

  In some embodiments, the dispersion further comprises a surfactant, such as an anionic surfactant, such as sodium lauryl sulfate or docusate sodium. In some embodiments, the surfactant is present in the dispersion in an amount from about 0.1% to about 20%, such as from about 1% to about 10%.

  In some embodiments, the dispersion includes a plurality of surfactants.

  In some embodiments, the dispersion further comprises an additional polymer, such as a water soluble polymer.

  In some embodiments, (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- ( The AUC of 4-chlorobenzyl) -piperidin-4-yl] amide is (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoro] in the undispersed preparation. Methyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide AUC at least about 1.25 times, such as 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, (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- ( The AUC of 4-chlorobenzyl) -piperidin-4-yl] amide is (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoro] in the undispersed preparation. Methyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide AUC at least about 1.25 times, such as 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, (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 amorphous for 2 weeks at 40 ° C./75% relative humidity. In some embodiments, (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl)- Piperidin-4-yl] amide is substantially amorphous and remains substantially amorphous for 2 weeks at 40 ° C./75% relative humidity.

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

  In one embodiment, the invention provides a compound of formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -piperidin-4-yl] amide, or an active metabolite thereof, or (2R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- Features particles coated with (4-chlorobenzyl) -piperidin-4-yl] amide and polymer.

  In some embodiments, the particles are non-pariel, lactospril, microcrystalline cellulose, or starch.

  In some embodiments, the active metabolite is (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4 -Chlorobenzyl) -piperidin-4-yl] amide. In some embodiments, the active metabolite is (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4 -Chlorobenzyl) -piperidin-4-yl] amide.

In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro Benzyl) -piperidin-4-yl] amide, or at least a portion of its active metabolite, is dispersed in the polymer. In some embodiments, the dispersion is substantially homogeneous. In some embodiments, the T _g of the dispersion is at least about 40K higher than RT at a relative humidity of about 60% to about 75%. In some embodiments, the T _g of the dispersion is from about 65 ° C to about 155 ° C. In some embodiments, the dispersion has a single T _g. In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro benzyl) - piperidin-4-yl] amide or active metabolite is substantially amorphous, and the dispersion is at least 15 months 25 ° C., maintaining a single T _g of at 60% relative humidity To do. In some embodiments, the dispersion is a 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) At least one heterogeneous region enriched with -2- (4-chlorobenzyl) -piperidin-4-yl] amide. In some embodiments, the dispersion is (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine. It includes at least one heterogeneous region enriched with -4-yl] amide. In some embodiments, the compound of Formula I in the dispersion, 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 amorphous, for example a compound of formula I in a dispersion, 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, 4 ) -Quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide 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 amorphous. In some embodiments, the dispersion further comprises a surfactant, such as an anionic surfactant, such as sodium lauryl sulfate or docusate sodium. In some embodiments, the surfactant is present in the dispersion in an amount from about 0.1% to about 20%, such as from about 1% to about 10%. In some embodiments, the dispersion includes a plurality of surfactants.

  In some embodiments, a compound of formula I when administered to a subject, 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 AUC is a compound of formula I in an undispersed preparation, 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 At least about 1.25 times the AUC of 4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide, such as 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 polymer is a water soluble polymer.

  In some embodiments, the polymer is HPMCAS. In some embodiments, the compound of Formula I in the dispersion, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- The ratio of (4-chlorobenzyl) -piperidin-4-yl] amide, or its active metabolite 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 some embodiments, HPMCAS dissolves at pH ≧ 5.5, such as at pH ≧ 6.0, or at pH ≧ 6.5. In some embodiments, the HPMCAS is HPMCAS-LF.

  In some embodiments, the particles are further coated with an additional polymer, such as a water soluble polymer.

  In some embodiments, the polymer is PVP. In some embodiments, the compound of Formula I in the dispersion, 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 to PVP is from about 1: 5 to about 5: 1, for example from about 1: 3 to about 3: 1 The ratio includes about 1: 1 or about 3: 1. In some embodiments, a compound of formula I in a solid dispersion, 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- The weight percent of benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide is at least 50%, such as at least about 55%, at least about 60%, at least about 65%, at least about 70%, or at least About 75%. In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro The ratio of (benzyl) -piperidin-4-yl] amide to PVP is from about 1: 1 to about 5: 1, such as from about 2: 1 to about 4: 1, with an exemplified ratio of about 1: 1 or about Includes 3.5: 1. In some embodiments, the PVP is K29 / 32.

  In some embodiments, the particles are (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine- 4-yl] amide.

  In some embodiments, the particles are (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine- It is substantially free of active metabolites of 4-yl] amide.

  In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -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 substantially amorphous and remains substantially amorphous for 2 weeks at 40 ° C./75% relative humidity. In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -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 substantially amorphous and remains substantially amorphous for 2 weeks at 25 ° C./90% relative humidity.

  In one aspect, the invention features a solid dosage formulation comprising a particle described herein, a dispersion described herein.

  In some embodiments, the formulation further comprises one or more of excipients, diluents, binders, tablet disintegrants, lubricants, lubricants, and / or surfactants.

  In some embodiments, the dosage formulation is a tablet. In some embodiments, the dosage formulation is a capsule.

  In some embodiments, the dosage formulation further comprises a coating, such as an enteric polymer, such as a cellulosic polymer.

  In some embodiments, the solid dosage formulation is a compound of formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- Contains about 20 mg of (4-chlorobenzyl) -piperidin-4-yl] amide. In some embodiments, the solid dosage formulation is a compound of formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- Contains about 40 mg of (4-chlorobenzyl) -piperidin-4-yl] amide. In some embodiments, the solid dosage formulation is a compound of formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- Contains about 160 mg of (4-chlorobenzyl) -piperidin-4-yl] amide. In some embodiments, the solid dosage formulation is a compound of formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- Contains about 320 mg of (4-chlorobenzyl) -piperidin-4-yl] amide.

In some embodiments, the solid dosage formulation has the following ingredients:
(2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide;
PVP;
DOSS;
Microcrystalline cellulose;
Croscarmellose;
SLS; and
Magnesium stearate;
including.

  In some embodiments, (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine-4- Yl] amide and PVP form a solid dispersion.

In some embodiments, the solid dosage formulation has the following ingredients:
About 20 to about 30% by weight of (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine-4- Yl] amide;
From about 20 to about 30% by weight of PVP;
From about 0.2 to about 1.0% by weight of DOSS;
From about 30 to about 50% by weight of microcrystalline cellulose;
From about 5 to about 10% by weight of croscarmellose;
From about 0.5 to about 3% by weight of SLS; and
From about 1 to about 2% by weight of magnesium stearate;
including.
In some embodiments, the solid dosage formulation has the following ingredients:
About 25% by weight of (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide ;
About 25% by weight of PVP;
About 0.6% by weight of DOSS;
About 40% by weight of microcrystalline cellulose;
About 7.5% by weight of croscarmellose;
About 1% by weight of SLS; and
About 1.5% by weight of magnesium stearate;
including.

In some embodiments, the solid dosage formulation has the following ingredients:
(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
Magnesium stearate;
including.

  In some embodiments, (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine-4- Yl] amide and HPMCAS form a solid dispersion.

In some embodiments, the solid dosage formulation has the following ingredients:
About 20 to about 30% by weight of (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine-4- Yl] amide;
From about 20 to about 30% by weight of HPMCAS;
From about 15 to about 25% by weight of microcrystalline cellulose;
From about 15 to about 25% by weight dicalcium phosphate;
From about 2 to about 8% by weight of croscarmellose;
From about 0.2 to about 0.8% by weight of SLS;
About 0.2 to about 0.8 weight percent silicon dioxide; and
From about 1 to about 2% by weight of magnesium stearate;
including.

In some embodiments, the solid dosage formulation has the following ingredients:
About 25% by weight of (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide ;
About 25% by weight of HPMCAS;
About 21% by weight of microcrystalline cellulose;
About 21% by weight of dicalcium phosphate;
About 5% by weight of croscarmellose;
About 0.5% by weight of SLS;
About 0.5% by weight silicon dioxide; and
About 1.5% by weight of magnesium stearate;
including.

In some embodiments, the solid dosage formulation has the following ingredients:
(2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide;
PVP;
DOSS;
Microcrystalline cellulose; and
SLS;
In some embodiments comprising (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine- 4-yl] amide and PVP are coated on microcrystalline cellulose.

  In some embodiments, (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine-4- Yl] amide and PVP form a solid dispersion.

In some embodiments, the solid dosage formulation has the following ingredients:
About 20% to about 30% by weight of (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine-4 -Yl] amide;
From about 7% to about 10% by weight of PVP;
From about 0.1% to about 0.5% by weight of DOSS;
About 60% to about 70% by weight of microcrystalline cellulose; and
From about 0.2% to about 0.8% by weight of SLS;
including.

In some embodiments, the solid dosage formulation has the following ingredients:
About 27% by weight of (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide ;
About 8% by weight of PVP;
About 0.3% by weight of DOSS;
About 64% by weight of microcrystalline cellulose; and
About 0.5% by weight of SLS;
In some embodiments, the solid dosage formulation comprises:
(2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide;
DOSS;
SLS;
PVP;
Croscarmellose;
lactose;
Crospovidone; and
Magnesium stearate;
including.

  In some embodiments, (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine-4- Yl] amide and PVP are coated on lactose.

  In some embodiments, (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine-4- Yl] amide and PVP form a solid dispersion.

In some embodiments, the solid dosage formulation has the following ingredients:
About 25% to about 35% by weight of (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine-4 -Yl] amide;
About 3% to about 5% by weight of DOSS;
From about 1% to about 3% by weight of SLS;
From about 7% to about 11% by weight of PVP;
From about 8% to about 12% by weight of croscarmellose;
About 25% to about 45% by weight of lactose;
From about 5% to about 9% by weight of crospovidone; and
From about 0.2% to about 0.8% by weight of magnesium stearate;
including.

In some embodiments, the solid dosage formulation has the following ingredients:
About 29% by weight of (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide ;
About 4% by weight of DOSS;
About 2% by weight of SLS;
About 9% by weight of PVP;
About 10% by weight of croscarmellose;
About 38% by weight lactose;
About 7% by weight of crospovidone; and
About 0.5% by weight of magnesium stearate;
including.

In one embodiment, the invention provides a compound of formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -piperidin-4-yl] amide, or an active metabolite thereof, or (2R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- Features a method of making a carrier coated with (4-chlorobenzyl) -piperidin-4-yl] amide, the method comprising the following steps:
A compound of formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl ] Amides, or active metabolites thereof, or (2R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine Providing particles comprising -4-yl] amide;
Suspending the particles in an aqueous solution containing a water-soluble polymer; and
The compounds 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 Obtaining a carrier coated with-(4-chlorobenzyl) -piperidin-4-yl] amide and a water-soluble polymer;
including.

  In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -piperidin-4-yl] amide is substantially amorphous.

  In some embodiments, the solvent is methanol.

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

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

In one embodiment, the invention provides a compound of formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -piperidin-4-yl] amide, or an active metabolite thereof, or (2R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- Features a method of making particles comprising (4-chlorobenzyl) -piperidin-4-yl] amide, the method comprising the following steps:
A compound of formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl ] Amides, or active metabolites thereof, or (2R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine -4-yl] amide is dissolved in a solvent and polymer to give a 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] to obtain a solution of amide and polymers;
The solution of the formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl), is obtained by spray drying the solution. ) -Piperidin-4-yl] amide, or an active metabolite thereof, or (2R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- ( Obtaining a dispersion comprising 4-chlorobenzyl) -piperidin-4-yl] amide and a polymer;
including.

  In some embodiments, the polymer in the dispersion is PVP. In some embodiments, the polymer in the dispersion is HPMCAS.

  In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -piperidin-4-yl] amide, or an active metabolite thereof, or (2R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- The solvent dissolving the (4-chlorobenzyl) -piperidin-4-yl] amide and polymer is selected from the group consisting of ethyl acetate, methanol, acetone, and ethanol.

  In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -piperidin-4-yl] amide, or an active metabolite thereof, or (2R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- The solvent in which (4-chlorobenzyl) -piperidin-4-yl] amide and polymer are dissolved is methanol or ethanol.

  In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -piperidin-4-yl] amide, or an active metabolite thereof, or (2R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- The solvent in which (4-chlorobenzyl) -piperidin-4-yl] amide and polymer are dissolved is a mixture of organic solvents.

  In some embodiments, the resulting particles have a bulk density of about 0.20 g / ml to about 0.30 g / ml.

In some embodiments, the resulting particles have a D ₅₀ of less than about 1 μm.

In some embodiments, the T _{out of the} spray dryer is about 70 ° C to about 150 ° C.

  In some embodiments, a compound of formula I in solution, 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) The solid loading of 2- (4-chlorobenzyl) -piperidin-4-yl] amide and polymer is 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 related disorder, the method comprising administering to a subject a particle or dispersion described herein.

  In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -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, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -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 is not eating at least 1 hour before administration or 2 hours after administration.

  In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -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 subjects who have eaten within 60 minutes prior to administration, or within 120 minutes after administration.

  In some embodiments, the method comprises a 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)- Administering a dose comprising about 1 to about 1000 mg of 2- (4-chlorobenzyl) -piperidin-4-yl] amide.

  In some embodiments, the method comprises a 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)- Administration of a dose comprising about 40 mg of 2- (4-chlorobenzyl) -piperidin-4-yl] amide.

  In some embodiments, the method comprises a 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)- Administration of a dose comprising about 320 mg of 2- (4-chlorobenzyl) -piperidin-4-yl] amide.

  In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -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 a day.

  In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -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 twice a day.

  In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -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 three times a day.

  In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -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 with an additional therapeutic agent.

  In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -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 and the additional therapeutic agent are administered in a combined dosage form.

  In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -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 orally.

  In some embodiments, a compound of Formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro (Benzyl) -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 topically.

  The amorphous form of the drug may exhibit different properties than the crystalline form. To improve the stability of amorphous solids (generally less stable than the crystalline form), an amorphous solid dispersion system is formed with the drug by using a polymer or polymer mixture. be able to. In some embodiments, a “solid solution,” which is a system that does not phase separate over time, or a solid dispersion, has limited pharmaceutically significant long-term (eg, 2 years) drug recrystallization at ambient temperature. Or can be formulated to be slowed down.

  A compound of formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl The solid dispersion of amide is an undispersed compound of formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- ( 4-chlorobenzyl) -piperidin-4-yl] amide, for example a crystalline compound of formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl Improved bioavailability upon oral administration compared to administration of -benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide. In some embodiments, these solid dispersions are in a solid state that can be conveniently stored and administered. The production of the solid dispersion can be successfully carried out and scaled up by selecting an organic solvent or solvent mixture (eg methanol, acetone, etc.). In some embodiments, the solid dispersion can have improved chemical and physical stability. For example, in some cases, the solid dispersion is chemically and / or physically at conventional storage conditions (room temperature) for at least 1 year, such as at least 15 months, 18 months, 2 years, or longer. Can be stable.

  The details of one or more embodiments 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 a discovery of the present invention that various factors and ingredients are important for the stability and bioavailability of pharmaceutical compositions, particularly formulations containing solid dispersions of water-insoluble drugs. Accordingly, the present invention provides solid dispersion formulations and methods of making those formulations.

Compounds of Formula I The solid dispersions herein are represented by the following formula I:

Wherein X is CH, N, or N—O; Y is CH, N, or N—O; Z is halogen, preferably chloro; and R is H or OH. Including a compound, or a pharmaceutically acceptable salt or solvate thereof. In some preferred embodiments, X is CH or N (eg, CH); Y is N or N—O, and R is H. In some preferred embodiments, X is CH, N; Y is CH, N or N—O; Z is halogen; preferably chloro and ROH. Formula I includes compounds that can be formed in the body via metabolic pathways and are further encompassed herein as a component of the solid dispersions described herein. The exemplified active metabolite is (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl)- Piperidin-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 formula I are: (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl)- Piperidin-4-yl] amide; (2R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine-4- Yl] amide, (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine-4- Yl] amide (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine- -Yl] amide; or (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine- 4-yl] amide, or a salt or solvate thereof. Following formula:

(2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide having the formula Is a highly preferred embodiment of the compound.

  The compounds described herein include various solid forms thereof, including polymorphic forms, solvates and salts thereof. The compounds described herein also include tautomers thereof.

Dispersions of compounds of formula I Dispersions comprising compounds of formula I, or active metabolites thereof, and polymers, such as water soluble polymers, are described herein. Preferred polymers include HPMCAS and PVP.

  As used herein, “dispersion” refers to a dispersion in which one substance, the dispersed phase, is distributed in separate units throughout the second substance (continuous phase or vehicle). The size of the discrete units of the dispersed phase can vary greatly (eg, single molecule to nanometer sized colloidal particles, ˜multimicron size). Generally, the dispersed phase can be a solid, liquid, or gas. In the case of a solid dispersion, both the dispersed and continuous phases are solid. In pharmaceutical applications, the solid dispersion is a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase) or an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase). ) Can be included. In some embodiments, the amorphous solid dispersion includes a polymer that constitutes the dispersed phase and the drug constitutes the continuous phase.

  The term “amorphous solid dispersion” generally refers to a solid dispersion of two or more components, usually a drug and a polymer, or a combination of polymers, but possibly other components such as an interface. Also contains an active agent or other pharmaceutical excipient, in which case the drug is in an amorphous phase (eg, substantially all of the drug is in an amorphous phase) and the amorphous drug Its physical stability and / or solubility and / or solubility is enhanced by other components.

  An exemplary solid dispersion is (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl ] Co-precipitate or co-melt of amide and HPMCAS or PVP. A “co-precipitate” is the product after dissolving the drug and polymer in a solvent or solvent mixture and then removing the solvent or solvent mixture. Optionally the polymer is suspended in the solvent or solvent mixture. The solvent or solvent mixture includes organic solvents and supercritical fluids. In some cases, the solid dispersion is made by adding the drug solution and solid polymer, then mixing, and removing the solvent. Vacuum removal, spray drying, box drying, freeze drying, and other drying procedures may be applied to remove the solvent. By applying these methods in accordance with the present invention using appropriate processing parameters, (2R, 4S) -quinoline-4-carboxylic acid in the amorphous state in the final solid dispersion product [1- (3 , 5-Bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide.

Dispersions comprising HPMCAS and / or PVP Solid dispersions can have any form suitable for pharmaceutical use. For example, the solid dispersion can be in the form of a powder or a coating on a substrate (eg, the solid dispersion can be spray coated onto particles such as lactose or microcrystalline cellulose).

  The ratio of polymer to compound of formula I affects the properties of the solid dispersion. For example, if the ratio of polymer to compound of formula I is relatively high, the compound of formula I is a molecular dispersion or a dispersion having a very small domain of water-insoluble drug dispersed in a water-soluble polymer phase. There is a tendency to form things. However, if the ratio of polymer to compound of formula I is high, the concentration of the water-insoluble drug in the solid dispersion will be low, thereby causing a large amount of solid dispersion in the pharmaceutical composition containing the solid dispersion. Necessary. Furthermore, low concentrations of the compound of formula I can reduce the rate of absorption of the compound of formula I in the patient.

  If the ratio of polymer to compound of formula I is relatively low, the compound of formula I is not a molecular dispersion of the compound of formula I in the polymer, but the fraction of the compound of formula I in the polymer phase. There is a tendency to form a regional dispersion. However, if the ratio of the polymer to the compound of formula I is too low, the dispersed domain of the compound of formula I is too large, which reduces the dissolution and absorption of the drug in the patient and thereby the bioavailability of the compound of formula I Will be reduced. The appropriate ratio of polymer to compound of formula I will depend on the compound, the polymer and the intended use.

  Exemplary solid dispersions are compounds of formula I, for example (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, and HPMCAS.

  The amount of compound of formula I relative to HPMCAS can vary. For example, the dispersion can be predominantly a compound of formula I, predominantly HPMCAS, or a relative equivalent of a compound of formula I and HPMCAS. The ratio of compound of formula I to polymer can be varied to tailor the properties of the solid dispersion. For example, in some embodiments it is preferred to have a ratio of compound of formula I to polymer that results in a homogeneous dispersion, whereas in some embodiments, the compound of formula I is enriched. The ratio of the compound of the formula I to the polymer is such that a region is obtained. Exemplary ratios of compounds of Formula I to HPMCAS include from about 1:20 to about 5: 1, such as from about 1: 4 to about 4: 1, from about 1: 2 to about 3: 1, such as about 1: 1. To do.

  In another embodiment, the composition of the solid dispersion may include a combination of a compound of formula I and a polymer such as HPMCAS and PVP. Exemplary ratios of HPMCAS: PVP are about 5: 1, 4: 1, 3: 1, 2: 1, 1.5: 1, 1: 1, 1: 1.5, 1: 2, 1: 3, Includes 1: 4 or 1: 5. The polymer ratio may be adjusted to optimize the physical stability and / or manufacturability (ie flow, compression, etc.) of the solid dispersion.

  Another exemplary solid dispersion is a 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, and PVP, wherein the amount of compound of formula I in the dispersion is at least about 25%, such as 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 5%, at least about 80%, at least about 85%, at least about 90%, or than this high. Exemplary ratios of the compound of Formula I to PVP include about 1: 2 to about 5: 1, such as about 1: 1 to about 4: 1. In some preferred embodiments, the compound of Formula I and PVP are present in a ratio of about 1: 1 or about 3.5: 1.

Dispersions of compounds of formula I and polymers Dispersions comprising compounds and polymers of formula I, such as water soluble polymers, are encompassed by the present invention. For example (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide And a dispersion of polymers or (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine A dispersion of -4-yl] amide and polymer is described herein.

  Exemplary polymers include water soluble polymers. The term “water-soluble polymer” refers to either a natural or synthetic polymer, which has an apparent viscosity of less than 100 mPs · s when 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, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, and Carboxymethyl ethyl cellulose; cellulose esters such as hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropyl cellulose acetate phthalate (HPCAP), hydroxypropyl methylcellulose acetate Starch; Pectins such as carboxymethyl amylopectin sodium; Chitin derivatives such as chitosan; Polysaccharides such as alginic acid and its alkali metal and ammonium salts; Carrageenan; Galactomannan; Tragacanth Gum arabic; guar gum; xanthan gum; polyacrylic and polymethacrylic acid and salts thereof; acrylate and methacrylate copolymers; polyvinyl alcohol; polyvinylpyrrolidone; polyvinylpyrrolidone and vinyl acetate copolymers; and polyalkylene oxides such as poly Includes ethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide.

  The ratio of the compound of formula I to the polymer includes the ratios described above, such as the above dispersions including HPMCAS and / or PVP.

Additional Ingredients Other pharmaceutically acceptable ingredients can also be included in the dispersions described herein, including, for example, surfactants or additional polymers such as water soluble polymers.
Surfactant The surfactant is generally from about 0.1 to about 20%, such as from about 1 to about 15% (eg, about 9%), such as from about 0.5 to about 10%, about 0% in the dispersion. Present in an amount of from about 5 to about 5%, or from about 1 to about 2%. The weight ratio of the compound of formula I to surfactant will range from about 300: 1 to about 1: 1, such as from about 50: 1 to about 20: 1, such as about 25: 1 or about 4: 1.

  Suitable surfactants include anionic surfactants, cationic surfactants, and nonionic surfactants. An anionic surfactant is an amphiphilic molecule having a negative charge. Non-limiting examples of suitable anionic surfactants include alkyl, aryl, or arylalkyl carboxylates, sulfonates, sulfates, phosphates, or acylated protein hydrolysates. Suitable carboxylated surfactants include, for example, soaps (ie fatty acid salts), bile salts, polyalkoxycarboxylates and N-acyl sarcosinates. Suitable sulfonated surfactants include, for example, alkyl sulfonates, alkyl benzene sulfonates, alkyl allene sulfonates, short chain lignosulfates, naphthalene sulfonates, α-olefin sulfonates, petroleum sulfonates, and sulfonates having ester, amide, or ether linkages. To do. Suitable sulfated surfactants include, for example, sulfate esters of aliphatic alcohols, sulfated alkylphenols, sulfated acids, amides, and esters, and natural sulfated fats and fats. Suitable phosphonated surfactants include fatty alcohol mono- and diesters of orthophosphoric acid.

  In some embodiments, an anionic surfactant is preferred. Exemplary anionic surfactants include, for example, fatty acid salts such as sodium caproate, sodium caprylate, sodium caprate, sodium laurate, sodium myristate, sodium myristate, sodium palmitate, sodium palmitate, oleic acid Sodium, sodium ricinoleate, sodium linoleate, sodium linolenate, sodium stearate, sodium lauryl sulfate (SLS), sodium tetradecyl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, etc .; bile salts such as sodium cholate, tarocol Acid sodium, sodium glycocholate, sodium deoxycholate, sodium taurodeoxycholate, sodium glycodeoxycholate Sodium, sodium ursodeoxycholate, sodium chemodeoxycholic acid, sodium glycochemodeoxycholic acid, sodium cholylsarcosinate, sodium N-methyl taurocholate, sodium lithocholic acid, etc .; phosphoric acid esters, for example, esterification products of aliphatic alcohols Or fatty alcohol ethoxylates with phosphoric acid or anhydride, etc .; carboxylates such as ether alkyl carboxylates formed by oxidation of terminal OH groups of aliphatic alcohol ethoxylates, succinylated monoglycerides, sodium stearyl filmalate, succinic acid Stearoyl hydrogen propylene glycol, mono / diacetylated tartaric acid esters of mono and diglycerides, citrate esters of mono and diglycerides, glyceryl la of fatty acids Ester, fatty acid lactate, stearoyl 2-calcium lactate / sodium, stearoyl calcium lactate / sodium alginate, propylene glycol alginate, etc .; sulfates and sulfonates such as ethoxylated alkyl sulfates, alkylbenzene sulfonates, α-olefin sulfonates Acyl isethionate, acyl taurate, acyl glyceryl ether sulfonate, octyl sulfosuccinate disodium (ie dioctyl sodium sulfosuccinate (DOSS) or sodium docusate), 2 sodium undecylenamide-MEA-sulfosuccinate Etc.

  Preferred surfactants include sodium lauryl sulfate and sodium docusate, which can be used alone or in combination. An example is a mixture of sodium lauryl sulfate and sodium docusate.

  In some embodiments, two or more surfactants are used in combination. Where the composition of the present invention includes a mixture of two or more surfactants, the two or more surfactants can be selected from the same class of surfactants (eg, two or more surfactants). Each agent can be an anionic surfactant), or can be selected from different classes of surfactants (eg one of the two or more surfactants is any nonionic surfactant) And at least one other surfactant can be an anionic surfactant). When a mixture of surfactants is present in the composition of the invention, for example in the case of two surfactants, the weight ratio of the two surfactants should be in the range of about 5: 1 to about 1: 1. Can do. For example, the weight ratio of the two surfactants can be about 5: 1, 4: 1, 3: 1, 2: 1, or 1: 1.

Additional Polymers In some embodiments, the dispersions described herein include a compound of Formula I and two or more polymers. For example, a dispersion, such as a dispersion of a compound of formula I and HPMCAS or a dispersion of a compound of formula I and PVP, can include a second polymer, such as a water-soluble polymer, whereby two Compounds of formula I can be obtained dispersed in a polymer, for example in HPMCAS and a second polymer, or in PVP and a second polymer. In some cases, the two polymers are selected for their complementary properties such as solubility, compressibility, flowability, ease of handling, cost, and the like. The ratio of the first polymer to the second polymer can vary and is generally about 1: 4 to about 4: 1, such as about 1: 3 to about 3: 1, about 1: 2 A range of about 2: 1, for example about 1: 1.

Dispersion Characteristics As noted above, the dispersion can be homogeneous or it can be non-homogeneous, for example, having a region where the compound of Formula I is rich. The particle size distribution of the enriched region (eg, discontinuous phase) distributed within the dispersed phase can be monomodal or bimodal. In one embodiment, more than 90% of the domains of the compound of formula I dispersed in the polymer (ie HPMCAS or PVP) have a particle size in the range of 10 nm to 1000 nm, or 100 nm to 800 nm, or 100 nm to 500 nm. Have

  In some embodiments, the compound of formula I in the dispersion is substantially amorphous (eg, at least about 50% of the compound of formula I is amorphous, or at least About 55% is amorphous, at least about 60% of the compound of formula I is amorphous, at least about 65% of the compound of formula I is amorphous, Whether at least about 70% is amorphous, at least about 75% of the compound of formula I is amorphous, or at least about 80% of the compound of formula I is amorphous, or a compound of formula I At least about 85% of the compound of formula I is at least about 90% amorphous, at least about 95% of the compound of formula I is amorphous, At least about 98% of the compound is amorphous or at least about 99% of the compound of formula I is amorphous Or it is, substantially all of the compounds of Formula I is amorphous).

  As used herein, the term “amorphous” refers to a solid material that does not have long range order at the position of its atoms. Amorphous solids are generally supercooled liquids where there is no well-defined arrangement by arranging the molecules in a random manner and there is no long-range order. Amorphous solids are generally isotropic, that is, exhibit similar properties in all directions and do not have a well-defined melting point. For example, an amorphous material is a solid material that does not have a sharp characteristic crystal peak in its X-ray powder diffraction (XRPD) pattern (ie, it is not crystalline as measured by XRPD). Rather, one or several broad peaks (eg halos) appear in the XRPD pattern. The broad peak is characteristic for amorphous solids. Reference can be made to US 2004/0006237 for a comparison of XRPD of amorphous and crystalline materials.

  In the present specification, the “crystalline solid” means a compound in which a crystalline solid has a rigid long-range order by being arranged in a geometric pattern or lattice in which structural units are fixed, or Refers to the composition. The units constituting the crystal structure can be atoms, molecules or ions. Crystalline solids exhibit a distinct melting point.

In some embodiments, the dispersion has a single glass transition temperature (T _g ). _Tg is a characteristic temperature at which a glassy substance undergoes a rapid physical change from a glassy state to a rubbery state upon heating. T _g can be measured by several commonly accepted techniques such as differential scanning calorimetry (DSC) or by mechanical mechanical analyzer (DMA). It is generally preferred that the T _g of the dispersion be at least about 50K higher than storage conditions at room temperature and relative humidity conditions (eg, 25 ° C., 60% RH). For example, for solid dispersions comprising a compound of Formula I and HPMCAS in equal ratios, the T _g of the dispersion at room temperature / humidity conditions is generally about 98 ° C. to about 102 ° C. (eg, about 100 ° C. or 101 ° C.). It is. For solid dispersions comprising a compound of formula I and PVP in equal ratios, the T _g of the dispersion at room temperature / humidity conditions is generally from about 130 ° C to about 135 ° C. Of course, the T _g of the dispersion is a number of factors, such as components (ie, its structure, interactions, etc.), its weight fraction, and the equilibrium solvent and / or moisture of the dispersion, to name a few. It depends on the content. Furthermore, the T _g of a homogeneous blend of amorphous components (ie polymer and compound) can be estimated in many cases by the Gordon-Taylor equation, in which case the weight fraction of each component and their respective _Is used to estimate the T _g of the dispersion. Preferably, the ratio of compound of formula I to polymer in the dispersion is such that a therapeutically sufficient amount of formula I is of conventional size using conventional techniques (eg roller compaction, wet granulation, etc.). It is such that it can be produced in conventional dosage forms (ie from 650 mg to preferably 1300 mg) and that the dispersion has a single T _g that is at least 50K higher than expected storage conditions.

The solid dispersions described herein are generally stable, for example chemically and physically stable. For example, in some preferred embodiments, the solid dispersion is both chemically 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 assessed for the content of the amorphous form of the compound of formula I via XRPD, DSC, and / or microscopy. For example, in a solid dispersion comprising a compound of formula I and PVP in equal ratios, the T _g at room temperature / humidity conditions is generally from about 130 ° C. to about 135 ° C., and the same dispersion at 40 ° C./75% storage for 2 weeks _{T g} of the object is about 130 ° C. ~ about 135 ° C., the _{T g} of the last at least 2 weeks 25 ° C. / 90% identical dispersion in storage is about 130 ° C. ~ about 135 ° C.. In another embodiment, the dispersion of PVP and the compound of formula I coated on lactose and then blended with common excipients and filled into gelatin capsules is subject to room temperature and relative humidity conditions. It is stable for at least 15 months at (eg, 25 ° C., 60% RH).

The solid dispersion described herein can be used as a component of a pharmaceutical composition, for example, as a component of an oral powder, tablet, capsule or the like. In general, the solid dispersions described herein have a bulk density of about 0.20 g / ml to about 0.30 g / ml and a tap density of about 0.34 g / ml to about 0.40 g / ml. . The solid dispersion generally has a D ₅₀ of less than about 1 μm.

  In another embodiment, the composition of the compound of formula I has a level of compound of formula I in the blood of the animal that does not contain the solid dispersion after administration of the composition containing the solid dispersion to the animal. At least about 20% higher than observed after administration of a compound of formula I, such as at least about 25% higher, at least about 50% higher, at least about 100% higher, at least about 200% higher, at least about 300% higher or at least about It consists of a solid dispersion present in an amount sufficient to be 400% higher. In another embodiment, the composition of the present invention has an increased bioavailability of at least 1.25-fold, 1.50-fold, or at least 2.0-fold over the bioavailability of an unformulated water-insoluble drug. Bring.

Particles Comprising a Compound of Formula I Described herein are particles of a compound of formula I. For example, particles comprising an amorphous compound of formula I are described herein, for example, particles containing a substantially amorphous compound of formula I are described herein. Amorphous compounds of formula I can be made, for example, by spray drying a compound of formula I to form particles of a compound of formula I suitable for formulation into a pharmaceutical composition such as an oral dosage formulation.

  As noted above, the compounds of formula I and dispersions containing the compounds of formula I described herein can be used as ingredients in pharmaceutical compositions. In some embodiments, the dispersion is formulated directly into the composition. In some embodiments, a dispersion comprising a compound of formula I, such as a compound of formula I described herein, is coated onto the particles and the particles are formulated onto a pharmaceutical composition.

  A compound of formula I, for example an amorphous compound of formula I, can be coated on the particles, for example with a water-soluble polymer. In some embodiments, the dispersion described herein is coated on the surface of the particles. Exemplary particles useful when coating with the dispersions described herein include non-pareils such as lactose or microcrystalline cellulose or starch.

  The compound or dispersion of formula I described herein is applied to the surface of the particles in a spray coating process, such as a suspension of a compound of formula I, for example an amorphous compound of formula I or a dispersion described herein. Coating can be accomplished by providing a suspension or slurry and particles and spraying the suspension or slurry to form particles coated with the compound of Formula I. In some embodiments, the surface of the particles can also be coated with additional components, such as enteric coatings.

  The coated particles can then be formed into a suitable dosage form, for example by encapsulation. Alternatively, the coated substrate may be mixed with one or more of the additional ingredients disclosed herein using processing techniques known in the pharmaceutical art, such as wet or dry granulation, milling, etc., and For example, it can be formed into an appropriate dosage form by encapsulation, tableting, or pelletization.

Methods for Making Dispersions Comprising Compounds of Formula I Any method for obtaining solid dispersions can be used in the context of the present dispersions described herein. Commonly usable methods include those that rapidly remove the solvent from the mixture or cool the molten sample. Such methods include, but are not limited to, rotary evaporator evaporation, freeze drying (ie freeze drying), vacuum drying, melt solidification, and melt extrusion. However, a preferred embodiment of the present invention uses an amorphous solid dispersion obtained by spray drying. Thus, in another embodiment, the present invention allows the product obtained by spray drying to be dried to remove the solvent.

  The preparations disclosed herein, eg, pharmaceutical compositions, can be obtained by spray drying a mixture comprising a compound of formula I, HPMCAS and / or PVP, and a suitable solvent (eg, acetone). Spray drying is, for example, a method of atomizing a liquid mixture containing a solid and a solvent and removing the solvent. Atomization may be effected, for example, via a nozzle or on a rotating disk. Spray drying is a process that converts a liquid feed into a dried particulate form. Optionally, the residual solvent may be reduced to a pharmaceutically acceptable level by using a secondary drying process such as fluid bed drying or vacuum drying. Typically, spray drying involves contacting a highly dispersed liquid suspension or solution with a sufficient volume of hot air to cause evaporation and drying the liquid droplets. The preparation to be spray dried can be any solution, coarse suspension, slurry, colloidal dispersion, or paste that can be atomized using the selected spray drying apparatus. In standard operating procedures, the preparation is sprayed into a stream of hot filtered air that evaporates the solvent and delivers the dried product to a collector (eg, a cyclone). The spent air is then evacuated with the solvent, or the spent air is sent to a condenser to capture the solvent and make it recyclable. Spray drying may be performed using commercially available types of equipment. For example, a commercially available spray dryer is available from Buchi Ltd. And manufactured by Niro (for example, the PSD series of spray dryers manufactured by Niro) (see for example US 2004/0105820; US 2003/0144257).

  Spray drying typically uses a solids loading of about 2% to about 25% material (ie compound of formula I and excipients), preferably at least about 4% or 5%. In general, the upper limit of the solid loading is determined by the viscosity of the resulting solution (for example, the ability to deliver liquid) and the solubility of the components in the solution.

  Techniques and methods for spray drying are described in Perry's Chemical Engineering Handbook, 6th edition, R.C. H. Perry, D.C. W. Green & J. O. (Maloney), McGraw-Hill book co. (1984); and Marshall "Atomization and Spray-Drying" 50, Chem. Eng. Prog. Monogr. It is described in Series 2 (1954).

  Generally, spray drying is performed at an inlet temperature of about 60 ° C to about 200 ° C, such as about 130 ° C to about 180 ° C. Spray drying is generally performed at an outlet temperature of about 70 ° C to about 150 ° C, such as about 80 ° C to about 110 ° C.

  Preferred solvents are compounds of formula I at least about 10 mg / ml (eg at least about 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 40 mg / ml, 45 mg / ml, 50 mg / ml, 75 mg). / Ml, 100 mg / ml, 125 mg / ml, 150 mg / ml, 175 mg / ml, 200 mg / ml, or higher).

  Suitable solvents include esters, ketones, and alcohols. Exemplary solvents that can be used include ethyl acetate, methanol, acetone, and ethanol. Some preferred embodiments include ethyl acetate. In some embodiments, a mixture of solvents is used. In a preferred embodiment, the co-solvent dissolves both the compound of formula I and the polymer (ie HPMCAS and / or PVP).

  The removal of the solvent is performed by a subsequent drying step such as tray drying, fluidized bed drying (eg, about room temperature to about 100 ° C.), vacuum drying, microwave drying, rotary drum drying, or biconical vacuum drying (eg, about room temperature to about 200 ° C.). You may need it.

  The resulting dispersed particles (eg after spray drying) generally have an average particle size of less than 1 μm, such as an average particle size of about 100 nm to about 900 nm, such as about 850 nm, about 800 nm, about 750 nm, about 700 nm, about 650 nm, It has an average particle size including 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, about 150 nm, and all ranges and subranges therebetween. The particle size distribution of the dispersed particles can be essentially monomodal or bimodal. When the particle size distribution is essentially unimodal, at least 50% of the particles have a particle size of less than 1 μm. For example, at least 50% of the particles have a particle size that includes less than 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, or 200 nm, and all ranges and subranges therebetween.

Particle Coating In some embodiments, a dispersion comprising a compound of formula (I) or a compound of formula (I) and a polymer is on a carrier, for example solid particles such as lactose or microcrystalline cellulose or starch. Coated. A compound of formula (I) or a dispersion of a compound of formula (I) and a polymer described herein is suspended in a solution of water and a water-soluble polymer (eg, PVP). The suspension is laminated onto a carrier such as solid particles such as lactose or microcrystalline cellulose globules (eg, 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 the case of a dispersion that includes two or more polymers). ).

  Generally, the solids loading of the water soluble polymer in the coating process is from about 10 to about 60% by weight.

Compositions comprising dispersions of compounds of formula I The solid dispersions described herein and the particles coated with the solid dispersions described herein may be formulated with additional pharmaceutically acceptable excipients. To form a dosage form for administration to a subject.

  The weight percent of the compound of Formula I in the compositions described herein can range from about 99% to about 15% by weight. For example, the weight percent of the water-insoluble drug is 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% by weight.

  The unit dose used may vary depending on the requirements of the patient and the condition to be treated. For convenience, the total daily dose may be divided and administered in portions during the day as needed. The amount of water insoluble drug in the composition of the present invention ranges from about 1 mg to about 500 mg per unit dose. For example, the amount of water-insoluble drug per unit dose of the composition of the present invention is about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg. 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 250 mg, 300 mg, 320 mg, 350 mg, 400 mg, 450 mg, 480 mg, 500 mg, 640 mg, 750 mg, 100 mg, and the like.

  The weight percent of water-soluble polymer in the composition of the present invention can range from about 90 to about 5% by weight. For example, the weight percent of the water-insoluble polymer in the composition is about 90, about 85, about 80, about 75, about 70, about 65, about 60, about 55, about 50, about 45, about 40, about 35, It can be about 30, about 25, about 20, about 15, about 10, and about 5% by weight.

  When present, the weight percent of the total amount of one or more additional ingredients in the composition of the present invention can range from about 90 to about 5% by weight. For example, the weight percent of the total amount of one or more additional ingredients in the composition is about 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, and 20 weights. %.

  Exemplary pharmaceutically acceptable excipients include diluents or fillers, drug complexing or solubilizing agents, tablet disintegrating agents, binders, lubricants, lubricants, pH adjusting agents, and surfactants. . Examples of suitable diluents or fillers include lactose, mannitol, xylitol, microcrystalline cellulose, dicalcium phosphate, and starch. Examples of drug complexing or solubilizing agents include polyethylene glycol, caffeine, xanthene, gentisic acid, and cyclodextrin. Examples of tablet disintegrants include sodium starch glycolate, sodium alginate, sodium carboxymethylcellulose, methylcellulose, croscarmellose sodium, and crospovidone, preferably croscarmellose sodium and / or crospovidone. Examples of binders include methylcellulose, povidone, microcrystalline cellulose, starch, hydroxypropylcellulose, hydroxymethylpropylcellulose, and gums such as gua and tragacanth, preferably povidone. Examples of lubricants include magnesium stearate, stearic acid, sodium stearyl fumarate. An example of a lubricant is silicon dioxide. Examples of pH adjusting agents include acids, such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, and buffer substances containing mixtures of any of the above acids and salts thereof.

  Examples of the surfactant are as described above. Preferred surfactant excipients include DOSS and SLS. The weight percent of surfactant in the composition of the present invention can range from about 0.1% to about 20% by weight. For example, the weight percent of surfactant in the composition is 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 0.0. It can be 1% by weight.

  The additional ingredients can independently include one or more individual ingredients selected from each of the classes of pharmaceutically acceptable excipients described herein. That is, the compositions described herein include, for example, one or more diluents or fillers and tablet disintegrants, a single diluent or filler and two or more tablet disintegrants, fillers, tablet disintegrations. Agents, binders, lubricants and the like can be included.

  In some embodiments, the compositions described herein include an additional therapeutic agent, eg, for co-administration of a compound of formula I with a second therapeutic agent. The term “therapeutic agent” is used herein in its conventional sense and is a compound or any synthesis having beneficial prophylactic and / or therapeutic properties when administered to a mammal, particularly a human. Or refers to a naturally occurring entity. Non-limiting examples of suitable water-insoluble drugs include, for example, drugs from various known classes of drugs, such as proteins, peptides, nucleotides, anti-obesity drugs, nutraceuticals, corticosteroids, elastase inhibitors, analgesics Agent, antifungal agent, cancer treatment agent, antiemetic agent, cardiovascular agent, anti-inflammatory agent, anthelmintic agent, antiarrhythmic agent, antibiotic, anticoagulant agent, antiepileptic agent, antidiabetic agent, antiepileptic agent, antihistamine agent, Antihypertensive, antimuscarinic, antimicrobial, anti-neoplastic, immunosuppressive, antithyroid, antiviral, anxiolytic, sedative, astringent, β-adrenergic receptor blocking agent, blood product and Alternative, cardiotonic agent, cholinesterase inhibitor, contrast agent, corticosteroid, cough, diagnostic agent, diagnostic imaging agent, diuretic, dopaminergic agent, hemostatic agent, immunological agent, lipid Nodal, intestinal motility regulator, muscle relaxant, parasympathomimetic, parathyroid calcitonin and biphosphonate, prostaglandins, radiopharmaceuticals, sex hormones, antiallergic agents, stimulants and appetite suppressants, sympathetic Includes agonists, 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 the solid dispersion are mixed with one or more additional ingredients disclosed herein using unit processing known in the pharmaceutical field, such as wet or dry granulation, milling, and then for example capsules It can be formed into a suitable dosage form by forming, pelletizing, or tableting.

  The compositions of the invention can be provided in any dosage form suitable for delivery of a therapeutically effective dose of a water-insoluble drug to a patient. Non-limiting examples of suitable dosage forms include minicapsules, capsules, tablets, and implants, troches, lozenges, suspensions, spherules, suppositories, wafers, chewable tablets, fast or fast dissolving tablets, effervescent Tablets, solids for mouth or sublingual, granules, films, pellets, beads, pills, powders, strips, or pouches.

  The compositions of the invention can be formulated for oral, sublingual, buccal, nasal, intraocular, pulmonary, intraurethral, transmucosal, intravaginal, topical, or rectal delivery. In one embodiment, a composition of the invention is formulated such that it is orally administered to a subject and is suitable for incorporation into the subject's system, for example, via the gastrointestinal tract. In some preferred embodiments, the compositions described herein are formulated for oral administration as, for example, tablets, capsules, or powders for oral suspension, preferably tablets or capsules. When formulated as minicapsules or capsules, the capsules can be hard or soft gelatin capsules, starch capsules, or cellulosic capsules.

  The compositions of the present invention can also be used for immediate release, wavy release, controlled release, extended release, delayed release, targeted release, synchronized release, or targeted delayed release, for example to control the rate of disintegration in the gastrointestinal tract. It can also be coated with one or more coatings to provide Such coatings can include enteric coatings, film coatings, barrier coatings, compression coatings, rapid disintegration coatings, enzyme degradable coatings, and the like.

Methods Using Dispersions Comprising Compounds of Formula I The compounds and solid dispersions described herein, particles including solid dispersions, and compositions including compounds and solid dispersions are for example NK-1 related disorders Can be used in therapy to treat. A therapeutically effective amount of a solid dispersion (and / or a composition comprising a solid dispersion and / or a particle comprising a solid dispersion) comprising a compound of formula I as described herein, eg, such NK-1-related disorders can be treated by administering to a subject in need of treatment.

  The term “therapeutically effective amount” is the amount of a water-insoluble drug that provides a clinically useful effect, such as reducing or alleviating symptoms or preventing or ameliorating a disease or condition.

  Exemplary NK-1 related disorders are depression, anxiety, cognitive and memory deficits, acute and chronic pain, allergic disorders, asthma, chronic obstructive pulmonary disease, skin disorders, incontinence, inflammation, nausea, irritable bowel Syndrome, sleep disorders, substance withdrawal symptoms, immune system disorders, inflammatory disorders such as osteoarthritis, rheumatoid arthritis, and other arthritis, inflammatory bowel disease, scleritis, visceral disorders such as pelvic inflammatory disorders, small Includes disorders such as cystitis and sexual pain. In some preferred embodiments, a compound or dispersion described herein or a composition comprising a compound or dispersion described herein is a social anxiety disorder, incontinence, and / or irritable bowel syndrome. Administered to a subject for treatment of

  The compounds and dispersions described herein can be administered with or without food. In some embodiments, the dispersions described herein have been eaten within 2 hours of administration of the solid dispersion, or will be eaten within 1 hour after administration of the solid dispersion. To be administered. The frequency of dosing can vary depending on a number of factors, such as the disorder to be treated, dosage form, dosage, and patient. Thus, the compounds or dispersions described herein can be administered once daily, twice daily, three times daily, or four times daily.

  The following examples are intended to be illustrative and are not intended to explicitly or implicitly limit the invention in any aspect, shape, or form. They are typical of those that can be used, but other operating methods, methodologies, or techniques well known to those skilled in the art may alternatively be used.

Example 1: Solid Dispersion Comprising PVP or HPMCAS Various drug / polymers and drug / polymer / surfactant combinations are dissolved in various solvents and then spray dried to form solid dispersion particles. Formed.

  The polymer, solvent, surfactant concentration (% docusate sodium),% solids and drug / polymer ratio are shown in Table 1 below.

* (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide ** docusate Sodium The physical form of the solid dispersion in Table 1 was evaluated to evaluate the drug form (ie, amorphous or crystalline) in the dispersion and the glass transition point of the solid dispersion was measured as shown in Table 2. did. The method used to measure the form and The T _g were respectively variants of the XRPD and DSC.

* (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide ** docusate Sodium Example 2: Stability under stress of solid dispersions comprising PVP or HPMCAS The exemplified solid dispersion from Table 1 is 25 ° C / 90% RH for 2 weeks and 40 ° C / 75% RH for 2 weeks. When subjected to the included accelerated stability conditions, the results shown in Table 3 were obtained. T _g was measured at mDSC. The form of the drug in the dispersion was further evaluated by microscopic examination.

* (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide ** docusate Sodium Example 3: Formulated oral dosage forms The dispersions described herein can be prepared and further formulated into oral dosage forms such as tablets or capsules. Alternatively, the solid dispersion may be formulated into dosage forms by first coating on lactose or an acceptable carrier and then processing into capsules or tablets.

  The composition of Table 4 is obtained from (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) in a common organic solvent. Prepared by dissolving -piperidin-4-yl] amide and the selected polymer (PVP or HPMCAS). The resulting solution was spray dried to obtain nano-sized solid dispersion particles with about 50% having a diameter of about 0.8 um or less. The solid dispersion particles were further processed by blending a diluent, a lubricant, and a portion of the lubricant that was densified by slugging and subsequent milling into a tablet dosage form. The tablet disintegrant and the remaining lubricant were added to the milled granules and blended. The lubricated granules were compression molded into tablets. Tablets can also be coated with functional or non-functional film coatings.

The GMP # 3 composition in Table 5 was prepared from (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl)- Prepared by dissolving piperidin-4-yl] amide and docusate sodium. The resulting solution was spray dried to give (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine- Nanosized particles of 4-yl] amide and docusate sodium were obtained. About 50% of the nano-sized particles had a diameter of about 0.8 μm or less. The nano-sized particles were then added to an aqueous solution of povidone and the resulting suspension was spray coated onto lactose prills. The dried coated lactose prill was then dry blended with croscarmellose sodium, crospovidone, and sodium lauryl sulfate. Magnesium stearate was added to the mixture, blended, and then encapsulated.

  In other exemplary dosage forms, X608PFCA003 was produced in the same manner as GMP # 3 except that the PVP: drug suspension was laminated onto microcrystalline cellulose (Celssphere) prior to encapsulation.

Example 4: Stability under stress of formulated oral dosage forms Exemplary solid dispersions formulated in pharmaceutical products (Tables 4 and 5) were prepared at 25 ° C / 90% RH for 2 weeks and 2 weeks, 5 weeks, 3 weeks, Accelerated stability conditions including months and 6 months 40 ° C./75% RH were applied. Table 6 shows the T _g measured by mDSC for the 2 week time point analysis. The form of the drug in the dispersion was further evaluated by microscopic examination.

* (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide Tables 7 and 8 And 9 show the appearance, tests, related substances, and dissolution results for formulations X608OCTA001, X608OCTA002, and X608PFCA003, which were stored at 40 ° C./75% for various times, respectively. Test and impurity results reveal the chemical stability of the formulation, and dissolution results represent a minimal change if adequately suppressed from the initial state, which is an appropriate substitute for crystallization of the drug form. ing.

* Free-flowing pellets in off-white "00" HPMC capsules Example 5: Improved dissolution of selected solid dispersions A notable difficulty of solid dispersion tablets is that they have very long disintegration and dissolution times. It is. These extended times may result in rate limited absorption in both humans and dogs. Most of the water-soluble polymers, such as PVP, HPMC, HPC, etc. are also used as binders, so the slow disintegration and dissolution time is not surprising. However, solid dispersion tablets containing HPMCAS or solid dispersion laminated pellets containing PVP provide a significant improvement in dissolution time compared to PVP solid dispersion tablets. This is evident when considering the dissolution times shown in Tables 7-9 for the formulations shown in Tables 4 and 5.

Example 6: Bioavailability of selected oral dosage formulations in dogs A number of formulations have been tested in dogs. The results of the dog study are predictive of the exposure trends observed in human studies. Two active metabolites for bioavailability studies in dogs are (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-Chlorobenzyl) -piperidin-4-yl] amide and (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4) including (4-chlorobenzyl) -piperidin-4-yl] amide The AUC of -chlorobenzyl) -piperidin-4-yl] amide is shown in Table 10. It has been observed that there is a much greater AUC advantage for solid dispersions based on the formulation of the active ingredient (and two active metabolites) compared to a non-dispersed formulation of the active drug ingredient. Results were obtained from two separate dog trials, separated by a table split after the ninth row.

The composition of the latter 4 formulations is as already shown in Tables 4 and 5. The other three formulations (ie, “101”, WG # 2 and WG # 3) are as shown in Table 11. The PVP in formulations WG # 2 and WG # 3 is additive mixed and is not present as a dispersion.

* WG # 2 was spray dried from 1: 3 methanol: acetone solvent; WG # 3 was spray dried from methylene chloride.

Example 7: Bioavailability of selected formulations for oral administration in humans Several formulations have been tested in human clinical trials. Composition of GMP # 3, (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl Illustrated solid dispersions of amide and PVP, as well as a non-solid dispersion control, GMP # 2, are shown in Table 12. Two active metabolites, (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl)- Piperidin-4-yl] amide and (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl)- (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine- including piperidin-4-yl] amide The values of AUC and Cmax for 4-yl] amide are also shown in Table 13. AUC of the parent molecule, (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide , And two metabolites, (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine -4-yl] amide and (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine The AUC value of -4-yl] amide is significantly higher for the exemplified solid dispersion formulation GMP # 3 compared to the AUC value of the control formulation, GMP # 2. Furthermore, the parent (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide And the two metabolites, (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) ) -Piperidin-4-yl] amide and (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) The Cmax value of) -piperidin-4-yl] amide is significantly higher for the exemplified solid dispersion formulation GMP # 3 compared to the Cmax value of the control formulation, GMP # 2.

* (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide ** (2R , 4S) -2-Hydroxy-quinoline-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] amide
^α Two unit dose capsules of the composition described in Table 11 were administered.
^β AUC and Cmax values are from the first day of dosing at 24 hours.

  Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. Such equivalents are intended to be encompassed by the following claims.

Claims (54)

Formula I below:
[Wherein X is CH, N, or N—O;
Y is CH, N, or N—O;
Z is a halogen; and
R is H or OH] and a solid dispersion comprising PVP, wherein the weight percent of the compound of formula I in the solid dispersion is at least about 50 wt%.   The solid dispersion of claim 1, wherein the weight percent of the compound of Formula I is at least about 70% by weight.   The compound of formula I is (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] The solid dispersion of claim 1 which is an amide.   The compound of formula I is (2R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] The solid dispersion of claim 1 which is an amide.   The compound of formula I is (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine- The solid dispersion of claim 1 which is 4-yl] amide.   The compound of formula I is (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine- The solid dispersion of claim 1 which is 4-yl] amide.   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.   The solid dispersion of claim 1, wherein the dispersion is substantially homogeneous. T _g is at least about 50K higher than 298K at a relative humidity of about 50% to about 90%, solids dispersion according to claim 1. T _g is at least about 50K higher than 298K at a relative humidity of about 60% to about 75%, solids dispersion according to claim 10. The solid dispersion of claim 1, wherein the dispersion has a single T _g .   The solid dispersion of claim 1, wherein the dispersion comprises at least one heterogeneous region enriched with the compound of formula I.   The solid dispersion of claim 1, wherein at least about 50% of the compound of Formula I is amorphous.   The solid dispersion of claim 1, wherein substantially all of the compound of formula I is amorphous.   The solid dispersion of claim 1, wherein the PVP is K29 / 32.   The solid dispersion of claim 1, wherein the PVP has a molecular weight of about 30,000 to about 100,000 daltons.   The solid dispersion according to claim 1, further comprising a surfactant.   The solid dispersion of claim 18, wherein the surfactant is present in the dispersion in an amount of about 0.1 to about 20 wt%.   19. A solid dispersion according to claim 18, wherein the surfactant is selected from sodium lauryl sulfate and docusate sodium.   Activity of (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide The solid dispersion of claim 1, which is substantially free of metabolites.   The solid dispersion of claim 1, wherein the AUC of the compound of formula I when dosed to a subject is at least about 1.25 times the AUC of the compound of formula I in the undispersed preparation.   23. The solid dispersion of claim 22, wherein the AUC of the compound of formula I when dosed to a subject is at least about 3 times the AUC of the compound of formula I in the undispersed preparation. Formula I below:
[Wherein X is CH, N, or N—O;
Y is CH, N, or N—O;
Z is a halogen; and
R is H or OH] and particles coated with a polymer.   25. Particles according to claim 24, wherein the particles are non-pareils, lactose prill, microcrystalline cellulose or starch.   The compound of formula I is (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] 25. A particle according to claim 24 which is an amide.   The compound of formula I is (2R, 4S) -quinazoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] 25. A particle according to claim 24 which is an amide.   The compound of formula I is (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine- 25. The particle of claim 24, which is 4-yl] amide.   The compound of formula I is (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine- 25. The particle of claim 24, which is 4-yl] amide.   25. The particle of claim 24, wherein at least a portion of the compound of Formula I is dispersed in a polymer.   32. Particles according to 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. The _{T g} of the dispersion is at least about 50K higher than 298K at a relative humidity of about 60% to about 75%, particle of claim 30. It said dispersion has a single T _g, the particles of claim 30.   32. The particle of claim 30, wherein the dispersion comprises at least one non-homogeneous region enriched with the compound of Formula I.   25. The particle of claim 24, wherein at least about 50% of the compound of Formula I is amorphous.   40. The particle of claim 36, wherein 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 the polymer.   38. The particle of claim 37, wherein substantially all of the compound of Formula I is amorphous.   32. 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 about 30,000 to about 100,000 daltons.   32. 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.   43. The particle of claim 42, wherein the surfactant is present in the dispersion in an amount of about 0.1 to about 20%.   32. The particle of claim 30, wherein the AUC of the compound of formula I when dosed to a subject is at least about 1.25 times the AUC of the compound of formula I in the undispersed preparation.   46. The particle of claim 45, wherein the AUC of the compound of formula I when dosed to a subject is at least about 3 times the AUC of the compound of formula I in the undispersed preparation.   32. The particle of claim 30, wherein the polymer is PVP and the ratio of the compound of formula I to PVP is from about 1: 5 to about 5: 1 in the dispersion.   31. The particle of claim 30, wherein the polymer is PVP and the ratio of the compound of formula I to PVP is about 3.5: 1 within the dispersion.   32. The particle of claim 30, wherein the polymer is PVP and the weight percent of the compound of formula I is at least about 50%.   32. The particle of claim 30, wherein the polymer is PVP and the weight percent of the compound of formula I is at least about 70%.   32. The particle of claim 30, wherein the compound of Formula I is substantially amorphous and remains substantially amorphous at 40 [deg.] C / 75% relative humidity for at least 2 weeks.   31. The compound of formula I has an accelerated dissolution profile at least 3 times in 30 minutes compared to the dissolution profile of the same dispersion of the compound of formula I formulated in the tablet into the dispersion. Particles described in   53. The compound of formula I has an accelerated dissolution profile at least 3 times in 60 minutes compared to the dissolution profile of the same dispersion of the compound of formula I formulated into the tablet in the dispersion. Particles described in   54. The compound of formula I has an accelerated dissolution profile at least 3 times in 120 minutes compared to the dissolution profile of the same dispersion of the compound of formula I formulated into the tablet in the dispersion. Particles described in