KR20090118982A - Pharmaceutical formulation - Google Patents

Abstract

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

Description

Pharmaceutical Formulations {PHARMACEUTICAL FORMULATION}

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

Field of invention

The present invention provides (2R, 4S) -quinolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl ] Amide, or active metabolite thereof, or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -Piperidin-4-yl] amide, methods for their preparation and methods for their use.

Water-insoluble drugs present many numerous challenges to formulation scientists in the development of dosage forms suitable for oral administration. The solubility, dissolution, and permeability of the compound all contribute to the bioavailability of the drug. The incorporation of certain excipients into the formulation for improved permeability has been studied, but the results are not critical and are not widely accepted as a means for improving the bioavailability of water insoluble drug candidates. Micronization of drug substance is an established technology platform that improves dissolution and potentially bioavailability through reduced particle size and associated surface area increase. Processability and physical stability, such as excessive flocculation or agglomeration, are a challenge present in micronization platforms. Other techniques, such as co-formulation with cyclodextrins and lipid-based formulations, are typically limited to lower drug loading. Solid dispersions of insoluble drugs eluted in polymeric carriers or carriers provide a means for improving oral bioavailability. Drug substances are typically present in their amorphous form and, when dispersed at the molecular level, provide endpoints in particle size reduction and improved dissolution and solubility. That is, its surface area is at its maximum and there is no crystal packing energy to overcome. There are several methods for the production of solid dispersions, including spray drying and hot melt extrusion, both of which have some manufacturing problems. Some of the problems with the use of solid dispersions for the delivery of water insoluble drug candidates are the difficulty in processing the solid dispersion into suitable pharmaceuticals and the lack of adequate physical stability associated with the amorphous drug required for pharmaceuticals that have been at least two years at room temperature and humidity. . Thus, there is a need for additional solid dispersions of water insoluble drugs with improved physical stability and processability.

Summary of the Invention

Applicants have found certain solid forms, such as (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -pi Ferridin-4-yl] amide, or an active metabolite thereof, (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- ( 4-Chlorobenzyl) -piperidin-4-yl] amides have been found to provide desirable properties including solubility, bioavailability, and stability (eg, physical and chemical stability).

In one embodiment, the present invention provides 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) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoro] Methyl-benzoyl) -2- (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-chloro Benzyl) -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 active metabolite thereof, or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl ) -2- (4-chlorobenzyl) -piperidin-4-yl] amide to HPMCAS ratio is about 1: 5 to about 5: 1, for example about 1: 3 to about 3: 1, illustrative Typical ratios include about 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 maintains a single T _g for at least 2 weeks at 25 ° C., 60% relative humidity. In some embodiments, the dispersion maintains a single T _g for at least 2 weeks at 25 ° C., 75% relative humidity. In some embodiments, the dispersion maintains a single T _g for at least 2 weeks at 25 ° C., 90% relative humidity.

In some embodiments, T _g is at least about 5 OK greater than 25 ° C. at about 50% to about 90% relative humidity. In some embodiments, T _g is at least about 5 OK greater than 25 ° C. at about 60% to about 75% relative humidity. In some embodiments, T _g is about 98 ° C. to about 102 ° C. at 25 ° C., 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) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl -Benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] at least one non-uniform region rich in amide.

In some embodiments, the dispersion is (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine -4-yl] at least one non-uniform region rich in amide.

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

In some embodiments, the HPMCAS elutes at pH> 5.5, for example 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 of about 0.1% to about 20%, for example 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 comprises an addition polymer such as 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 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 -4-yl] substantially free of the active metabolite of the 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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl)- A (UC) of 2- (4-chlorobenzyl) -piperidin-4-yl] amide, when administered to a subject, 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) About 1.25 of the AUC of -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide At least about 1.5 times, at least about 2 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 All.

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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl)- 2- (4-chlorobenzyl) -piperidin-4-yl] amide is substantially amorphous and remains substantially amorphous for two weeks at 40 ° C./75% relative humidity for two 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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl)- 2- (4-chlorobenzyl) -piperidin-4-yl] amide is substantially amorphous and remains substantially amorphous for two weeks at 25 ° C./90% relative humidity for two weeks.

In one embodiment, the present invention provides 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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl- Benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] solid dispersion comprising an amide and PVP, wherein the compound of formula I in the solid dispersion is 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 % By weight of) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide At least about 50% by weight, such as at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, Relates to a solid dispersion of 90 wt%.

In some embodiments, the active metabolite is (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro Benzyl) -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 to PVP ratio of about 1: 1 to about 5: 1, for example about 2: 1 to about 4: 1, and exemplary ratios are about 1: 1 or About 3.5: 1.

In some embodiments, the dispersion is substantially uniform.

In some embodiments, T _g is at least 5 OK greater than 25 ° C. at about 50% to about 90% relative humidity, eg, T _g is at least 5 OK greater than 25 ° C. at about 60% to about 75% relative humidity.

In some embodiments, T _g is at least about 100 ° C. at 25 ° C. and 60% relative humidity, eg, 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 for at least 2 weeks at 25 ° C., 60% relative humidity. In some embodiments, the dispersion maintains a single T _g for at least 2 weeks at 40 ° C., 75% relative humidity. In some embodiments, the dispersion maintains a single T _g for at least 2 weeks at 25 ° C., 90% 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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl ) -2- (4-chlorobenzyl) -piperidin-4-yl] at least one non-uniform region enriched in amide.

In some embodiments, the dispersion is (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine -4-yl] at least one non-uniform region rich in amide.

In some embodiments, 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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl- Benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] at least about 50% of the 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 ( Of 2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide At least about 75% is amorphous or in a solid dispersion is a compound of formula (I), preferably (2R, 4S) -quinoline-4-car Leric acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide or an active metabolite thereof or (2R, 4S) Substantially all of the -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide It 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, for example an anionic surfactant. In some embodiments, the surfactant is present in the dispersion in an amount from about 0.1% to about 20% by weight, such as from 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 comprises a plurality of surfactants.

In some embodiments, the dispersion further comprises an addition polymer, for example 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 -4-yl] substantially free of the active metabolite of the 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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl)- A (UC) of 2- (4-chlorobenzyl) -piperidin-4-yl] amide, when administered to a subject, 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) About 1.25 of the AUC of -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide At least about 1.5 times, at least about 2 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 All.

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 its active metabolite or (2R, 4S) -quinazolin-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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl)- 2- (4-chlorobenzyl) -piperidin-4-yl] amide is substantially amorphous and remains substantially amorphous for two weeks at 25 ° C./90% relative humidity for two weeks.

In one embodiment, the present 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-trifluoro] Romethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] and a solid dispersion of amide and polymer.

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

In some embodiments, the dispersion is substantially uniform.

In some embodiments, T _g is at least 5 OK greater than 25 ° C. at about 50% to about 90% relative humidity. In some embodiments, T _g is at least 5 OK greater 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 maintains a single T _g for at least 2 weeks at 25 ° C., 60% relative humidity. In some embodiments, the dispersion maintains a single T _g for at least 2 weeks at 40 ° C., 75% relative humidity. In some embodiments, the dispersion maintains a single T _g for at least 2 weeks at 25 ° C., 90% relative humidity.

In some embodiments, the dispersion comprises (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -Piperidin-4-yl] at least one non-uniform region rich in amide. In some embodiments, the dispersion is (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl ) -Piperidin-4-yl] at least one non-uniform region rich in amide.

In some embodiments, (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) in a solid dispersion. At least about 50% of the) -piperidin-4-yl] amide is amorphous, for example in (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5) in a solid dispersion. -Bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] 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 are amorphous.

In some embodiments, (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro in a solid dispersion At least about 50% of the benzyl) -piperidin-4-yl] amide is amorphous, for example in (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3) in a solid dispersion. , 5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] at least about 55%, at least about 60%, at least about 65%, about 70% At least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or substantially all of them is 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 of about 0.1% to about 20%, for example about 1% to about 10%.

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

In some embodiments, the dispersion further comprises an addition polymer, for example a water soluble polymer.

In some embodiments, (2R, 4S) -quinoline N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperi Din-4-yl] amide, when administered to a subject, is a (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoro) in a non-dispersed formulation. Romethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide at least about 1.25 times, for example at least about 1.5 times, at least about 2 times, at least about 2.5 times, At least about 3 times, at least about 4 times, at least about 5 times, or at least about 10 times.

In some embodiments, (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl)- The AUC of piperidin-4-yl] amide, when administered to a subject, is the (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis) in a non-dispersed formulation. -Trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] at least about 1.25 times the AUC of the amide, for example at least about 1.5 times, at least about 2 times, about 2.5 At least about 3 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) -pi Ferridin-4-yl] amide is substantially amorphous and remains substantially amorphous for two weeks at 40 ° C./75% relative humidity for two weeks. 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 two weeks at 40 ° C./75% relative humidity for two weeks.

In one embodiment, the present invention relates to a solid formulation of a dispersion described herein, for example a dispersion of a compound of formula (I).

In one embodiment, the present invention provides 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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl- Benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide and polymer coated particles.

In some embodiments, the particles are non-pariel, lactose prills, 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 the active metabolite thereof is dispersed in the polymer. In some embodiments, the dispersion is substantially uniform. In some embodiments, the T _g of the dispersion is at least about 4 OK greater than RT at about 60% to about 75% relative humidity. In some embodiments, the T _g of the dispersion is 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 its active metabolite is substantially amorphous and the dispersion has a single T _g for at least 15 months at 25 ° C./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) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl- Benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] at least one non-uniform region rich in amide. In some embodiments, the dispersion is (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine -4-yl] at least one non-uniform region rich in 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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl ) -2- (4-chlorobenzyl) -piperidin-4-yl] at least about 50% of the amide is amorphous, for example in the dispersion 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, About 55 of 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide 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 Practically all are amorphous. In some embodiments, the dispersion further comprises surfactants such as anionic surfactants such as sodium lauryl sulfate and docusate sodium. In some embodiments, the surfactant is present in the dispersion in an amount of about 0.1% to about 20%, for example about 1% to about 10%. In some embodiments, the dispersion comprises a plurality of surfactants.

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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl)- A (UC) of 2- (4-chlorobenzyl) -piperidin-4-yl] amide, when administered to a subject, 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) About 1.25 of the AUC of -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide At least about 1.5 times, at least about 2 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 All.

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- (4 -Chlorobenzyl) -piperidin-4-yl] amide or active metabolite thereof to HPMCAS is about 1.5 to about 5: 1, for example about 1: 3 to about 3: 1, and exemplary ratios are About 1: 1, or about 3: 1. In some embodiments, the HPMCAS elutes at pH> 5.5, for example 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 additional polymers, such as water soluble polymers.

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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl ) -2- (4-chlorobenzyl) -piperidin-4-yl] ratio of amide to PVP is about 1: 5 to about 5: 1, for example about 1: 3 to about 3: 1, illustrative Typical ratios include about 1: 1, or about 3: 1. In some embodiments, 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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl- Benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide, by weight, is at least about 50%, for example at least about 55%, at least about 60%, at least about 65%, about 70 At least%, 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 Benzyl) -piperidin-4-yl] amide to PVP ratio of about 1: 1 to about 5: 1, for example about 2: 1 to about 4: 1, and exemplary ratios are about 1: 1 or About 3.5: 1. In some embodiments, the PVP is K29 / 32.

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

In some embodiments, the particles comprise (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine -4-yl] substantially free of the active metabolite of the 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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl)- 2- (4-chlorobenzyl) -piperidin-4-yl] amide is substantially amorphous and remains substantially amorphous for two weeks at 40 ° C./75% relative humidity for two 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 its active metabolite or (2R, 4S) -quinazolin 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 for 2 weeks

In one embodiment, the present invention relates to a solid dose formulation comprising the particles described herein in a dispersion described herein.

In some embodiments, the formulation further comprises one or more excipients, diluents, binders, disintegrants, glidants, glidants, 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 cellulose polymer.

In some embodiments, the solid dose formulation 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. In some embodiments, the solid dose formulation 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. In some embodiments, the solid dose formulation 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. In some embodiments, the solid dose formulation 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.

In some embodiments, the solid dose formulation is

(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

It includes.

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 dose formulation is

From about 20 to about 30% by weight of the compound of formula I, preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- ( 4-chlorobenzyl) -piperidin-4-yl] amide;

About 20 to about 30 weight percent of PVP;

About 0.2 to about 1.0 weight percent DOSS;

About 30 to about 50 weight percent of microcrystalline cellulose;

About 5 to about 10 weight percent of croscarmellose;

About 0.5 to about 3 weight percent SLS; And

About 1 to about 2 weight percent magnesium stearate

It includes.

In some embodiments, the solid dose formulation is

About 25% by weight of (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine-4 -Yl] amide;

About 25% PVP;

About 0.6 wt.% DOSS;

About 40% by weight of microcrystalline cellulose;

About 7.5 weight percent croscarmellose;

About 1 wt.% SLS; And

About 1.5% magnesium stearate

It includes.

In some embodiments, the solid dose formulation is

(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

It includes.

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 dose formulation is

From about 20 to about 30% by weight of (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperi Din-4-yl] amide;

About 20 to about 30 weight percent HPMCAS;

About 15 to about 25 weight percent of microcrystalline cellulose;

About 15 to about 25 weight percent dicalcium phosphate;

About 2 to about 8 weight percent of croscarmellose;

About 0.2 to about 0.8 weight percent SLS;

About 0.2 to about 0.8 weight percent silicon dioxide; And

About 1 to about 2 weight percent magnesium stearate

It includes.

In some embodiments, the solid dose formulation is

About 25% by weight of (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine-4 -Yl] amide;

About 25% by weight HPMCAS;

About 21% microcrystalline cellulose;

About 21 weight percent dicalcium phosphate;

About 5 weight percent croscarmellose;

About 0.5% SLS;

About 0.5% silicon dioxide; And

About 1.5% magnesium stearate

It includes.

In some embodiments, the solid dose formulation is

(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

It includes.

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 onto 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 dose formulation is

From about 20% to about 30% by weight of (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl)- Piperidin-4-yl] amide;

About 7 wt% to about 10 wt% PVP;

About 0.1 wt% to about 0.5 wt% DOSS;

About 60 wt% to about 70 wt% microcrystalline cellulose; And

About 0.2 wt% to about 0.8 wt% SLS

It includes.

In some embodiments, the solid dose formulation is

About 27% by weight of (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine-4 -Yl] amide;

About 8% by weight of PVP;

About 0.3 wt.% DOSS;

About 64% by weight of microcrystalline cellulose; And

0.5 wt% SLS

It includes.

In some embodiments, the solid dose formulation is

(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

It includes.

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 dose formulation is

From about 25% to about 35% by weight of (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl)- Piperidin-4-yl] amide;

About 3 wt% to about 5 wt% DOSS;

About 1 wt% to about 3 wt% SLS;

About 7 wt% to about 11 wt% PVP;

About 8 wt% to about 12 wt% croscarmellose;

About 25 wt% to about 45 wt% lactose;

About 5% to about 9% crospovidone; And

From about 0.2% to about 0.8% magnesium stearate

It includes.

In some embodiments, the solid dose formulation is

About 29% by weight of (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine-4 -Yl] amide;

About 4% DOSS;

About 2% SLS;

About 9% by weight of PVP;

About 10% by weight croscarmellose;

About 38% lactose;

About 7% crospovidone; And

About 0.5% by weight magnesium stearate

It includes.

In one embodiment, the present invention provides 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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl- Benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide;

Compound of formula (I), preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperi Din-4-yl] amide or its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4- Chlorobenzyl) -piperidin-4-yl] amide;

Suspending the particles in an aqueous solution comprising a water soluble polymer; And

The particles are spray coated on a carrier 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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl ) -2- (4-chlorobenzyl) -piperidin-4-yl] providing a carrier coated with an amide and a water soluble polymer.

It relates to a method comprising a.

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 present invention provides 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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl- Benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide;

Compound of formula (I), preferably (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperi Din-4-yl] amide or its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4- Chlorobenzyl) -piperidin-4-yl] amide is eluted 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) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] providing a solution of amide and polymer; And

The solution is spray dried to give 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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl)- Providing a dispersion comprising 2- (4-chlorobenzyl) -piperidin-4-yl] amide and a polymer

It relates to a method comprising a.

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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl)- 2- (4-chlorobenzyl) -piperidin-4-yl] amide and the solvent eluting the polymer are 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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl)- 2- (4-chlorobenzyl) -piperidin-4-yl] The solvent eluting the amide and the polymer 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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl)- 2- (4-chlorobenzyl) -piperidin-4-yl] The solvent eluting the amide and the polymer is a mixture of organic solvents.

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

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

In some embodiments, the T _out of the spray drier is about 70 ° C to about 150 ° C.

In some embodiments, the 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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl ) -2- (4-chlorobenzyl) -piperidin-4-yl] solid fill of the amide and the polymer is from about 1% to about 20% by weight, for example about 5% by weight.

In one aspect, the invention relates to a method of treating an NK-I related disorder, 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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl)- 2- (4-chlorobenzyl) -piperidin-4-yl] amide is administered to a dieted subject.

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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl)- 2- (4-chlorobenzyl) -piperidin-4-yl] amide is administered to a subject who does not eat 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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl)- 2- (4-chlorobenzyl) -piperidin-4-yl] amide is administered to subjects who eat within 60 minutes before or 120 minutes after administration.

In some embodiments, the process 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) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl -Benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] administering a dose comprising about 1 to about 1000 mg of an amide.

In some embodiments, the process 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) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl -Benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] administering a dose comprising about 40 mg of amide.

In some embodiments, the process 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) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl Administering a dose comprising about 320 mg of -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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl)- 2- (4-chlorobenzyl) -piperidin-4-yl] amide is administered once daily.

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 its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl)- 2- (4-chlorobenzyl) -piperidin-4-yl] amide is administered twice daily.

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 its active metabolite or (2R, 4S) -quinazolin-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 its active metabolite or (2R, 4S) -quinazolin-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 its active metabolite or (2R, 4S) -quinazolin-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 formulation.

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 its active metabolite or (2R, 4S) -quinazolin-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 its active metabolite or (2R, 4S) -quinazolin-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. In order to improve the stability of the amorphous solid (which is generally less stable than the crystalline form), the polymer or polymer mixture can be used with the drug to form an amorphous solid dispersion system. In some embodiments, a "solid solution", or solid dispersion, which is a system in which phases do not separate over time, may be formulated, wherein recrystallization of the drug is performed at a pharmacologically long period of time at ambient temperature (e.g., For example, two years) or limited.

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

The details of one or more embodiments of the invention are set forth in conjunction with the description below. Other features, objects, and advantages of the invention are apparent from the specification and claims.

Detailed description of the invention

The finding of the present invention is that various factors and components are important for the stability and bioavailability of pharmaceutical compositions, especially formulations comprising solid dispersions of water insoluble drugs. Accordingly, the present invention provides formulations of solid dispersions and methods of making such formulations.

Compound of formula (I)

Solid dispersions herein include a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof:

In the above formula,

X is CH, N, or N-O;

Y is CH, N, or N-O;

Z is halogen, preferably chloro;

R is H or OH.

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 R is OH.

Formula I includes compounds that can be formed in the body via metabolic pathways and is also included herein as components of the solid dispersions described herein. Exemplary active metabolites include (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl)- 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 the following compounds: (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) -piperidin-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) -pi Ferridin-4-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 salts or solvates thereof. (2R, 4S) -Quinoline-4-carboxylic acid having the formula: [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine-4- General] Amides are very preferred embodiments of the compounds of formula (I):

The compounds described herein include their various solid forms (including their polymorphic forms, solvates and salts). The compounds described herein also include their tautomeric forms.

Dispersion of Compounds of Formula (I)

Dispersions comprising a compound of Formula (I), or an active metabolite thereof, and a polymer, such as a water soluble polymer, are described herein. Preferred polymers include HPMCAS and PVP.

As used herein, "dispersion" means a dispersion system in which one substance, the dispersed phase, is distributed over a second substance (continuous phase or vehicle). The size of the discrete units in the disperse phase can vary considerably (eg, single molecule, nanometer-sized colloidal particles, in size to multiple microns). In general, 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 use, the solid dispersion may comprise a crystalline drug (disperse phase) in an amorphous polymer (continuous phase) or, alternatively, an amorphous drug (disperse phase) in an amorphous polymer (continuous phase). In some embodiments, the amorphous solid dispersion comprises the polymer comprising the dispersed phase and the drug constitutes the continuous phase.

The term "amorphous solid dispersion" generally means a solid dispersion of two or more components, generally a drug and a polymer or a combination of polymers, but possibly containing other components such as surfactants or other pharmaceutical excipients, The drug is in the amorphous phase (eg, substantially all of the drug is in the amorphous phase), and the physical stability and / or dissolution and / or solubility of the amorphous drug is enhanced by other components.

Exemplary solid dispersions include (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine-4 -Yl] co-precipitate or co-melt of amide with HPMCAS or PVP. "Coprecipitation" is the product after eluting the drug and polymer in a solvent or solvent mixture and removing the solvent or solvent mixture. Occasionally, the polymer may be suspended in a solvent or solvent mixture. The solvent or solvent mixture includes an organic solvent and a supercritical fluid. In some cases, solid dispersions are prepared by adding a solution of drug and a solid polymer followed by mixing and removing the solvent. To remove the solvent, vacuum drying, spray drying, tray drying, lyophilization, and other drying procedures can be used. According to the present invention, using any such method with appropriate processing parameters, the (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis) in the amorphous state in the final solid dispersion product may be used. -Trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide is provided.

HPMCAS  And / or PVP Dispersion containing

The solid dispersion may have any form suitable for pharmaceutical use. For example, the solid dispersion may be in the form of a powder, or a coating on a substrate (eg, the solid dispersion may 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, when the ratio of polymer to compound of formula (I) is relatively high, the compound of formula (I) tends to form dispersions with very few domains of water insoluble drugs dispersed on molecular dispersions or water soluble polymers. However, when the ratio of polymer to compound of formula I is higher, the concentration of the water insoluble drug in the solid dispersion is low, requiring a large amount of solid dispersion in the pharmaceutical composition comprising the solid dispersion. In addition, low concentrations of the compound of formula I may reduce the rate of absorption of the compound of formula I in a patient.

When the ratio of polymer to compound of formula I is relatively low, the compound of formula I tends to form a dispersion of the domain of the compound of formula I in the polymer phase rather than a molecular dispersion of the compound of formula I in the polymer. However, if the ratio of polymer to compound of formula (I) is too low, the dispersion domain of the compound of formula (I) is so large that the dissolution and absorption of the drug in the patient is reduced, thereby reducing the bioavailability of the compound of formula (I). The appropriate ratio of polymer to compound of formula (I) depends on the compound, the polymer, and the intended use.

Exemplary solid dispersions are compounds of formula I, such as (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -Piperidin-4-yl] amide or its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide, and HPMCAS.

The amount of the compound of formula I to HPMCAS may vary. For example, the dispersion may be mainly a compound of formula (I), mainly HPMCAS, or a relatively equal amount of compound of formula (I) and HPMCAS. The ratio of compound of formula (I) to polymer can be varied to alter the properties of the solid dispersion. For example, in some embodiments, it is desirable to have a ratio of the compound of formula I to the polymer that provides a uniform dispersion, and in some embodiments, the compound of formula I versus the compound of formula I provides a rich region. It is preferred to have a ratio of polymers. Exemplary ratios of compounds of Formula I to HPMCAS are 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: Contains 1.

In another embodiment, the composition of the solid dispersion may comprise a compound of formula I and a combination or 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, 1: 4, or Includes 1: 5. The polymer ratio can 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, such as (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro Benzyl) -piperidin-4-yl] amide or its active metabolite or (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl)- 2- (4-chlorobenzyl) -piperidin-4-yl] amide, and PVP, wherein the amount of the compound of formula I in the dispersion is at least about 25%, for example at least about 30%, at least about 35% , At least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85% , About 90% or more. Exemplary ratios of compounds of formula I to PVP include about 1: 2 to about 5: 1, for example 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 of formula I and polymers, such as water soluble polymers, are included herein. For example, (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine-4- Japanese] Dispersions of amides and polymers or (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4- Chlorobenzyl) -piperidin-4-yl] dispersions of amides and polymers are disclosed herein.

Exemplary polymers include water soluble polymers. The term “water soluble polymer” means any natural or synthetic polymer and has an apparent viscosity of less than 100 mPs · s as measured for a 2% aqueous solution of a water soluble polymer at 20 ° C. Non-limiting examples of suitable water soluble polymers include cellulose ethers such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose. Hydroxybutyl cellulose, hydroxyethyl methylcellulose. Hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, and carboxymethylethylcellulose; Cellulose esters such as hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate ( HPMCAP), and methylcellulose acetate phthalate (MCAP); Starch; Pectin, such as sodium carboxymethylamylopectin; Chitin derivatives such as chitosan; Polysaccharides such as alginic acid, and alkali metal and ammonium salts thereof; Carrageenan; Galactomannan; Tragacanth; Agar-agar; Arabian gum; Guar gum; Xanthan gum; Polyacrylic acid and polymethacrylic acid and salts thereof; Acrylate and methacrylate copolymers; Polyvinyl alcohol; Polyvinylpyrrolidone; Copolymers of polyvinylpyrrolidone and vinyl acetate; And polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide.

The ratio of the compound of formula 1 and the polymer includes such dispersions comprising such above described ratios, for example HPMCAS and / or PVP.

Additional ingredient

Other pharmaceutically acceptable components such as surfactants or addition polymers such as water soluble polymers may also be included in the dispersions described herein.

Surfactants

Surfactants are generally from about 0.1 to about 20 weight percent, such as from about 1 to about 15 weight percent (eg, about 9 weight percent), for example from about 0.5 to about 10 weight percent, from about 0.5 to about 5 weight percent. It is present in the dispersion in an amount of weight percent, or about 1 to about 2 weight percent. The weight ratio of compound of formula I to surfactant ranges 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. Anionic surfactants are amphoteric molecules with negative charges. Non-limiting examples of suitable anionic surfactants include alkyl, aryl, or aryl alkyl carboxylates, sulfonates, sulfates, phosphates, or acylated protein hydrolysates. Suitable carboxylated surfactants include, for example, 솝 (ie, fatty acid salts), bile salts, polyalkoxycarboxylates, and N-acylsarcosinates. Suitable sulfonated surfactants include, for example, alkylsulfonates, alkylbenzenesulfonates, alkylarenesulfonates, short-chain lignosulfates, naphthalenesulfonates, α-olefinsulfonates with ester, amide, or ether linkages. , Petroleum sulfonates, and sulfonates. Suitable sulfated surfactants include, for example, sulfate esters of fatty alcohols, sulfated alkylphenols, sulfated acids, amides, and esters, and sulfated natural oils and fats. Suitable phosphonated surfactants include fatty alcohol mono- and diesters of orthophosphoric acid.

In some embodiments, anionic surfactants are preferred. Exemplary anionic surfactants include, for example, fatty acid salts such as sodium caproate, sodium caprylate, sodium caprate, sodium laurate, sodium myristate, sodium myristolate, sodium palmitate, sodium palmitate, Sodium oleate, sodium ricinoleate, sodium linoleate, sodium linoleate, sodium stearate, sodium lauryl sulfate (SLS), sodium tetradecyl sulfate, sodium lauryl sarcosinate, sodium dioctylsulfosuccinate, etc. ; Bile salts such as sodium chelate, sodium tarocholate, sodium glycolate, sodium deoxycholate, sodium taurodeoxycholate, sodium glycodeoxycholate, sodium ursodeoxycholate, sodium chemodeoxycholate, sodium glycokemodeoxy Cholate, sodium cholysarcosinate, sodium N-methyl taurocholate, sodium lidocalate, and the like; Phosphoric acid esters such as esterification products of fatty alcohols or fatty alcohol carboxylates with phosphoric acid or anhydrides, and the like; Carboxylates such as ether alkyl carboxylates formed by oxidation of the terminal -OH groups of fatty alcohol ethoxylates, succinylation monoglycerides, sodium stearyl fumarate, stearoyl propylene glycol hydrogen succinate, mono And mono / diacetylated tartaric acid esters of diglycerides, citric acid esters of mono- and diglycerides, glyceryl-lacto esters of fatty acids, lactic acid esters of fatty acids, calcium / sodium stearoyl-2-lactylate, calcium Sodium stearoyl lactylate, alginate salt, propylene glycol alginate and the like; Sulfates and sulfonates such as ethoxylated alkyl sulfates, alkyl benzene sulfonates, α-olefin sulfonates, acyl isethionates, acyl taurates, acyl glyceryl ether sulfonates, octyl sulfosuccinate disodium (ie dioctyl Sodium sulfosuccinate (DOSS) or sodium docusate), disodium undecyleneamido-MEA-sulfosuccinate, and the like.

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

In some embodiments, two or more surfactants are used in combination. When the composition of the present invention comprises a mixture of two or more surfactants, the two or more surfactants may be selected from the same kind of surfactant (eg, two or more surfactants may each be an anionic surfactant). Or may be selected from different kinds of surfactants (eg, one of two or more surfactants may be any nonionic surfactant, and one or more other surfactants may be anionic surfactants). . When a mixture of surfactants, for example two surfactants, is present in the composition of the present invention, the weight ratio of the two surfactants may range from about 5: 1 to about 1: 1. For example, the weight ratio of the two surfactants may be about 5: 1, 4: 1, 3: 1, 2: 1, or 1: 1.

Addition polymer

In some embodiments, the dispersions described herein comprise a compound of Formula (I) and two or more polymers. For example, a dispersion, for example a dispersion of the compound of formula (I) and HPMCAS or a dispersion of the compound of formula (I) and PVP may comprise two polymers, including a second polymer, such as a water soluble polymer, for example HPMCAS and a second polymer or It is possible to provide compounds of formula (I) dispersed in PVP and a second polymer. In some cases, 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, for example about 1: 3 to about 3: 1, about 1: 2 to about 2: 1, for example For example in the range of about 1: 1.

Dispersion Characteristics

As described herein, the dispersion may be homogeneous or non-uniform, for example having a rich region of the compound of formula (I). The size distribution of the domains of the rich region (eg, discontinuous phase) distributed within the dispersion phase may be unimodal or bimodal. In one embodiment, at least 90% of the domains of the compound of formula (I) dispersed in a polymer (ie, HPMCAS or PVP) have a size ranging from 10 nm to 1000 nm, or 100 nm to 800 nm, or 100 nm to 500 nm. Has

In some embodiments, the compound of formula (I) in the dispersion is substantially amorphous, for example at least about 50% of the compound of formula (I) is amorphous, and at least about 55% of the compound of formula (I) is amorphous, or is a compound of formula (I) At least about 60% of the compounds of formula I are amorphous, at least about 65% of the compounds of formula I are amorphous, at least about 70% of the compounds of formula I are amorphous, or at least about 75% of the compounds of formula I are amorphous, or At least about 80% of the compound of formula is amorphous, at least about 85% of the compound of formula I is amorphous, at least about 90% of the compound of formula I is amorphous, or at least about 95% of the compound of formula I is amorphous, At least about 98% of the compound of formula (I) is amorphous, at least about 99% of the compound of formula (I) is amorphous, or substantially all of the compound of formula (I) is amorphous.

As used herein, the term “amorphous” means a solid material that does not have a long range order at the position of its atoms. Amorphous solids are generally supercooled liquids in which molecules are arranged in a random manner, so that there is no very limited arrangement and no long range order. Amorphous solids are generally isotropic. That is, they exhibit similar properties in all directions and do not have a limited melting point. For example, an amorphous material is a solid material that does not have sharp characteristic crystal peak (s) in its X-ray powder diffraction (XRPD) pattern (ie, it is not a crystal when measured by XRPD). Instead, one or several broad peaks (eg halo) appear in their XRPD pattern. Broad peaks are characteristic of amorphous solids. For a comparison of XRPDs of amorphous and crystalline materials, reference may be made to US 2004/0006237.

As used herein, “crystalline solid” means a compound or composition having a long range order in which the structural units are arranged in a defined geometric pattern or lattice, where the crystalline solid is fixed. The units constituting the crystal structure may be atoms, molecules, or ions. Crystalline solids show a limited melting point.

In some embodiments, the dispersion has a single glass transition temperature (“T _g ”). T _g is the characteristic temperature at which the glassy material undergoes a rapid physical change from the glassy state to the rubbery state when heated. T _g can be _measured by some commonly recognized techniques, such as differential scanning calorimetry (DSC) or dynamic mechanical analyzer (DMA). The T _g of the dispersion is generally preferably at least about 5 OK greater than storage conditions at room temperature and relative humidity conditions (eg, 25 ° C., 60% RH). For example, in a solid dispersion comprising the compound of formula (I) and HPMCAS in the same ratio, the T _g of the dispersion at room temperature / humidity conditions is generally from about 98 ° C. to about 102 ° C. (eg, about 100 ° C. or 101 ° C.). )to be. In solid dispersions comprising compounds of formula I and PVP in equal proportions, the T _g of the dispersion at room temperature / humidity conditions is generally from about 130 ° C to about 135 ° C. It is well understood that the T _g of a dispersion depends on many factors, such as the weight fraction of the component (ie its structure, interactions, etc.) thereof, and the equilibrium solvent and / or water content of the dispersion, to name a few. In addition, a uniform blend of the amorphous component (that is, polymers and compounds) T _g is Gordon Taylor used to evaluate the weight fraction and a T _g of their respective T _g is the dispersion of individual components, in many cases (Gordon Taylor) can be evaluated by the equation. The ratio of the compound of formula (I) to the polymer in the dispersion is such that a sufficient therapeutic amount of the compound of formula (I) is 650 mg rather than the usual size (ie, 1300 mg) using conventional techniques (e.g. roller compaction, wet granulation, etc.). It is desirable to have a single T _g which allows it to be prepared in conventional formulations), and that the dispersion is at least 5 OK greater than the expected storage conditions.

Solid dispersions described herein are generally stable, for example chemically and physically stable. For example, in some preferred embodiments, the solid dispersion is stable both chemically and physically for at least two weeks under accelerated storage conditions such as 40 ° C./75% and / or 25 ° C./90%. The physical stability of the dispersion can be assessed for the content of amorphous forms of the compounds of formula (I) by XRPD, DSC, and / or microscopic observation. For example, in a solid dispersion comprising compounds of formula I and PVP in equal proportions, at room temperature / humidity conditions, T _g is generally about 130 ° C. to about 135 ° C., and the same at 40 ° C./75% storage for two weeks. The T _g of the dispersion stays at about 130 ° C. to about 135 ° C., and finally, the T _g of the same dispersion at 25 ° C./90% storage for at least two weeks is about 130 ° C. to about 135 ° C. In another embodiment, dispersions of PVP and compounds of formula (I) coated on lactose and subsequently blended with common excipients and filled with gelatin capsules are subjected to room temperature and relative humidity conditions (eg, 25 ° C., 60% RH). Stable for more than 15 months.

The solid dispersions described herein can be used as components in pharmaceutical compositions, for example, as powders for oral suspensions, tablets, capsules and 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. Solid dispersions generally have a D ₅₀ of less than about 1 μm.

In another embodiment, a composition of a compound of formula (I) is administered to an animal after administration of a composition comprising a solid dispersion to the administration of a compound of formula (I) wherein the level of the compound of formula (I) in the blood of the animal does not comprise a solid dispersion. At least about 20% more, for example at least about 25% more, at least about 50% more, at least about 100% more, at least about 200% more, at least about 300% more, or as observed by It consists of a solid dispersion present in a sufficient amount of at least about 400%. In another embodiment, the compositions of the present invention provide increased bioavailability of at least 1.25 fold, 1.50 fold, or at least 2.0 fold over the bioavailability of the unformulated water insoluble drug.

Particles of Compounds of Formula I

Particles of compounds of formula (I) are described herein. For example, particles comprising an amorphous compound of formula (I) are described herein, for example particles comprising a substantially amorphous compound of formula (I) are described herein. Amorphous compounds of formula (I) can be prepared, for example, by spray drying the compounds of formula (I) to provide particles of a compound of formula (I) suitable for formulation into pharmaceutical compositions, such as oral dosage formulations.

As described above, dispersions comprising a compound of formula (I) and a compound of formula (I) described herein may be used as a component in a pharmaceutical composition. In some embodiments, the dispersion is formulated directly into the composition. In some embodiments, a dispersion comprising a compound of Formula (I), eg, a compound of Formula (I) described herein, is coated on the particles, and the particles are formulated into a pharmaceutical composition.

Compounds of formula (I), for example amorphous compounds of formula (I), can be coated onto the particles, for example by water soluble polymers. In some embodiments, the dispersions described herein are coated on the particle surface. Exemplary particles useful for coating with the dispersions described herein include non-Pariel, such as lactose or microcrystalline cellulose or starch.

A compound of formula (I) or a dispersion described herein can be prepared by, for example, providing a suspension or slurry of a compound of formula (I), for example an amorphous compound of formula (I) or a dispersion described herein, and particles and spraying the suspension or slurry By providing particles coated with a compound of, it can be coated on the particle surface by a spray coating process. In some embodiments, the particle surface may also be coated with additional components such as an enteric coating.

The coated particles can then be formed into a suitable formulation, for example by encapsulation. Alternatively, the coated substrate can be mixed with one or more additional ingredients disclosed herein using processes known in the pharmaceutical art, such as wet or dry granulation, milling, and the like, followed by encapsulation, It can be formed into a suitable formulation by compression, or pelletization.

Process for preparing a dispersion comprising a compound of formula (I)

Any method for obtaining a solid dispersion is used in connection with the dispersion described herein. In general, methods of use include those involving rapid removal of a solvent from a mixture or cooling of a melt sample. Such methods include, but are not limited to, rotary evaporation, freeze drying (ie, lyophilization), vacuum drying, melt congealing, and melt extrusion. However, preferred embodiments of the present invention include amorphous solid dispersions obtained by spray drying. Thus, in another embodiment, the present invention provides a step of removing the solvent by drying the product obtained by spray drying.

The formulations disclosed herein, such as 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 comprising atomization of a liquid mixture comprising a solid and a solvent, and removal of the solvent. Atomization can be carried out, for example, via a nozzle or on a rotating disk. Spray drying is the process of converting a liquid feed into dried particulate form. Optionally, a second drying process, such as fluid bed drying or vacuum drying, can be used to reduce residual solvent to a pharmaceutically acceptable level. Spray drying typically involves contacting a highly dispersed liquid suspension or solution, and a sufficient volume of hot air to evaporate and dry the liquid droplets. The formulation to be spray dried may be any solution, crude suspension, slurry, colloidal dispersion, or paste that can be atomized using a selected spray drying apparatus. In a standard procedure, the formulation is sprayed with a stream of warm filtered air that evaporates the solvent and transfers the dried product to a collector (eg cyclone). The spent air is then discharged by the solvent, or alternatively the spent air is sent to the condenser to capture and possibly recycle the solvent. Commercially available forms of the device can be used to perform spray drying. For example, conventional spray dryers are manufactured by Buchi Ltd. and Niro (e.g., PSD lines of spray dryers manufactured by Niro) (see US 2004) / 0105820; US 2003/0144257).

Spray drying typically utilizes solid filling of about 2% to about 25%, preferably about 4% or 5% of the material (ie, compounds of formula (I) and excipients). In general, the upper limit of solid filling is governed by the viscosity of the solution obtained (eg the ability to pump the solution obtained) and the solubility of the components in the solution.

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

Generally, spray drying is performed at an inlet temperature of about 60 ° C. to about 200 ° C., for example about 130 ° C. to about 180 ° C. Spray drying is generally carried out at discharge temperatures of about 70 ° C. to about 150 ° C., for example about 80 ° C. to about 110 ° C.

Preferred solvents are those in which the compound of formula I is at least about 10 mg / ml (e.g., 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 greater) .

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 general solvent elutes both the compound of formula (I) and the polymer (ie HPMCAS and / or PVP).

Removal of the solvent may be carried out in subsequent drying steps such as tray drying, fluid bed drying (eg, from about room temperature to about 100 ° C.), vacuum drying, microwave drying, rotary drum drying or biconical vacuum drying (eg , From room temperature to about 200 ° C.).

The dispersed particles obtained (eg, dispersed particles obtained after spray drying) generally have an average particle size of less than 1 μm, for example about 850 nm, about 800 nm, about 750 nm, about 700 nm, about 650 nm, From about 100 nm to about 600 nm, about 550 nm, about 500 nm, about 450 nm, about 400 nm, about 350 nm, about 300 nm, about 250 nm, about 200 nm, and about 150 nm It has an average particle size up to about 900 nm and includes all ranges and subranges therebetween. The particle size distribution of the dispersed particles can be essentially unimodal or bimodal. If 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 of less than 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, or 200 nm, including all ranges and subranges therebetween. do.

Particle coating

In some embodiments, a dispersion comprising a compound of formula (I) or a compound of formula (I) and a polymer is coated on a carrier, such as solid particles, such as particles, such as lactose or microcrystalline cellulose or starch. 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 layered on a carrier such as a sphere of solid particles such as lactose or microcrystalline cellulose (eg Celsphere).

In some embodiments, the water soluble polymer is the same polymer as the polymer in the solid dispersion (or polymer in the solid dispersion in the example of a dispersion comprising one or more polymers).

Generally, the solid filling of the water soluble polymer in the coating process is about 10 to about 60 weight percent.

A composition comprising a dispersion of a compound of formula (I)

The solid dispersions described herein and particles coated with the solid dispersions described herein can be formulated with additional pharmaceutically acceptable excipients to provide a dosage formulation for administration to a subject.

The weight percentage of the compound of formula (I) in the compositions described herein may range from about 99% to about 15% by weight. For example, the weight percentage of the water insoluble drug may be about 99, about 95, about 90, about 85, about 80, about 75, about 70, about 65, about 60, about 55, about 50, about 45, about 40, About 35, about 30, about 25, about 20, and about 15 weight percent.

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 several batches over the required number of days. 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 may be 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, 1000 mg and the like.

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

When present, the weight percentage of the total amount of one or more additional ingredients in the compositions of the present invention may range from about 90 to about 5 weight percent. 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 May be%.

Exemplary pharmaceutically acceptable excipients include diluents or fillers, drug complexing or solubilizing agents, disintegrants, binders, glidants, glidants, pH modifiers, and surfactants. Examples of suitable diluents or fillers include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and starch. Examples of drug complexing or solubilizing agents include polyethylene glycol, caffeine, xanthene, gentisic acid, and cyclodextrins. Examples of disintegrants include sodium starch glycolate, sodium alginate, carboxymethylcellulose sodium, methylcellulose, croscarmellose sodium, and crospovidone, preferably croscarmellose sodium and / or crospovidone. Examples of binders include methylcellulose, povidone, microcrystalline cellulose, starch, hydroxypropyl cellulose, hydroxymethyl propyl cellulose, and gums such as guar and tragacanth, preferably povidone. Examples of glidants include magnesium stearate, stearic acid, sodium stearyl fumarate. An example of a glidant is silicon dioxide. Examples of pH modifiers are buffers including acids, such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, and mixtures of any of the aforementioned acids and salts thereof.

Examples of surfactants are provided above. Preferred surfactant excipients include DOSS and SLS. The weight percentage of surfactant in the composition of the present invention may range from about 0.1% to about 20% by weight. For example, the weight percent of surfactant in the composition may be about 20, about 19, about 18, about 17, about 16, about 15, about 14, about 13, about 12, about 1 1, about 10, about 9, About 8, about 7, about 6, about 5.5, about 5.0, about 4.5, about 4.0, about 3.5, about 3.0, about 2.5, about 2.0, about 1.5, about 1.0, about 0.9, about 0.8, about 0.7, about 0.6 , About 0.5, about 0.4, about 0.3, about 0.2, about 0.1 weight percent.

The additional component may independently comprise one, or two or more separate components selected from each of the types of pharmaceutically acceptable excipients described herein. That is, the compositions included herein can include, for example, one or more diluents or fillers and disintegrants, single diluents or fillers and two or more disintegrants, fillers, disintegrants, binders, glidants, and the like.

In some embodiments, the compositions described herein comprise an additional therapeutic agent, for example to provide simultaneous administration of a second therapeutic agent and a compound of Formula (I). As used herein, the term “therapeutic agent” is used in its conventional sense and refers to a compound or any synthetic or natural entity having beneficial prophylactic and / or therapeutic properties when administered to a mammal, especially a human. Non-limiting examples of suitable water-insoluble drugs include, for example, proteins, peptides, nucleotides, anti-obesity drugs, nutraceuticals, corticosteroids, elastase inhibitors, analgesics, antifungal agents, tumor therapies, anti-nausea agents, cardiovascular agents, anti-inflammatory agents Antiparasitic, antiarrhythmic, antibiotic, anticoagulant, antidepressant, antidiabetic, antiepileptic, antihistamine, antihypertensive, antimuscarinic, antituberculosis, antineoplastic, immunosuppressant, antithyroid, antiviral, anxiolytic, sedative, astringent, β-adrenergic receptor blockers, blood products and substitutes, cardiovascular agents, cholinesterase inhibitors, contrast agents, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopamine agonists, hemostatic agents, immunologic agents, lipid modulators, small intestinal motility Modulators, muscle relaxants, parasympathetic neurostimulants, parathyroid calcitonin and biphosphonates, prostaglandins, radiation It includes drugs, sex hormones, anti-allergic agents, stimulants and appetite inhibitors, sympathomimetic agents, gapsangseonje, vasodilator, and drugs from the various known classes of drugs, including xanthine.

The particles of the solid dispersion can then be formed into suitable formulations, for example by encapsulation. Alternatively, the coated substrate may be mixed with one or more additional ingredients disclosed herein using processes known in the art of pharmacy, such as wet or dry granulation, grinding, and the like, followed by encapsulation, tableting, or It can be formed into a suitable formulation by pelletization.

The compositions of the present invention may be provided in any formulation suitable for delivering a therapeutically effective amount of a water insoluble drug to a patient. Non-limiting examples of suitable formulations include minicapsules, capsules, tablets, and implants, troches, lozenges, suspensions, ovules, suppositories, wafers, chewable tablets, quick-dissolved tablets or rapid tablets, boiling tablets. Intra-ball or sublingual solids, granules, films, pellets, beads, pills, powders, strips, or sachets.

Compositions of the invention may be formulated for oral, sublingual, intranasal, nasal, ocular, lung, urethral, mucosal, intravaginal, topical, or rectal delivery. In one embodiment, the compositions of the present invention are formulated for oral administration to a subject and suitable for entry into the subject system, for example via the gastrointestinal tract. In some preferred embodiments, the compositions described herein are formulated for oral administration, for example as tablets, capsules, or powders for oral suspensions, preferably as tablets or capsules. When formulated as a mini capsule or capsule, the capsule may be a hard or soft gelatin capsule, a starch capsule, or a cellulose capsule.

The compositions of the present invention also provide for immediate release, pulsatile release, controlled release, extended release, delayed release, targeted release, simultaneous release. The coating may be coated with one or more coatings to provide synchronized release, or targeted delayed release properties, for example to control the rate of disintegration in the digestive tract. Such coatings may include enteric coatings, film coatings, barrier coatings, compression coatings, rapid disintegration coatings, enzymatic degradation coatings, and the like.

Method of Use of Dispersion Containing Compound of Formula (I)

Compounds and solid dispersions, particles comprising solid dispersions and compositions comprising compounds and solid dispersions described herein can be used, for example, in the treatment to treat NK-I related disorders. A therapeutically effective amount of a solid dispersion (and / or a particle comprising a solid dispersion and / or a composition comprising a solid dispersion) comprising a compound of Formula (I) described herein may be used to treat a subject, e.g., to treat a NK-I related disorder. For example, to a subject in need of such treatment.

The term “therapeutically effective amount” is an amount of a water insoluble drug that provides a clinically useful effect, eg, reduces or alleviates signs, or prevents or alleviates a disease or condition.

Exemplary NK-I related disorders include disorders such as depression, anxiety, cognitive and memory deficits, acute and chronic pain, allergic disorders, asthma, chronic obstructive pulmonary disease, skin disease, incontinence, inflammation, vomiting, irritable bowel syndrome, sleep disorders , Substance withdrawal, immune system disorders, inflammatory diseases such as osteoarthritis, rheumatoid arthritis, and other arthritis, inflammatory bowel disease, scleritis, visceral disorders such as pelvic inflammatory disorders, semicystitis and dyspareunia. In some preferred embodiments, the compound or a dispersion described herein or a composition comprising the compound or dispersion described herein is administered to a subject for the treatment of social anxiety disorder, incontinence, and / or irritable bowel syndrome.

The compound and dispersions described herein can be administered with or without food. In some embodiments, the dispersions described herein are administered to a subject who eats within 2 hours of administration of the solid dispersion or within 1 hour after administration of the solid dispersion. The frequency of administration may vary depending on several factors, including the disorder to be treated, the dosage formulation, the dosage amount, and the patient. Thus, the compounds or dispersions described herein may be administered once daily, twice daily, three times daily, or four times daily.

The following examples illustrate the invention but are not intended to limit the invention in any way, shape, or form, clearly or implicitly. Although the present examples are well-characterized for those used, other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used.

Example  One: PVP  or HPMCAS Solid dispersion containing

Various drug / polymer and drug / polymer / surfactant combinations were eluted in various solvents and then spray dried to form solid dispersion particles.

Polymer, solvent, surfactant concentrations (% docusate sodium), solids (%) and drug / polymer ratios are listed in Table 1 below:

Lot menstruum polymer Drug ^* : Polymer DOSS ^** (%) Solid content (%) A001 Ethyl acetate NA * NA 5.00 A002 Ethanol 200 PVP (K29 / 32) 1: 3 NA 5.00 A003 Ethanol 200 PVP (K29 / 32) 1: 1 NA 5.00 A004 Ethanol 200 PVP (K29 / 32) 3: 1 NA 3.33 A005 Ethanol 200 PVP (K29 / 32) 1: 1 1.50 4.76 A006 Ethanol 200 PVP (K29 / 32) 1: 1 2.00 4.76 A007 Ethanol 200 PVP (K29 / 32) 1: 1 9.00 4.76 A008 Ethanol 200 NA * NA 2.50 A009 Methanol NA * NA 5.00 A010 Methanol PVP (K29 / 32) 1: 1 1.00 5.00 A011 Methanol PVP (K29 / 32) 1: 1 NA 5.00 A012 Acetone HPMCAS-LF 1: 1 1.00 5.00 A013 Acetone HPMCAS-LF 1: 1 NA 5.00 D007 Ethyl acetate NA * 12.20 5.00

* (2R, 4S) -Quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide

** Docusate Sodium

Physical analysis of the solid dispersion from Table 1 was performed to assess the drug form (ie amorphous or crystalline) in the dispersion and to determine the glass transition temperature of the solid dispersions set forth in Table 2. The methods used to determine the form and T _g were XRPD and controlled DSC, respectively.

Lot polymer Drug ^* : Polymer DOSS ^** (%) shape T _g (℃) 25 ℃ / 60% XRPD >2 weeks mDSC A001 NA * NA Amorphous 91 A002 PVP (K29 / 32) 1: 3 NA Amorphous 152 A003 PVP (K29 / 32) 1: 1 NA Amorphous 135 A004 PVP (K29 / 32) 3: 1 NA Amorphous 115 A005 PVP (K29 / 32) 1: 1 1.50 Amorphous 133 A006 PVP (K29 / 32) 1: 1 2.00 Amorphous 130 A007 PVP (K29 / 32) 1: 1 9.00 Amorphous 119 A008 NA * NA Amorphous 94 A009 NA * NA Amorphous 94 A012 HPMCAS-LF 1: 1 1.00 Amorphous 100 A013 HPMCAS-LF 1: 1 NA Amorphous 101 D007 NA * 12.20 Amorphous 66

* (2R, 4S) -Quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide

** Docusate Sodium

Example  2: PVP  or HPMCAS Stable Stability of Solid Dispersions Containing

Exemplary solid dispersions from Table 1 were subjected to accelerated stability conditions comprising 25 ° C./90% RH for two weeks and 40 ° C./75% RH for two weeks, the results are shown in Table 3. T _g was measured by mDSC. Further evaluation of the drug form in the dispersion was performed by microscopic measurement.

Lot polymer Drug ^* : Polymer DOSS ^** (%) shape T _g (℃) 25 ℃ / 60% T _g (℃) 40 ℃ / 75% T _g (℃) 25 ℃ / 90% Microscopic observation >2 weeks 2 weeks 2 weeks mDSC mDSC mDSC A003 PVP (K29 / 32) 1: 1 NA No birefringence 135 125 135 A004 PVP (K29 / 32) 3: 1 NA No birefringence 115 116 117 A007 PVP (K29 / 32) 1: 1 NA No birefringence 119 119 --- A008 NA AV608 NA No birefringence 94 92 94

* (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 Formulations

The dispersions described herein can be prepared and further formulated in oral formulations such as tablets or capsules. Alternatively, the solid dispersion can be first formulated into a formulation by coating onto lactose or an acceptable carrier and subsequently processed into capsules or tablets.

The composition of Table 4 was formulated as (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine- 4-yl] amides and selected polymers (PVP or HPMCAS) were prepared by eluting in a general organic solvent. The resulting solution was spray dried to obtain nano-sized solid dispersion particles having a diameter of approximately 50% or less. The solid dispersion was further processed into a tablet formulation by blending with some of the diluents, glidants, and glidants, which were densified by slugging and subsequently milled. Disintegrant and residual glidant were added to the ground granules and blended. Sliding granules were extruded into tablets. Tablets may also be coated with a functional or nonfunctional film coat.

Lot X608OCTA001 X608OCTA002 density 160 mg tablets 160 mg tablets ingredient (%) (%) (2R, 4S) -Quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide 24.7 25.0 Povidone (PVP) 24.7 0.0 HPMCAS 0.0 25.0 Docusate sodium 0.6 0.0 Croscarmellose sodium 7.5 5.0 Silicon dioxide 0.0 0.5 Sodium lauryl sulfate 1.0 0.5 Microcrystalline cellulose 40.0 21.25 Dicalcium Phosphate 0.0 21.25 Magnesium stearate 1.5 1.5 Sum 100 100

The GMP # 3 compositions of Table 5 were formulated as (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperi Din-4-yl] amide and docusate sodium were prepared by eluting in ethyl acetate. The resulting solution was spray dried to give (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine -4-yl] nano sized particles of amide and docusate sodium were obtained. Approximately 50% of the nano-sized particles have a diameter of about 0.8 μm or less. Nano-sized particles were then added to an aqueous solution of povidone and the suspension obtained was spray coated onto lactosprill. The dried, coated lactose prills were then dry blended with croscarmellose sodium, crospovidone, and sodium lauryl sulfate. Magnesium stearate was added to the mixture, blended and subsequently encapsulated.

In another exemplary formulation, X608PFCA003 was prepared in the same manner as GMP # 3, except that the PVP: drug suspension was layered on microcrystalline cellulose before encapsulation.

Lot GMP # 3 X608PFCA003 Unit capacity 160 mg tablets 160 mg tablets ingredient (%) (%) (2R, 4S) -Quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide 29.0 27.3 Docusate sodium 4.1 0.3 Sodium lauryl sulfate 2.3 0.5 Povidone (PVP) 9.2 7.7 Croscarmellose sodium 10.0 0.0 Lactose 37.9 0.0 Crospovidone 7.0 0.0 Microcrystalline cellulose 0.0 64.20 Magnesium stearate 0.5 0.0 Sum 100 100

Example  4: Severe Stability of Formulated Oral Formulations

Exemplary solid dispersions formulated with pharmaceuticals (Tables 4 and 5) were subjected to accelerated stability conditions comprising 25 ° C./90% RH for 2 weeks and 40 ° C./75% RH for 2, 5, 3 and 6 months. Treated with. Table 6 shows the T _g measured by mDSC for the two week time point analysis. Further evaluation of the drug form in the dispersion was performed by microscopic measurement.

Lot polymer Drug ^* : Polymer shape T _g (℃) 40 ℃ / 75% T _g (℃) 25 ℃ / 90% Microscopic observation 2 weeks 2 weeks mDSC mDSC X608OCTA001 PVP 1: 1 No birefringence 138 --- X608OCTA002 HPMCAS 1: 1 No birefringence 102 102 X608PFCA003 PVP 3.5: 1 No birefringence 94 93

* (2R, 4S) -Quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide

Tables 7, 8, and 9 show the properties, assays, associated substances, and elution results for Formulations X608OCTA001, X608OCTA002, and X608PFCA003, respectively, stored at 40 ° C./75% for various times. Assay and impurity results show that the chemical stability and elution results for the formulation (when significantly reduced from the beginning, are a suitable substitute for crystallization of the drug form) exhibit minimal changes.

Formulation X608OCTA001 Stored at 40 ° C./75% of Conditions exam Early 5 Weeks 3 months 6 months Constellation White White White (stained) light ash color black(%) 95.5 96.5 96.7 94.6 Total Associated Substance (%) <0.05 <0.05 <0.05 0.05 Elution (% release) 15 minutes 2 3 3 4 30 minutes 3 5 5 6 45 minutes 5 8 7 8 60 minutes 7 10 10 11 120 minutes 14 22 20 21

Formulation X608OCTA002 Stored at 40 ° C./75% of Conditions exam Early 5 Weeks 3 months 6 months Constellation White White White White black(%) 94.9 96.9 97.2 94.8 Total Associated Substance (%) <0.05 <0.05 <0.05 0.07 Elution (% release) 15 minutes 26 27 21 22 30 minutes 33 34 28 31 45 minutes 39 40 35 39 60 minutes 45 46 40 45 120 minutes 59 61 55 57

Formulation X608PFCA003 Stored at Conditions 40 ° C./75% exam Early 5 Weeks 3 months 6 months Constellation * * * * black(%) 95.3 100.2 99.6 101.7 Total Associated Substance (%) 0.05 <0.05 <0.05 0.05 Elution (% release) 15 minutes 17 16 14 13 30 minutes 26 25 27 25 45 minutes 36 36 36 36 60 minutes 43 49 44 45 120 minutes 71 79 73 76

* Free flowing pellets in off-white "00" HPMC capsules

Example  5: Improved Elution of Selective Solid Dispersions

An important disadvantage of the solid dispersion purification is its extremely long disintegration and dissolution time. This extended time can result in rate limited absorption in both humans and dogs. Since many water soluble polymers are also used as binders such as PVP, HPMC, HPC, etc., slow disintegration and dissolution time is expected. However, solid dispersion tablets comprising HPMCAS or solid dispersion multilayer pellets comprising PVP provide a substantial improvement in elution time as compared to solid dispersion tablets of PVP. This is evident when the elution times described in Tables 7-9 are tested for the formulations listed in Tables 4 and 5.

Example  6: of oral dosage formulation selected from dogs Bioavailability

Various formulations were tested in dogs. Results from dog studies allow us to predict exposure trends seen in human studies. Two active metabolites for bioavailability studies in dogs, (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- (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoro] including benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide Romethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amides are listed in Table 10. There appears to be even more AUC benefits for solid dispersions based on the formulation of the active ingredient (and two active metabolites) compared to non-dispersion formulations of the active drug component. Results are described from two separate dog studies separated by table division after the ninth row.

Formulation Capacity (mg / kg) AUC-Drugs and Metabolites (0-72 hr.ng/ml) 101 10 23,630 WG # 2 10 21,304 WG # 3 10 22,894 GMP # 3 10 72,380 101 80 92,390 WG # 2 80 86,870 WG # 3 80 77,950 GMP # 3 80 427,410 X608OCTA001 80 392,830 X608OCTA002 80 545,077 X608PFCA003 80 482,335 GMP # 3 80 524,774

The compositions of the last four formulations are already described in Tables 4 and 5. The compositions of the other three agents (ie '101', WG # 2 and WG # 3) are described in Table 11. Note that PVP in formulations WG # 2 and WG # 3 are mixed and do not exist as a dispersion.

Formulation 101 WG # 2 ^* WG # 3 ^* density 160 mg tablets 160 mg tablets 160 mg tablets ingredient (%) (%) (%) (2R, 4S) -Quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide 47.0 35.0 35.0 Povidone (PVP) 0.0 2.0 2.0 Crospovidone 0.0 6.9 6.9 Docusate sodium 0.0 4.9 4.9 Lactose Monohydrate 53.0 0 0 Sodium lauryl sulfate 0.0 2.3 2.3 Microcrystalline cellulose 0.0 38.6 38.6 Croscarmellose sodium 0.0 9.8 9.8 Magnesium stearate 0.0 0.5 0.5 Sum 100 100 100

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

Example  7: of oral dose formulation selected in humans Bioavailability

Several formulations have been tested in human clinical studies. Non-solid dispersion control group, (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) with GMP # 2 -Piperidin-4-yl] The composition of GMP # 3, an exemplary solid dispersion of amide and PVP, is 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) -piperidin-4-yl] amide, including (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2 A (UC) and C _max values of-(4-chlorobenzyl) -piperidin-4-yl] amide are also provided in Table 13. Parent molecule, (2R, 4S) -quinolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl ] AUC of amide, and 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) -piperidin-4-yl] amide was significant for the exemplary solid dispersion formulation, GMP # 3 compared to the control group formulation, AUC value for GMP # 2. Is higher. In addition, the parent molecule, (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidine-4 _-Yl ] C _max value of the amide, and 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-trifluoro methyl-benzoyl) -2- (4-chloro-benzyl) -piperidin-4-yl] -amide C _max value of the control group preparations, exemplary solid dispersion formulation, compared to the C _max value for GMP GMP # 2 Significantly higher for # 3.

Lot GMP # 2 GMP # 3 Unit capacity 160 mg capsule 160 mg capsule ingredient (%) (%) (2R, 4S) -Quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperidin-4-yl] amide 38.0 29.0 Docusate sodium 0.0 4.1 Sodium lauryl sulfate 2.5 2.3 Povidone (PVP) 0.0 9.2 Croscarmellose sodium 10.0 10.0 Lactose 42.0 37.9 Crospovidone 7.0 7.0 Magnesium stearate 0.5 0.0 Sum 100 100

Formulation GMP # 2 ^α GMP # 3 ^α AUC (0-24 hr.ng/ml) AUC (0-24 hr.ng/ml) ^β AUC (0-24 hr.ng/ml) ^β AV608 ^* 723.7 3340 AV609 ^** 3198 12467 AV810 ^*** 5439 171195 C _max (ng / ml) C _max (ng / ml) ^β C _max (ng / ml) ^β AV608 ^* 87.4 360.3 AV609 ^** 209.0 722.1 AV810 ^*** 343.9 955.6

* (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) -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

^α Two unit dose capsules of the compositions described in Table 11 were administered.

^β AUC and C _max values are obtained from daily dosing at 24 hours.

Those skilled in the art can recognize, or identify many equivalents to the specific embodiments of the invention described herein using only routine experimentation. Such equivalents are intended to be encompassed by the following claims:

Claims (54)

A solid dispersion comprising a compound of formula (I) and PVP, wherein the weight dispersion of the compound of formula (I) in the solid dispersion is at least about 50% by weight: Formula I

In the above formula, X is CH, N, or N-O; Y is CH, N, or N-O; Z is halogen; R is H or OH. The solid dispersion of claim 1, wherein the weight percent of the compound of formula I is at least about 70 weight percent. The compound of formula I according to claim 1, wherein the compound of formula I is (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -Piperidin-4-yl] solid dispersion. The compound of formula I according to claim 1, wherein the compound of formula I is (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl ) -Piperidin-4-yl] amide. The compound of formula I according to claim 1, wherein the compound of formula I is (2R, 4S) -quinoline-N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4 -Chlorobenzyl) -piperidin-4-yl] amide. The compound of claim 1, wherein the compound of formula I is selected from (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- ( 4-chlorobenzyl) -piperidin-4-yl] amide. The solid dispersion of claim 1, wherein the ratio of compound of formula I to PVP is about 1: 1 to about 5: 1. The solid dispersion of claim 7 wherein the ratio of compound of formula I to PVP is about 3.5: 1. The solid dispersion of claim 1, wherein the dispersion is substantially uniform. The solid dispersion of claim 1, wherein T _g is at least about 5 OK greater than 298 K at about 50% to about 90% relative humidity. The solid dispersion of claim 10, wherein T _g is at least about 5 OK greater than 298 K at about 60% to about 75% relative humidity. The solid dispersion of claim 1, wherein the dispersion has a single T _g . The solid dispersion of claim 1, wherein the dispersion comprises one or more non-uniform regions rich in 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 of claim 1, further comprising a surfactant. The solid dispersion of claim 18, wherein the surfactant is present in the dispersion in an amount from about 0.1% to about 20% by weight. The solid dispersion of claim 18, wherein the surfactant is selected from sodium lauryl sulfate and docusate sodium. The method of claim 1, wherein the dispersion is (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -piperi Din-4-yl] solid dispersion substantially free of the active metabolite of the amide. The solid dispersion of claim 1, wherein the AUC of the compound of formula I is at least about 1.25 times the AUC of the compound of formula I in a non-dispersed formulation when administered to a subject. The solid dispersion of claim 22, wherein the AUC of the compound of formula I is at least about three times the AUC of the compound of formula I in a non-dispersed formulation when administered to a subject. Particles coated with a compound of formula (I) and a polymer Formula I

In the above formula, X is CH, N, or N-O; Y is CH, N, or N-O; Z is halogen; R is H or OH. The particle of claim 24, wherein the particle is a non-pariel, lactose prill, microcrystalline cellulose, or starch. The compound of claim 24, wherein the compound of formula I is (2R, 4S) -quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl) -Piperidin-4-yl] solid dispersion. The compound of claim 24, wherein the compound of formula I is (2R, 4S) -quinazolin-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chlorobenzyl ) -Piperidin-4-yl] amide. The compound of claim 24, wherein the compound of formula I is (2R, 4S) -quinazolin N-oxide-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4 -Chlorobenzyl) -piperidin-4-yl] amide. The compound of claim 24, wherein the compound of formula I is selected from (2R, 4S) -2-hydroxy-quinoline-4-carboxylic acid [1- (3,5-bis-trifluoromethyl-benzoyl) -2- ( 4-chlorobenzyl) -piperidin-4-yl] amide. The particle of claim 24, wherein at least a portion of the compound of formula I is dispersed in a polymer. The particle of claim 30, wherein substantially all of the compound of formula I is dispersed in a polymer. The particle of claim 30, wherein the dispersion is substantially uniform. The particle of claim 30, wherein the T _g of the dispersion is at least about 5 OK greater than 298 K at about 60% to about 75% relative humidity. The particle of claim 30, wherein the dispersion has a single T _g . The particle of claim 30, wherein the dispersion comprises one or more non-uniform regions rich in compound of formula (I). The particle of claim 24, wherein at least about 50% of the compound of formula I is amorphous. The particle of claim 36, wherein at least a portion of the compound of formula I is dispersed in the polymer. The particle of claim 37, wherein substantially all 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 amorphous. The particle of claim 30, wherein the PVP is K29 / 32. The particle of claim 40, wherein the PVP has a molecular weight of about 30,000 to about 100,000 Daltons. 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. The particle of claim 42, wherein the surfactant is present in the dispersion in an amount from about 0.1% to about 20%. The particle of claim 30, wherein the AUC of the compound of formula I is at least about 1.25 times the AUC of the compound of formula I in a non-dispersed formulation when administered to a subject. The particle of claim 45, wherein the AUC of the compound of formula I is at least about three times the AUC of the compound of formula I in a non-dispersed formulation when administered to a subject. The particle of claim 30, wherein the polymer is PVP and the ratio of compound of formula I to PVP in the dispersion is about 1: 5 to about 5: 1. The particle of claim 30, wherein the polymer is PVP and the ratio of compound of formula I to PVP in the dispersion is about 3.5: 1. 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%. 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%. The particle of claim 30, wherein the compound of formula I is substantially amorphous and remains substantially amorphous for at least two weeks at 40 ° C./75% relative humidity. The particle of claim 30, wherein the compound of formula I has an accelerated elution profile at 30 minutes or more compared to the dissolution profile of the same dispersion of the compound of formula I, and the dispersion is formulated into a tablet. The particle of claim 52, wherein the compound of formula I has an accelerated elution profile at 60 minutes or more than three times relative to the elution profile of the same dispersion of the compound of formula I, and the dispersion is formulated into a tablet. The particle of claim 53, wherein the compound of Formula I has an accelerated elution profile at 120 minutes or more than the elution profile of the same dispersion of the compound of Formula I, and the dispersion is formulated into a tablet.