CN101668527A

CN101668527A - Pharmaceutical preparation

Info

Publication number: CN101668527A
Application number: CN200880013347A
Authority: CN
Inventors: 克里斯托弗·J·凯默勒; 丹尼斯·查普曼; 杰夫·F·麦凯尔维; 乔·O·西弗特; 理查德·约翰逊
Original assignee: Avera Pharmaceuticals Inc
Current assignee: Avera Pharmaceuticals Inc
Priority date: 2007-02-23
Filing date: 2008-02-22
Publication date: 2010-03-10
Also published as: WO2008103914A1; CA2679028A1; JP2010519312A; KR20090118982A; EP2124949A1; AU2008218248A1

Abstract

Describe the dispersion of formula I chemical compound and polymer such as HPMCAS and/or PVP, comprised the compositions that comprises this dispersion, prepared the method for this dispersion and the method for this dispersion of use.

Description

Pharmaceutical preparation

Prioity claim

The application requires the priority of the U.S. Provisional Application submitted on February 23rd, 2007 number 60/891,272, and its whole contents is hereby incorporated by.

Technical field

The present invention relates to (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide; or its active metabolite; or (2R; 4S)-dosage form (form) and the preparation of quinazoline-4-carboxylic acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide and use their method.

Background technology

Water-insoluble drug is used for solid dosage forms for oral administration (dosage form) in exploitation formulation science man is had many problems.The dissolubility of chemical compound, dissolution and permeability all influence bioavailability of medicament.In preparation, mix some excipient improving permeability although studied, consequently uncertain and be not widely accepted means as the bioavailability of improving the water-insoluble drug material standed for.The micronization of medicine is the technique platform of having set up, and it improves dissolution by the minimizing of particle diameter and the corresponding increase of surface area, thereby may improve bioavailability.Processing and physical stability, for example overflocculation or reunion is the problem that the micronization platform exists.Other technology is as having limitation usually with cyclodextrin and lipid-based formulation are compound, and it reduces drug loading.The solid dispersion that is scattered in the not soluble drug in the polymer support provides the means of improving oral administration biaavailability.This medicine is usually with its amorphous existence, and if disperse with molecular level, then particle diameter is reduced to the limit and improve dissolution and dissolubility, promptly surface area is maximum and need not to overcome the crystal accumulation energy.Exist certain methods to be used to produce solid dispersion, comprise that spray drying and heat fusing extrude, all have some manufacturing issues.Some problems in using solid dispersion transporting water insoluble drugs material standed for are to be difficult to solid dispersion is processed into the suitable drug products drug products required suitable physical stability relevant with amorphous drug with shortage, and the physical stability of this requirement is for to be at least 2 years in room temperature and indoor humidity.Other solid dispersion that therefore, need have the water-insoluble drug of the physical stability of improvement and processability.

The invention summary

The applicant has been found that some solid form; for example; (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite, (2R, 4S)-solid dispersion of quinazoline-4-carboxylic acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide provides ideal character; comprise dissolubility, bioavailability and stability (for example, physics and chemical stability).

On the one hand; the solid dispersion that comprises formula I chemical compound and HPMCAS that is characterized as of the present invention; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; this active metabolite is (2R; 4S)-quinoline-[1-(3 for N-oxidation-4-carboxylic acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or (2R; 4S)-2-hydroxyl-Cinchonic Acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; the ratio of formula I chemical compound and HPMCAS is about 1: 5 to about 5: 1; for example; about 1: 3 to about 3: 1; the ratio of example comprises about 1: 1 or about 3: 1; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments, this dispersion is uniform substantially.In some embodiments, this dispersion has single T _gIn some embodiments, this dispersion keeps single T under 25 ℃, 60% relative humidity _gAt least 2 weeks.In some embodiments, this dispersion keeps single T under 40 ℃, 75% relative humidity _gAt least 2 weeks.In some embodiments, this dispersion keeps single T under 25 ℃, 90% relative humidity _gAt least 2 weeks.

In some embodiments, about 50% to about 90% relative humidity this T _gHigher than 25 ℃ at least about 50K.In some embodiments, about 60% to about 75% relative humidity this T _gHigher than 25 ℃ at least about 50K.In some embodiments, at 25 ℃, this T during 60% relative humidity _gBe about 98 ℃ to about 102 ℃.

In some embodiments; this dispersion comprises at least one non-homogeneous zone of being rich in formula I chemical compound; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments, this dispersion comprise at least one be rich in (2R, 4S)-the non-homogeneous zone of Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; formula I chemical compound at least about 50% in solid dispersion is unbodied; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite; or (2R; 4S)-[1-(3 for quinazoline-4-carboxylic acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide; for example; formula I chemical compound at least about 75% in solid dispersion is unbodied; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite; or (2R; 4S)-[1-(3 for quinazoline-4-carboxylic acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide; or in the solid dispersion basically all formula I chemical compounds be unbodied; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite; or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments, this HPMCAS for example, dissolves in pH 〉=6.0 in pH 〉=5.5 dissolvings, or in pH 〉=6.5 dissolvings.In some embodiments, this HPMCAS is HPMCAS-LF.

In some embodiments, this dispersion also comprises surfactant.In some embodiments, this surfactant is an anion surfactant.In some embodiments, the amount that described surfactant exists in dispersion is about 0.1% to about 20%, for example, and about 1% to about 10%.In some embodiments, this surfactant is selected from sodium lauryl sulfate and docusate sodium.

In some embodiments, this dispersion also comprises the kinds of surface activating agent.

In some embodiments, this dispersion comprises other polymer, for example, and water-soluble polymer such as PVP.In some embodiments, the ratio of HPMCAS and PVP is about 5: 1 to about 1: 5, for example about 3: 1 to 1: 3, or 1: 1.

In some embodiments, this dispersion comprise (2R, 4S)-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments, this dispersion do not go up substantially and contain (2R, 4S)-active metabolite of Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; (this formula I chemical compound is preferably (2R when giving experimenter's up-to-date style I chemical compound; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite; or (2R; 4S)-[1-(3 for quinazoline-4-carboxylic acid; 5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide) AUC for (this formula I chemical compound is preferably (2R at not dispersive preparation Chinese style I chemical compound; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite; or (2R; 4S)-[1-(3 for quinazoline-4-carboxylic acid; 5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide) AUC 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; formula I chemical compound is gone up substantially to unbodied and keep under 40 ℃/75% relative humidity essentially amorphous 2 weeks that reached; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.In some embodiments; formula I chemical compound is gone up substantially to unbodied and keep under 25 ℃/90% relative humidity essentially amorphous 2 weeks that reached; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

On the one hand; the solid dispersion that comprises formula I chemical compound and PVP that is characterized as of the present invention; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite; or (2R; 4S)-[1-(3 for quinazoline-4-carboxylic acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide; wherein the percentage by weight of solid dispersion Chinese style I chemical compound is at least about 50% weight; for example at least about 55% weight; 60% weight, 65% weight, 70% weight; 75% weight; 80% weight, 85% weight or 90% weight, this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite; or (2R, 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; formula I chemical compound, preferred (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] ratio of amide and PVP is about 1: 1 to about 5: 1; for example; about 2: 1 to about 4: 1, the ratio of example comprised about 1: 1 or about 3.5: 1.

In some embodiments, this dispersion is uniform substantially.

In some embodiments, about 50% to about 90% relative humidity this T _gThan 25 ℃ high at least about 50K, for example, about 60% to about 75% relative humidity this T _gHigher than 25 ℃ at least about 50K.

In some embodiments, this T _gUnder 25 ℃ and 60% relative humidity, be at least about 100 ℃, for example, this T _gBe about 115 ℃ to about 155 ℃.

In some embodiments, this dispersion has single T _gIn some embodiments, this dispersion keeps single T under 25 ℃, 60% relative humidity _gAt least 2 weeks.In some embodiments, this dispersion keeps single T under 40 ℃, 75% relative humidity _gAt least 2 weeks.In some embodiments, this dispersion keeps single T under 25 ℃, 90% relative humidity _gAt least 2 weeks.

In some embodiments; formula I chemical compound at least about 50% in the solid dispersion is unbodied; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite; or (2R; 4S)-[1-(3 for quinazoline-4-carboxylic acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide; for example; formula I chemical compound at least about 75% in the solid dispersion is unbodied; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite; or (2R; 4S)-[1-(3 for quinazoline-4-carboxylic acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide; or in the solid dispersion basically all formula I chemical compounds be unbodied; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite; or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments, described PVP is K29/32.In some embodiments, the molecular weight of described PVP is about 30,000 to about 100,000 dalton.

In some embodiments, this dispersion also comprises surfactant, for example, anion surfactant.In some embodiments, the amount that described surfactant exists in dispersion is about 0.1% to about 20% weight, and for example, about 1% to about 10% weight.In some embodiments, this surfactant is selected from sodium lauryl sulfate and docusate sodium.In some embodiments, this dispersion comprises the kinds of surface activating agent.

In some embodiments, this dispersion also comprises other polymer, for example, and water-soluble polymer such as HPMCAS.

In some embodiments; when giving the experimenter; (this formula I chemical compound is preferably (2R to formula I chemical compound; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite; or (2R; 4S)-[1-(3 for quinazoline-4-carboxylic acid; 5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide) AUC (this formula I chemical compound is preferably (2R for the formula I chemical compound in the not dispersive preparation; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite; or (2R; 4S)-[1-(3 for quinazoline-4-carboxylic acid; 5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide) AUC 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; formula I chemical compound is gone up substantially to unbodied and keep essentially amorphous 2 weeks that reached at 40 ℃/75% relative humidity; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.In some embodiments; formula I chemical compound is gone up substantially to unbodied and keep essentially amorphous 2 weeks that reached at 25 ℃/90% relative humidity; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

On the one hand; the solid dispersion that is characterized as formula I chemical compound and polymer of the present invention; this formula I chemical compound is preferably (2R; 4S)-quinoline-[1-(3 for N-oxidation-4-carboxylic acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or (2R; 4S)-2-hydroxyl-Cinchonic Acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments, this dispersion comprise (2R, 4S)-quinoline-N-oxidation-4-carboxylic acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.In some embodiments, this dispersion comprise (2R, 4S)-2-hydroxyl-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments, this polymer is a water-soluble polymer, for example, and HPMCAS or PVP.

In some embodiments, this dispersion is uniform substantially.

In some embodiments, about 50% to about 90% relative humidity this T _gHigher than 25 ℃ at least about 50K.In some embodiments, about 60% to about 75% relative humidity this T _gHigher than 25 ℃ at least about 50K.

In some embodiments, this dispersion comprise at least one be rich in (2R, 4S)-the non-homogeneous zone of quinoline-N-oxidation-4-carboxylic acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.In some embodiments, this dispersion comprise at least one be rich in (2R, 4S)-the non-homogeneous zone of 2-hydroxyl-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; in the solid dispersion at least about 50% (2R; 4S)-quinoline-[1-(3 for N-oxidation-4-carboxylic acid; 5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide is unbodied; for example; in the solid dispersion 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 basically all (2R, 4S)-quinoline-N-oxidation-4-carboxylic acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide is unbodied.

In some embodiments; in the solid dispersion at least about 50% (2R; 4S)-[1-(3 for 2-hydroxyl-Cinchonic Acid; 5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide is unbodied; for example; in the solid dispersion 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 basically all (2R, 4S)-2-hydroxyl-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide is unbodied.

In some embodiments, this dispersion also comprises surfactant, for example, anion surfactant such as sodium lauryl sulfate or docusate sodium (docusate sodium).In some embodiments, the amount that described surfactant exists in dispersion is about 0.1% to about 20%, for example, and about 1% to about 10%.

In some embodiments, this dispersion comprises the kinds of surface activating agent.

In some embodiments, this dispersion also comprises other polymer, for example, and water-soluble polymer.

In some embodiments; (2R when giving the experimenter; 4S)-quinoline-[1-(3 for N-oxidation-4-carboxylic acid; 5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] AUC of amide is the (2R in the not dispersive preparation; 4S)-quinoline-[1-(3 for N-oxidation-4-carboxylic acid; 5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide AUC 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 when giving the experimenter; 4S)-[1-(3 for 2-hydroxyl-Cinchonic Acid; 5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] AUC of amide is (2R in the not dispersive preparation; 4S)-[1-(3 for 2-hydroxyl-Cinchonic Acid; 5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide AUC 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; be somebody's turn to do (2R; 4S)-quinoline-N-oxidation-4-carboxylic acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide is essentially unbodied and keeps essentially amorphous 2 weeks that reached at 40 ℃/75% relative humidity.In some embodiments; be somebody's turn to do (2R; 4S)-2-hydroxyl-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide is essentially unbodied and keeps essentially amorphous 2 weeks that reached at 40 ℃/75% relative humidity.

On the one hand, the solid dosage forms that is characterized as dispersion as herein described (for example dispersion of formula I chemical compound) of the present invention.

On the one hand; the granule that is characterized as with formula I chemical compound and polymer coating (coat) of the present invention; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments, this granule is sucrose granules (non-pariel), lactose granule (lactoseprill), microcrystalline Cellulose or starch.

In some embodiments, this active metabolite be (2R, 4S)-quinoline-N-oxidation-4-carboxylic acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.In some embodiments, this active metabolite be (2R, 4S)-2-hydroxyl-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; at least segment bounds I chemical compound is scattered in the polymer; this formula I chemical compound be preferably (2R, 4S)-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite.In some embodiments, this dispersion is uniform substantially.In some embodiments, the T of dispersion _gAbout 60% to about 75% relative humidity than room temperature height at least about 40K.In some embodiments, the T of dispersion _gBe about 65 ℃ to about 155 ℃.In some embodiments, this dispersion has single T _gIn some embodiments; formula I chemical compound is gone up substantially to unbodied; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite, and this dispersion has single T under 25 ℃ of 60% relative humidity _gReach at least 15 months.In some embodiments; this dispersion comprises at least one non-homogeneous zone of being rich in formula I chemical compound; preferred (the 2R of this formula I chemical compound; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.In some embodiments, this dispersion comprise at least one be rich in (2R, 4S)-the non-homogeneous zone of Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.In some embodiments; formula I chemical compound at least about 50% in the dispersion is unbodied; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite; or (2R; 4S)-[1-(3 for quinazoline-4-carboxylic acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide; for example, in the dispersion 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 basically all formula I chemical compounds be unbodied, this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite; or (2R, 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.In some embodiments, this dispersion also comprises surfactant, for example, anion surfactant such as sodium lauryl sulfate and docusate sodium.In some embodiments, the amount that described surfactant exists in dispersion is about 0.1% to about 20%, for example, and about 1% to about 10%.In some embodiments, this dispersion comprises the kinds of surface activating agent.

In some embodiments; (this formula I chemical compound is preferably (2R when giving experimenter's up-to-date style I chemical compound; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite; or (2R; 4S)-[1-(3 for quinazoline-4-carboxylic acid; 5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide) AUC (this formula I chemical compound is preferably (2R for not dispersive preparation Chinese style I chemical compound; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite; or (2R; 4S)-[1-(3 for quinazoline-4-carboxylic acid; 5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide) AUC 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, this polymer is a water-soluble polymer.

In some embodiments, this polymer is HPMCAS.In some embodiments, the ratio of dispersion Chinese style I chemical compound and HPMCAS is about 1: 5 to about 5: 1, for example, and about 1: 3 to about 3: 1; The ratio of example comprises about 1: 1, or about 3: 1, this formula I chemical compound be preferably (2R, 4S)-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite.In some embodiments, this HPMCAS for example, dissolves in pH 〉=6.0 dissolvings or in pH 〉=6.5 in pH 〉=5.5 dissolvings.In some embodiments, this HPMCAS is HPMCAS-LF.

In some embodiments, this granule further by other polymer, as the water-soluble polymer coating.

In some embodiments, described polymer is PVP.In some embodiments, the ratio of dispersion Chinese style I chemical compound and PVP is about 1: 5 to about 5: 1, for example, and about 1: 3 to about 3: 1; The ratio of example comprises about 1: 1 or about 3: 1; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.In some embodiments; the percentage by weight of solid dispersion Chinese style I chemical compound is at least about 50%; for example; at least about 55%; at least about 60%; at least about 65%; at least about 70% or at least about 75%; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R, 4S)-quinazoline-4-carboxylic acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.In some embodiments, the ratio of formula I chemical compound and PVP is about 1: 1 to about 5: 1, for example, and about 2: 1 to about 4: 1; The ratio of example comprises about 1: 1 or about 3.5: 1, this formula I chemical compound be preferably (2R, 4S)-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.In some embodiments, described PVP is K29/32.

In some embodiments, described granule comprise (2R, 4S)-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments, described granule be substantially free of (2R, 4S)-active metabolite of Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

On the one hand, the solid dosage forms that comprises granule as herein described dispersion as herein described that is characterized as of the present invention.

In some embodiments, described preparation further comprises one or more excipient, diluent, binding agent, disintegrating agent, fluidizer, lubricant and/or surfactant.

In some embodiments, described dosage form is a tablet.In some embodiments, described dosage form is a capsule.

In some embodiments, described dosage form also comprises coating, for example, and enteric polymer such as cellulosic polymer.

In some embodiments, solid dosage forms comprises about 20mg formula I chemical compound, this formula I chemical compound be preferably (2R, 4S)-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.In some embodiments, solid dosage forms comprises about 40mg formula I chemical compound, this formula I chemical compound be preferably (2R, 4S)-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.In some embodiments, solid dosage forms comprises about 160mg formula I chemical compound, this formula I chemical compound be preferably (2R, 4S)-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.In some embodiments, solid dosage forms comprises about 320mg formula I chemical compound, this formula I chemical compound be preferably (2R, 4S)-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments, solid dosage forms comprises

(2R, 4S)-Cinchonic Acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide;

PVP；

DOSS；

Microcrystalline Cellulose;

Cross-linked carboxymethyl cellulose;

SLS; With

Magnesium stearate.

In some embodiments, should (2R, 4S)-Cinchonic Acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide and PVP formation solid dispersion.

In some embodiments, solid dosage forms comprises

About 20 to about 30% weight (2R, 4S)-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide;

About 20 PVP to about 30% weight;

About 0.2 DOSS to about 1.0% weight;

About 30 microcrystalline Cellulose to about 50% weight;

About 5 cross-linked carboxymethyl cellulose to about 10% weight;

About 0.5 SLS to about 3% weight; With

About 1 magnesium stearate to about 2% weight.

In some embodiments, solid dosage forms comprises

About 25% weight (2R, 4S)-Cinchonic Acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide;

The PVP of about 25% weight;

The DOSS of about 0.6% weight;

The microcrystalline Cellulose of about 40% weight;

The cross-linked carboxymethyl cellulose of about 7.5% weight;

The SLS of about 1% weight; With

The magnesium stearate of about 1.5% weight.

In some embodiments, solid dosage forms comprises

HPMCAS；

Microcrystalline Cellulose;

Dicalcium phosphate

Cross-linked carboxymethyl cellulose;

SLS；

Silicon dioxide; With

Magnesium stearate.

In some embodiments, should (2R, 4S)-Cinchonic Acid's [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide and

HPMCAS forms solid dispersion.

In some embodiments, solid dosage forms comprises

About 20 HPMCAS to about 30% weight;

About 15 microcrystalline Cellulose to about 25% weight;

About 15 dicalcium phosphates to about 25% weight

About 2 cross-linked carboxymethyl cellulose to about 8% weight;

About 0.2 SLS to about 0.8% weight;

About 0.2 silicon dioxide to about 0.8% weight; With

About 1 magnesium stearate to about 2% weight.

In some embodiments, solid dosage forms comprises

The HPMCAS of about 25% weight;

The microcrystalline Cellulose of about 21% weight;

The dicalcium phosphate of about 21% weight

The cross-linked carboxymethyl cellulose of about 5% weight;

The SLS of about 0.5% weight;

The silicon dioxide of about 0.5% weight; With

The magnesium stearate of about 1.5% weight.

In some embodiments, solid dosage forms comprises

PVP；

DOSS；

Microcrystalline Cellulose; With

SLS。

In some embodiments, should (2R, 4S)-Cinchonic Acid's [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide and PVP coating be on microcrystalline Cellulose.

In some embodiments, solid dosage forms comprises

About 20% to about 30% weight (2R, 4S)-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide;

About 7% PVP to about 10% weight;

About 0.1% DOSS to about 0.5% weight;

About 60% microcrystalline Cellulose to about 70% weight; With

About 0.2% SLS to about 0.8% weight.

In some embodiments, solid dosage forms comprises

About 27% weight (2R, 4S)-Cinchonic Acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide;

The PVP of about 8% weight;

The DOSS of about 0.3% weight;

The microcrystalline Cellulose of about 64% weight; With

The SLS of about 0.5% weight.

In some embodiments, solid dosage forms comprises

DOSS；

SLS；

PVP；

Cross-linked carboxymethyl cellulose;

Lactose;

Crospolyvinylpyrrolidone; With

Magnesium stearate.

In some embodiments, and wherein (2R, 4S)-Cinchonic Acid's [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide and PVP coating be on lactose.

In some embodiments, and wherein (2R, 4S)-Cinchonic Acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide and PVP formation solid dispersion.

In some embodiments, solid dosage forms comprises

About 25% to about 35% weight (2R, 4S)-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide;

About 3% DOSS to about 5% weight;

About 1% SLS to about 3% weight;

About 7% PVP to about 11% weight;

About 8% cross-linked carboxymethyl cellulose to about 12% weight;

About 25% lactose to about 45% weight;

About 5% crospolyvinylpyrrolidone to about 9% weight; With

About 0.2% magnesium stearate to about 0.8% weight.

In some embodiments, solid dosage forms comprises

About 29% weight (2R, 4S)-Cinchonic Acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide;

The DOSS of about 4% weight;

The SLS of about 2% weight;

The PVP of about 9% weight;

The cross-linked carboxymethyl cellulose of about 10% weight;

The lactose of about 38% weight;

The crospolyvinylpyrrolidone of about 7% weight; With

The magnesium stearate of about 0.5% weight.

On the one hand; the method that is characterized as the carrier of system standby mode I chemical compound coating of the present invention; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-and quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide, this method comprises

The granule that comprises formula I chemical compound is provided; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide

This granule is suspended in the aqueous solution that comprises water-soluble polymer; With

With this particle spray coating on carrier so that the carrier with formula I chemical compound and water-soluble polymer coating to be provided; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments, formula I chemical compound is gone up substantially to unbodied, this formula I chemical compound be preferably (2R, 4S)-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments, this solvent is a methanol.

In some embodiments, this water-soluble polymer is PVP.In some embodiments, this water-soluble polymer is HPMCAS.

In some embodiments, this carrier comprises lactose granule.In some embodiments, this carrier comprises microcrystalline Cellulose.

On the one hand; of the present invention being characterized as prepares the particulate method that comprises formula I chemical compound; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-and quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide, this method comprises

(this formula I chemical compound is preferably (2R with formula I chemical compound, 4S)-[1-(3 for the Cinchonic Acid, 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite, or (2R, 4S)-[1-(3 for quinazoline-4-carboxylic acid, 5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide) be dissolved in that (this formula I chemical compound is preferably (2R so that formula I chemical compound to be provided in solvent and the polymer, 4S)-[1-(3 for the Cinchonic Acid, 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite, or (2R, 4S)-quinazoline-4-carboxylic acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide) and the solution of polymer;

This solution of spray drying is to provide the dispersion that comprises formula I chemical compound and polymer; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

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

In some embodiments; the solvent of dissolution type I chemical compound and polymer is selected from ethyl acetate, methanol, acetone and ethanol; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; the solvent of dissolution type I chemical compound and polymer is methanol or ethanol; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; the solvent of dissolution type I chemical compound and polymer is an ORGANIC SOLVENT MIXTURES; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments, the particulate bulk density of gained (bulk density) is that about 0.20g/ml is to about 0.30g/ml.

In some embodiments, the particulate D of gained ₅₀Less than about 1 μ m.

In some embodiments, the T of spray dryer _OutletBe about 70 ℃ to about 150 ℃.

In some embodiments; formula I chemical compound and the polymer solid supported amount in solution is about 1% to about 20% weight; for example; about 5% weight; this formula I chemical compound be preferably (2R, 4S)-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

On the one hand, the method that is characterized as treatment NK-1 relevant disease of the present invention, this method comprises to experimenter's administration granule as herein described or dispersion.

In some embodiments; the experimenter that formula I chemical compound is given to have taken food; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; of the present invention being characterized as gives the experimenter that do not have feed or two hours after administration not to take food in preceding 1 hour in administration at least with formula I chemical compound; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; with formula I chemical compound give administration taken food in preceding 60 minutes or administration after in 120 minutes with the experimenter of feed; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; this method comprises that administration comprises the dosage of about 1 to about 1000mg formula I chemical compound; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; this method comprises that administration comprises the dosage of about 40mg formula I chemical compound; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; this method comprises that administration comprises the dosage of about 320mg formula I chemical compound; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; formula I chemical compound is administered once every day; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; formula I chemical compound is administered twice every day; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; formula I chemical compound is administered three times every day; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; formula I chemical compound is with other therapeutic agent administration; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; formula I chemical compound and other therapeutic agent are with combination dosage forms (combineddosage form) administration; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; formula I chemical compound oral administration; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

In some embodiments; formula I chemical compound topical; this formula I chemical compound is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

The amorphous form of medicine is compared crystal form can have different character.For improving the stability of amorphous solid (it is more unstable than crystal form usually), can use polymer or polymeric blends to form unbodied solid dispersion system with medicine.In some embodiments, can prepare " solid solution " (its system) or solid dispersion, wherein be limited or slow down at the significant recrystallization of (for example, 2 years) interior medicine for a long time of pharmacy at ambient temperature for not being separated in time.

(be preferably (2R with respect to the not dispersive formula I chemical compound of administration; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide); for example; crystalline formula I chemical compound (is preferably (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide); oral administration formula I chemical compound (is preferably (2R; 4S)-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide) solid dispersion the bioavailability of improvement can be provided.In some embodiments, these solid dispersion are solid-state and can conveniently store and administration.The manufacturing of solid dispersion can be undertaken by selecting organic solvent or solvent mixture (for example, methanol, acetone etc.) and successfully amplify.In some embodiments, solid dispersion can have the chemistry and the physical stability of improvement.For example, in some cases this solid dispersion can conventional condition of storage (room temperature) chemistry and/or physically stable reach at least 1 year, for example, at least 15 months, 18 months, 2 years or longer.

The details of one or more embodiments of the present invention is set forth in the following description.Other features, objects and advantages of the invention will be tangible according to description and claim.

Detailed Description Of The Invention

The present invention finds that multiple factor and composition are important to the stability and the bioavailability of pharmaceutical composition, especially comprise the preparation of the solid dispersion of water-insoluble drug.Therefore the invention provides the method for preparation and these preparations of preparation of solid dispersion.

Formula I chemical compound

The solid dispersion of this paper comprises formula I chemical compound or acceptable salt of its pharmacy or solvate.

Wherein X is CH, N or N-O; Y is CH, N or N-O; Z is a halogen, preferred chlorine; And R is H or OH.In some preferred embodiments, X be CH or N (for example, CH); Y is that N or N-O and R are H.In some preferred embodiments, X is CH, N; Y is CH, N or N-O; Z is a halogen; Preferred chlorine and R OH.Formula I comprises the chemical compound that can form in vivo by metabolic pathway, and it is also included within herein the composition as solid dispersion as herein described.Exemplary active metabolite comprises (2R; 4S)-quinoline-[1-(3 for N-oxidation-4-carboxylic acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide and (2R; 4S)-2-hydroxyl-Cinchonic Acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

Preferred formula I chemical compound comprises following: (2R, 4S)-Cinchonic Acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide; (2R, 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide; (2R, 4S)-quinoline-N-oxidation-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide; (2R, 4S)-quinoline-N-oxidation-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide; Or (2R, 4S)-2-hydroxyl-Cinchonic Acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its salt or solvate.Have following formula (2R, 4S)-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide:

Embodiment for highly preferred formula I chemical compound.

Chemical compound as herein described comprises its various solid forms, comprises its polymorphic forms, solvate and salt.Chemical compound as herein described also can comprise its tautomeric form.

The dispersion of formula I chemical compound

This paper has described and has comprised formula I chemical compound or its active metabolite, and polymer, as the dispersion of water-soluble polymer.Preferred polymers comprises HPMCAS and PVP.

As described herein, " dispersion " is meant dispersion, wherein a kind of material, and decentralized photo distributes with discrete unit, spreads all over second kind of material (continuous phase or carrier).The size of the discrete unit of decentralized photo can obviously change (for example nano-scale to the single molecule of several micron-scales to colloidal solid).Usually, this decentralized photo can be solid, liquid or gas.Under the situation of solid dispersion, this decentralized photo and continuous phase all are solid.In medicinal application, solid dispersion can be included in the crystalline drug (decentralized photo) in the amorphous polymer (continuous phase), perhaps the amorphous drug (decentralized photo) in amorphous polymer (continuous phase).In some embodiments, unbodied solid dispersion comprises polymer that constitutes decentralized photo and the medicine that constitutes continuous phase.

Term " unbodied solid dispersion " is often referred to the solid dispersion of two or more compositions, be generally the solid dispersion of medicine and polymer or combination of polymers, but can comprise other composition such as surfactant or other medicines excipient, its Chinese medicine be amorphous phase (for example, wherein all medicines are amorphous phase basically), and the physical stability of amorphous drug and/or dissolution and/or dissolubility become branch to strengthen by other.

The exemplary solid dispersion be (2R, 4S)-coprecipitate or the eutectic of Cinchonic Acid's [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide and HPMCAS or PVP." coprecipitate " product for obtaining after medicine and polymer dissolution are removed in solvent or solvent mixture and with solvent or solvent mixture.Sometimes this polymer can be suspended in solvent or the solvent mixture.This solvent or solvent mixture comprise organic solvent and supercritical fluid (supercritical fluids).In some cases, this solid dispersion mixes then and removes solvent and prepare by adding drug solution and solid polymer.For removing solvent, can apply vacuum drying, spray drying, tray drying, lyophilizing and other drying means.According to the present invention; use suitable machined parameters to apply any of these methods; with be provided at amorphous state in the final solid dispersion product (2R, 4S)-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

The dispersion that comprises HPMCAS and/or PVP

Solid dispersion can have any form that is suitable for medicinal usage.For example, this solid dispersion can be powder type, or the coating on substrate (for example, this solid dispersion can be sprayed on granule such as lactose or the microcrystalline Cellulose).

The character of the scale effect solid dispersion of polymer and formula I chemical compound.For example, if polymer is relative high with the ratio of formula I chemical compound, formula I chemical compound will be easy to form molecular dispersoid or have the dispersion in very little water-insoluble drug (its be scattered in water-soluble polymer mutually in) zone (domains).Yet if the ratio of polymer and formula I chemical compound is higher, the concentration of water-insoluble drug in solid dispersion can reduce, thereby needs a large amount of solid dispersion in comprising the pharmaceutical composition of solid dispersion.In addition, the formula I chemical compound of low concentration can reduce the absorbance of formula I chemical compound in the patient.

If polymer is relative low with the ratio of formula I chemical compound, formula I chemical compound will be easy to form the dispersion in the zone of formula I chemical compound in polymer phase, rather than the molecular dispersoid of formula I chemical compound in polymer.Yet if the ratio of polymer and formula I chemical compound is too low, the dispersive zone of this formula I chemical compound can be very big, makes at the dissolution of patient's Chinese medicine and absorb and will reduce, thereby reduce the bioavailability of formula I chemical compound.The proper ratio of polymer and formula I chemical compound will depend on the purposes of chemical compound, polymer, expection.

The exemplary solid dispersion comprises formula I chemical compound; as (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite or (2R; 4S)-quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide and HPMCAS.

The amount of the relative HPMCAS of formula I chemical compound can change.For example, this dispersion can be mainly formula I chemical compound, is mainly HPMCAS, or the relative impartial balance with HPMCAS of formula I chemical compound.The ratio that can change formula I chemical compound and polymer is to change the feature of solid dispersion.For example, in some embodiments, preferably have a certain proportion of formula I chemical compound and polymer so that uniform dispersion to be provided, and in some embodiments, have a certain proportion of formula I chemical compound and polymer so that the zone of being rich in formula I chemical compound to be provided.Exemplary formula I chemical compound and the ratio of HPMCAS comprise about 1: 20 to about 5: 1, for example, about 1: 4 to about 4: 1, about 1: 2 to about 3: 1, for example, about 1: 1.

In another embodiment, the compositions of solid dispersion can comprise the combination of formula I chemical compound and polymer such as HPMCAS and PVP.The exemplary ratios of HPMCAS: PVP comprises about 5: 1,4: 1, and 3: 1,2: 1,1.5: 1,1: 1,1: 1.5,1: 2,1: 3,1: 4 or 1: 5.Can adjust this polymer ratio with the physical stability of optimizing solid dispersion and/or manufacturability (promptly flow, compacting etc.).

Another exemplary solid dispersion comprises formula I chemical compound; as (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide or its active metabolite; or (2R; 4S)-and quinazoline-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide and PVP, wherein the amount of dispersion Chinese style I chemical compound 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%, at least about 90% or bigger.The exemplary ratios of formula I chemical compound and PVP comprises about 1: 2 to about 5: 1, for example, and about 1: 1 to about 4: 1.In some preferred embodiments, the ratio of formula I chemical compound and PVP existence is about 1: 1 or about 3.5: 1.

The dispersion of formula I chemical compound and polymer

This paper comprises the dispersion that contains formula I chemical compound and polymer (as water-soluble polymer).For example; (2R; 4S)-quinoline-[1-(3 for N-oxidation-4-carboxylic acid; 5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] dispersion or the (2R of amide and polymer; 4S)-dispersion of 2-hydroxyl-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide and polymer is open at this.

Illustrative polymers is drawn together water-soluble polymer.Term " water-soluble polymer " is meant any natural or synthetic polymer, its 20 ℃ of apparent viscosities that 2% aqueous solution of water-soluble polymer is measured less than 100mPss.The limiting examples of suitable water-soluble polymer comprises cellulose ether such as methylcellulose, hydroxy-methyl cellulose, hydroxy ethyl cellulose, hydroxy propyl cellulose, the hydroxybutyl cellulose, hydroxy ethylmethylcellulose, HYDROXY PROPYL METHYLCELLULOSE, carboxy methyl cellulose, sodium carboxy methyl cellulose and carboxy methyl ethyl cellulose; Cellulose esters such as acetic acid succinic acid HYDROXY PROPYL METHYLCELLULOSE (HPMCAS), acetic acid 1,2,4-benzenetricarboxylic acid cellulose (CAT), cellulose acetate phthalate (CAP), acetic acid phthalic acid hydroxy propyl cellulose (HPCAP), acetic acid Monophalic acid ester of hydroxypropyl (HPMCAP) and acetic acid O-phthalic acid methyl cellulose (MCAP); Starch; Pectin such as carboxyl methyl branch Starch Sodium; Chitin derivative such as chitosan; Polysaccharide such as alginic acid, and alkali metal and ammonium salt; Carrageenin; Galactomannan; Tragacanth; Agar; Arabic gum; Guar gum; Xanthan gum; Polyacrylic acid and polymethylacrylic acid and salt thereof; Acrylate and methacrylate copolymer; Polyvinyl alcohol; Polyvinylpyrrolidone; The copolymer of polyvinylpyrrolidone and vinyl acetate; Copolymer with polyalkylene oxide such as polyethylene glycol oxide and polypropylene oxide and oxirane and expoxy propane.

The ratio of formula I chemical compound and polymer comprises those above-mentioned ratios, for example comprises the dispersion of HPMCAS and/or PVP.

Other composition

The acceptable composition of other pharmacy also can be included in the dispersion as herein described, as surfactant or other polymer, for example water-soluble polymer.

Surfactant

Usually the amount of surfactant in dispersion is about 0.1 to about 20% weight, and for example, about 1 to about 15% weight (for example, about 9%), and for example, about 0.5 to about 10%, about 0.5 to about 5%, or about 1 to about 2%.The weight ratio of formula I chemical compound and surfactant is about 300: 1 to about 1: 1, for example, and about 50: 1 to about 20: 1, for example, about 25: 1 or about 4: 1.

Suitable surfactant comprises anion surfactant, cationic surfactant and non-ionic surface active agent.Anion surfactant is the amphipathic molecule with negative charge.The limiting examples of suitable anion surfactant comprises carboxylate, sulfonate, sulfate, the phosphate of alkyl, aryl or aryl alkyl, or the acylated protein hydrolyzate.Suitable carboxylation surfactant comprises, for example, and soap (that is soap), bile salts, poly-alkoxyl carboxylate and N-acyl sarcosinates.Suitable sulfonated surfactants comprises, alkylsulfonate for example, alkylbenzenesulfonate, alkylated aromatic sulfonic acid salt (alkylarenesulfonates), short chain lignin-sulphonate, naphthalene sulfonate, alpha-alkene sulfonate, petroleum sulfonate, with have ester, amide or ether be connected the base sulfonate.Suitable sulfated surfactants comprises, the sulfuric ester of aliphatic alcohol for example, sulphation alkyl phenol, Sulfated acid (sulfated acids), amide, and ester, and the natural oil ﹠ fat of sulphation.Suitable phosphonic acids surfactant comprises ortho-phosphoric aliphatic alcohol list and diester.

In some embodiments, preferred anionic surfactant.The anion surfactant of example comprises, for example, and soap such as Sodium caproate, sodium caprylate, Capric acid sodium salt, sodium laurate, Sodium myristate, myristoleic acid sodium, sodium palmitate, palmitoleic acid sodium, enuatrol, sodium ricinoleate, linoleic acid sodium, linolenic acid sodium, sodium stearate, sodium lauryl sulfate (SLS), sodium tetradecyl sulfate, sodium lauryl sarcosinate, dioctyl sodium sulphosuccinate etc.; Cholate such as sodium cholate, sodium taurocholate (sodiumtarocholate), NaGC, NaTDC, sodium taurodeoxycholate, glycodesoxycholic acid sodium, ursodesoxycholic acid sodium, chenodeoxy cholic acid sodium (sodium chemodeoxycholate), glycochenodeoxycholate sodium, CHOLYLSARCOSINE sodium, N-methyl sodium taurocholate, lithocholic acid sodium etc.; The esterification products of phosphate ester such as aliphatic alcohol or alcohol ethoxylate and phosphoric acid or phosphoric anhydride etc.; The ether alkyl carboxylate that carboxylate (carboxylate) forms as the end-OH by the following material of oxidation: alcohol ethoxylate, succinylated monoglycerides, stearyl Filixic Acids sodium, stearyl propylene glycol hydrogen succinate ester (stearoylpropyleneglycol hydrogen succinate), list/diacetyl the tartrate of list and two-glyceride, the citrate of list and two glyceride, glyceryl-the lactate of fatty acid, the lactate of fatty acid, stearyl-2-calcium lactate/sodium, stearyl calcium lactate/sodium, alginate, propylene glycol alginate (propyleneglycol alginate) etc.; Sulfate (sulfate) and sulfonate (sulfonate) are as ethoxylated alkyl sulfates, alkylbenzenesulfonate, alpha-alkene sulfonate, acyl-hydroxyethyl sulfonate, acyl taurine salt, acylglycerol base ether sulfonate, octyl group disodium sulfosuccinate (promptly; 2-Sulfosuccinic acid dioctyl sodium (DOSS) or docusate sodium), endecatylene amide groups-MEA-disodium sulfosuccinate etc.

Preferred surfactant comprises sodium lauryl sulfate and docusate sodium, and it can be used alone or in combination.For example, the mixture of sodium lauryl sulfate and docusate sodium.

In some embodiments, two or more combinations-of surfactants are used.If compositions of the present invention comprises two or more surfactant mixtures, the surfactant that these two or more surfactants can be selected from same type (for example, these two or more surfactants can respectively be anion surfactant), maybe (for example can be selected from dissimilar surfactants, a kind of in two or more surfactants can be any non-ionic surface active agent, and another kind of at least surfactant can be anion surfactant).When surfactant mixtures is present in the compositions of the present invention, for example, when having two kinds of surfactants, the weight ratio of two kinds of surfactants can be about 5: 1 to about 1: 1.For example, the weight ratio of two kinds of surfactants can be about 5: 1, and 4: 1,3: 1,2: 1, or 1: 1.

Other polymer

In some embodiments, dispersion as herein described comprises formula I chemical compound and two or more polymer.For example, this dispersion for example, the dispersion of the dispersion of formula I chemical compound and HPMCAS or formula I chemical compound and PVP, can comprise second polymer,, be scattered in two kinds of polymer to provide as water-soluble polymer, for example, the formula I chemical compound in the HPMCAS and second polymer or PVP and second polymer.In some cases, for their complementary characteristic, as dissolubility, compressibility, flowability, the easily property handled, cost etc. and select this two kinds of polymer.First polymer: the ratio of second polymer can change and be 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, about 1: 1.

The feature of dispersion

As mentioned above, this dispersion can be uniformly or can be heterogeneous, for example has the zone of being rich in formula I chemical compound.The distribution of sizes that is distributed in the zone that disperses the enrichment region (for example, discontinuous phase) in the bulk phase can be Unimodal Distribution (unimodal) or bimodal distribution (bimodal).In one embodiment, the zone that is scattered in the formula I chemical compound in the polymer (that is, HPMCAS or PVP) is of a size of 10nm to 1000nm more than 90%, or 100nm to 800nm, or 100nm to 500nm.

In some embodiments, formula I chemical compound in the dispersion be essentially amorphous (for example, at least about 50% formula I chemical compound is unbodied, at least about 55% formula I chemical compound is unbodied, at least about 60% formula I chemical compound is unbodied, at least about 65% formula I chemical compound is unbodied, at least about 70% formula I chemical compound is unbodied, at least about 75% formula I chemical compound is unbodied, at least about 80% formula I chemical compound is unbodied, at least about 85% formula I chemical compound is unbodied, at least about 90% formula I chemical compound is unbodied, is unbodied at least about 95% formula I chemical compound, is unbodied at least about 98% formula I chemical compound, at least about 99% formula I chemical compound is unbodied, or all formula I chemical compounds are unbodied basically.

As described herein, term " unbodied " is meant that the position of its atom does not have the solid material of long-range order (longrange order).Unbodied solid is generally supercooled liquid, and wherein molecule is arranged with random fashion and made do not have clear and definite arrangement and do not have long-range order.Unbodied solid is generally isotropic, promptly shows similar character and does not have definite fusing point in all directions.For example, the solid material (that is, by XRPD measure be not crystal) of unbodied material in its X-ray powder diffraction (XRPD) figure, not having sharp-pointed characteristic crystal peak.On the contrary, one or more broad peaks (for example, dizzy (halos)) appear in its XRPD figure.Broad peak is the feature of amorphous solid.Referring to, US 2004/0006237 is to compare the XRPDs of amorphous materials and crystalline material.

Term used herein " crystalline solid " is meant chemical compound or compositions, and wherein construction unit makes crystalline solid have inflexible long-range order with fixed geometric model or lattice arrangement.The unit that constitutes crystal structure can be atom, molecule or ion.Crystalline solid shows the fusing point of determining.

In some embodiments, this dispersion has single glass transition temperature (" T _g").This T _gBe characteristic temperature, wherein glassy material when heating, experiences the rapid physical variation from glassy state to rubbery state.This T _gCan or pass through dynamic mechanical analysis device (DMA) and measure by multiple common acceptable technology such as differential scanning calorimetry (DSC).The T of preferred dispersions _g(for example, 25 ℃, 60%RH) big than condition of storage usually in room temperature and relative humidity condition at least about 50K.For example, in the solid dispersion of formula I chemical compound that comprises equal proportion and HPMCAS, the T of dispersion _gUnder room temperature/damp condition, be generally about 98 ℃ to about 102 ℃ (for example, about 100 ℃ or 101 ℃).In the solid dispersion of formula I chemical compound that comprises equal proportion and PVP, the T of dispersion _gUnder room temperature/damp condition, be generally about 130 ℃ to about 135 ℃.Understand the T of dispersion easily _gDepend on many factors, as composition (being their structure, interaction etc.), the weight fraction of dispersion and the balance solvent and/or the moisture of dispersion.And, the T of the homogeneous mixture of amorphous composition (being polymer and chemical compound) _gCan pass through the Gordon-Taylor equation estimation in many cases, wherein use weight percent and their T separately of each composition _g' s with the estimation dispersion T _gPreferred dispersions Chinese style I and polymer have such ratio so that the formula I of enough therapeutic doses can use routine techniques (for example to roll (roller compaction), wet granulation etc.) be prepared into stock size (promptly, 650mg is preferably to 1300mg) regular dosage form, and the single T that has of dispersion _gAt least than the big 50K of condition of storage that expects.

Solid dispersion as herein described is normally stable, and is for example chemical and physically stable.For example, in some preferred embodiments, this solid dispersion at the condition of storage that quickens as 40 ℃/75% and/or 25 ℃/90% chemistry and at least 2 weeks of physically stable.The physical stability of dispersion can be by XRPD, DSC and/or microscopic examination amorphous form the content of formula I chemical compound assess.For example, in the solid dispersion of formula I chemical compound that comprises equal proportion and PVP, the T under room temperature/damp condition _gBe generally about 130 ℃ to about 135 ℃, identical dispersion stores 2 week back T 40 ℃/75% _gBe maintained at about 130 ℃ to about 135 ℃, final, the T of identical dispersion after 25 ℃/90% at least 2 weeks of storage _gBe about 130 ℃ to about 135 ℃.In another embodiment, coating is on lactose and mixes with ordinary excipients subsequently and the dispersion that is filled to PVP in the gelatine capsule and formula I chemical compound (for example, 25 ℃, 60%RH) was stablized 15 months in room temperature and relative humidity condition at least.

Solid dispersion as herein described, the composition in the useful as drug compositions is for example as the composition of the powder of oral administration mixed suspension, tablet, capsule etc.Usually, the bulk density of solid dispersion as herein described (bulk density) is extremely about 0.30g/ml of about 0.20g/ml, and real density (tap density) is that about 0.34g/ml is to about 0.40g/ml.The D that this solid dispersion has usually ₅₀Less than about 1 μ m.

In another embodiment, the solid dispersion that has q.s in the compositions of formula I chemical compound (formation solid dispersion), make after comprising the compositions of solid dispersion to animals administer, the level of formula I chemical compound in animal blood compared formula I chemical combination object height that administration do not comprise solid dispersion at least about 20%, and be for example, high at least about 25%, high at least about 50%, high at least about 100%, high, high at least about 300% or high at least about 400% at least about 200%.In another embodiment, compositions of the present invention provides the bioavailability of increase, and it is at least 1.25 times of water-insoluble drug bioavailability of non-preparation, doubly, and 1.50 times or at least 2.0 times.

The granule that comprises formula I chemical compound

The granule of formula I chemical compound is described at this.For example, the granule that comprises unbodied formula I chemical compound is described at this, and for example, the granule that comprises essentially amorphous formula I chemical compound is described at this.Can prepare unbodied formula I chemical compound, for example, by spray drying formula I chemical compound so that the granule of the formula I chemical compound that is suitable for being mixed with pharmaceutical composition such as peroral dosage form to be provided.

As mentioned above, formula I chemical compound as herein described and comprise composition in the dispersion useful as drug compositions of formula I chemical compound.In some embodiments, dispersion directly is mixed with compositions.In some embodiments, with formula I chemical compound, for example, the dispersion coating that comprises formula I chemical compound as herein described becomes pharmaceutical composition with this particle formulation on granule.

Formula I chemical compound, for example, unbodied formula I chemical compound, but coating is on granule, for example with water-soluble polymer.In some embodiments, with dispersion coating as herein described on particulate surface.Be used for comprising sucrose granules, as lactose or microcrystalline Cellulose or starch with the exemplary granule of dispersion coating as herein described.

Formula I chemical compound or dispersion as herein described can be with the spraying process coating on particulate surfaces, for example, by formula I is provided chemical compound, the suspension of for example unbodied formula I chemical compound or dispersion as herein described or serosity, and granule, and spray this suspension or serosity to provide by formula I chemical compound coated granules.In some embodiments, also available other composition coating, for example enteric coating of particulate surface.

This coated granules can form suitable dosage form then, for example by envelope capsule (encapsulation).Perhaps use the known method of drug world, the substrate of this coating can be mixed with one or more other compositions disclosed herein, form suitable dosage form then, for example by envelope capsule, tabletting or granulation as wet method or dry granulation, mill etc.

Preparation comprises the method for the dispersion of formula I chemical compound

The method of any acquisition solid dispersion can be used for dispersion as herein described.Usually, spendable method comprise relate to from mixture remove fast solvent method or the cooling fusing sample method.These methods include, but not limited to rotary evaporation, lyophilization (that is lyophilizing), vacuum drying, fusion is freezed and melt extrude.Yet the preferred embodiments of the invention relate to the unbodied solid dispersion that obtains by spray drying.Therefore, in another embodiment, the invention provides the product that spray drying is obtained and carry out drying to remove solvent.

Preparation disclosed herein, for example, pharmaceutical composition can comprise formula I chemical compound, HPMCAS and/or PVP by spray drying, and the mixture of suitable solvent (for example, acetone) and obtaining.Spray drying is a kind of method, and it comprises that atomizing comprises for example liquid mixture of solid and solvent, and removes solvent.Atomizing can be carried out by for example nozzle or on rotating disk.Spray drying is for being the method for dried granules form with the liquid feedstock conversion.Randomly, can use second drying means such as fluid bed drying or vacuum drying residual solvent is reduced to the acceptable level of pharmacy.Usually, spray drying comprises that liquid suspension or solution with high degree of dispersion contact to produce the evaporation and the drying of drop with the hot-air of enough volumes.The exsiccant preparation of waiting to spray can be any solution, coarse grain suspension, serosity, colloidal dispersion or the paste of the spray-drying installation atomizing that can use selection.In standard procedure, preparation is sprayed in the warm FA stream this air flow evaporating solvent and exsiccant product is delivered to catcher (for example, cyclone (cyclone)).Then waste gas is exhausted with solvent, or waste gas is delivered to condenser to capture and can this solvent of recirculation.The device that can use commercially available type is to carry out spray drying.For example, the commercial spray dryer of making by Buchi Ltd. and Niro (for example, the PSD series of the spray dryer of making by Niro) (referring to, US 2004/0105820; US 2003/0144257).

The solid supported amount of the normally used material of spray drying is about 2% to about 25%, and (that is, formula I chemical compound and excipient) is preferably at least about 4% or 5%.Usually, the upper limit of solid supported amount is determined by the viscosity (for example, pumpability) and the dissolubility of composition in solution of gained solution.

Spray-dired technology and method can be referring to Perry ' s Chemical Engineering Handbook, the 6th edition, R.H.Perry, D.W.Green﹠amp; J.O.Maloney, eds.), McGraw-Hill book co. (1984); And Marshall " Atomization and Spray-Drying " 50, Chem.Eng.Prog.Monogr.Series 2 (1954).

Usually, carrying out spray-dired inlet temperature is about 60 ℃ to about 200 ℃, for example, and about 130 ℃ to about 180 ℃.Carrying out the outlet temperature that spray drying has usually is about 70 ℃ to about 150 ℃, for example about 80 ℃ to about 110 ℃.

Preferred solvent for the dissolubility of those its Chinese styles I chemical compound be at least about 10mg/ml (for example, at least about 15mg/ml, 20mg/ml, 25mg/ml, 30mg/ml, 35mg/ml, 40mg/ml, 45mg/ml, 50mg/ml, 75mg/ml, 100mg/ml, 125mg/ml, 150mg/ml, 175mg/ml, 200mg/ml or bigger) solvent.

Suitable solvent comprises ester, ketone and alcohol.Spendable example solvents comprises ethyl acetate, methanol, acetone and ethanol.Certain preferred embodiments comprises ethyl acetate.In some embodiments, use the mixture of solvent.In a preferred embodiment, usual solvents dissolution type I chemical compound and polymer (that is, HPMCAS and/or PVP) both.

The removal solvent can need drying steps subsequently, as tray drying, and fluid bed drying (for example, about room temperature is to about 100 ℃), vacuum drying, microwave drying, drum drying or bipyramid (biconical) vacuum drying (for example, about room temperature is to about 200 ℃).

The common mean diameter of gained dispersed particles (for example, after the spray drying) is less than 1 μ m, and for example mean diameter is about 100nm about 900nm extremely, comprise that mean diameter is about 850nm, about 800nm, about 750nm, about 700nm, about 650nm, about 600nm, about 550nm, about 500nm, about 450nm, about 400nm, about 350nm, about 300nm, about 250nm, about 200nm and about 150nm comprise all scopes and subrange between them.The particle size distribution of dispersed particles can be Unimodal Distribution (unimodal) or bimodal distribution (bimodal) basically.If particle size distribution is Unimodal Distribution basically, then the particle diameter that has of at least 50% granule is less than 1 μ m.For example, the particle diameter that at least 50% granule has is less than 900nm, 800nm, and 700nm, 600nm, 500nm, 400nm, 300nm, or 200nm comprise all scopes and subrange between them.

Granule coating (particle coating)

In some embodiments, the chemical compound of formula (I) or comprise the chemical compound of formula (I) and the dispersion coating of polymer on carrier such as solid particle, for example, granule such as lactose or microcrystalline Cellulose or starch.The dispersion of formula I chemical compound or formula I chemical compound as herein described and polymer is suspended in water and water-soluble polymer (for example, in solution PVP).This suspension lamination is arrived on carrier such as solid particle such as lactose or the spherical microcrystalline Cellulose (for example Celsphere).

In some embodiments, this water-soluble polymer and polymer phase in solid dispersion are with (or for comprising more than the polymer in the solid dispersion in a kind of example of dispersion of polymer).

Usually the solid supported of water-soluble polymer is about 10 to about 60% weight in coating method.

The compositions that comprises the dispersion of formula I chemical compound

Solid dispersion as herein described and can prepare to be provided for delivering medicine to experimenter's dosage form with the acceptable excipient of other pharmacy with solid dispersion coated granules as herein described.

The percentage by weight of compositions Chinese style I chemical compound as herein described can be about 99wt.% to about 15wt.%.For example, the percentage by weight of water-insoluble drug can be about 99, about 95, about 90, about 85, about 80, about 75, about 70, about 65, about 60, about 55, about 50, about 45, about 40, about 35, about 30, about 25, about 20 and about 15wt%.

The unit dose of using can change according to patient's the demand and the symptom of treatment.For convenience's sake, divisible this total daily dose and administration in batches during administration on demand.The scope of the amount of water-insoluble drug in compositions of the present invention for the about 1mg of per unit dosage to about 500mg.For example, the amount of water-insoluble drug can be about 1mg, 5mg, 10mg, 15mg, 20mg, 25mg in the per unit dosage compositions of the present invention, 30mg, 35mg, 40mg, 45mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 250mg, 300mg, 320mg, 350mg, 400mg, 450mg, 480mg, 500mg, 640mg, 750mg, 1000mg etc.

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

When existing, the percentage by weight of the total amount of one or more other compositions in compositions of the present invention can be about 90 to about 5wt.%.For example, the percentage by weight of the total amount of one or more other compositions in compositions can be about 90,85,80,75,70,65,60,55,50,45,40,35,30,25 and 20wt.%.

The acceptable excipient of the pharmacy of example comprises diluent or filler, medicine chelating agent or cosolvent, disintegrating agent, binding agent, lubricant, fluidizer, pH regulator agent and surfactant.The example of suitable diluent or filler comprises lactose, mannitol, xylitol, microcrystalline Cellulose, calcium pyrophosphate and starch.The example of medicine chelating agent or cosolvent comprises Polyethylene Glycol, caffeine, xanthene, gentisic acid and cyclodextrin.The example of disintegrating agent comprises primojel, sodium alginate, sodium carboxy methyl cellulose, methylcellulose, cross-linking sodium carboxymethyl cellulose and crospolyvinylpyrrolidone, preferred cross-linking sodium carboxymethyl cellulose and/or crospolyvinylpyrrolidone.The example of binding agent comprises methylcellulose, polyvinylpyrrolidone, microcrystalline Cellulose, starch, hydroxy propyl cellulose, hydroxymethyl propyl cellulose and glue such as guar gum and Tragacanth, preferably polyethylene ketopyrrolidine.The example of lubricant comprises magnesium stearate, stearic acid, stearyl fumaric acid sodium.The example of fluidizer is a silicon dioxide.The example of pH regulator agent comprises acid as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid and comprises the buffer agent of the mixture of above-mentioned arbitrarily acid and its salt.

The example of surfactant as above provides.The preferred surfactants excipient comprises DOSS and SLS.The percentage by weight of surfactant in compositions of the present invention can be about 0.1wt.% to about 20wt.%.For example, the percentage by weight of surfactant in compositions can be about 20, about 19, about 18, about 17, about 16, about 15, about 14, about 13, about 12, about 11, about 10, about 9, about 8, about 7, about 6, about 5.5, about 5.0, about 4.5, about 4.0, about 3.5, about 3.0, about 2.5, about 2.0, about 1.5, about 1.0, about 0.9, about 0.8, about 0.7, about 0.6, about 0.5, about 0.4, about 0.3, about 0.2, about 0.1wt.%.

Other composition can comprise composition a kind of or that two or more are independent independently, and it is selected from the every type as herein described acceptable excipient of pharmacy.That is to say that the compositions that this paper comprises for example can comprise, one or more diluent or filler and disintegrating agent, independent diluent or filler and two or more disintegrating agents, filler, disintegrating agent, binding agent, lubricant etc.

In some embodiments, compositions as herein described comprises other therapeutic agent, for example so that the co-administered of the formula I chemical compound and second therapeutic agent to be provided.Term used herein " therapeutic agent " uses its conventional meaning, and expression has the useful chemical compound that prevents and/or treats characteristic or any synthetic or naturally occurring entity when to mammal especially people's administration.The limiting examples of suitable water-insoluble drug comprises, for example, medicine available from multiple known type medicine comprises protein, peptide, nucleotide, antiadipositas drug, dietetic product, corticosteroid, elastase inhibitor, analgesics, antifungal, tumor therapeutic agent, antiemetic, cardiovascular agents, antiinflammatory, anthelmintic, anti-dysrhythmia agents, antibiotic, anticoagulant, antidepressant, antidiabetic, Anti-epileptics, hydryllin, hypotensive agent, muscarine antagonist, the mycobacteria agent, antitumor agent, immunosuppressant, antithyroid drug, antiviral agent, antianxiety drug, tranquilizer, astringent, the receptor, blocker, blood products and sub, the heart inotropic agent, cholinesterase inhibitor, contrast agent, corticosteroid, cough medicine, diagnostic agent, diagnosing developing agent, diuretic, dopaminergic, hemorrhage, immune drug, the blood lipid regulation medicine, the intestinal motility regulator, muscle relaxant, parasympathomimetic agent, parathyroid gland calcitonin and diphosphonate, prostaglandin, radiopharmaceuticals, gonadal hormone, anti-allergic agent, analeptic and anoretic, sympathomimetic, the thyroid medicine, vasodilation and xanthine.

The granule of this solid dispersion can form suitable dosage form then, for example by the envelope capsule.Perhaps the granule of this solid dispersion can mix with one or more other compositions disclosed herein, uses the known device, method of drug world, as wet method or dry granulation, mill etc., forms suitable dosage form then, for example by envelope capsule, granulation or tabletting.

Compositions of the present invention can provide to any dosage form of the water-insoluble drug of patient's delivery treatments effective dose being suitable for.The limiting examples of dosage forms comprises microencapsulation, capsule, tablet and implant, tablet (troche), lozenge, suspensoid, pearl agent (ovule), suppository, wafer (wafer), chewable tablet, dissolving tablet, effervescent tablet, oral cavity or Sublingual solid, granule, thin film, piller, pearl (bead), pill, powder, bar (strip) or wafer.

Compositions of the present invention can be formulated as oral, the Sublingual, and buccal, nose, eye, lung, urethra is worn mucosa, vagina, the part, or rectum is sent.In one embodiment, prepare compositions of the present invention and make it be suitable for the orally give experimenter and absorbed by whole body, for example, stomach/intestinal.In some preferred embodiments, compositions as herein described is formulated as oral administration, for example as tablet, capsule or be used for powder, preferred tablet or the capsule of oral administration mixed suspension.When being formulated as microencapsulation or capsule, this capsule can be hard or Perle, starch capsule or cellulose capsule.

Also available one or more dress material coatings of compositions of the present invention are with the control disintegration rate, for example the disintegration rate in digestive tract postpones release characteristics to provide release immediately, pulsed release, sustained release, prolongation to discharge, postpone release, targeting release, release synchronously or targeting.These coatings can comprise enteric coating, film coating, contagion gown (barrier coatings), pressed coated (compress coatings), quick disintegrate coating, enzyme degradable coating etc.

Use comprises the method for the dispersion of formula I chemical compound

Described chemical compound and solid dispersion, the compositions that comprises the granule of solid dispersion and comprise chemical compound as herein described and solid dispersion can be used for treatment, for example treat the relevant disease of NK-1.The solid dispersion that comprises formula I chemical compound as herein described of treatment effective dose (and/or comprise the granule of solid dispersion and/or comprise the compositions of solid dispersion) can give the experimenter, the experimenter who for example needs this treatment is with the relevant disease of treatment NK-1.

Term " treatment effective dose " is the amount of water-insoluble drug that clinical useful effect is provided, for example minimizing or mitigation symptoms or prevention or improve the amount of disease or disease.

The disease that exemplary NK-1 is relevant comprises following disease, gives up (substancewithdrawal), immune system obstacle, inflammatory diseases such as osteoarthritis, rheumatoid arthritis and other arthritis, inflammatory bowel, scleritis, viscera disease such as inflammatory pelvic disease, seminal vesiculitis (vesicultis) and dyspareunia as depression, anxiety, cognition and memory impairment, acute and chronic pain, allergic disease, asthma, chronic obstructive pulmonary disease, dermatosis, incontinence, inflammation, vomiting, irritable bowel syndrome, sleep disorder, material.In some preferred embodiments, give the experimenter with treatment social anxiety disorder, incontinence and/or irritable bowel syndrome with chemical compound as herein described or dispersion or the compositions that comprises chemical compound as herein described or dispersion.

Chemical compound as herein described and dispersion can give or give not together with food.In some embodiments, give the experimenter with dispersion as herein described, this experimenter give solid dispersion taken food in 2 hours or giving solid dispersion after will take food in 1 hour.Administration frequency can change according to multiple factor, comprises the disease, dosage form, dosage and the patient that are treated.Therefore, chemical compound as herein described or dispersion can be once a day, twice of every day, every day three times or four administrations every day.

Embodiment

Following examples are tasks of explanation, and never in any form, style or form, clearly or impliedly limit the present invention.Although they are available typical in those, the also replaceable use of other process well known by persons skilled in the art, method or technology.

Embodiment 1: the solid dispersion that comprises PVP or HPMCAS

Multiple drug/polymer and drug/polymer/combinations-of surfactants are dissolved in the multiple solvent, and spray drying is to form the solid dispersion granule then.

This polymer, solvent, surfactant concentration (docusate sodium percent (%)), percent solids (%) and drug/polymer ratio are illustrated in following table 1:

Table 1.

??LOT	Solvent	Polymer	Medicine ^＊: polymer	DOSS ^＊＊(％)	Solid (%)
??LOT	Solvent	Polymer	Medicine ^＊: polymer	DOSS ^＊＊(％)	Solid (%)	??A001	Ethyl acetate	??NA	??*	??NA	??5.00
??A002	Ethanol 200	??PVP??(K29/32)	??1∶3	??NA	??5.00	??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	??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	??A005	Ethanol 200	??PVP??(K29/32)	??1∶1	??1.50	??4.76

??A007	Ethanol 200	??PVP??(K29/32)	??1∶1	??9.00	??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	??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	??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	??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)-Cinchonic Acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide

^*Docusate sodium (docusate sodium)

The physical analysis of carrying out the solid dispersion of table 1 disperses the form (being unbodied or crystalline) of drug disposition with assessment and measures the glass transition temperature of the solid dispersion in the table 2.

Be used for mensuration form and T _gMethod be respectively XRPD and synthetic DSC.

Table 2.

^*Docusate sodium

Embodiment 2: solid dispersion stress (Stressed) stable that comprises PVP or HPMCAS The property

With the stability condition that the exemplary solid dispersion of table 1 stands to quicken, comprise that 25 ℃/90%RH keeps 2 weeks and 40 ℃/75%RH to keep for 2 weeks, the results are shown in table 3.This T _g' s use mDSC mensuration.The further assessment of dispersion Chinese medicine form is undertaken by the microscope evaluation.

Table 3.

^*Docusate sodium

Embodiment 3: the peroral dosage form of preparation

Dispersion as herein described can be produced and further be formulated as peroral dosage form such as tablet or capsule.Perhaps, this solid dispersion can be processed into capsule on the lactose or on the acceptable carrier or tablet is formulated as dosage form then by coating at first.

The compositions of table 4 by will (2R, 4S)-Cinchonic Acid's [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide and selected polymer (PVP or HPMCAS) be dissolved in the organic solvent commonly used and prepare.To obtain the solid dispersion granule of nano-scale, wherein about 50% diameter is about 0.8um or littler with gained solution spray drying.By further being processed into Tabules with diluent, fluidizer and part mix lubricant, it is by compressing (slugging) densification and milling subsequently with solid dispersion.Be added in the granule of milling the lubricant of disintegrating agent and surplus and mixing.Lubricated granule is pressed into tablet.The also available functional or non-functional clothing film coating of this tablet.

Table 4.

??LOT	??X608OCTA001	??X608OCTA002
??LOT	??X608OCTA001	??X608OCTA002	Dose concentration (Dosage Strength)	The 160mg tablet	The 160mg tablet
Composition	??(％)	??(％)	Dose concentration (Dosage Strength)	The 160mg tablet	The 160mg tablet
Composition	??(％)	??(％)	(2R, 4S)-Cinchonic Acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidines-4-yl] amide	??24.7	??25.0
Polyvinylpyrrolidone (PVP)	??24.7	??0.0		??24.7	??25.0
Polyvinylpyrrolidone (PVP)	??24.7	??0.0	??HPMCAS	??0.0	??25.0
Docusate sodium	??0.6	??0.0	??HPMCAS	??0.0	??25.0
Docusate sodium	??0.6	??0.0	Cross-linking sodium carboxymethyl cellulose	??7.5	??5.0
Silicon dioxide	??0.0	??0.5	Cross-linking sodium carboxymethyl cellulose	??7.5	??5.0
Silicon dioxide	??0.0	??0.5	Sodium lauryl sulfate	??1.0	??0.5
Microcrystalline Cellulose	??40.0	??21.25	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	Dicalcium phosphate	??0.0	??21.25
Magnesium stearate	??1.5	??1.5	Amount to	??100	??100

The GMP#3 compositions of table 5 by will (2R, 4S)-Cinchonic Acid's [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide and docusate sodium be dissolved in the ethyl acetate and prepare.With gained solution spray drying with obtain nano-scale (2R, 4S)-granule of Cinchonic Acid's [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide and docusate sodium.The particulate diameter of about 50% nano-scale is about 0.8 μ m or littler.Then the granule of this nano-scale is added in the aqueous solution of polyvinylpyrrolidone and and is sprayed on the lactose granule the gained suspension.Then with lactose granule and cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone and sodium lauryl sulfate dry mixed dry, coating.Magnesium stearate is added into this mixture and mixing, seals capsule then.

In another exemplary dosage form, X608PFCA003 prepares by the mode identical with GMP#3, except the envelope capsule before PVP: drug suspension is that lamination arrives on the microcrystalline Cellulose (Celsphere).

Table 5.

??LOT	??GMP#3	??X608PFCA003
??LOT	??GMP#3	??X608PFCA003	Unit dose	The 160mg capsule	The 160mg tablet
Composition	??(％)	??(％)	Unit dose	The 160mg capsule	The 160mg tablet
Composition	??(％)	??(％)	(2R, 4S)-Cinchonic Acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide	??29.0	??27.3
Docusate sodium	??4.1	??0.3		??29.0	??27.3
Docusate sodium	??4.1	??0.3	Sodium lauryl sulfate	??2.3	??0.5
Polyvinylpyrrolidone (PVP)	??9.2	??7.7	Sodium lauryl sulfate	??2.3	??0.5
Polyvinylpyrrolidone (PVP)	??9.2	??7.7	Cross-linking sodium carboxymethyl cellulose	??10.0	??0.0
Lactose	??37.9	??0.0	Cross-linking sodium carboxymethyl cellulose	??10.0	??0.0
Lactose	??37.9	??0.0	Crospolyvinylpyrrolidone	??7.0	??0.0
Microcrystalline Cellulose (Celsphere)	??0.0	??64.20	Crospolyvinylpyrrolidone	??7.0	??0.0
Microcrystalline Cellulose (Celsphere)	??0.0	??64.20	Magnesium stearate	??0.5	??0.0
Amount to	??100	??100	Magnesium stearate	??0.5	??0.0

Embodiment 4: the peroral dosage form of preparation stress (Stressed) stability

With the stability condition that the exemplary solid dispersion (table 4 and 5) that is formulated as drug products stands to quicken, comprise that 25 ℃/90%RH reached for 2 weeks and 40 ℃/75%RH reaches 2 weeks, 5 weeks, 3 months and 6 months.Table 6 is set forth the T that measures with mDSC _g' s, be used for 2 time-of-week point analysiss.Further assessment to medicament forms in dispersion is undertaken by microscopic evaluation.

Table 6.

Table 7,8 and 9 is presented at 40 ℃/75% respectively and stores formulation X 608OCTA001, the X608OCTA002 of different time and outward appearance, assay (assay), related impurities content (related substances) and the stripping result of X608PFCA003.This assay and impurity result confirm the chemical stability and the stripping result of described preparation, and the result when relatively initially obviously being suppressed is the suitable surrogate of drug crystallization form, and it shows minimum variation.

The formulation X 608OCTA001 that table 7. stores under 40 ℃/75% condition

Test	Initially	5 weeks	3 months	6 months
Test	Initially	5 weeks	3 months	6 months	Outward appearance	White	White	White, spottiness	Canescence
Assay (%)	??95.5	??96.5	??96.7	??94.6	Outward appearance	White	White	White, spottiness	Canescence
Assay (%)	??95.5	??96.5	??96.7	??94.6	Total correlation impurity content (%)	??＜0.05	??＜0.05	??＜0.05	??0.05
Dissolution (% release)					Total correlation impurity content (%)	??＜0.05	??＜0.05	??＜0.05	??0.05
Dissolution (% release)					15 minutes	??2	??3	??3	??4
30 minutes	??3	??5	??5	??6	15 minutes	??2	??3	??3	??4
30 minutes	??3	??5	??5	??6	45 minutes	??5	??8	??7	??8
60 minutes	??7	??10	??10	??11	45 minutes	??5	??8	??7	??8
60 minutes	??7	??10	??10	??11	120 minutes	??14	??22	??20	??21

The formulation X 608OCTA002 that table 8. stores under 40 ℃/75% condition

Test	Initially	5 weeks	3 months	6 months
Test	Initially	5 weeks	3 months	6 months	Outward appearance	White	White	White	White

Assay (%)	??94.9	??96.9	??97.2	??94.8
Assay (%)	??94.9	??96.9	??97.2	??94.8	Total correlation impurity content (%)	??＜0.05	??＜0.05	??＜0.05	??0.07
Dissolution (% release)					Total correlation impurity content (%)	??＜0.05	??＜0.05	??＜0.05	??0.07
Dissolution (% release)					15 minutes	??26	??27	??21	??22
30 minutes	??33	??34	??28	??31	15 minutes	??26	??27	??21	??22
30 minutes	??33	??34	??28	??31	45 minutes	??39	??40	??35	??39
60 minutes	??45	??46	??40	??45	45 minutes	??39	??40	??35	??39
60 minutes	??45	??46	??40	??45	120 minutes	??59	??61	??55	??57

The formulation X 608PFCA003 that table 9. stores under 40 ℃/75% condition

Test	Initially	5 weeks	3 months	6 months
Test	Initially	5 weeks	3 months	6 months	Outward appearance	??*	??*	??*	??*
Assay (%)	??95.3	??100.2	??99.6	??101.7	Outward appearance	??*	??*	??*	??*
Assay (%)	??95.3	??100.2	??99.6	??101.7	Total correlation impurity content (%)	??0.05	??＜0.05	??＜0.05	??0.05
Dissolution (% release)					Total correlation impurity content (%)	??0.05	??＜0.05	??＜0.05	??0.05
Dissolution (% release)					15 minutes	??17	??16	??14	??13
30 minutes	??26	??25	??27	??25	15 minutes	??17	??16	??14	??13
30 minutes	??26	??25	??27	??25	45 minutes	??36	??36	??36	??36
60 minutes	??43	??49	??44	??45	45 minutes	??36	??36	??36	??36
60 minutes	??43	??49	??44	??45	120 minutes	??71	??79	??73	??76

^*Free-pouring ball (pellets) in canescence " 00 " HPMC capsule

Embodiment 5: the dissolution of the improvement of the solid dispersion of selection

The remarkable shortcoming of solid dispersion tablet is its extremely long disintegrate and dissolution time.The time of these prolongations can cause in people and Canis familiaris L. absorption rate limited.Because many water-soluble polymers are also as binding agent, for example PVP, HPMC, HPC etc., this disintegrate slowly and dissolution time are not unexpected.Yet when comparing with the solid dispersion tablet of PVP, the piller (pellet) that comprises the solid dispersion tablet of HPMCAS or comprise the solid dispersion layer of PVP provides obvious improvement aspect dissolution time.During the dissolution time of this preparation in detecting table 4 and 5 (listing in table 7-9) is tangible.

Embodiment 6: the bioavailability of the peroral dosage form of selection in Canis familiaris L..

Several formulations is tested in Canis familiaris L..The measurable trend that in people's research, shows of result in the research of Canis familiaris L..(2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide; comprise two kinds of active metabolite (2R; 4S)-quinoline-[1-(3 for N-oxidation-4-carboxylic acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide and (2R; 4S)-[1-(3 for 2-hydroxyl-Cinchonic Acid; 5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] AUC of amide provides at table 10, and it is used for the bioavailability study of Canis familiaris L..With respect to the non-dispersive preparation of active pharmaceutical ingredient, the preparation based on solid dispersion of active component (with two kinds of active metabolites) has very large AUC benefit.The result is derived from two independent Canis familiaris L. researchs, and the table cut-off rule after it is gone by the 9th is separated.

Table 10.

Preparation	Dosage (mg/kg)	AUC-medicine and metabolite (0-72hrng/mL)
Preparation	Dosage (mg/kg)	AUC-medicine and metabolite (0-72hrng/mL)	??101	??10	??23,630
??WG#2	??10	??21,304	??101	??10	??23,630
??WG#2	??10	??21,304	??WG#3	??10	??22,894
??GMP#3	??10	??72,380	??WG#3	??10	??22,894
??GMP#3	??10	??72,380	??101	??80	??92,390
??WG#2	??80	??86,870	??101	??80	??92,390
??WG#2	??80	??86,870	??WG#3	??80	??77,950
??GMP#3	??80	??427,410	??WG#3	??80	??77,950
??GMP#3	??80	??427,410	??X608OCTA001	??80	??392,830
??X608OCTA002	??80	??545,077	??X608OCTA001	??80	??392,830
??X608OCTA002	??80	??545,077	??X608PFCA003	??80	??482,335
??GMP#3	??80	??524,774	??X608PFCA003	??80	??482,335

The composition of last 4 preparations provides in table 4 before and 5.The composition of other 3 kinds of preparations (promptly ' 101 ', WG#2 and WG#3) provides in table 11.PVP in preparation WG#2 and WG#3 is mixed in attention, and does not exist with dispersion.

Table 11.

Preparation	??101	??WG#2 ^＊	??WG#3 ^＊
Preparation	??101	??WG#2 ^＊	??WG#3 ^＊	Dose concentration	The 160mg tablet	The 160mg tablet	The 160mg tablet
Composition	??(％)	??(％)	??％	Dose concentration	The 160mg tablet	The 160mg tablet	The 160mg tablet
Composition	??(％)	??(％)	??％	(2R, 4S)-Cinchonic Acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide	??47.0	??35.0	??35.0
Polyvinylpyrrolidone (PVP)	??0.0	??2.0	??2.0		??47.0	??35.0	??35.0
Polyvinylpyrrolidone (PVP)	??0.0	??2.0	??2.0	Crospolyvinylpyrrolidone	??0.0	??6.9	??6.9
Docusate sodium	??0.0	??4.9	??4.9	Crospolyvinylpyrrolidone	??0.0	??6.9	??6.9
Docusate sodium	??0.0	??4.9	??4.9	Lactose-hydrate	??53.0	??0	??0
Sodium lauryl sulfate	??0.0	??2.3	??2.3	Lactose-hydrate	??53.0	??0	??0
Sodium lauryl sulfate	??0.0	??2.3	??2.3	Microcrystalline Cellulose	??0.0	??38.6	??38.6
Cross-linking sodium carboxymethyl cellulose	??0.0	??9.8	??9.8	Microcrystalline Cellulose	??0.0	??38.6	??38.6
Cross-linking sodium carboxymethyl cellulose	??0.0	??9.8	??9.8	Magnesium stearate	??0.0	??0.5	??0.5
Total amount	??100	??100	??100	Magnesium stearate	??0.0	??0.5	??0.5

^*WG#2 was from 1: 3 methanol: acetone solvent carries out spray drying; WG#3 carries out spray drying from dichloromethane.

Embodiment 7: the bioavailability of the peroral dosage form of selection in the people

In people's clinical research, tested several formulations.GMP#3, (2R, 4S)-exemplary solid dispersion and the non--solid dispersion contrast of Cinchonic Acid's [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide and PVP, the composition of GMP#2 is listed in table 12.(2R; 4S)-[1-(3 for the Cinchonic Acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide; comprise two kinds of active metabolite (2R; 4S)-quinoline-[1-(3 for N-oxidation-4-carboxylic acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide and (2R; 4S)-AUC and the cmax value of 2-hydroxyl-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide also provide in table 13.AUC value than control formulation GMP#2; for exemplary solid dispersion formulations GMP#3; its parent molecule (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] AUC of amide; and two kinds of metabolite (2R; 4S)-quinoline-[1-(3 for N-oxidation-4-carboxylic acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide and (2R; 4S)-the AUC value of 2-hydroxyl-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide is significantly higher.In addition; cmax value than control formulation GMP#2; for exemplary solid dispersion formulations GMP#3; its parent (2R; 4S)-[1-(3 for the Cinchonic Acid; 5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] cmax value of amide; and two kinds of metabolite (2R; 4S)-quinoline-[1-(3 for N-oxidation-4-carboxylic acid; 5-pair-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide and (2R; 4S)-cmax value of 2-hydroxyl-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide is significantly higher.

Table 12.

??LOT	??GMP#2	??GMP#3
??LOT	??GMP#2	??GMP#3	Unit dose	The 160mg capsule	The 160mg capsule
Composition	??(％)	??(％)	Unit dose	The 160mg capsule	The 160mg capsule
Composition	??(％)	??(％)	(2R, 4S)-Cinchonic Acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide	??38.0	??29.0
Docusate sodium	??0.0	??4.1		??38.0	??29.0
Docusate sodium	??0.0	??4.1	Sodium lauryl sulfate	??2.5	??2.3
Polyvinylpyrrolidone (PVP)	??0.0	??9.2	Sodium lauryl sulfate	??2.5	??2.3
Polyvinylpyrrolidone (PVP)	??0.0	??9.2	Cross-linking sodium carboxymethyl cellulose	??10.0	??10.0
Lactose	??42.0	??37.9	Cross-linking sodium carboxymethyl cellulose	??10.0	??10.0
Lactose	??42.0	??37.9	Crospolyvinylpyrrolidone	??7.0	??7.0
Magnesium stearate	??0.5	??0.0	Crospolyvinylpyrrolidone	??7.0	??7.0
Magnesium stearate	??0.5	??0.0	Amount to	??100	??100

Table 13.

Preparation	??GMP#2 ^α	??GMP#3 ^α
Preparation	??GMP#2 ^α	??GMP#3 ^α	??AUC(0-24hr·ng/mL)	??AUC(0-24hr·ng/mL) ^β	??AUC(0-24hr·ng/mL) ^β

??AV608 ^*	??723.7	??3340
??AV608 ^*	??723.7	??3340	??AV609 ^**	??3198	??12467
??AV810 ^***	??5439	??171195	??AV609 ^**	??3198	??12467
??AV810 ^***	??5439	??171195	??Cmax(ng/ml)	??Cmax(ng/ml) ^β	??Cmax(ng/ml) ^β
??AV608 ^*	??87.4	??360.3	??Cmax(ng/ml)	??Cmax(ng/ml) ^β	??Cmax(ng/ml) ^β
??AV608 ^*	??87.4	??360.3	??AV609 ^**	??209.0	??722.1
??AV810 ^***	??343.9	??955.6	??AV609 ^**	??209.0	??722.1

^*(2R, 4S)-2-hydroxyl-Cinchonic Acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide

^{* *}(2R, 4S)-quinoline-N-oxidation-4-carboxylic acid [1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide

^αTwo kinds of unit dose capsules of the described compositions of administration table 11

^βAUC and cmax value are in the 1st day 24 hours value of administration.

Those skilled in the art will recognize that maybe and can confirm, only use normal experiment can obtain many equivalents (equivalents) of the specific embodiments of invention described herein.Think that these equivalents are included in the claims.

Claims

1. the solid dispersion that comprises formula I chemical compound and PVP,

Wherein X is CH, N or N-O;

Y is CH, N or N-O;

Z is a halogen; With

R is H or OH,

Wherein the percentage by weight of solid dispersion Chinese style I chemical compound is at least about 50% weight.

2. the solid dispersion of claim 1, the percentage by weight of its Chinese style I chemical compound is at least about 70% weight.

3. the solid dispersion of claim 1, wherein said formula I chemical compound be (2R, 4S)-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

4. the solid dispersion of claim 1, wherein said formula I chemical compound be (2R, 4S)-quinazoline-4-carboxylic acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

5. the solid dispersion of claim 1, wherein said formula I chemical compound be (2R, 4S)-quinoline-N-oxidation-4-carboxylic acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

6. the solid dispersion of claim 1, wherein said formula I chemical compound be (2R, 4S)-2-hydroxyl-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

7. the solid dispersion of claim 1, the ratio of its Chinese style I chemical compound and PVP is about 1: 1 to about 5: 1.

8. the solid dispersion of claim 7, the ratio of its Chinese style I chemical compound and PVP is about 3.5: 1.

9. the solid dispersion of claim 1, wherein said dispersion is uniform substantially.

10. the solid dispersion of claim 1, wherein about 50% to about 90% relative humidity T _gThan 298K height at least about 50K.

11. the solid dispersion of claim 10, wherein about 60% to about 75% relative humidity T _gThan 298K height at least about 50K.

12. the solid dispersion of claim 1, wherein said dispersion has single T _g

13. the solid dispersion of claim 1, wherein said dispersion comprise at least one non-homogeneous zone of being rich in formula I chemical compound.

14. the solid dispersion of claim 1 is unbodied at least about 50% formula I chemical compound wherein.

15. the solid dispersion of claim 1, wherein all formula I chemical compounds are unbodied basically.

16. the solid dispersion of claim 1, wherein said PVP are K29/32.

17. the solid dispersion of claim 1, the molecular weight of wherein said PVP are about 30,000 to about 100,000 dalton.

18. the solid dispersion of claim 1, also comprises surfactant.

19. the solid dispersion of claim 18, the amount that wherein said surfactant exists in dispersion are about 0.1% to about 20% weight.

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

21. the solid dispersion of claim 1, wherein dispersion do not go up substantially and contain (2R, 4S)-active metabolite of Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

22. the solid dispersion of claim 1, wherein when giving the experimenter, the AUC of formula I chemical compound be the AUC of not dispersive preparation Chinese style I chemical compound at least about 1.25 times.

23. the solid dispersion of claim 22, wherein when giving the experimenter, the AUC of formula I chemical compound be the AUC of not dispersive preparation Chinese style I chemical compound at least about 3 times.

24. with the granule of formula I chemical compound and polymer coating,

Wherein X is CH, N or N-O;

Y is CH, N or N-O;

Z is a halogen; With

R is H or OH.

25. the granule of claim 24, wherein this granule is sucrose granules, lactose granule, microcrystalline Cellulose or starch.

26. the solid dispersion of claim 24, wherein said formula I chemical compound be (2R, 4S)-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

27. the solid dispersion of claim 24, wherein said formula I chemical compound be (2R, 4S)-quinazoline-4-carboxylic acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

28. the solid dispersion of claim 24, wherein said formula I chemical compound be (2R, 4S)-quinoline-N-oxidation-4-carboxylic acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

29. the solid dispersion of claim 24, wherein said formula I chemical compound be (2R, 4S)-2-hydroxyl-Cinchonic Acid [1-(3,5-is two-trifluoromethyl-benzoyl)-2-(4-benzyl chloride base)-piperidin-4-yl] amide.

30. the granule of claim 24, wherein segment bounds I chemical compound is scattered in the polymer at least.

31. the granule of claim 30, wherein all formula I chemical compounds are scattered in the polymer basically.

32. the granule of claim 30, wherein said dispersion are uniform substantially.

33. the granule of claim 30, wherein about 60% to about 75% relative humidity the T of dispersion _gThan 298K height at least about 50K.

34. the granule of claim 30, wherein said dispersion has single T _g

35. the granule of claim 30, wherein said dispersion comprise at least one non-homogeneous zone of being rich in formula I chemical compound.

36. the granule of claim 24 is unbodied at least about 50% formula I chemical compound wherein.

37. the granule of claim 36, wherein segment bounds I chemical compound is scattered in the polymer at least.

38. the granule of claim 37, wherein all formula I chemical compounds are scattered in the polymer basically.

39. the granule of claim 37, wherein all formula I chemical compounds are unbodied basically.

40. the granule of claim 30, wherein said PVP are K29/32.

41. the granule of claim 40, the molecular weight of wherein said PVP are about 30,000 to about 100,000 dalton.

42. the granule of claim 30, also comprises surfactant.

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

44. the granule of claim 42, the amount that wherein said surfactant exists in dispersion are about 0.1% to about 20%.

45. the granule of claim 30, wherein when giving the experimenter, the AUC of formula I chemical compound be the AUC of not dispersive preparation Chinese style I chemical compound at least about 1.25 times.

46. the granule of claim 45, wherein when giving the experimenter, the AUC of formula I chemical compound be the AUC of not dispersive preparation Chinese style I chemical compound at least about 3 times.

47. the granule of claim 30, wherein said polymer is PVP, and the ratio of formula I chemical compound and PVP is about 1: 5 to about 5: 1 in dispersion.

48. the granule of claim 30, wherein said polymer is PVP, and the ratio of formula I chemical compound and PVP is about 3.5: 1 in dispersion.

49. the granule of claim 30, wherein said polymer are PVP, and the percentage by weight of formula I chemical compound is at least about 50%.

50. the granule of claim 30, wherein said polymer are PVP, and the percentage by weight of formula I chemical compound is at least about 70%.

51. the granule of claim 30, wherein said formula I chemical compound is gone up substantially to unbodied, and keeps under 40 ℃/75% relative humidity essentially amorphous at least 2 weeks that reached.

52. the granule of claim 30, the dissolution that its Chinese style I chemical compound had at 30 minutes is for wherein with formulated being at least 3 times of dissolution of identical dispersion of the formula I chemical compound of tablet.

53. the granule of claim 52, the dissolution that its Chinese style I chemical compound had at 60 minutes is for wherein with formulated being at least 3 times of dissolution of identical dispersion of the formula I chemical compound of tablet.

54. the granule of claim 53, the dissolution that its Chinese style I chemical compound had at 120 minutes is for wherein with formulated being at least 3 times of dissolution of identical dispersion of the formula I chemical compound of tablet.