HK1170170A - Solid preparation containing npy y5 receptor antagonist - Google Patents

Description

Solid preparation containing NPYY5 receptor antagonist

Technical Field

The present invention relates to formulations for improving the aqueous solubility of NPYY5 receptor antagonists. In particular, it relates to a solid preparation characterized by containing trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide as an amorphous stabilizer.

Background

Neuropeptide Y (hereinafter referred to as NPY) is a peptide containing 36 amino acid residues and was isolated from pig brain in 1982. NPY is widely distributed in the central nervous system and peripheral tissues of humans and animals.

In the conventional reports, it has been clarified that NPY has an action of promoting eating, an action of antispasmodic action, an action of promoting learning, an action of anxiolytic action, an action of anti-stress action, etc. in the central nervous system, and may be closely related to central nervous system diseases such as depression, dementia of alzheimer type, parkinson's disease, etc. In addition, NPY is also considered to be involved in circulatory diseases because it causes contraction of smooth muscles such as blood vessels and cardiac muscles in peripheral tissues. In addition, it is known to be associated with metabolic diseases such as obesity, diabetes, and hormonal abnormality (trends pharmaceutical Sciences, vol.15, 153 (1994)). Therefore, NPY receptor antagonists are likely to be preventive or therapeutic agents against various diseases related to NPY receptors as described above.

The subtypes Y1, Y2, Y3, Y4, Y5 and Y6 have been found so far in NPY receptors (Trends in pharmaceutical Sciences, Vol.18, 372 (1997)). The Y5 receptor is associated with at least feeding function, suggesting that its antagonists may act as antiobesity agents (Peptides, Vol.18, 445 (1997)).

As such NPYY5 receptor antagonists, it has been shown that the compounds described in International pamphlets WO01/37826, WO03/076374, particularly trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide shows a high anti-obesity effect. Although the drug is orally administered, the present inventors have found that the drug has low water solubility and the absorption amount is reduced because the drug is not sufficiently dissolved in the digestive tract. Such a drug has a decreased absorption rate with an increase in the amount of the drug to be administered, and the absorption rate is more likely to fluctuate due to digestive movement during eating (mechanical stimulation due to contraction movement of the digestive tract, an increase in the amount of secretion of digestive juice, an increase in the retention time in the digestive tract, and the like) than in the fasting state, and therefore, there is a possibility that the desired therapeutic effect cannot be obtained or an unexpected adverse effect is caused. Therefore, increasing the dissolution rate of a drug from a solid preparation is particularly important in developing an orally administered preparation.

As a means for improving the solubility of a poorly water-soluble drug in a solid preparation with respect to water, a solid dispersion in which drug molecules are uniformly dispersed in a matrix in a solid state and the drug molecules are in a state of not forming crystals (amorphous state) can be used. As such a solid dispersion, a preparation containing a drug, an amorphous stabilizer and an amorphization inducer has been studied. For example, patent document 1 discloses a solid dispersion characterized by subjecting a preparation containing nicardipine hydrochloride, 15 wt% of urea as an amorphization inducer, and hydroxypropylmethylcellulose as an amorphous stabilizer to a heat treatment or a mechanochemical treatment. Patent document 2 discloses a solid dispersion characterized by subjecting a preparation containing efonidipine hydrochloride, 11 wt% urea as an amorphization inducer, and hydroxypropylmethylcellulose acetate succinate as an amorphous stabilizer to a heat treatment or a mechanochemical treatment. Further, non-patent document 1 discloses a solid dispersion containing nifedipine, polyvinylpyrrolidone and 7 wt% of urea.

However, the solid dispersions of patent documents 1 and 2 are prepared by applying an excessive load to the drug, such as high-temperature heating or mechanochemical treatment, and there is a concern that the drug may be decomposed. Further, although patent document 3 describes that efonidipine hydrochloride has an increased water solubility, patent document 4 describes that cyclosporin a has an increased water solubility, patent document 5 describes that bicalutamide has an increased water solubility, patent document 6 describes that amifostine has an increased water solubility, patent document 7 describes that itraconazole has an increased water solubility, patent document 8 describes that 6-hydroxy-5, 7-dimethyl-2-methylamino-4- (3-pyridylmethyl) benzothiazole has an increased water solubility, non-patent document 1 describes that nifedipine has an increased water solubility, non-patent document 2 describes that "-O- (4-methoxyphenyl) acetyltyrosine has an increased water solubility, however, the optimum amorphous stabilizer and the optimum amorphous transition inducer may not be the same in terms of the type or the optimum blending amount for the drug. Patent document 9 describes a solid dispersion of a poorly water-soluble drug, but does not specifically describe a preparation containing an NPYY5 receptor antagonist incorporated in the solid preparation of the present invention.

Note that, although the present applicant has filed a patent for a solid preparation of NPYY5 receptor antagonist, carboxymethyl ethyl cellulose is not used (PCT/JP 2008/066818).

Documents of the prior art

Patent document

Patent document 1: international publication No. 97/06781 pamphlet

Patent document 2: japanese laid-open patent publication No. 9-309834

Patent document 3: japanese laid-open patent publication No. 2-49728

Patent document 4: japanese Kokai publication Hei-2004-528358

Patent document 5: japanese patent laid-open publication No. 2004-143185

Patent document 6: japanese Kohyo publication 2002-529519

Patent document 7: japanese laid-open patent publication No. 2004-67606

Patent document 8: japanese laid-open patent publication No. 9-309828

Patent document 9: international publication No. 2007/108463 pamphlet

Non-patent document

Non-patent document 1: research focus on human science such as drug design in 17 years, report No. KH31024, topic No. 3 (release date: 2006, 7 and 31)

Non-patent document 2: pharmaceutics Vol.53, No.4, p.221-228

Disclosure of Invention

Problems to be solved by the invention

Therefore, there is a need to develop new solid formulations that improve the solubility of NPYY5 receptor antagonists, in particular trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide.

Means for solving the problems

Accordingly, the present inventors have intensively studied and found that, when carboxymethylethylcellulose (hereinafter, also referred to as CMEC) is contained in a solid preparation of an NPYY5 receptor antagonist, and an amorphization inducer is contained as required, the solubility of the NPYY5 receptor antagonist, particularly trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide, can be improved.

Namely, the present invention relates to:

(1) a solid preparation comprising a compound represented by the formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate of either thereof and carboxymethyl ethyl cellulose:

[ in the formula, R¹Is a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent or an aryl group which may have a substituent,

R²is hydrogen or a lower alkyl group,

R¹and R²May be taken together to form a lower alkylene group,

n is 1 or 2, and n is a hydrogen atom,

x is

Lower alkylene which may have a substituent,

Lower alkenylene which may have a substituent,

-CO-lower alkylene which may have a substituent,

-CO-lower alkenylene which may have a substituent or

(in the formula, R³、R⁴、R⁵And R⁶Each independently is hydrogen or lower alkyl,

is cycloalkylene which may have a substituent, cycloalkenylene which may have a substituent, bicycloalkenylene (ビシクロアルキレン bicycloalkylene) which may have a substituent, arylene which may have a substituent or heterocyclodiyl which may have a substituent, p and q are each independently 0 or 1),

-NR²x-can be

(in the formula, wherein,

is piperidinediyl, piperazinediyl, pyridinediyl, pyrazinediyl, pyrrolidinediyl or pyrrolediyl, U is a single bond, lower alkylene or lower alkenylene),

y is OCONR⁷、CONR⁷、CSNR⁷、NR⁷CO or NR⁷CS，

R⁷Is hydrogen or lower alkylThe base group is a group of a compound,

z is lower alkyl which may have a substituent, lower alkenyl which may have a substituent, amino which may have a substituent, lower alkoxy which may have a substituent, cycloalkyl which may have a substituent, heterocyclic group which may have a substituent ];

(2) a solid preparation described in the above (1) which comprises a compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate of the salt and carboxymethyl ethyl cellulose:

[ solution 6]

(wherein X is

Is a heterocyclic diradical, R¹An alkyl group having 3 to 10 carbon atoms which may have a substituent or a cycloalkyl group having 5 to 6 carbon atoms which may have a substituent, and the other symbols have the same meanings as in the above (1);

(3) a solid preparation described in the above (1) which comprises a compound represented by the following formula, a pharmaceutically acceptable salt thereof or a solvate of the salt and carboxymethyl ethyl cellulose:

(in the formula, R¹Is a lower alkyl group, and is,

R²is hydrogen or a lower alkyl group,

z is lower alkyl which may have a substituent, lower alkenyl which may have a substituent, amino which may have a substituent, lower alkoxy which may have a substituent, cycloalkyl which may have a substituent, or heterocyclic group which may have a substituent);

(4) the solid preparation according to any one of the above (1) to (3), wherein the content of the compound represented by the formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof in the preparation is 5 to 50% by weight;

(5) the solid preparation according to the above (4), wherein the content of the compound represented by the formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate of either thereof in the preparation is 15 to 30% by weight;

(6) the solid preparation according to the above (4), wherein the content of the compound represented by the formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate of either thereof in the preparation is 25 to 30% by weight;

(7) the solid preparation according to any one of the above (1) to (6), wherein the compound represented by the formula (I) in the preparation is trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide;

(8) the solid preparation according to the above (7), which comprises 5 to 50% by weight of trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide and 50 to 95% by weight of carboxymethylethylcellulose;

(9) the solid preparation according to the above (7), which comprises 15 to 30% by weight of trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide and 70 to 85% by weight of carboxymethylethylcellulose;

(10) the solid preparation according to the above (7), which comprises 25 to 30% by weight of trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide and 70 to 75% by weight of carboxymethylethylcellulose;

(11) the solid preparation according to any one of the above (1) to (10), wherein the blending ratio of trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide to carboxymethylethylcellulose is 1: 1 to 1: 19;

(12) the solid preparation according to the above (11), wherein the blending ratio of trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide to carboxymethylethylcellulose is 1: 2.33 to 1: 5.67;

(13) the solid preparation according to the above (11), wherein the ratio of trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide to carboxymethylethylcellulose is 1: 2.33 to 1: 3;

(14) the solid preparation according to any one of (1) to (13) above, further comprising an amorphization-inducing agent;

(15) the solid preparation according to the above (14), wherein the amorphization-inducing agent is at least one selected from the group consisting of 1 or 2 of amino acids or salts thereof, aspartame (アスパルテ - ム asparatame), erythorbic acid or salts thereof, ascorbic acid or salts thereof, stearates, taurine, inositol, ethylurea, citric acid or salts thereof, glycyrrhizic acid or salts thereof, gluconic acid or salts thereof, creatinine, salicylic acid or salts thereof, tartaric acid or salts thereof, succinic acid or salts thereof, calcium acetate, saccharin sodium, aluminum hydroxide, sorbic acid or salts thereof, dehydroacetic acid or salts thereof, sodium thiomalate, nicotinamide, urea, fumaric acid or salts thereof, polyethylene glycols, maltose, maltitol, mannitol, deoxyglucamine, sodium cholate and phosphatidylcholine;

(16) the solid preparation according to the above (14), wherein the amorphization inducing agent is urea;

(17) the solid preparation according to any one of (14) to (16) above, wherein the content of the amorphization inducing agent in the preparation is less than 8% by weight;

(18) the solid preparation according to the above (17), wherein the content of the amorphization inducing agent in the preparation is 0.1 to 6% by weight;

(19) the solid preparation according to the above (17), wherein the content of the amorphization inducing agent in the preparation is 2 to 4% by weight;

(20) the solid preparation according to any one of (1) to (13) above, which does not contain an amorphization-inducing agent;

(21) the solid preparation according to any one of the above (1) to (20), wherein the solid preparation is a solid dispersion;

(22) the solid preparation according to any one of the above (1) to (21) obtained by a spray drying method;

(23) a tablet comprising the solid preparation according to any one of (1) to (22) above;

(24) the tablet according to the above (23), wherein the weight of each 1 tablet is 450 to 550 mg;

(25) a method for producing the solid preparation described in (22) above by a spray drying method;

(26) a method for improving the solubility of trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide, which is characterized by adding carboxymethylethylcellulose to a solid preparation containing trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide;

(27) a method for improving the solubility of trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide, which is characterized by adding an amorphization-inducing agent to a solid preparation comprising trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide and carboxymethylethylcellulose;

(28) a method comprising controlling the dissolution rate of trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide to 60% or more 60 minutes after the start of the test and to 70% or more 180 minutes after the start of the test in the dissolution test solution 2 of the Japanese pharmacopoeia dissolution test method by containing carboxymethylethylcellulose.

ADVANTAGEOUS EFFECTS OF INVENTION

The solid preparation of the present invention can increase the dissolution of NPYY5 receptor antagonist, particularly trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide, from the preparation. The solid preparation of the present invention is preferably a stable preparation which can maintain an amorphous state even after long-term storage. Further, it is preferable to reduce the size of the preparation (for example, tablet) and to improve the ease of administration.

Drawings

[ FIG. 1] changes in the dissolution concentration of S-2367 in CMEC-containing preparations

[ FIG. 2] Change in dissolution Rate of S-2367 in CMEC-containing preparation

[ FIG. 3] X-ray diffraction Pattern of CMEC-containing preparation immediately after preparation

[ FIG. 4] X-ray diffraction Pattern of CMEC-containing preparation after storage with time

FIG. 5 dissolution behavior of a preparation containing CMEC and urea (containing 15% S-2367)

FIG. 6 dissolution behavior of a preparation containing CMEC and urea (20% S-2367 content)

[ FIG. 7] X-ray diffraction Pattern of a preparation containing CMEC and Urea immediately after preparation

[ FIG. 8] X-ray diffraction Pattern of a preparation containing CMEC and Urea after storage with time

Best Mode for Carrying Out The Invention

The NPYY5 receptor antagonist as the main drug used in the present invention is preferably a compound represented by the above formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate of either, and is described in WO01/37826 pamphlet and WO03/076374 pamphlet.

In the present specification, "halogen" includes fluorine, chlorine, bromine and iodine. Fluorine and chlorine are particularly preferred.

The "lower alkyl group" includes a linear or branched alkyl group having 1 to 10 carbon atoms, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, a hexyl group, an isohexyl group, an n-heptyl group, an isoheptyl group, an n-octyl group, an isooctyl group, an n-nonyl group, and an n-decyl group.

R¹The "lower alkyl group" in (1) is preferably a C3-10, more preferably a C3-6, most preferably an isopropyl group or a tert-butyl group.

In other cases, the "lower alkyl group" preferably has 1 to 6 carbon atoms, and more preferably has 1 to 4 carbon atoms.

Examples of the substituent for the "lower alkyl group which may have a substituent" in Z include

(1) Halogen; (2) a cyano group;

(3) and (ii) a lower alkoxy group, (iii) a mercapto group, (iv) a lower alkylthio group, (v) an acyl group, (vi) an acyloxy group, (vii) a carboxyl group, (viii) a lower alkoxycarbonyl group, (ix) an imino group, (x) a carbamoyl group, (xi) a thiocarbamoyl group, (xii) a lower alkylcarbamoyl group, (xiii) a lower alkylthiocarbamoyl group, (xiv) an amino group, (xv) a lower alkylamino group, or (xvi) a heterocyclic carbonyl group, each of which may be substituted with 1 or more substitutable groups selected from the substituent group β defined below.

"lower alkyl group which may have substituent(s)" other than Z (for example, R)¹And the like) may be substituted with 1 or more groups selected from substituent group β, and these substituents may be substituted at arbitrary positions.

The substituent group β means a group containing halogen, hydroxy group which may be protected, mercapto group, lower alkoxy group, lower alkenyl group, amino group, lower alkylamino group, lower alkoxycarbonylamino group, lower alkylthio group, acyl group, carboxyl group, lower alkoxycarbonyl group, carbamoyl group, cyano group, cycloalkyl group, phenyl group, phenoxy group, lower alkylphenyl group, lower alkoxyphenyl group, halophenyl group, naphthyl group and heterocyclic group.

The lower alkyl moiety of "lower alkoxy", "lower alkoxycarbonyl lower alkyl", "lower alkylphenyl", "lower alkoxyphenyl", "lower alkylcarbamoyl", "lower alkylthiocarbamoyl", "lower alkylamino", "halogeno-lower alkyl", "hydroxy-lower alkyl", "phenyl-lower alkoxy", "lower alkylthio", "phenyl-lower alkylthio", "lower alkoxycarbonylamino", "lower alkoxycarbonyl-lower alkenyl", "lower alkylsulfinyl", "lower alkylsulfonyl", "aryl-lower alkoxycarbonyl", "lower alkylbenzoyl" and "lower alkoxybenzoyl" is the same as the above-mentioned "lower alkyl".

Examples of the substituent for the "lower alkoxy group which may have a substituent" include 1 or more groups selected from the substituent group β, and preferably a phenyl group, a lower alkylphenyl group, a lower alkoxyphenyl group, a naphthyl group or a heterocyclic group.

The "cycloalkyl group" includes a cyclic alkyl group having 3 to 8 carbon atoms, preferably 5 or 6 carbon atoms. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Examples of the substituent of the "cycloalkyl group which may have a substituent" include 1 or more groups selected from the substituent group α, and any position may be substituted.

The "bicycloalkyl group" includes a group obtained by removing 1 hydrogen from an aliphatic ring having 5 to 8 carbon atoms and having 2 or more atoms in common to 2 rings. Specific examples thereof include bicyclo [2.1.0] pentyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, and bicyclo [3.2.1] octyl.

The "lower alkenyl group" includes a linear or branched alkenyl group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms, which has 1 or more double bonds at any position. Specifically, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, isoprenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl and the like are included.

The "lower alkenyl" moiety in "lower alkoxycarbonyl lower alkenyl" is the same as the above-mentioned "lower alkenyl".

Examples of the substituent of the "lower alkenyl group which may have a substituent(s)" include halogen, lower alkoxy, lower alkenyl, amino, lower alkylamino, lower alkoxycarbonylamino, lower alkylthio, acyl, carboxyl, lower alkoxycarbonyl, carbamoyl, cyano, cycloalkyl, phenyl, lower alkylphenyl, lower alkoxyphenyl, naphthyl and/or heterocyclic group, and the like.

The "acyl group" includes (1) a linear or branched alkylcarbonyl or alkenylcarbonyl group having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 4 carbon atoms, (2) a cycloalkylcarbonyl group having 4 to 9 carbon atoms, preferably 4 to 7 carbon atoms, and (3) an arylcarbonyl group having 7 to 11 carbon atoms. Specific examples thereof include formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, pivaloyl group, hexanoyl group, acryloyl group, propioloyl group, methacryloyl group, crotonyl group, cyclopropylcarbonyl group, cyclohexylcarbonyl group, cyclooctylcarbonyl group and benzoyl group.

The acyl moiety of "acyloxy" is also the same as described above.

The "cycloalkenyl group" includes groups having 1 or more double bonds at any position in the cycloalkyl ring, and specific examples thereof include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cyclohexadienyl.

Examples of the substituent of the "cycloalkenyl group which may have a substituent" include 1 or more groups selected from the substituent group β.

As the substituent for the "amino group which may have a substituent", there may be mentioned a substituent group β, a benzoyl group which may have a substituent and/or a heterocyclic carbonyl group which may have a substituent (wherein the substituent means a hydroxyl group, a lower alkyl group, a lower alkoxy group and/or a lower alkylthio group).

"aryl" refers to monocyclic or polycyclic cyclic aromatic hydrocarbon groups including phenyl, naphthyl, anthryl, and phenanthryl. In addition, aryl groups condensed with other non-aromatic cyclic hydrocarbon groups are also included, and specific examples thereof include indanyl, indenyl, biphenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like. Phenyl is particularly preferred.

The aryl moiety of "aryl lower alkoxycarbonyl" is also the same.

The "aryl group which may have a substituent" and the "phenyl group which may have a substituent" in Z include "aryl group", "phenyl group" which may be substituted with substituent group α, lower alkyl group substituted with 1 or more substitutable groups selected from substituent group α, and the like.

Examples of the substituent for the "aryl group which may have a substituent" and the "phenyl group which may have a substituent" other than Z include 1 or more groups selected from the substituent group β.

"cycloalkyl" includes "cycloalkyl", "cycloalkenyl", "bicycloalkyl" and "aryl" described above.

"non-aromatic cyclic hydrocarbon group" includes the above-mentioned "cycloalkyl group", "cycloalkenyl group" and "bicycloalkyl group".

The "cyclic hydrocarbon group which may have a substituent" includes the above-mentioned "cycloalkyl group which may have a substituent", "cycloalkenyl group which may have a substituent", "bicycloalkyl group which may have a substituent" and "aryl group which may have a substituent".

"Heterocyclyl" includes heterocycles containing 1 or more heteroatoms selected from O, S and N in the ring, and specifically includes pyrrolyl, imidazolyl, pyrazolyl, pyridyl and pyridazinylAzinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isozylAzolyl group,Azolyl group,5-6 membered aromatic heterocycle such as oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl and thienyl; indolyl, isoindolyl, indazolyl, indolizinyl, indolinyl, isoindolinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl (プリニル), pteridinyl, benzopyranyl, benzimidazolyl, benzisoxazinylAzolyl, benzoAzolyl, benzo2-ring condensed heterocyclic groups such as oxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, benzotriazolyl, imidazopyridinyl, triazolopyridinyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolinyl, isoquinolinyl, naphthyridinyl, dihydropyridinyl, tetrahydroquinolinyl, tetrahydrobenzothiophenyl and the like; carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenothiazineRadical (フエノキサチイニル), thiopheneCondensed heterocyclic group having 3 rings such as oxazinyl group and dibenzofuranyl group; dioxygenNon-aromatic heterocyclic groups such as a heterocyclic hexyl group, a thiacyclopropyl group, an epoxyethyl group, an oxathiolanyl group (オキサチオラニル), an azetidinyl group (アゼチジニル), a thiaalkyl group, a pyrrolidinyl group, a pyrrolinyl group, an imidazolidinyl group, an imidazolinyl group, a pyrazolidinyl group, a pyrazolinyl group, a piperidyl group, a pyrazinyl group, a morpholinyl group, a morpholino group, a thiomorpholino group, a dihydropyridinyl group, a tetrahydrofuryl group, a tetrahydropyranyl group, a tetrahydrothiazolyl group, and a tetrahydroisothiazolyl group.

Condensed heterocyclic groups condensed with rings other than heterocyclic rings (e.g., benzothiazolyl and the like) may have a connecting bond on any ring.

The substituent for the "heterocyclic group which may have a substituent" is the same as the above-mentioned "aryl group which may have a substituent".

The heterocyclic moiety of "heterocyclic carbonyl", "heterocyclic oxy", "heterocyclic thio" and "heterocyclic-substituted phenyl" is the same as the above-mentioned "heterocyclic group".

The "lower alkylene group" includes a 2-valent group in which 1 to 6, preferably 2 to 6, and more preferably 3 to 6 methylene groups are bonded, and specific examples thereof include a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, and a hexamethylene group. Particularly preferred is tetramethylene.

The lower alkylene moiety of the "lower alkylenedioxy group" is the same as the above-mentioned "lower alkylene group", and is preferably methylenedioxy group or ethylenedioxy group.

The "lower alkenylene group" refers to a 2-valent group in which 2 to 6, preferably 3 to 6, and more preferably 4 to 5 methylene groups are connected, and includes a group in which at least 1 of carbon-carbon bonds is a double bond.

"cycloalkylene" refers to a 2-valent radical resulting from the removal of 1 hydrogen atom from the above "cycloalkyl". As the "cycloalkylene group" in X, 1, 4-cyclohexanediyl group is preferred.

"Cycloalkenylene" includes groups having at least 1 double bond within the ring of the above cycloalkylene group.

The "bicycloalkenylene group" includes a group obtained by further removing 1 hydrogen from the above-mentioned "bicycloalkyl group". Specific examples thereof include bicyclo [2.1.0] pentyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, and bicyclo [3.2.1] octyl.

The "heterocyclodiyl" includes a 2-valent group obtained by removing 1 hydrogen atom from the above-mentioned "heterocyclic group". Preferably piperidinediyl, piperazinediyl, pyridyldiyl, pyrimidinediyl, pyrazinediyl, pyrrolidinediyl or pyrrolediyl, more preferably piperidinediyl.

The "arylene group" includes a 2-valent group obtained by removing 1 hydrogen atom from the above-mentioned "aryl group". Preferably phenylene.

"heteroarylene" includes groups having aromatic character as in "heterocyclodiyl" above. Specific examples thereof include pyrrolediyl, imidazolediyl, pyrazolediyl, pyridinediyl, pyridazindiyl, pyrimidinediyl, pyrazindiyl, triazoldiyl, triazinediyl and isopropylideneA diazoldiyl group,A diazoldiyl group,Oxadiazolyl, isothiazolediyl, thiazolediyl, thiadiazolediyl, furandiyl, thiophenediyl and the like.

Examples of the substituent for the "lower alkylene group which may have a substituent", "lower alkenylene group which may have a substituent", "cycloalkylene group which may have a substituent", "cyclohexylene group which may have a substituent", "bicycloalkylene group which may have a substituent", "cycloalkenylene group which may have a substituent", "phenylene group which may have a substituent", "heterocyclodiyl group which may have a substituent" and "piperidylene group which may have a substituent" include 1 or more substitutable groups selected from the substituent group β, and preferably include halogen, hydroxy, lower alkyl, halogenated lower alkyl, lower alkoxy, amino, lower alkylamino, acyl, carboxy, lower alkoxycarbonyl, and the like. These groups may be substituted at arbitrary positions.

Examples of the "pharmaceutically acceptable salt" include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; salts of organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid or citric acid; salts of organic bases such as ammonium, trimethylammonium, and triethylammonium; alkali metal salts such as sodium and potassium; and salts of alkaline earth metals such as calcium and magnesium.

"solvate" preferably refers to a hydrate, 1 molecule of a compound of the invention can coordinate to any number of water molecules.

"prodrug" refers to a derivative of a compound of the present invention having a chemically or metabolically decomposable group, which is a compound that forms a pharmaceutically active compound of the present invention in vivo by solvolysis or under physiological conditions. Methods for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of produgs, Elsevier, Amsterdam 1985.

For example, when the compound (I) of the present invention has a carboxyl group, prodrugs such as an ester derivative prepared by reacting the carboxyl group of the compound (I) with an appropriate alcohol, or an amide derivative prepared by reacting the carboxyl group of the compound (I) with an appropriate amine can be exemplified.

For example, when the compound (I) of the present invention has a hydroxyl group, a prodrug such as an acyloxy derivative prepared by reacting the hydroxyl group of the compound (I) with an appropriate acid halide or an appropriate acid anhydride can be exemplified.

For example, when the compound (I) of the present invention has an amino group, a prodrug such as an amide derivative prepared by reacting the amino group of the compound (I) with an appropriate acid halide or an appropriate mixed acid anhydride can be exemplified.

When the compound (I) of the present invention has an asymmetric carbon atom, it includes racemates, two enantiomer pairs and all stereoisomers (geometric isomers, epimers, enantiomers, etc.). In addition, when the compound (I) of the present invention has a double bond, any of the E isomer and the Z isomer may be contained when they may exist. When X is a cycloalkylene group, any of cis-isomer and trans-isomer is also included.

Preferred examples of the compound represented by the formula (I) include trans-N- (4- ((2S, 6R) -2, 6-dimethylmorpholino) phenyl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide, trans-N- (6- (5, 6-dihydropyridin-1 (2H) -yl) pyridin-3-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide, trans-N- (6- (4-trifluoromethyl) phenyl) pyridin-3-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide, trans-N- (6-fluorobenzo [ d ] thiazol-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide, and the like, trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide (hereinafter, also referred to as S-2367) or the following compounds.

[ solution 10]

A particularly preferred compound is trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide (S-2367). The compound is crystalline at room temperature.

The content of the NPYY5 receptor antagonist, particularly S-2367, in the preparation of the present invention is preferably a content that improves solubility and produces a medicinal effect, and is (1) usually 5 to 50% by weight, (2) preferably 10 to 40% by weight, (3) more preferably 15 to 30% by weight, (4) further preferably 20 to 30% by weight, and (5) particularly preferably 25 to 30% by weight, based on the total amount of the preparation. If the amount is less than this, there is a possibility that a sufficient drug effect cannot be obtained or the size of the preparation becomes large, and if it is more than this, the solubility may not be sufficiently improved.

The NPYY5 receptor antagonist in the preparation of the present invention is not particularly limited as long as it is an orally administrable drug, but a so-called poorly water-soluble drug having low water solubility is preferred. Here, the water solubility of the drug means the solubility of the drug at 37 ℃ in a buffer solution and water having a pH in the range of 1 to 8, which is considered to be an environment in the digestive tract, and typically, the solubility in the first solution in the dissolution test, the second solution in the dissolution test, and water in the japanese pharmacopoeia is 100 μ g/mL or less, or even 50 μ g/mL or less, or even 10 μ g/mL or less. In particular, even S-2367 (solubility: about 3.5. mu.g/mL according to the solubility test in the Japan pharmacopoeia (dissolution test 2 nd solution (37 ℃)), which is a poorly water-soluble drug, can improve the solubility.

The amorphous stabilizer is preferably a substance that stabilizes an amorphous state by interacting with a change state (change ) of the crystal lattice, based on the vibration (ゆる "" せる) of the crystal structure of the poorly water-soluble drug by the amorphization inducing agent. However, an amorphous stabilizer which does not contain an amorphization inducer and can control the crystallization of the compound to an amorphous state by itself is also included. Specifically, carboxymethyl ethyl cellulose (CMEC) is preferable.

CMEC refers to the mixed ester of carboxymethyl and ethyl groups of cellulose. The CMEC may be any one included in the pharmaceutical excipient standards, but preferably contains 8.9 to 14.9% of carboxymethyl group (-CH) according to the quantitative method defined in the pharmaceutical excipient standards₂COOH) and 32.5-43.0% of ethoxy (-OC)₂H₅) The substance (2) is not particularly limited. Specifically, CMEC (manufactured by sanyo chemical industries co., ltd.) can be exemplified.

The CMEC content in the preparation of the present invention is preferably a content that improves the solubility of the main drug, and is (1) usually 50 to 95 wt%, (2) preferably 60 to 90 wt%, (3) more preferably 70 to 85 wt%, (4) further preferably 70 to 80 wt%, and (5) particularly preferably 70 to 75 wt%, based on the total amount of the preparation. If the amount is less than this, the CMEC has a reduced crystallization-inhibiting effect, and therefore the drug may crystallize in the production process, and an amorphous preparation may not be obtained.

In 1 preferred embodiment of the solid preparation of the present invention, (1) the NPYY5 receptor antagonist is usually 5 to 50 wt% and the CMEC is 50 to 95 wt% based on the total amount of the preparation. (2) Preferably, the NPYY5 receptor antagonist accounts for 10-40 wt%, and the CMEC accounts for 60-90 wt%. (3) More preferably, the NPYY5 receptor antagonist accounts for 15-30 wt%, and the CMEC accounts for 70-85 wt%. (4) Further preferably, the NPYY5 receptor antagonist accounts for 20-30 wt%, and the CMEC accounts for 70-80 wt%. (5) Particularly preferably, the NPYY5 receptor antagonist accounts for 25-30 wt%, and the CMEC accounts for 70-75 wt%.

In 1 preferred embodiment of the solid preparation of the present invention, (1) usually 5 to 50% by weight of S-2367 and 50 to 95% by weight of CMEC are used, based on the total amount of the preparation. (2) Preferably, the S-2367 content is 10 to 40% by weight and the CMEC content is 60 to 90% by weight. (3) More preferably, S-2367 is 15 to 30% by weight and CMEC is 70 to 85% by weight. (4) More preferably, the amount of S-2367 is 20 to 30% by weight and the amount of CMEC is 70 to 80% by weight. (5) Particularly preferably, S-2367 is 25 to 30% by weight and CMEC is 70 to 75% by weight.

In 1 preferred embodiment of the solid preparation of the present invention, the weight ratio (1) of S-2367 to CMEC is usually 1: 1 to 1: 19. (2) Preferably S-2367 and CMEC are 1: 1.5-1: 9. (3) More preferably S-2367 and CMEC is 1: 2.33-1: 5.67. (4) More preferably S-2367 to CMEC of 1: 2.33 to 1: 4. (5) Particularly preferably S-2367 and CMEC are 1: 2.33-1: 3.

The amorphization inducer used in the present invention is a compound having a function and property of changing the lattice energy of a poorly water-soluble drug in a low energy direction and increasing the lattice vibration (ゆらぎ) at the same temperature. Specific examples thereof include amino acids or salts thereof (e.g., aspartic acid and sodium salts thereof, magnesium salts thereof, glycine, alanine, glutamic acid hydrochloride, etc.), aspartame, erythorbic acid or salts thereof, ascorbic acid or salts thereof (sodium salts), stearic acid esters, aminoethanesulfonic acid, inositol, ethylurea, citric acid or salts thereof (e.g., trisodium, disodium, and sodium dihydrogen salts, potassium salts), glycyrrhizic acid or salts thereof (e.g., sodium salts such as trisodium and disodium, ammonium salts such as diammonium and monoammonium, and potassium salts), gluconic acid or salts thereof (e.g., sodium salts, calcium salts, and magnesium salts), creatinine, salicylic acid or salts thereof (e.g., sodium salts), tartaric acid or salts thereof (e.g., sodium salts, potassium sodium salts, and potassium salts), succinic acid or salts thereof (e.g., sodium salts such as disodium and monosodium), calcium acetate, sodium saccharin, aluminum hydroxide, sorbic acid or salts thereof (e.g., potassium salts), calcium acetate, sodium saccharin, sodium hydroxide, dehydroacetic acid or its salt (sodium salt, etc.), sodium thiomalate, nicotinamide, urea, fumaric acid or its salt (sodium salt, etc.), polyethylene glycols, maltose, maltitol, maleic acid, mannitol, meglumine, sodium deoxycholate, phosphatidylcholine, and the like.

Examples of the amorphization inducer include amino acids or salts thereof (e.g., aspartic acid and sodium salts thereof, magnesium salts thereof, glycine, alanine, glutamic acid hydrochloride, etc.), ascorbic acid or salts thereof (e.g., sodium salts), stearic acid esters, taurine, ethylurea, citric acid or salts thereof (e.g., trisodium, disodium, sodium dihydrogen, etc., potassium salts), glycyrrhizic acid or salts thereof (e.g., sodium salts such as trisodium, disodium, ammonium salts such as diammonium, monoammonium, etc., potassium salts, etc.), creatinine, tartaric acid or salts thereof (e.g., sodium salts, sodium potassium salts, hydrogen potassium salts, etc.), succinic acid or salts thereof (e.g., sodium salts such as disodium, monosodium, etc.), saccharin sodium, nicotinamide, urea, fumaric acid or salts thereof (e.g., sodium salts), polyethylene glycols, maltose, maltitol, mannitol, and meglumine.

More preferable examples of the amorphization inducer include amino acids or salts thereof (e.g., aspartic acid and sodium salts thereof, magnesium salts thereof, glycine, alanine, glutamic acid hydrochloride, etc.), ethylurea, glycyrrhizic acid or salts thereof (e.g., sodium salts such as trisodium and disodium, ammonium salts such as diammonium and monoammonium, potassium salts, etc.), tartaric acid or salts thereof (e.g., sodium salts, sodium-potassium salts, and hydrogen-potassium salts), succinic acid or salts thereof (e.g., sodium salts such as disodium and monosodium), saccharin sodium, nicotinamide, urea, maltose, maltitol, mannitol, and meglumine. Urea is particularly preferred.

The content of the amorphization inducing agent in the preparation of the present invention is a content that improves solubility, and is (1) usually less than 8% by weight, (2) preferably 0.1 to 6% by weight, (3) more preferably 0.5 to 5% by weight, (4) further preferably 1 to 4.5% by weight, and (5) particularly preferably 2 to 4% by weight, based on the total amount of the preparation. Two or more types of amorphization inducers may be used in combination, but when used together, the combined amount thereof may be within the above-mentioned content range. If the amount is less than this, there is a possibility that the solubility of the drug cannot be increased, and if it is more than this, the solubility of the drug may be lowered to cause a side effect of the amorphization inducing agent, and further, since the effect of suppressing crystallization of the amorphous stabilizer (particularly, a water-soluble polymer) is lowered in the production process, the drug is easily crystallized when the solvent is removed, and it is difficult to obtain an amorphous preparation.

In 1 preferred embodiment of the solid preparation of the present invention, (1) usually 5% by weight or more of NPYY5 receptor antagonist, 50% by weight or more of CMEC, and less than 8% by weight of amorphization inducer, (2) preferably 10 to 40% by weight of NPYY5 receptor antagonist, 54 to 89.9% by weight of CMEC, and 0.1 to 6% by weight of amorphization inducer, (3) more preferably 10 to 30% by weight of NPYY5 receptor antagonist, 65 to 89.5% by weight of CMEC, and 0.5 to 5% by weight of amorphization inducer, (4) further preferably 10 to 20% by weight of NPYY5 receptor antagonist, 75.5 to 89% by weight of CMEC, 1 to 4.5% by weight of amorphization inducer, and (5) particularly preferably 15 to 20% by weight of NPYY5 receptor antagonist, 76 to 83% by weight of CMEC, and 2 to 4% by weight of amorphization inducer are used for the total amount of the preparation.

In 1 preferred embodiment of the solid preparation of the present invention, (1) usually 5% by weight or more of S-2367, 50% by weight or more of CMEC, and less than 8% by weight of urea, (2) preferably 10 to 40% by weight of S-2367, 54 to 89.9% by weight of CMEC, 0.1 to 6% by weight of urea, (3) more preferably 10 to 30% by weight of S-2367, 65 to 89.5% by weight of CMEC, and 0.5 to 5% by weight of urea, (4) further preferably 10 to 20% by weight of S-2367, 75.5 to 89% by weight of CMEC, and 1 to 4.5% by weight of urea, (5) particularly preferably 15 to 20% by weight of S-2367, 76 to 83% by weight of CMEC, and 2 to 4% by weight of urea are used for the total amount of the preparation.

Even if the solid preparation of the present invention does not substantially contain an amorphization inducing agent, the elution property of the main ingredient (particularly S-2367) can be sufficiently improved, but the amorphous inducing agent may be preferably contained due to the content of the main ingredient. In particular, when S-2367 is 20%, the dissolution property is improved by the addition of the amorphization-inducing agent.

The preparation method of the present invention preferably comprises dissolving the NPYY5 receptor antagonist (particularly S-2367), CMEC, and desired amorphization inducer in a solvent, removing the solvent, and pulverizing the obtained solid to a suitable particle size. The solvent may be any solvent that dissolves these raw materials. Specific solvents are water, ethanol, acetone, halocarbons and mixtures thereof. Further, as a method for removing the solvent, heating under reduced pressure or spray drying (spray drying) can be mentioned.

In the case of the spray drying method, a spray dryer is preferably used. The production conditions may be conditions under which the preparation of the present invention can be produced with a good yield. For example, a liquid containing a main drug having a solid content of about 1 to 20% is sprayed at an outlet temperature of 50 to 110 ℃.

It has been clarified that the amounts of CMEC and amorphization inducer as amorphous stabilizers in the solid formulation of the present invention affect the solubility and stability of NPYY5 receptor antagonist. The stability of the main drug in the preparation of the present invention was evaluated by confirming the amorphous state by powder X-ray diffraction measurement.

The solid preparation of the present invention is obtained in the form of solid powder, granules, blocks, or the like. Even if the preparation of the present invention is obtained in the form of a block, a powder can be obtained by pulverization or the like. The powder may also be contained in granules or tablets. As the excipient, binder, lubricant, etc. used in the granules or tablets, those conventionally used in pharmaceutical formulation can be used. Examples of the excipient include excipients such as D-mannitol, disintegrants such as carboxymethylcellulose calcium, binders such as hydroxypropylcellulose, lubricants such as magnesium stearate, and coating agents such as hydroxypropylmethylcellulose.

In the case of performing an elution test of a preparation containing 20mg of the main drug (e.g., S-2367) in accordance with the method 2 (paddle method, 50rpm, elution test solution 2, 900mL) of the japanese pharmacopoeia, the solid preparation of the present invention has an elution rate of (1) usually 4% or more in 30 minutes, 7% or more in 60 minutes, and 15% or more in 180 minutes, (2) preferably 10% or more in 30 minutes, 15% or more in 60 minutes, and 30% or more in 180 minutes, (3) more preferably 30% or more in 30 minutes, 40% or more in 60 minutes, and 50% or more in 180 minutes, (4) further preferably 30% or more in 30 minutes, 50% or more in 60 minutes, and 60% or more in 180 minutes, and (5) particularly preferably 30% or more in 30 minutes, 60% or more in 60 minutes, and 70% or more in 180 minutes.

Among the solid preparations of the present invention, the stable preparation means a preparation which can maintain an amorphous state even after storage over time, particularly a solid preparation which can maintain an amorphous state of a main drug (e.g., S-2367) even when stored at 60 ℃ for 1 week in a tight glass bottle stopper.

Since the solid preparation of the present invention can improve the dissolution of the main ingredient, the amount of the main ingredient to be incorporated into the tablet can be reduced, for example, and as a result, the tablet can be miniaturized. Specifically, the weight of S-2367 tablets per 1 tablet before the solid preparation of the present invention is used is about 840mg, whereas the weight of S-2367 tablets per 1 tablet after the solid preparation of the present invention is used is about 450 to 550mg, preferably about 500mg, and the administration property is improved.

Examples

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

(preparation method of CMEC-containing preparation)

trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide (S-2367) as an NPYY5 receptor antagonist, urea (manufactured by Wako pure chemical industries, Ltd.) as an amorphization inducer, and carboxymethylethylcellulose (CMEC, manufactured by Sanyo chemical industries, Ltd., a product meeting the pharmaceutical excipient standards) were used. S-2367 is produced by a method described in WO 01/37826. S-2367 and CMEC were dissolved by adding them to acetone in the amounts prescribed in Table 1. Subsequently, when urea is added, a prescribed amount of urea is dissolved by adding it to ethanol. These solutions were mixed, and spray-dried at an outlet temperature of about 80 ℃ using a spray dryer B-290/B-295 (manufactured by Buchi (ビユツヒ)) to prepare a powder, thereby preparing a solid preparation of the present invention.

(dissolution test method)

The solid preparation of the present invention prepared by the above method was subjected to an elution test according to the method specified in the japanese pharmacopoeia, 15 th edition. The concentration of S-2367 was measured by an autosampler system (autosampler W PAS-615 (manufactured by Fushan industries Co., Ltd.), spectrophotometer UV-1700 (manufactured by Shimadzu corporation)) or spectrophotometer model 8453 (manufactured by Agilent). The dissolution test conditions are as follows.

Test methods: japanese pharmacopoeia formula 2 (Paddle method) rotation speed of 50rpm

Test solutions: dissolution test solution 2 (900mL, 37 ℃ C.)

The time of collection of the eluate: 0.5, 10, 15, 20, 25, 30, 45, 60, 75, 90, 105, 120, 150, 180 minutes

Detection wavelength: 243nm

Optical path length: 5mm

(conditions for HPLC measurement)

Detection wavelength: 242nm

Column chromatography: capcell Pak C18 MG, 3 μm, 3.0X 50mm, Zishengtang

Column temperature: 35 deg.C

The mobile phase: HPLC using methanol/water mixture (27: 73)

Flow rate: about 0.6 mL/min

Sample introduction amount: 15 μ L

The S-2367 content in the eluate was determined by the following equation.

(formula 1)

Ws: s-2367 amount of Standard substance (mg)

As: peak area of standard solution

At: peak area of test solution

1/500: dilution factor

(powder X-ray diffraction measurement)

The powder X-ray diffraction pattern of the solid preparation of the present invention was measured by a powder X-ray diffraction apparatus RINT2000 (manufactured by Rigaku Corporation, リガク). The powder X-ray diffraction measurement was carried out for the preparation immediately after the preparation and the preparation after 1 week of storage under the tight conditions of a glass stopper at 60 ℃.

Test example 1 dissolution behavior of CMEC-containing preparation

The solid formulations of the present invention, which were prepared by the above method without urea and with the contents of S-2367 and CMEC as shown in Table 1, were prepared. For these preparations, dissolution tests were performed by the above-described method.

[ Table 1]

(wt%)

	Example 1	Example 2	Example 3	Example 4	Reference example 1
						S-2367	15.0	20.0	25.0	30.0	50.0
CMEC	85.0	80.0	75.0	70.0	50.0
						Total up to	100.0	100.0	100.0	100.0	100.0

As shown in FIG. 1, the results of measuring the elution concentration of S-2367 over time indicate that the elution behavior changes similarly when the content of S-2367 is 15 to 30% by weight (examples 1 to 4), and the elution concentration is about 15 to 16. mu.g/mL 60 minutes after the start of the test. After 60 minutes a substantially constant concentration can be maintained. On the other hand, when the content of S-2367 is 50% by weight (reference example 1), the dissolution rate exceeds that of S-2367 itself, but the dissolution property is not so improved.

The results of converting the elution concentration of S-2367 into the elution rate are shown in FIG. 2. If the content of S-2367 is 15 to 30% by weight, the change in dissolution rate is substantially the same, and is about 60% or more after 60 minutes from the start of the test and 70% or more after 180 minutes.

Test example 2 storage stability of CMEC-containing preparation

In order to confirm the state of the main drug (S-2367) in the preparation of table 1, powder X-ray diffraction measurement was performed. As a result, as shown in FIG. 3, no crystal peak of S-2367 was detected in all the preparations immediately after the preparation, and S-2367 was amorphous. On the other hand, when the preparation is stored for 1 week at 60 ℃ under a tight glass bottle stopper condition, as shown in FIG. 4, the preparation with 15-30 wt% of S-2367 has no crystal peak of S-2367, can maintain an amorphous state, and is stable; however, the main crystal peaks (2 θ: 16.9, 17.9, 18.9, and 20.1 °) of S-2367 were detected in 50 wt% of the preparation, and the amorphous state could not be maintained.

Test example 3 dissolution behavior of CMEC-and Urea-containing formulations

As shown in tables 2 and 3, preparations containing 15 to 20 wt% of S-2367 and 4 wt% of urea were prepared according to the above-mentioned methods, and the elution behavior was examined.

[ Table 2] (wt%)

	Example 1	Example 5
			S-2367	15.0	15.0
CMEC	85.0	81.0
			Urea	-	4.0
Total up to	100.0	100.0

[ Table 3] (wt%)

	Example 2	Example 6
			S-2367	20.0	20.0
CMEC	80.0	76.0
			Urea	-	4.0
Total up to	100.0	100.0

As shown in fig. 5 and 6, in the case of the preparation containing S-2367 in 15 wt%, the dissolution rate was almost unchanged even when urea was added, but in the case of the preparation containing S-2367 in 20 wt%, the dissolution rate was increased when urea was added. Test example 4 storage stability of CMEC-and Urea-containing formulations

In order to confirm the state of the main drug (S-2367) in the urea-containing preparations of tables 2 and 3, powder X-ray diffraction measurement was performed. As a result, as shown in fig. 7 and 8, immediately after the preparation, no crystal peak of S-2367 was observed at any time point after the storage for 1 week under the tight condition of the glass stopper at 60 ℃.

Industrial applicability

The present invention provides formulations of NPYY5 receptor antagonists, particularly trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide (S-2367), with improved water solubility and high stability.

Claims (28)

1. A solid preparation characterized by containing a compound represented by the formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate of either thereof and carboxymethyl ethyl cellulose,

in the formula, R¹Is lower alkyl which may have substituents, cycloalkyl which may have substituents or

An aryl group having a substituent(s),

R²is hydrogen or a lower alkyl group,

R¹and R²May be taken together to form a lower alkylene group,

n is 1 or 2, and n is a hydrogen atom,

x is

Lower alkylene which may have a substituent,

Lower alkenylene which may have a substituent,

-CO-lower alkylene which may have a substituent,

-CO-lower alkenylene which may have a substituent or

Is cycloalkylene which may have a substituent, cycloalkenylene which may have a substituent, bicycloalkenylene which may have a substituent, arylene which may have a substituent or heterocyclodiyl which may have a substituent, p and q are each independently 0 or 1,

-NR²x-can be

In the formula (I), the compound is shown in the specification,

is piperidinediyl, piperazinediyl, pyridinediyl, pyrazinediyl, pyrrolidinediyl or pyrrolediyl, U is a single bond, lower alkylene or lower alkenylene,

y is OCONR⁷、CONR⁷、CSNR⁷、NR⁷CO or NR⁷CS，

R⁷Is hydrogen or a lower alkyl group,

z is lower alkyl which may have substituents, lower alkenyl which may have substituents, amino which may have substituents, lower alkoxy which may have substituents, cycloalkyl which may have substituents, heterocyclic group which may have substituents.

2. The solid preparation according to claim 1, which comprises a compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof and carboxymethyl ethyl cellulose,

in the formula, X is

Is a heterocyclic diradical, R¹An alkyl group having 3 to 10 carbon atoms which may have a substituent or a cycloalkyl group having 5 to 6 carbon atoms which may have a substituent, and the other symbols have the same meanings as defined in claim 1.

3. The solid preparation according to claim 1, which comprises a compound represented by the following formula, a pharmaceutically acceptable salt thereof or a solvate thereof and carboxymethyl ethyl cellulose,

in the formula, R¹Is a lower alkyl group, and is,

R²is hydrogen or a lower alkyl group,

z is a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, an amino group which may have a substituent, a lower alkoxy group which may have a substituent, a cycloalkyl group which may have a substituent, or a heterocyclic group which may have a substituent.

4. The solid preparation according to any one of claims 1 to 3, wherein the content of the compound represented by the formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof in the preparation is 5 to 50% by weight.

5. The solid preparation according to claim 4, wherein the content of the compound represented by the formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof in the preparation is 15 to 30% by weight.

6. The solid preparation according to claim 4, wherein the content of the compound represented by the formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof in the preparation is 25 to 30% by weight.

7. The solid preparation according to any one of claims 1 to 6, wherein the compound represented by the formula (I) in the preparation is trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide.

8. The solid preparation according to claim 7, which comprises 5 to 50% by weight of trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide and 50 to 95% by weight of carboxymethylethylcellulose.

9. The solid preparation according to claim 7, which comprises 15 to 30% by weight of trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide and 70 to 85% by weight of carboxymethylethylcellulose.

10. The solid preparation according to claim 7, which comprises 25 to 30% by weight of trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide and 70 to 75% by weight of carboxymethylethylcellulose.

11. The solid preparation according to any one of claims 1 to 10, wherein trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide and carboxymethylethylcellulose are blended in a ratio of 1: 1 to 1: 19.

12. The solid preparation according to claim 11, wherein the trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide and the carboxymethylethylcellulose are blended in a ratio of 1: 2.33 to 1: 5.67.

13. The solid preparation according to claim 11, wherein the trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide and the carboxymethylethylcellulose are blended in a ratio of 1: 2.33 to 1: 3.

14. The solid preparation according to any one of claims 1 to 13, which further comprises an amorphization inducing agent.

15. The solid preparation according to claim 14, wherein the amorphization-inducing agent is 1 or more than 2 selected from the group consisting of amino acids or salts thereof, aspartame, erythorbic acid or salts thereof, ascorbic acid or salts thereof, stearates, taurine, inositol, ethylurea, citric acid or salts thereof, glycyrrhizic acid or salts thereof, gluconic acid or salts thereof, creatinine, salicylic acid or salts thereof, tartaric acid or salts thereof, succinic acid or salts thereof, calcium acetate, saccharin sodium, aluminum hydroxide, sorbic acid or salts thereof, dehydroacetic acid or salts thereof, sodium thiomalate, niacinamide, urea, fumaric acid or salts thereof, polyethylene glycols, maltose, maltitol, mannitol, meglumine, sodium deoxycholate, and phosphatidylcholine.

16. The solid preparation according to claim 14, wherein the amorphization inducing agent is urea.

17. The solid preparation according to any one of claims 14 to 16, wherein the content of the amorphization inducing agent in the preparation is less than 8% by weight.

18. The solid preparation according to claim 17, wherein the content of the amorphization inducing agent in the preparation is 0.1 to 6% by weight.

19. The solid preparation according to claim 17, wherein the content of the amorphization inducing agent in the preparation is 2 to 4% by weight.

20. The solid preparation according to any one of claims 1 to 13, which does not contain an amorphization inducer.

21. The solid preparation according to any one of claims 1 to 20, wherein the solid preparation is a solid dispersion.

22. The solid preparation of any one of claims 1 to 21, which is prepared by a spray drying method.

23. A tablet comprising the solid preparation according to any one of claims 1 to 22.

24. The tablet of claim 23, wherein the weight per 1 tablet is 450 to 550 mg.

25. A method for preparing the solid preparation of claim 22 by a spray drying method.

26. A method for improving the solubility of trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide, which comprises adding carboxymethylethylcellulose to a solid preparation containing trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide.

27. A method for improving the solubility of trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide, which is characterized by adding an amorphization-inducing agent to a solid preparation comprising trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide and carboxymethylethylcellulose.

28. A method comprising controlling the dissolution rate of trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tert-butylsulfonylamino) cyclohexanecarboxamide to 60% or more 60 minutes after the start of the test and to 70% or more 180 minutes after the start of the test in the dissolution test solution 2 of the Japan Bureau of medicine dissolution test method by containing carboxymethylethylcellulose.