JPH07324086A - Solid dispersion of thiazolidine derivative or pharmaceutical preparation of solid dispersion - Google Patents

Abstract

PURPOSE:To obtain a solid dispersion, containing a specific thiazolidine derivative (salt) and (hydroxypropyl)methyl cellulose, etc., in a specific ratio and capable of maintaining a complete dissolution level for a long period. CONSTITUTION:This solid dispersion comprises (A) 1 pt.wt. thiazolidine derivative (salt) of the formula [R<1> and R<2> are each H or an alkyl; R<2> and R<3> are each H, an alkyl(carbonyl), carboxyl, etc.; W is methylene, carbonyl or >C=N-OH; (n) is 1, 2 or 3], (B) 0.001-2 pts.wt. hydroxypropyl methyl cellulose and/or methyl cellulose and (C) a water-soluble polymer other than the component (B). Furthermore, 5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2methoxy) benzyllthiazolidine-2,4-dione is cited as an example of the component (A).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a solid dispersion or a solid dispersion preparation of a thiazolidine derivative or a salt thereof.

[0002]

2. Description of the Related Art It is known that a poorly soluble compound is dispersed in a water-soluble polymer to form a solid dispersion, which improves solubility and absorbability. For example, Griseofulvi
n) is dispersed in a water-soluble polymer, Polyethylene Glycol Polymers, to form a solid dispersion, and its solubility is improved (J. Pharm
． Sci. , 60 (9), 1281-1302 (1971)). In addition, a solid dispersion of polyvinylpyrrolidone and sulfathiazole (J. Ph
arm. Sci. , 58 (5), 538-549 (1969)), fisoxazole and sulfamethizole (sulfamet).
hizole) and polyvinylpyrrolido
ne) solid dispersion (Chem. Pharm. Bull., 27 (5), 12
23-1230 (1979)) is known. Further, as a thiazolidine derivative formulation, for example, by dispersing a thiazolidine derivative or a salt thereof in a water-soluble polymer in JP-A-5-4919, the solubility is improved and the bioavailability is improved. Is listed.
However, the publication describes that the water-soluble polymer is used in an amount of 0.1 to 9 times (weight) with respect to the thiazolidine derivative 1. An example using propylmethylcellulose is described in Example 1. Only. Moreover, Example 1.
Describes that 4-fold amount (weight) of hydroxypropylmethylcellulose is used with respect to thiazolidine derivative 1. An example using methyl cellulose as the water-soluble polymer is not specifically described.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have further diligently conducted research and development on an oral solid preparation of a thiazolidine derivative or a salt thereof described in JP-A-5-4919. That is, the dissolution behavior of a solid dispersion obtained by dispersing a thiazolidine derivative or a salt thereof in a high concentration water-soluble polymer for a long time was observed. As a result, in solid dispersions consisting of hydroxypropylmethylcellulose and water-soluble polymers other than methylcellulose, although almost the complete dissolution level (supersaturated state) was reached, this complete dissolution level could not be maintained for a long time, and eventually dissolved. The rate has dropped.

In contrast, hydroxypropyl methylcellulose and solid dispersions with methylcellulose maintained a level of complete dissolution for a long time. Therefore, as a result of further studies on solid dispersions of hydroxypropylmethylcellulose and methylcellulose, it was found that even if a small amount of hydroxypropylmethylcellulose and / or methylcellulose was added to a solid dispersion of a water-soluble polymer other than hydroxypropylmethylcellulose and methylcellulose, thiazolidine. It was found that the complete dissolution level of the derivative or its salt was maintained for a long time. Further, not only when producing a solid dispersion, but also during or after the production of a solid dispersion preparation (eg, a coating process).
Also in the above, the present invention has been completed by finding that the complete dissolution level of the thiazolidine derivative or a salt thereof can be maintained for a long time by adding a small amount of hydroxypropylmethylcellulose and / or methylcellulose.

That is, the inventors of the present invention, among many water-soluble polymers, particularly hydroxypropylmethylcellulose and / or methylcellulose alone, in the solid dispersion or outside the solid dispersion, and by adding a very small amount thereof, a thiazolidine derivative or The present invention has been completed by finding that the salt, after reaching the complete dissolution level, maintains this complete dissolution level for a long time.

[0006]

[Means for Solving the Problems]

 (1) The present invention has the general formula (I)

[0007]

[Chemical 4]

(In the formula, R ¹ and R ⁴ are the same or different and each represents a hydrogen atom or an alkyl group.

R ² and R ³ are the same or different and each is a hydrogen atom, an alkyl group, an alkylcarbonyl group, a carboxyl group, an alkoxycarbonyl group, a hydroxy group, an alkylcarbonyloxy group, an alkoxy group which may have a substituent, Indicates a sulfoxy group or a halogen atom.

W is a methylene group, a carbonyl group or a formula
> C represents a group represented by N-OH.

N is an integer of 1 to 3. ) Or a salt thereof, a water-soluble polymer (provided that
Excludes hydroxypropyl methylcellulose and methylcellulose. ) And hydroxypropyl methylcellulose and / or methylcellulose (provided that the amount of hydroxypropylmethylcellulose and / or methylcellulose is 0.001 to 2 parts by weight per 1 part by weight of the thiazolidine derivative or salt thereof having the general formula (I)). It relates to a solid dispersion.

(2) Further, the present invention provides the compound represented by the general formula (I)

[0013]

[Chemical 5]

(Wherein R ¹ , R ² , R ³ , R ⁴ , W and n have the same meanings as described above), a thiazolidine derivative or a salt thereof, and a water-soluble polymer (provided that hydroxypropyl is used). Methylcellulose and methylcellulose) and a small amount of hydroxypropylmethylcellulose and / or methylcellulose in the formulation step in a small amount of hydroxypropylmethylcellulose and / or methylcellulose (however, a thiazolidine derivative having the general formula (I) or its derivative). salt
The total amount of hydroxypropylmethyl cellulose and / or methyl cellulose is 0.001 to 2 parts by weight per 1 part by weight).

(3) Further, the present invention provides the compound represented by the general formula (I)

[0016]

[Chemical 6]

(Wherein R ¹ , R ² , R ³ , R ⁴ , W and n have the same meanings as defined above) or a salt thereof and a water-soluble polymer (provided that hydroxypropyl is used). Hydroxypropylmethylcellulose and / or methylcellulose (provided that the thiazolidine derivative having the general formula (I) or a salt thereof is used in an amount of 1 part by weight of hydroxypropylmethylcellulose and / or Or methylcellulose is 0.001 to 2 parts by weight).

When R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents an alkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-methylpropyl, t-butyl, Pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, hexyl, neohexyl, 1-methylpentyl, 3-methylpentyl, 1,3-dimethylbutyl, 2-ethylbutyl, heptyl, 1-methylhexyl, 1-propyl Butyl, 4,4-dimethylpentyl,
Octyl, 1-methylheptyl, 2-ethylhexyl,
5,5-dimethylhexyl, 1,1,3,3-tetramethylbutyl, nonyl, decyl, 1-methylnonyl, 3,
Examples thereof include linear or branched alkyl groups having 1 to 10 carbon atoms such as 7-dimethyloctyl and 7,7-dimethyloctyl.

R ¹ , R ² , R ³ and R ⁴ are preferably linear or branched alkyl groups having 1 to 8 carbon atoms. R ¹ , R ² and R ⁴ are more preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or an isobutyl group, and most preferably a methyl group.
R ³ is more preferably a methyl group, an ethyl group, a propyl group,
Isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, 1,1,3,3-tetramethylbutyl group, most preferably methyl group, t-butyl group,
Especially, it is a methyl group.

When R ² and R ³ are the same or different and each represents an alkylcarbonyl group, it has 2 carbon atoms such as acetyl, propionyl, butyryl and isobutyryl.
Examples thereof include linear or branched alkylcarbonyl groups having 4 to 4. R ² and R ³ are preferably acetyl groups.

When R ² and R ³ are the same or different and each represents an alkoxycarbonyl group, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
Examples thereof include linear or branched alkoxycarbonyl groups having 2 to 5 carbon atoms such as isopropoxycarbonyl, butoxycarbonyl and isobutoxycarbonyl. R ² is preferably a methoxycarbonyl group, an ethoxycarbonyl group or a t-butoxycarbonyl group.

When R ² and R ³ are the same or different and each represents an alkylcarbonyloxy group, a straight-chain or branched chain having 2 to 5 carbon atoms, such as acetoxy, propionyloxy, butyryloxy, isobutyryloxy. A branched alkylcarbonyloxy group can be mentioned. R ² and R ³ are preferably acetoxy groups.

When R ² and R ³ are the same or different and each represents an optionally substituted alkoxy group, the alkoxy moiety is, for example, methoxy, ethoxy, propoxy,
A straight-chain or branched-chain alkoxy having 1 to 5 carbon atoms, such as isopropoxy, butoxy, isobutoxy, 1-methylpropoxy, t-butoxy, pentoxy, isopentoxy, the alkoxy being 1 to 3
It may have a number of substitutions, and as the substitutions,
(1) Carboxyl; (2) having 2 to 5 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, 1-methylpropoxycarbonyl, t-butoxycarbonyl. Linear or branched alkoxycarbonyl; (3) Formula
A group represented by —CONR ⁵ R ⁶ (R ⁵ and R ⁶ are the same or different and are a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-methylpropyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl,
A linear or branched alkyl group having 1 to 5 carbon atoms such as, or R ⁵ and R ⁶ together with a nitrogen atom to form a saturated 5 to 7 membered ring group, The group may further contain one oxygen atom. Examples of such a group include heterocyclic groups such as 1-pyrrolidinyl, piperidino, and morpholino. );

Examples of such R ² and R ³ include
(a) methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, 1-methylpropoxy,
t-butoxy, pentoxy, isopentoxy, (b) carboxymethoxy, 2-carboxyethoxy, 3-carboxypropoxy, 3-carboxybutoxy, 3-carboxy-1-methylpropoxy, 1-carboxy-1-
Methylethoxy, (c) methoxycarbonylmethoxy, 3
-Methoxycarbonylpropoxy, 2-propoxycarbonylethoxy, 3-methoxycarbonyl-1-methylpropoxy, 1-methoxycarbonyl-1-methylethoxy, t-butoxycarbonylmethoxy, 3- (t-butoxycarbonyl) propoxy, 1- ( t-butoxycarbonyl) -1-methylethoxy, (d) carbamoylmethoxy, 2-carbamoylethoxy, 4-carbamoylbutoxy, (e) methylaminocarbonylmethoxy, 2-propylaminocarbonylethoxy, 3-
(N ′, N′-dimethylaminocarbonyl) propoxy, 4- (N-methyl-N-ethylaminocarbonyl)
Butoxy, 3- (N, N-dipentylaminocarbonyl) -1-methylpropoxy, (f) 1-pyrrolidinylcarbonylmethoxy, piperidinocarbonylmethoxy,
Morpholino carbonyl methoxy, etc. can be mentioned.

R ² and R ³ may optionally have one substituent on the alkoxy moiety,
Carboxyl, linear or branched alkoxycarbonyl having 2 to 5 carbon atoms,
Carbamoyl, or a group represented by the formula —CONR ^{5 ′} R ^{6 ′} (where R ^{5 ′} and R ^{6 ′} together with the nitrogen atom are saturated 5
To 7-membered ring group, which is a heterocyclic group which may further contain one oxygen atom), having 1 to 3 carbon atoms.
It is a straight-chain or branched alkoxy group having 1 unit.

R ² is more preferably carboxymethoxy group, 3-carboxypropoxy group, 1-carboxy-1.
-Methylethoxy group, methoxycarbonylmethoxy group,
3-methoxycarbonylpropoxy group, 1-methoxycarbonyl-1-methylethoxy group, t-butoxycarbonylmethoxy group, 3- (t-butoxycarbonyl) propoxy group, 1- (t-butoxycarbonyl) -1-methylethoxy group , A carbamoylmethoxy group, a piperidinocarbonylmethoxy group, and a morpholinocarbonylmethoxy group, and most preferably a carboxymethoxy group, a 3-carboxypropoxy group, and a 1-carboxy-1-methylethoxy group.

When R ² and R ³ are the same or different and each represents a halogen atom, examples thereof include chloro, fluoro, bromo and the like. R ² is preferably chloro or fluoro, more preferably fluoro.

When n represents an integer of 1 to 3, it is preferably 1 to 2, and more preferably 1.

Examples of the salt of the thiazolidine derivative having the general formula (I) of the present invention include salts of alkali metals such as lithium, sodium and potassium; calcium,
Examples thereof include salts of alkaline earth metals such as barium; aluminum salts; salts of basic amino acids such as lysine and arginine. Also, when the salt represents, for example, an alkali metal salt, it can be in the form of its mono-, di-, or tri-salt. It is preferably an alkali metal salt.

The thiazolidine derivative having the general formula (I) has various isomers. For example, the 2-position of the chroman ring and the 5-position of the thiazolidine ring are asymmetric carbon atoms, and stereoisomers thereof exist.
In the general formula (I), these isomers and the equal and non-equivalent mixtures of these isomers are all represented by a single formula. Therefore, the present invention includes all of these isomers and a mixture of these isomers.

In the compound having the general formula (I), R ¹ is preferably a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms.

R ² is (A) a hydrogen atom, (B) a linear or branched alkyl group having 1 to 4 carbon atoms, (C) a linear or branched alkyl group having 2 to 4 carbon atoms, or Branched alkylcarbonyl group, (D) carboxyl group, (E) hydroxy group, (F) linear or branched alkylcarbonyloxy group having 2 to 5 carbon atoms, (G) alkoxy The moiety may have one substituent, which is (1) carboxyl, (2) a linear or branched alkoxycarbonyl having 2 to 5 carbon atoms, or (3 ) A group represented by the formula: -CONR ^{5 "} R ^6" (R ^{5 "} and R ^6" are the same or different and are hydrogen; a linear or branched alkyl group having 1 to 5 carbon atoms; or R ⁵ showing a; heterocyclic ^{group "and} R ^6" to form a 5 to 7 membered saturated ring together with the nitrogen atom ) Is a straight-chain or branched alkoxy group having 1 to 3 carbon atoms, showing a, (H) sulfoxy group, or (I) chloro atom or a fluoro atom. R ³ is (A) a hydrogen atom, (B) a linear or branched alkyl group having 1 to 8 carbon atoms, (C) a hydroxy group, or (D) an alkoxy group having one substituent. Optionally having 1 to 3 carbon atoms, wherein the substituent is (1) carboxyl, or (2) a linear or branched alkoxycarbonyl having 2 to 5 carbon atoms. And a linear or branched alkoxy group having.

R ⁴ represents a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms.

W represents a methylene group or a carbonyl group.

N is 1 or 2.

In the compound having the general formula (I), R ¹ is more preferably a hydrogen atom or a methyl group. R ² is (A) hydrogen atom, (B) methyl group, (C) acetyl group, (D) carboxyl group, (E) hydroxy group, (F)
An acetoxy group, (G) a linear or branched alkoxy group having 1 to 3 carbon atoms having one carboxyl as a substituent in the alkoxy moiety, or (H) a fluoro atom. R ³ is a hydrogen atom, a methyl group, a t-butyl group or 1,1,3,3
-Indicates a tetramethylbutyl group. R ⁴ represents a hydrogen atom or a methyl group. W represents a methylene group or a carbonyl group. n represents 1.

In the compound having the above general formula (I), R ¹ most preferably represents a hydrogen atom or a methyl group.
R ² represents a hydroxy group, a carboxymethoxy group, a 3-carboxypropoxy group or a 1-carboxy-1-methylethoxy group. R ³ represents a methyl group, a t-butyl group or a 1,1,3,3-tetramethylbutyl group.
R ⁴ represents a hydrogen atom or a methyl group. W represents a methylene group. n represents 1.

Specific examples of the thiazolidine derivative having the above general formula (I) or a salt thereof of the present invention include the compounds listed in the following table.

[0039]

[Chemical 7]

[0040]

[Table 1] ─────────────────────────────────── Compound R ¹ R ² R ³ R ⁴ R ⁷ W number ─────────────────────────────────── 1 HHHHH CH ₂ 2 HHHH Na CH ₂ 3 HHHHH CO 4 HFHHH CH ₂ 5 HFHHH CO 6 Me H Me HH CH ₂ 7 Me H Me HH CO 8 Me Me Me Me H CH ₂ 9 HH OH Me H CH ₂ 10 HH OH Me H CO 11 HH OCH ₂ COOH Me H CH ₂ 12 HH OCH ₂ COOH Me H CO 13 HH OCOMe Me H CH ₂ 14 HHO (CH ₂ ) ₃ COOH Me H CH ₂ 15 HHO (CH ₂ ) ₃ COOEt Me H CH ₂ 16 HH OC (Me) ₂ COOMe Me H CH ₂ 17 HH OCH ₂ CONH ₂ Me H CH ₂ 18 HH OCH ₂ CON (Me) ₂ Me H CH ₂ 19 HH OCH ₂ COPirro Me H CH ₂ 20 HHO (CH ₂ ) ₃ COPipe Me H CH ₂ 21 HHO (CH ₂ ) ₃ COMor Me H CH ₂ 22 Me OH Me Me H CH ₂ 23 Me OH Me Me Na CH ₂ 24 Me ONa Me Me Na CH ₂ 25 Me OH Me Me H CO 26 H OH t-Bu HH CH ₂ 27 H OH TMB HH CH ₂ 28 Me OSO ₃ H Me Me H CH ₂ 29 Me OSO ₃ Na Me Me H CH ₂ 30 Me OCOMe Me Me H CH ₂ 31 Me OCOMe Me Me H CO 32 H OCH ₂ COOH t-Bu HH CH ₂ 33 H OCH ₂ COOH TMB HH CH ₂ 34 H OCH ₂ COOH t-Bu HH CO 35 H OCH ₂ COOH TMB HH CO 36 H OC (Me) ₂ COOH t-Bu HH CH ₂ 37 H OC (Me) ₂ COOH TMB HH CH ₂ 38 H OC (Me) ₂ COOH t-Bu HH CO 39 H OC (Me) ₂ COOH TMB HH CO 40 HO (CH ₂ ) ₃ COOH t-Bu HH CH ₂ 41 Me OCH ₂ COOH Me Me H CH ₂ 42 Me OCH ₂ COOH Me Me H CO 43 Me OCH ₂ COONa Me Me H CH ₂ 44 Me OCH ₂ COOt-Bu Me Me H CH ₂ 45 Me O (CH ₂ ) ₃ COOH Me Me H CH ₂ 46 Me O (CH ₂ ) ₃ COONa Me Me H CH ₂ 47 Me OC (Me) ₂ COOH Me Me H CH ₂ 48 Me OC (Me) ₂ COOH Me Me H CO 49 Me OC (Me) ₂ COONa Me Me H CH ₂ 50 Me OC (Me) ₂ COONa Me Me H CO 51 H OCH ₂ CONH ₂ Me HH CH ₂ 52 Me OCH ₂ CONH ₂ Me Me H CH ₂ 53 Me OCH ₂ CONH ₂ Me Me H CO 54 Me OCH ₂ CON (Me) ₂ Me Me H CH ₂ 55 Me OCH ₂ COPirro Me Me H CH ₂ 56 Me OCH ₂ COPipe Me Me H CH ₂ 57 Me OCH ₂ COMor Me Me H CH ₂ 58 Me OCH ₂ COMor Me Me H CO 59 Me O (CH ₂ ) ₃ CONH ₂ Me Me H CH ₂ 60 Me O (CH ₂ ) ₃ CONHEt Me Me H CH ₂ 61 Me O (CH ₂ ) ₃ CONMeBu Me Me CH H ₂ 62 HO (CH ₂ ) ₃ COMor t-Bu HH CH ₂ 63 Me OC (Me) ₂ CONH ₂ Me Me H CH ₂ 64 Me OC (Me) ₂ COPirro Me Me H CH ₂ 65 H COOH HHH CH ₂ 66 H COOH HHH CO 67 H COOEt HHH CH ₂ 68 H COOt-Bu HHH CH ₂ 69 HH COOH HH CH ₂ 70 H COMe OH Me H CO 71 H COMe OCOMe Me H CH ₂ 72 Me OH Me Me H N-OH 73 H OH COMe HH CH ₂ 74 H OH COMe HH CO 75 H OCOMe COMe HH CH ₂ 76 H OCH ₂ COOH COMe HH CH ₂ 77 HO (CH ₂ ) ₃ COOH COMe HH CH ₂ 78 H OC (Me) ₂ COOH COMe HH CH ₂ ─────────────────────────────── ──── In Table 1, Me = methyl; Et = ethyl;
Bu = Butyl; t-Bu = Tertiary Butyl; TM
B = 1,1,3,3-tetramethylbutyl; Pirro
= 1-pyrrolidinyl; Pipe = piperidino; Mor
= Morpholino; is displayed. In the thiazolidine having the general formula (I) or a salt thereof of the present invention, preferably, Table 1. Compound No. 1,
2, 8, 9, 10, 22, 23, 25, 26, 27, 3
2, 33, 34, 35, 36, 37, 41, 42, 4
3, 45, 46, 47, 48, 49, 50, 52, 5
6, 57, 65, 66, and 70. More preferably, Table 1. Compound Nos. 8, 22, 34, 35, 47,
And 48. Optimally Table 1. Compound No. 22
Is.

The thiazolidine derivative having the general formula (I) or a salt thereof of the present invention can be obtained, for example, from JP-A-60-51.
189, JP-A-61-36284, JP-A-62-5.
980, JP-A-62-123186, JP-A-64-
It is a known compound described in, for example, No. 38090. (A). The solid dispersion of the thiazolidine derivative or its salt of the present invention can be prepared, for example, by the following method. That is, 1) A water-soluble polymer (excluding hydroxypropylmethylcellulose and methylcellulose) and a small amount of hydroxypropylmethylcellulose and / or methylcellulose are added to a thiazolidine derivative or a salt thereof in an appropriate organic solvent in any order and dissolved. Alternatively, a solid dispersion can be produced by a method in which the organic solvent is dispersed and then the organic solvent is distilled off under reduced pressure or under normal pressure by a conventional method, that is, a so-called solvent method. 2) After heating the thiazolidine derivative or a salt thereof by heating to a temperature higher than the melting point, melt the water-soluble polymer (excluding hydroxypropylmethylcellulose and methylcellulose) and a small amount of hydroxypropylmethylcellulose and / or methylcellulose in any order. In addition, it can be manufactured by a method of melting or dispersing, followed by quenching, a so-called melting method. 3) It can be produced by adding a water-soluble polymer (excluding hydroxypropylmethylcellulose and methylcellulose) and a small amount of hydroxypropylmethylcellulose and / or methylcellulose to a thiazolidine derivative or a salt thereof, and mixing and grinding.

Here, the term "mixing and pulverizing" means pulverizing a mixture obtained by using a mixing device or the like with a pulverizing device or the like.

The water-soluble polymer used here is a water-soluble polymer other than hydroxypropylmethylcellulose and methylcellulose, such as hydroxyalkylcellulose such as hydroxypropylcellulose; alkylcellulose such as ethylcellulose; polyvinylpyrrolidone. Such polyalkenylpyrrolidone; polyalkylene glycol such as polyethylene glycol; and the like. Two or more kinds of these water-soluble polymers may be mixed and used. The amount of these water-soluble polymers used is not particularly limited, but is preferably 0.1 with respect to the thiazolidine derivative or its salt 1.
To 9 times, especially 0.3 to 5 times (weight ratio).

Further, the amount of hydroxypropylmethylcellulose and / or methylcellulose used is 0.001 to 2 times, especially 0.005 to 0.5 times (weight ratio) the amount of the thiazolidine derivative or its salt 1.
Is.

Furthermore, an organic solvent is used in the above method 1). The organic solvent used is not particularly limited as long as it can dissolve the thiazolidine derivative or its salt and the water-soluble polymer. Such solvents include, for example, aliphatic halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform; ketones such as acetone; methanol, ethanol, propanol, butanol, monomethoxyethanol, ethylene glycol monomethyl ether. Alcohols; ethers such as diethyl ether, dibutyl ether, diisobutyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether; aliphatic hydrocarbons such as n-hexane, cyclohexane, n-heptane;
Aromatic hydrocarbons such as benzene, toluene, xylene; Esters such as ethyl acetate; Ketones such as acetone and methyl ethyl ketone; Nitriles such as acetonitrile; Organic acids such as acetic acid and propionic acid;
Examples thereof include amides such as dimethylformamide and dimethylacetamide; and mixed solvents thereof. Solvents having a low boiling point are preferable, for example, ketones, alcohols and esters. Particularly preferred are acetone, ethanol and ethyl acetate. Next, when the organic solvent is distilled off, the operating conditions such as the treatment temperature and the treatment time vary depending on the raw material compound used, the solvent, etc., but are usually room temperature to about 200 ° C., and a few minutes to a dozen hours. is there.

(B). The solid dispersion of the thiazolidine derivative or salt thereof thus obtained can be used as it is, but further processed into a preparation, for example, a mixing step, a granulation processing step, a tableting step, a capsule filling step, It can be used as a solid dispersion formulation through a formulation process such as a coating process. Then, a smaller amount of hydroxypropylmethylcellulose and / or methylcellulose may be added during this formulation step. However, the amount of hydroxypropyl methylcellulose and / or methylcellulose contained in the total amount of the preparation is based on 1 of the thiazolidine derivative or its salt.
The amount does not exceed the range of 0.001 to 2 times (weight ratio).

Here, the mixing step means a step of mixing raw materials and the like using a mixing device or the like.

The granulation processing step refers to a step of granulating raw materials and the like using a granulating and mixing machine or the like. In addition, it includes mixing, sizing, and the like performed as necessary.

The tableting step means a step of tableting raw materials and the like using a tableting machine or the like. The capsule filling step refers to a step of filling raw materials and the like into capsules using a capsule filling device or the like.

The coating step is a step of coating, for example, raw materials with a coating agent.
In addition, the preparation of the coating liquid and the like performed as necessary are included. The preparation thus obtained includes various dosage forms such as fine granules, granules, tablets and capsules which are generally known as preparations for oral administration. In each step, if necessary, a coloring agent, a flavoring agent, an excipient (eg lactose, sucrose, starch, crystalline cellulose, etc.), a disintegrating agent (eg low-substituted hydroxypropylcellulose, croscarmellose sodium, crospovidone). , Sodium carboxymethyl starch, etc., lubricants (eg magnesium stearate etc.), surfactants (eg sodium lauryl sulphate etc.) etc. can be added. These additives are preferably added in the most suitable process.

(C). Furthermore, the solid dispersion preparation of the thiazolidine derivative or its salt of the present invention can be prepared, for example, by the following method. That is, the above (A). A step of processing a solid dispersion of a thiazolidine derivative or a salt thereof obtained according to the methods 1) to 3) and only a water-soluble polymer (excluding hydroxypropylmethylcellulose and methylcellulose) into a preparation, for example, a mixing step. , A granulation processing step, a tableting step, a capsule filling step, a coating step and the like formulation step, 0.001 to 2 times amount (weight ratio) of hydroxypropylmethylcellulose and / or the thiazolidine derivative or its salt 1 Alternatively, methylcellulose can be added to obtain a solid dispersion formulation.

Here, for example, a mixing step, a granulation processing step,
The tableting process, capsule filling process, and coating process have the same meanings as described above.

The thus obtained preparations include various dosage forms such as fine granules, granules, tablets and capsules which are generally known as orally administered preparations. If necessary, coloring agents, flavoring agents, excipients (eg lactose, sucrose, starch, crystalline cellulose, etc.), disintegrating agents (eg low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, carboxymethyl starch). Suitable additives such as sodium) and lubricants (eg magnesium stearate) and surfactants (eg sodium lauryl sulfate) can be added. These additives are preferably added in the most suitable process.

[0054]

In the present invention, what is finally administered to the human body is
Regardless of its dosage form etc., hydroxypropylmethylcellulose and / or methylcellulose 0.001 to 2 per 1 part by weight of a thiazolidine derivative or its salt
Those containing parts by weight maintain the complete dissolution level for a long time,
It showed an excellent effect.

[0055]

EXAMPLES Next, the present invention will be explained with reference to examples, control examples and test examples, but the present invention is not limited to these. Example 1.5- [4- (6-hydroxy-2,5,7,
8-Tetramethylchroman-2-methoxy) benzyl]
Thiazolidine-2,4-dione (Exemplified compound No. 22;
Hereinafter, "compound A") 1 g and hydroxypropylmethyl cellulose (trade name, TC-5E; manufactured by Shin-Etsu Chemical Co., Ltd.) 0.02 g are dissolved in a mixed solvent of dichloromethane 20 g and ethanol 20 g, and then a rotary evaporator is used. The organic solvent was distilled off under reduced pressure. The obtained solid was pulverized to obtain fine particles.

Example 2. Compound A 5g at 180 ℃
It is heated and melted on polyethylene glycol 6
10 g of 000 and 1 g of methyl cellulose were added and dissolved and dispersed. The reaction mixture was put in an ice bath and rapidly cooled, and then the obtained solid was pulverized to obtain granules.

Example 3. Compound A 4 g, polyvinylpyrrolidone 10 g and hydroxypropylmethylcellulose (trade name, TC-5E; manufactured by Shin-Etsu Chemical Co., Ltd.)
When 0.5 g was mixed and ground for 30 minutes using a vibration mill, a powder was obtained.

Example 4. 20 g of compound A and 20 g of polyvinylpyrrolidone were dissolved in a mixed solvent of 100 g of acetone and 100 g of ethanol, and 200 g of croscarmellose sodium was sprayed with the mixed solution using a fluidized bed granulator to obtain granules. Hydroxypropylmethyl cellulose (trade name, TC-
5E; manufactured by Shin-Etsu Chemical Co., Ltd.) 0.1 g and lactose
1.9 g was mixed. Next, No. 2 capsule was filled with 0.24 g of the obtained mixture to obtain a capsule. The capsule contains 0.1 g of Compound A per capsule.

Example 5. Compound A (1 g) and polyvinylpyrrolidone (1 g) were added to acetone (5 g) and ethanol (5 g).
g in a mixed solvent, and then the organic solvent was distilled off under reduced pressure using a rotary evaporator. The obtained solid was pulverized to obtain fine particles. Crystalline cellulose 0.25g, low-substituted hydroxypropylcellulose 0.25g, hydroxypropylmethylcellulose (trade name, TC-5E; Shin-Etsu Chemical Co., Ltd.)
(Manufactured by K.K.) 0.05 g, lactose 0.18 g and magnesium stearate 0.2 g were mixed and then tableted using a tablet machine to give tablets having a diameter of 10 mm and a weight of 0.35 g. Each tablet contains 0.1 g of Compound A.
Contains.

Example 6. Example 5. The tablets obtained in step 1 were crushed to obtain granules. The obtained granules into No. 1 capsule
0.35 g was filled. The capsule contains 0.1 g of Compound A per capsule. Example 7. Example 5. Microcrystalline cellulose (0.25 g), low-substituted hydroxypropylcellulose (0.25 g), lactose (0.23 g) and magnesium stearate (0.2 g) were mixed with 1 g of the fine granules obtained in (1), and the mixture was tableted using a tablet machine to give a diameter A tablet having a size of 10 mm and a weight of 0.35 g was obtained. Using a coating pan on this tablet, 5% hydroxypropylmethyl cellulose (trade name, TC-5
E; manufactured by Shin-Etsu Chemical Co., Ltd.) was sprayed to obtain a film-coated tablet coated with 0.01 g of hydroxypropylmethylcellulose as a solid content. Each film-coated tablet contains 0.1 g of Compound A.

Control Example 1. 1 g of compound A and 1 g of polyvinylpyrrolidone were dissolved in a mixed solvent of 20 g of dichloromethane and 20 g of ethanol, and then the organic solvent was distilled off under reduced pressure using a rotary evaporator. The obtained solid was pulverized to obtain fine particles.

Control Example 2. Compound A 5g at 180 ℃
It is heated and melted on polyethylene glycol 6
000 10 g was added and dissolved and dispersed. The reaction mixture was put in an ice bath and rapidly cooled, and then the obtained solid was pulverized to obtain granules.

Control Example 3. 4 g of Compound A and 10 g of polyvinylpyrrolidone were mixed and ground for 30 minutes using a vibration mill to obtain a powder.

Control Example 4. 20 g of compound A and 20 g of polyvinylpyrrolidone were dissolved in a mixed solvent of 100 g of acetone and 100 g of ethanol, and 200 g of croscarmellose sodium was sprayed with the mixed solution using a fluidized bed granulator to obtain granules. 2 g of lactose was mixed with 10 g of the obtained granules. Next, No. 2 capsule was filled with 0.24 g of the obtained mixture to obtain a capsule. The capsule contains 0.1 g of Compound A per capsule.

Control Example 5. 1 g of compound A and 1 g of polyvinylpyrrolidone were dissolved in a mixed solvent of 20 g of dichloromethane and 20 g of ethanol, and then the organic solvent was distilled off under reduced pressure using a rotary evaporator. The obtained solid was pulverized to obtain fine particles. Crystalline cellulose 0.25 g, low-substituted hydroxypropyl cellulose 0.25 g, lactose 0.2 per 1 g of the obtained fine particles.
After mixing 3 g and 0.2 g of magnesium stearate, the mixture was tableted using a tablet machine to give tablets having a diameter of 10 mm and a weight of 0.35 g. Each tablet is 0.1
g of Compound A.

(Effects of Examples) Test Example 1. Example 1. Through 7. And Control Example 1. Through 5. A dissolution test was performed using the sample (formulation) obtained in. That is, each sample (corresponding amount containing 0.1 g of compound A) was added to 500 ml of borate buffer solution (pH 9). Elution is based on the 12th revised Japanese Pharmacopoeia paddle method (rotation speed 1
00 rpm). The elution amount of Compound A in the eluate was measured with a spectrophotometer over time. The results are shown in Table 2. Shown in.

[0067]

[Table 2] Dissolution test (dissolution rate:%) Table 2. From Example 1. Through 7. The sample of Comparative Example 1. Through 5. Even after reaching the complete dissolution level, the complete dissolution level was maintained for a long time and the dissolution rate did not decrease as compared with the sample No. 2.
On the other hand, Comparative Example 1. Through 5. After reaching the complete dissolution level, the sample No. could not maintain this complete dissolution level for a long time, and the dissolution rate gradually decreased.

[0068]

INDUSTRIAL APPLICABILITY The solid dispersion and solid dispersion preparation of the thiazolidine derivative or a salt thereof of the present invention maintained a completely dissolved level for a long time and showed excellent effects.

Claims (9)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ and R ⁴ are the same or different and represent a hydrogen atom or an alkyl group. R ² and R ³ are the same or different and are a hydrogen atom, an alkyl group, an alkylcarbonyl group, a carboxyl group, an alkoxycarbonyl group, a hydroxy group. Group, an alkylcarbonyloxy group, an optionally substituted alkoxy group, a sulfoxy group or a halogen atom, W is a methylene group, a carbonyl group or a formula> C
Represents a group represented by = N-OH. n represents an integer of 1 to 3. A thiazolidine derivative or a salt thereof, a water-soluble polymer (excluding hydroxypropylmethylcellulose and methylcellulose) and hydroxypropylmethylcellulose and / or methylcellulose (a thiazolidine derivative or salt thereof having the general formula (I)) 1% by weight Hydroxypropyl methylcellulose and / or methylcellulose is 0.
001 to 2 parts by weight). 2. A compound represented by the general formula (I): (In the formula, R ¹ and R ⁴ are the same or different and represent a hydrogen atom or an alkyl group. R ² and R ³ are the same or different and are a hydrogen atom, an alkyl group, an alkylcarbonyl group, a carboxyl group, an alkoxycarbonyl group, a hydroxy group. Group, an alkylcarbonyloxy group, an optionally substituted alkoxy group, a sulfoxy group or a halogen atom, W is a methylene group, a carbonyl group or a formula> C
Represents a group represented by = N-OH. n represents an integer of 1 to 3. A thiazolidine derivative or a salt thereof, a water-soluble polymer (excluding hydroxypropylmethylcellulose and methylcellulose) and a small amount of hydroxypropylmethylcellulose and / or methylcellulose in a solid dispersion in a formulation step in a small amount of hydroxypropylmethylcellulose. And / or methylcellulose (however, the total amount of hydroxypropylmethylcellulose and / or methylcellulose is 0.001 to 2 parts by weight with respect to 1 part by weight of the thiazolidine derivative having the general formula (I) or a salt thereof). Solid dispersion formulation. 3. A compound represented by the general formula (I): (In the formula, R ¹ and R ⁴ are the same or different and represent a hydrogen atom or an alkyl group. R ² and R ³ are the same or different and are a hydrogen atom, an alkyl group, an alkylcarbonyl group, a carboxyl group, an alkoxycarbonyl group, a hydroxy group. Group, an alkylcarbonyloxy group, an optionally substituted alkoxy group, a sulfoxy group or a halogen atom, W is a methylene group, a carbonyl group or a formula> C
Represents a group represented by = N-OH. n represents an integer of 1 to 3. In a solid dispersion comprising a thiazolidine derivative or a salt thereof and a water-soluble polymer (provided that hydroxypropylmethylcellulose and methylcellulose are excluded) in the formulation step.
A solid dispersion preparation, which comprises adding 0.001 to 2 parts by weight of hydroxypropylmethylcellulose and / or methylcellulose to 1 part by weight of a thiazolidine derivative or a salt thereof. 4. A thiazolidine derivative having the general formula (I) or a salt thereof according to [claim 1], [claim 2] or [claim 3], wherein R ¹ is a hydrogen atom or 1 to 3 carbon atoms. A linear or branched alkyl group having is shown. R ² is (A) a hydrogen atom, (B) a linear or branched alkyl group having 1 to 4 carbon atoms, (C) a linear or branched chain having 2 to 4 carbon atoms -Like alkylcarbonyl group, (D) carboxyl group, (E) hydroxy group, (F) linear or branched alkylcarbonyloxy group having 2 to 5 carbon atoms, (G) 1 in the alkoxy moiety May have a substituent of 1, wherein the substituent is (1) a carboxyl, (2) a linear or branched alkoxycarbonyl having 2 to 5 carbon atoms, or (3) a formula- A group represented by CONR ^{5 "} R ^6" (R ^{5 "} and R ^6" are the same or different and are hydrogen; linear or branched alkyl having 1 to 5 carbon atoms; or R ^{5 "} and R ^{6 "a} heterocyclic group that forms a 5 to 7 membered saturated ring together with the nitrogen atom;. showing a) coal is Linear or branched alkoxy group having 1 to 3 number shows, (H) sulfoxy group, or (I) chloro atom or a fluoro atom. R ³ is (A) a hydrogen atom, (B) a linear or branched alkyl group having 1 to 8 carbon atoms, (C) a hydroxy group, or (D) an alkoxy moiety having one substituent. Optionally having 1 to 3 carbon atoms, wherein the substituent is (1) carboxyl, or (2) a linear or branched alkoxycarbonyl having 2 to 5 carbon atoms. A linear or branched alkoxy group having R ⁴ represents a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms. W represents a methylene group or a carbonyl group. n represents 1 or 2. A solid dispersion or solid dispersion preparation comprising a compound having the formula: 5. A thiazolidine derivative having the general formula (I) or a salt thereof according to [claim 1], [claim 2], [claim 3] or [claim 4], wherein R ¹ is a hydrogen atom or methyl. Indicates a group. R ² is (A)
Hydrogen atom, (B) Methyl group, (C) Acetyl group, (D) Carboxyl group, (E) Hydroxy group, (F) Acetoxy group, (G) Number of carbon atoms having one carboxyl as a substituent in the alkoxy moiety A linear or branched alkoxy group having 1 to 3 or (H) fluoro atom. R ³ is a hydrogen atom, a methyl group, a t-butyl group or 1,1,3,3
-Indicates a tetramethylbutyl group. R ⁴ represents a hydrogen atom or a methyl group. W represents a methylene group or a carbonyl group. n represents 1. A solid dispersion or solid dispersion preparation comprising a compound having the formula: 6. A general formula (I) of [claim 1], [claim 2], [claim 3], [claim 4] or [claim 5].
In the thiazolidine derivative or a salt thereof having R ¹ , R ¹ represents a hydrogen atom or a methyl group. R ² represents a hydroxy group, a carboxymethoxy group, a 3-carboxypropoxy group or a 1-carboxy-1-methylethoxy group. R ³ is a methyl group, a t-butyl group or 1, 1,
Indicates a 3,3-tetramethylbutyl group. R ⁴ represents a hydrogen atom or a methyl group. W represents a methylene group. n is 1
Indicates. A solid dispersion or solid dispersion preparation comprising a compound having the formula: 7. [Claim 1], [Claim 2], [Claim 3], [Claim 4], [Claim 5] or [Claim 6].
In the thiazolidine derivative having the general formula (I) or a salt thereof, 1) 5- [4- (2,5,6,7,8-pentamethylchroman-2-methoxy) benzyl] thiazolidine-2,
4-dione: 2) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-methoxy) benzyl] thiazolidine-2,4-dione: 3) 5- [4- ( 7-t-butyl-6-carboxymethoxy-2-methyl-4-oxochroman-2-methoxy) benzyl] thiazolidine-2,4-dione: 4) 5- [4- (7- (1,1,3, 3-Tetramethylbutyl) -6-carboxymethoxy-2-methyl-4-
Oxochroman-2-methoxy) benzyl] thiazolidine-2,4-dione: 5) 5- [4- (6- (1-carboxy-1,1-dimethylmethoxy) -2,5,7,8-tetramethylchroman -2-Methoxy) benzyl] thiazolidine-2,4-
Dione: 6) 5- [4- (6- (1-carboxy-1,1-dimethylmethoxy) -2,5,7,8-tetramethyl-4-
A solid dispersion or a solid dispersion preparation comprising a compound having the formula: oxochroman-2-methoxy) benzyl] thiazolidine-2,4-dione. 8. A general formula (Claim 1), [Claim 2], [Claim 3], [Claim 4], [Claim 5], [Claim 6] or [Claim 7] (claim 7) In the thiazolidine derivative having I) or a salt thereof, 1) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-methoxy) benzyl] thiazolidine-2,4-dione: A solid dispersion or solid dispersion preparation comprising the compound shown. 9. [Claim 1], [Claim 2], [Claim 3], [Claim 4], [Claim 5], [Claim 6],
In [Claim 7] or [Claim 8], 0.005 to 0.5 parts by weight of hydroxypropylmethylcellulose and / or methylcellulose is added to 1 part by weight of the thiazolidine derivative having the general formula (I) or a salt thereof. A solid dispersion or solid dispersion preparation consisting of