JPH07252213A - Tosyl acid suplatast having excellent absorbability and its production - Google Patents

Abstract

PURPOSE:To derive a crystal of a tosyl acid suplatast having excellent absorbabllity from the racemic modification of the tosyl acid suplatast. CONSTITUTION:This tosyl acid suplatast excellent in absorbabllity is obtained by dissolving the racemic modification of the tosyl acid suplatast in a solvent and then subjecting the solution to a recrystallization treatment in the presence of seed crystals of the optically active crystal of the tosyl acid suplatast.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to crystals of suplatast tosylate which are useful as antiallergic agents and have good absorbability, and a method for producing the same.

[0002]

2. Description of the Related Art Generally, it is represented by the following chemical formula:

[Chemical 1] Suplatast tosylate is known to be useful as an antiallergic agent, as disclosed in Japanese Patent Publication No. 3-70698. However, oral absorption of suplatast tosylate is low, and, for example, it has been revealed that the bioavailability of rat and mouse is about several percent (pharmacokinetics, 7,441 (1992)).

The inventors of the present invention have conducted studies to improve the above-mentioned low absorption of suplatast tosylate, and as a result, crystals of suplatast tosylate obtained by recrystallization by a certain method were orally and They have found that they are excellent in absorbability from the skin, and have completed the present invention.

[Means for Solving the Problems]

As a result of further intensive studies in view of such circumstances, the present inventors have found that a crystal having good absorption can be easily produced from racemic body of suplatast tosylate with a high yield and completed the present invention. did. And the present invention is specifically a crystal obtained by dissolving a racemate of suplatast tosylate in a solvent and then recrystallizing it by adding an optically active crystal of suplatast tosylate as a seed crystal. It is what Another feature is that the racemate of suplatast tosylate is dissolved in a solvent, and then optically active crystals of suplatast tosylate are added as seed crystals for recrystallization.

In carrying out the present invention, racemate of suplatast tosylate, which is a raw material thereof, is described in JP-B-3-70.
It can be easily obtained by the production method described in 698. The optically active crystal of suplatast tosylate used as a seed crystal includes any one of + -body crystal, −-body crystal and a mixture thereof, which are known optical resolution methods, specifically, for example, in advance. It can be produced by synthesis from raw materials optically resolved by liquid chromatography or the like.

The solvent used in the present invention includes alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, dimethylethanol and 2-methylpropanol, dichloromethane, chloroform and the like. Halogenated hydrocarbons,
Alkyl ketones such as acetone and methyl ether ketone,
Examples include aprotic polar solvents such as N, N-dimethylformamide, acetonitrile and dimethylsulfoxide, one kind of water and the like, or mixed solvents of the above various organic solvents.

The amount of the solvent used generally dissolves in a warm state,
It is sufficient that crystals are precipitated when left standing or cooled, and the concentration of suplatast tosylate at that time is usually 2
W / W% or more, preferably 10 to 50 W / W%. Crystals of suplatast tosylate with good absorbability are prepared by adding a solvent to the racemate of suplatast tosylate, heating and dissolving the crystals sufficiently, and returning to around room temperature and adding or storing the seed crystals. Can be manufactured in. The temperature for storage or cooling storage is usually from -50 ° C to
It is 40 ° C., preferably −30 ° C. to 25 ° C. Further, an insoluble solvent may be added instead of storage or cold storage, and examples of the insoluble solvent include ethers such as diethyl ether and diisopropyl ether, acetic acid esters such as methyl acetate and ethyl acetate, hexane, heptane and octane. Examples thereof include solvents such as aliphatic hydrocarbons.

The crystals of suplatast tosylate having good absorbency thus obtained are confirmed by an X-ray diffraction pattern, as shown in Examples below. That is, the X-ray diffraction pattern of the racemic body as a raw material is, as shown in FIG.
6 °, 13.3 °, 19.0 °, 20.0 °, 21.7
Peaks are observed at around 2 ° and 22.6 °, while the X-ray diffraction patterns of the products produced according to the present invention show diffraction angles of 5.7 °, 12.0 °, 17 as shown in FIGS. ．
4 °, 19.8 °, 21.7 °, 22.9 °, 24.0
A peak is observed around °. Incidentally, the absorbable suplatast crystals of good absorbency obtained by carrying out the present invention is an oral preparation such as tablets, capsules, granules or the like, which is crushed or while maintaining a solid state without crushing, It can be provided to the clinical site by processing into external preparations such as suppositories, inhalants, nasal drops, eye drops, ointments, plasters and aerosols.

[0009]

[Effect] According to the present invention, crystals of suplatast tosylate having good absorbability can be easily produced from a usual racemate with a high yield by this method.

[0010]

EXAMPLES The contents of the present invention will be described in more detail below with reference to some experimental examples together with comparative examples, but the present invention is not limited thereto.

[Experimental Example 1] 4 ml of isopropanol was added to 1.0 g of racemate of suplatast tosylate synthesized by the method described in Japanese Patent Publication No. 3-70698, and the mixture was heated to 70 ° C. and dissolved. The solution was cooled to 25 ° C. and seeded with (−)-Suplatast tosylate 2 m
After inoculation with g and storing at 25 ° C. for 7 days, the precipitated crystals were collected by filtration and dried under reduced pressure at room temperature for 1 day to obtain 0.929 g of optically inactive suplatast tosylate crystals (recovery rate 92 .9%). The X-ray diffraction result of the obtained crystal is shown in FIG.

[Experimental Example 2] 20 ml of 2-butanol was added to 5.0 g of racemate of suplatast tosylate and the mixture was heated to 70 ° C.
After dissolving by heating to, the solution was cooled to 25 ° C. and seeded with 3 mg of (−)-Suplatast tosylate as seed crystals,
After cooling and storage at 5 ° C for 3 days, the precipitated crystals were collected by filtration,
The crystals were dried at room temperature under reduced pressure for 1 day to obtain 4.82 g of optically inactive suplatast tosylate crystals (recovery rate 96.4).
%). The X-ray diffraction result of the obtained crystal is shown in FIG.

[Experimental Example 3] To 2.0 g of racemic suplatast tosylate was added 4 ml of ethanol and dissolved by heating at 70 ° C, 16 ml of isopropyl ether was added, and the solution was cooled to 25 ° C to seed crystals. As an inoculum, 3 mg of (+)-suplatast tosylate was stored under cooling at -30 ° C for 10 days, and the precipitated crystals were collected by filtration and dried under reduced pressure at room temperature for 1 day to give optically inactive crystals of suplatast tosylate. 1.93 g was obtained (recovery rate 96.5%). The X-ray diffraction result of the obtained crystal is shown in FIG.

[Experimental Example 4] To 3.0 g of racemate of suplatast tosylate was added 25 ml of acetone, and the mixture was heated to 70 ° C. to dissolve it, and then the solution was cooled to 25 ° C. to form (-)-tosyl as seed crystals. Inoculate 3 mg of acid suplatast, -30
After storing at 3 ° C for 3 days, the precipitated crystals were collected by filtration and dried under reduced pressure at room temperature for 1 day to obtain 2.85 g of optically inactive suplatast tosylate crystals (recovery rate 95.0%). The X-ray diffraction results obtained are shown in FIG.

[Experimental Example 5] 100 racemic crystals of suplatast tosylate and 100 crystals each obtained in Experimental Example 1
1.9 mg of petroleum jelly was crushed in a mortar and mixed well to give an ointment, and this ointment 40
0 mg was applied to the abdominal skin of hairless rats (application area 5.31 cm ² ) and fixed in a vertical cell, and 13 ml of water was used as a permeate to conduct a permeation experiment, and the time-dependent permeation amount was measured by liquid chromatography. did. The results are shown in FIG. 6. According to this, it was found that the crystal obtained in Experimental Example 1 had a permeation amount about three times higher than that of a normal racemic crystal.

[Brief description of drawings]

FIG. 1: Racemic X of normal suplatast tosylate
It is a line diffraction diagram.

2 is an X-ray diffraction diagram of suplatast tosylate obtained in Experimental Example 1. FIG.

FIG. 3 is an X-ray diffraction diagram of suplatast tosylate obtained in Experimental Example 2.

FIG. 4 is an X-ray diffraction diagram of suplatast tosylate obtained in Experimental Example 3.

5 is an X-ray diffraction diagram of suplatast tosylate obtained in Experimental Example 4. FIG.

FIG. 6 is a permeation amount curve of racemic crystals of suplatast tosylate and the crystals obtained in Experimental Example 1.

Claims (4)

[Claims] 1. A crystal having a good absorption property, which is obtained by dissolving a racemate of suplatast tosylate in a solvent and then recrystallizing it by adding an optically active crystal of suplatast tosylate as a seed crystal. Suplatast tosylate. 2. Obtained by dissolving a racemate of suplatast tosylate in a solvent, returning the temperature to around room temperature, and adding an optically active substance crystal of suplatast tosylate as a seed crystal, and storing or cooling to recrystallize. Suplatast tosylate with good absorbency, characterized by being crystalline. 3. Production of suplatast tosilate having good absorbability, which comprises dissolving a racemate of suplatast tosylate in a solvent and then recrystallizing it by adding an optically active crystal of suplatast tosylate as a seed crystal. Method. 4. A solution of the racemate of suplatast tosylate in a solvent, followed by cooling to around room temperature, and addition of an optically active crystal of suplatast tosylate as a seed crystal for storage or cold storage for recrystallization. A method for producing suplatast tosylate, which is characterized by good absorbability.