JPS5916820A - Solid pharmaceutical containing amorphous malotilate - Google Patents

Abstract

PURPOSE:The titlted composition, obtained by incorporating a crystalline malotilate with a porous material under stirring, having very improved stability, exhibiting a more rapid dissolution and improved absorbability through the digestive tracts, and having improved remedial effects on acute and chronic hepatic disorder. CONSTITUTION:A solid pharmaceutical prepared by pulverizing crystals of malotilate (diisopropyl 1,3-dithiol-2-ylidenemalonate) expressed by the formula in a pulverizer, e.g. a ball mill or jet mill, and incorporating the resultant powder with a porous material having preferably >=250cm<2>/g specific surface area, e.g. magnesium metasilicate aluminate or light anhydrous silicic acid, at room temperature or under heating, preferably 45-55 deg.C, and stirring. Alternatively, the pharmaceutical is obtained by dissolving the malotilate in an organic solvent, wetting the porous material completely with the solution, or wetting the porous material with an organic solvent capable of dissolving the malotilate, adding the malotilate thereto, fully stirring the mixture, and removing the organic solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides malotylate (common name: diisopropyl 1.3
- dithiol-2-ylidenemalonate).

Malotylate is a compound represented by the following structural formula: (), and has excellent therapeutic effects on acute and chronic liver disorders. It is expected to be a rare drug and is currently under development.

This malochilate has a tautomeric crystal polymorphism, and has a low-temperature stable form (type A crystal: melting point 50-53°C) and a high-temperature stable form (type B crystal: melting point 60-63°C), and is usually a doll crystal. It is a very common compound. Substances having such crystal polymorphisms may cause quality control problems.

Furthermore, Marothiller 1- is a poorly soluble drug that is poorly soluble in water, and it is said that the rate of absorption of poorly soluble drugs in the body is determined by the rate of dissolution of the drug from the formulation containing them. As such, in order to improve absorption in humans, it is desired to produce preparations with excellent dissolution properties through simple operations.

It is known that certain crystalline compounds, which have been traditionally used in medicine, can be made amorphous using specific means.

For example, in Japanese Patent Application Laid-Open No. 56-493, a method for amorphizing calcibin by whole-milling a specific pharmaceutical compound is disclosed.
In Publication No. 14, by adding specific additives (for example, human quinoprobyl methylcellulose-borivinylhyloridone, citric acid, etc.) to a solid drug, dissolving it in a plated solvent, and removing the vaginal solvent. Although a method for amorphousization has been disclosed, whether a crystalline compound used as a pharmaceutical becomes amorphous by itself or under what conditions is due to the unique properties of the substance, The method is complicated (it may not be applicable to all substances).

Note that amorphous forms are often crystallographically unstable and are said to be likely to transition to a more stable crystalline state over time.

Therefore, in order to improve the above-mentioned drawbacks of malotylate, the present inventor, Nagisa, has investigated a more stable formulation by making the usual crystalline form of malotylate amorphous, and after intensively studying their dissolution properties and absorbability from the gastrointestinal tract, we have unexpectedly discovered that Malotylate can also be used as an ordinary pharmaceutical additive by mixing and stirring at room temperature or under heating with a porous material, or by thoroughly moistening the porous material with a solution of malotylate dissolved in an organic solvent, and then removing the solvent. If the organic solvent is removed, or the porous material is wetted with an organic solvent that dissolves malothyrate in advance, malotylate is added, mixed and stirred, and the organic solvent is removed, it changes to an amorphous form, and the amorphous malotylate thus obtained is extremely stable. The present invention has been completed based on the discovery that the carrier has excellent properties, faster dissolution properties, and excellent absorbability from the gastrointestinal tract.The carrier used in the present invention preferably has a large specific surface area, especially about 25 On? , 'Fl or higher is preferable. Examples of these include magunium meta)7-ioic acid aluminate, light trading [water silicate-synthetic aluminum silicate, magnanium oxide/τtsuno., synthetic hyhydrotalcite, aluminum oxide, etc.] Can be mentioned.

The amount of these carriers used is approximately half to twice as much per 1 part by weight of malotylate crystals, which results in much less loss than the amount of carriers used in conventional methods, and allows for other additives and smaller dosage forms. Considering the above, the present invention is extremely superior in terms of industrial formulation technology.

When mixing and stirring malotylate crystals and a pharmaceutically acceptable carrier, first grind the malotylate crystals with a grinder commonly used as a grinder for pharmaceuticals, such as Whole Mill, Physonomyl, and Ethomil. Remove the crystallization carrier.
It is best to add 1 liter and mix and stir. For mixing the two, a normal pharmaceutical mixer such as a V-type mixer, a ribbon-type mixer, Nauta Miki →)-1, or a super mixer can be used, but it is also possible to use the above-mentioned pulverizer to mix the two at the same time. Heating during mixing and stirring of malochilate and the amorphous compound is not particularly limited, but it is particularly efficient to heat it at a temperature of 45 to 5°C. After dissolving in an organic solvent and completely wetting the porous material with this solution, the solvent is removed, or malotylate is added after wetting the porous material with an organic solvent in which malotylate is previously dissolved; It is obtained by stirring well and removing the organic solvent.

Organic solvents that can be used include any solvent that dissolves malothyrate, such as dichloromethane, chloroform, carbon tetrachloride, etc., rogogenated compounds, methanol-ethanol, aliphatic alcohols such as pronocentol, n-hexane, etc. , lower hydrocarbons such as xane, pentane, and heptane, ethers such as ethyl ether, propyl ether, and tetrahydrofuran-dioxane, acetone,
Examples include ketones such as methyl ethyl ketone, esters such as ethyl acetate-butyl acetate, and aromatic hydrocarbons such as benzene-toluene and xylene. The amount used is not particularly limited, but it is preferably 5 to 50 parts by weight per 1 part by weight of the porous material.

The organic solvent is removed at room temperature, preferably at a temperature above the crystal transition point, under normal pressure or reduced pressure. Specifically, a conventional heat drying method, a blade drying method, a freeze drying method, etc. can be used.

In the present invention, the term "amorphous" refers to a state in which a crystal peak peculiar to crystalline malotylate is not shown in the X-ray spectrum. That is, in a low temperature stable crystal, 2θ = 10.2
c, 20.5c and 269e, and 2θ = 7.6° for the high temperature stable crystal.

Although it has characteristic crystalline peaks at 18.8° and 227°, none of the above crystalline peaks are observed in the X-ray diffraction spectrum of the composition of the present invention.

The amorphous Malo 1,000 composition obtained by the method of the present invention is -
Although it can be used as an oral preparation, it can also be made into a suitable dosage form by adding other suitable additives, such as fine granules, granules, tablets, and suppositories.

Example 1 After pulverizing 1 g of crystals of malochilate in a mortar, magnesium aluminate metasilicate (specific table iIJ+ product 250
rr? /9') 15 and fJ are added and mixed uniformly. After heating and stirring the mixture at about 50°C for about 30 minutes,
Allow to cool at room temperature to obtain amorphous malotylate. Is this thing powder X-ray cycle 17? As a result of spectral measurement, it was found that the particular peak in the malotylate crystals had completely disappeared.

The thus obtained amorphous malotylate composition was heated at 5°C for 50 minutes.
1 at 0°C and 40°C 75% relative temperature Japanese Pharmacopoeia Dissolution Test Method 2 (τ dollar method) Test solution: Japanese Mulberry Pharmacopoeia No. 900111' Paddle rotation speed: 100 revolutions/min Example 3 10 g of malotylate crystals (type A) and magnenoum metasilicate aluminate (specific surface area 300rr?/9) 159
The mixture was then mixed uniformly with the mixture, heated and stirred at 50° C. for 30 minutes, and then allowed to cool at room temperature to obtain one-form malotirade. (Recognized as R based on powder X pure diffraction spectrum) - Fill amorphous malotylate (mixture of aluminometasilic acid makkonnoumikichi) 0.25II (oly as malotylate) into a No. 0 hard capsule and capsule as a drug.

The above cuff cell preparation was administered to subjects (male Peakle dogs, 6 dogs, body g).
i' 10.5 to 13.0kf'), the main metabolite of malotylate, in-70virnohydrogen 1,6-sithio-2-yritemalohydrogen (hereinafter abbreviated as M-1), was released. The plasma concentration of 1) was measured.

As a control, the plasma concentration of M, -1 was measured using 71 capsule-culm j filled with malotylate crystalline powder (form A) o2y. The results are shown in Table 3. The amorphous 3Y of the present invention and Malloy lard exhibited a collapsed absorption effect (Table 3A Absorption effect of the invented material)? -AU('; Area under the #degree curve in plasma ※※ Determination of N1-1; Fast Liquid Chroma 1-Cl 7 Method Example 4 5 og of crystalline powder of malochilate (Type B) and Mix 48 g of surface area (380 dll) and mix and stir at about 50°C for about 2 hours.Then, let it cool at room temperature and light up the amorphous malochilate.(Powder bed Granules A (Flow Coke Mini) were mixed with 74-II, amorphous malotylate (mixture) 8094 obtained by the above procedure, and hydroquinopropyl cellulose (11PL-C; manufactured by Honsoda ■)/lNol N solution. (29→100 m) 82 rtl was sprayed and fluidized granulation 1-, followed by fluidized drying. After drying 3
2 Metsutsuyu no Sieve 18: it! Example C malotylates 1 and 9 were dissolved in ethanol 5/7 to obtain fine granules. 1 kv was stirred and kneaded with a force of 11. The kneaded material was soufflé-dried at 80°C to obtain a composition of the present invention.

600 g of said composition, Avicel P) 41o11o.

〃, white sugar 180.9, carboxymethylcellulose 1007% were mixed, and this was kneaded with 20 g of hydrogy/glohil methylcellulose (h 59b-γ alcohol solution, granulated using extrusion granulation, and then dried. It was made into granules.

Example 6 Light alloy 1j or aluminum silicate (specification + l150
(1rr?/g) 1 kq was moistened with 51 chloroform, then 1 ky of malotylate was added and kneaded with stirring. The kneaded product was air-dried at 80° C. to obtain the silk product of the present invention. 200 g of the above composition, carboquinomethyl (nilulose 1
After mixing o9, hydroquinoprobyl cellulose 29 part 10
% alcohol solution underlined and granulated 0 After drying, magnonium stearate 4g, light anhydrous silica rW
5 & was mixed and filled into hard capsules to make a hard capsule.Reference Example 1 After crushing malochilate crystals 29 in a mortar, meta) 7
- Magnesium/aluminum ester (specific surface area 110i/g
)4. []Add 5+ and mix evenly until the 0 mixture is about 5
After heating and stirring at 0° C. for about 1 hour, the mixture is allowed to cool at room temperature.

As a result of measuring the above treated product using powder X-ray diffraction spectrum,
A malochilate crystal heater was confirmed.

Reference example 2 2 g of crystals of malochilate and light anhydrous silicic acid (specific surface area 2
00R/g) and the same operation as in Reference Example 1 was performed, but amorphous malotylate was not obtained (confirmed by powder Xi diffraction nupector).

Reference Example The same operation as in Example 5 was carried out using 2 g of malotylate crystals and 21 meta/1-isoic acid magzoum (specific surface area 2[]onr, Q), but amorphous malotylate was not obtained. (Confirmed by powder X-ray cycle V [spectrum]).

(1 year old or 1 person)

Claims (3)

[Claims] (1) Crystal form diisopropyl 1. Ro-dithiol-2-
After mixing and stirring ylidene malonate (hereinafter referred to as malotylate) with a porous material at room temperature or under heating, or dissolving crystalline malotylate in an organic solvent and sufficiently moistening the porous material with the solution. A solid pharmaceutical composition containing amorphous malotylate obtained by removing the solvent or wetting a porous material with an organic solvent in which malotylate is dissolved in advance, adding malotylate, mixing and stirring, and then removing the solvent. (2) Does the porous material have a specific surface area of 250 n? /F! Patent 1iWi consisting of one or more selected from the group consisting of the above synthetic aluminum silicate, magnesium metasilicate aluminate, synthetic hydrotalcite, and aluminum oxide.
The composition according to item 1. (3) The composition according to paragraph 1 of the patent, wherein the mixing ratio of crystalline malotylate and porous material is 1:0.5 to 2.0.