JPH0160452B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Field of Application) The present invention relates to an oral solid drug for the symptomatic treatment of epileptic seizures or convulsions. (Prior art and its problems) In recent years, 2-propylpentanoitsuccinic acid and its alkali metals or alkali metal salts (hereinafter referred to as valproic acid and valproate salts, respectively) have become useful for the treatment of epileptic seizures or convulsions. It is included in some medicines. Among these, valproic acid itself and valproate sodium have excellent medicinal efficacy, but the former is a liquid and is not suitable for producing oral drugs as it is, and the latter has the disadvantage of being extremely hygroscopic and having poor stability. There is. The object of the present invention is to provide an oral solid for the treatment of symptoms of epileptic seizures or convulsions, the main active ingredient of which is a non-hygroscopic crystalline solid compound that exhibits medicinal efficacy comparable to conventional valproic acid or its salts and is highly stable. The goal is to provide medicine. (Means for Solving the Problems) The above object of the present invention is to prepare a single crystalline compound having a molar ratio of valproic acid and sodium valproate of 1:1 with one or more pharmaceutically acceptable excipients or This is achieved by an oral solid drug for the treatment of symptoms of epileptic seizures or convulsions, which is characterized in that it is included together with a diluent. The compounds of the present invention are compounds that are represented by a single chemical molecule, have distinct physical properties, and have melting points of about 98-100°C. The structural unit formula of the compound of the present invention is (CH ₃ CH ₂ CH ₂ ) ₂ CHCO ₂ Na /(CH ₃ CH ₂ CH ₂ ) ₂ CHCO ₂ H, but its structure has not yet been determined. It is presumed to be an oligomer as shown below, in which both units are bound together through sodium. The above is just an estimate, and this compound is a single compound (oligomer) as understood from the melting point and the like. The compound of the present invention is prepared, for example, by dissolving 1 mole each of valproic acid and sodium valproate in 1000 ml of acetone at about 50°C. Solution at 0℃
or lower, and the generated new compound is filtered, and if necessary, washed with pre-cooled acetone and dried under reduced pressure to completely remove acetone. It can also be made in a two-component liquid medium containing, for example, acetone. That is, the target compound can also be prepared on the spot by adding valproic acid and 1/2 molar equivalent of NaOH to the valproic acid in a solvent consisting of acetone-NaOH compatible solvent, such as water. Separation of the compounds of the invention can be carried out by evaporating the solvent from the liquid phase. If necessary, it can be recrystallized from acetone/water, acetonitrile, etc., or purified by spray drying, freeze-vacuum drying, or chromatographic methods. The compounds of the present invention can be analyzed by microanalysis, nmr spectroscopy,
Mixed melting point measurements, IR spectra and/or
represented by a single chemical molecule as determined by line diffraction. This new compound is similar to the above-mentioned 2
It is a stable crystalline solid without the harmful physical properties of any of the starting materials. It is quite surprising that a useful compound with such unexpected properties could be prepared solely from valproic acid and its sodium salt. If other valproate salts are used, ie, potassium, ammonium or magnesium salts, the products do not crystallize out or form, or are only very unstable in the presence of atmospheric moisture. The compound of the present invention is combined with appropriate diluents and/or excipients in a conventional manner to form an oral solid drug. Here, diluents and excipients refer to any inactive ingredients in general solid drugs such as tablets, and include those indicated by the name of carriers and the like. For example, any pharmaceutically acceptable agent such as starch, talc powder, lubricant, disintegrant, seasoning, coloring agent, etc. may be used. Next, the present invention will be explained based on Examples, but these are not intended to limit the present invention. Reference Example 1 166 g of sodium valproate and 144 g of valproic acid were dissolved in 1000 ml of acetone at a temperature of about 50°C or higher.
The solution was cooled to about 0°C and filtered to remove the crystalline precipitate at about 0°C.
Washed with acetone pre-cooled to ℃. The yield of the new compound was 90% of the theoretical amount. The acetone filtrate was used next time to obtain more compound. The resulting compound is a stable white crystalline powder with a melting point of 98~
It was 100℃. This fact can be said to indicate that it is a single compound. Its water stability was confirmed by placing the compound sample in an environment of room temperature and relative humidity of 80% for 45 minutes. There was no weight increase under these conditions, whereas the simple sodium salt of valproic acid increased by 17 to 24% by weight due to water absorption under the same conditions. The infrared spectrum of the product compound is characterized by the following absorption bands: 2957, 2872, 2932, 1685,
Strong bands are shown at 1555 and 1370 cm ^-1 . The first two bands above represent various methyl groups, and the last two bands are due to the asymmetric and symmetric O-C-O-stretching vibrations of the carboxyl salt, respectively.
The remaining strong bands indicate stretching vibrations of C=O in various methyl and carboxylic acid groups;
The weak broad band at cm ^-1 is due to the intramolecularly bonded OH group of the carboxylic acid. From these and other analytical results, the product has the unit formula (CH ₃ CH ₂ CH ₂ ) ₂ CHCO ₂ Na / (CH ₃ CH ₂ CH ₂ ) ₂ CHCO ₂ H in a molar ratio of sodium valproate to valproic acid of 1:1. is estimated to be a single oligomer (formula above). Example 1 A: Valproic acid (stable, liquid) B: Sodium valproate (hygroscopic solid) C: Compound of Reference Example 1 (stable solid) Oral administration based on molar equivalents of valproic acid for comparison of anticonvulsant activity ED ₅₀ was determined by testing according to standard methods. The results were as follows:

Table: In bioefficacy studies conducted using A and C above in various animals, the peak plasma concentration of oral equimolar drug 30 minutes after drug administration was determined by standard methods.

[Table] From the above results, it is clear that the compound of the present invention has physiological properties equivalent to or superior to either valproic acid or sodium valproate. Since the compound of the invention has physical properties which are superior to either of the monomers from which it is derived, it makes it possible to produce solid pharmaceutical forms by weighing out specific amounts of starch and/or ) It was possible to mix with other binders to form a free-flowing powder and then granulate it into a standard tablet machine to make excellent tablets. Neither the hygroscopic sodium valproate nor the liquid valproic acid itself could be processed in this manner without special care or the use of absorbents.

Claims (1)

[Claims] 1. Epilepsy or convulsions characterized by containing a single crystalline compound having a molar ratio of valproic acid and sodium valproate of 1:1 together with one or more pharmaceutically acceptable excipients or diluents An oral solid drug for the symptomatic treatment of.