JPS6281309A - Slow-releasing tablet of valproate sodium - Google Patents

Abstract

PURPOSE:To provide the titled slow-releasing tablet containing magnesium metasilicate aluminate, etc., and valproate sodium, stable to moisture, capable of keeping the optimum concentration in blood by oral administration and useful for the remedy of epilepsy and prevention of fit. CONSTITUTION:A piece of the titled tablet contains (A) 100pts.(wt.) of valproate sodium which is a widely used antiepileptic agent, (B) 10-100pts. of magnesium metasilicate aluminate and (C) 2-80pts. of ethylcellulose. The tablet can be produced by dissolving valproate sodium having poor moisture-stability in water or organic solvent, absorbing the obtained solution is magnesium metasilicate aluminate, drying the product to obtain powder stable to moisture, adding ethylcellulose to the powder, homogeneously kneading the mixture in the presence of an organic solvent, drying the kneaded mixture and compression molding the composition by conventional method. The tablet is preferably packaged by PTP package (with polyvinyl chloride/aluminum foil) to ensure the long-term storage stability.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a sustained-release preparation of sodium valproate, which is widely used as an antiepileptic drug.

More specifically, one tablet contains 100% sodium valproate.
Part by weight, magnesium aluminate metasilicate 1o-to
The present invention relates to a sustained-release sodium valproate tablet, characterized in that it contains 2 to 80 parts by weight of sodium valproate and 2 to 80 parts by weight of ethyl cellulose.

[Conventional collision]

Sodium valproate is widely used as an anti-epileptic drug to treat epilepsy and prevent seizures, but sodium valproate does not maintain a sustained blood concentration when administered orally, and it is difficult to maintain an optimal blood concentration. Frequent administration is being carried out.

In addition, sodium valproate is extremely hygroscopic, and it is necessary to stabilize it against humidity during the manufacturing process and storage of the preparation.

[Problem that the invention seeks to solve]

The present inventors have conducted various studies on sodium valproate preparations that are stable against humidity and have an optimal persistence in the blood once administered orally.

[Means for solving problems]

The inventors have discovered that sodium valproate extended-release tablets, which are characterized by containing magnesium aluminate metasilicate and ethyl cellulose, are stable at temperatures of 754 degrees and maintain an optimal blood concentration. discovered that it has excellent characteristics, and completed something that had not yet been invented.

That is, the sodium valproate extended-release tablet of the present invention is prepared by dissolving sodium valproate, which is unstable against humidity, in -10% water or an organic solution and absorbing it in magnesium aluminate metasilicate. It is produced by dry-blasting to make a humidity-stable powder, adding ethyl cellulose, adding an organic solvent, kneading it evenly, and compression-molding the resulting product according to a conventional method.

Examples of the organic solvent include 1,2-dichloroethane.

Specifically, as the ethyl cellulose, for example, Etcel Shima (Standard 10, manufactured by Dow Chemical Company) is preferably used, and as the magnesium aluminate metasilicate, for example, Neusilin Shun (manufactured by Fuji Chemical T-Gyo Co., Ltd.) is preferably used.

The amount of magnesium aluminate metasilicate used is 10" l O per 100 tons of Valpro sodium resistant.
O parts by weight, preferably 20 to 70 parts by weight, and the used φ of ethyl cellulose is 2 to 80 parts by weight, preferably 5 to 50 parts by weight per 100 parts by weight of sodium valproate.
This is the heavy clothing area.

If the number of usage notifications for magnesium aluminate metasilicate is less than the above range, it is difficult to stabilize it at 78 degrees due to manufacturing process and storage, and conversely, if it is more than the above range, it is because the bulk density of magnesium aluminate metasilicate is large. However, the resulting extended-release tablets are too large to be taken properly.

If the amount of ethyl cellulose used is less than the range specified in h, the sustained release effect will not be sufficient, and if it is too much, the bioavailability will decrease, which is undesirable.

In addition to the above-mentioned magnesium aluminate metasilicate and ethyl cellulose, a small amount of commonly used additives such as lactose, crystalline cellulose, and magnesium stearate may be added for compression molding.

Furthermore, the sustained-release tablets obtained as described above can be film-coated using a polymeric coating polymer according to a conventional method.

As the polymer coating polymer, for example, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, or a mixture of these polymers and ethylcellulose is used.

The sodium valproate sustained release tablets obtained as described above are preferably packaged in FTP packaging (polyvinyl chloride/aluminum foil) for long-term storage.

The sodium valproate slow tablet of the present invention is stable against humidity and maintains an optimal blood concentration, and is suitably used for epilepsy treatment and seizure prevention.

For treatment, the dosage varies depending on the symptoms, body weight, age, etc., but the dosage is usually 1.
Orally administer 400 to 1200 mg per day or in two divided doses.

[Efficacy of invention! ]

As shown in the test results below, the extended-release sodium valproate tablets of the present invention are stable against humidity levels, and elution of sodium valproate from the tablets is moderately controlled, resulting in sustained optimal blood concentration. Excellent.

Test Example 1 (Dissolution Test) 1. Each sustained-release tablet manufactured in Sample Examples 1 to 3 (one tablet contains sodium valproate 200, 100, and 300B, respectively) and a normal commercially available preparation (Hiselenin Tablets Co., Ltd.) :Made by trowel spinning,
(1 tablet contains 200 mg of sodium valproate) 2. Test method A dissolution test was conducted in purified water at 37°C in accordance with the dissolution test method (paddle method) of the Japanese Pharmacopoeia, 10th edition.

The elution rate was determined by acidifying the eluate with hydrochloric acid and fixing the valproic acid extracted with ethyl acetate using gas chromatography.

Note that gas chromatography was performed under the following conditions.

Detector: FTD, sample vaporization chamber temperature: 220°C.

Column: DEC95% +H3PO41L Chro
mosorb W.

3mm (,3X2m, Column temperature: 150°C1Nitrogen flow rate: 401TIQ/ll1n.

3. Test results The results are shown in Table 1.

Table 1 Test Example 2 [Changes in serum concentration (dogs)] 1. Extended-release tablets manufactured in Sample Example 1 (containing 200 mg of sodium valproate in 1 tablet) and ordinary commercially available preparations (Iselenin Tablets I (manufactured by Kanebo Co., Ltd., 1 tablet contains 200 mg of sodium valproate) 2. Test method 1: 4 large male peagles (weight: 11-14 kg) fed extra food
), 212 samples were collected using the random crossover method.
(347 mg as valproic acid) was orally administered at 0.25.0.5.1.2.3.4. fl, lO
Blood was drawn at the hour, and Minoru Hata and Hiroyuki Atsume [Medical History,
The concentration of valproic acid in plasma was determined by gas chromatography according to the method of 1980 (1980).

Note that there was a one-week period of physical therapy between the administration of each sample.

3. Test results The results are shown in Figure 1.

Test Example 3 (Storage Stability Test) 1. Sample The extended-release tablet produced in Example 1 was FTP packaged and used as a sample.

2. Test method After leaving the old friend sample indoors and under conditions of 40° C. and 75% I'i, H for 3 months, its formulation properties (appearance, hardness, content, dissolution test) were investigated.

@Degree is ERWEKA hardness tester TB24
Measured using a mold.

Quantification of the adhesion and elution tests was carried out by gas chromatography under the same conditions as Test Example 1.

3. Test results 〔Example〕 The present invention will be explained in more detail with reference to Examples below.

Example 1 200 parts of sodium valproate was dissolved in 95 parts of water, added to 97 parts of magnesium aluminate metasilicate, mixed uniformly, and then dried. After adding 45 parts of ethyl cellulose to the dried powder, 100 parts of 1,2-dichloroethane was added and kneaded uniformly. After drying, this kneaded product was sized, 3 parts of magnesium stearate was added, and the mixture was compressed. 1i! Molded to make 345 mg tablets with a diameter of 10 mm.

Furthermore, 9 parts of hydroxypropyl methyl cellulose, 2 parts of ethyl cellulose, 2 parts of glycerin fatty acid ester,
A film coating solution consisting of 3 parts of titanium oxide, 120 parts of ethanol, and 150 parts of 1,2-dichloroethane is sprayed using a coating machine to form film-coated tablets weighing 1360 mg. (One tablet contains 20,011 g of sodium valproate) Example 2 100 parts of sodium valproate was dissolved in 50 parts of water, added to 45 parts of magnesium aluminate metasilicate, mixed uniformly, and then dried. After adding 43 parts of ethyl cellulose to the dried powder, 60 parts of 1,2-dichloroethane was added and kneaded uniformly. This kneaded product was dried and sized, and 2 parts of magnesium stearate was added and compressed. It is molded into tablets weighing 190 mg and having a diameter of 8 mm.

Furthermore, 9 parts of hydroxypropyl methyl cellulose, 2 parts of ethyl cellulose, 2 parts of glycerin fatty acid ester,
A film coating solution consisting of 3 parts of titanium oxide, 120 parts of ethanol, and 170 parts of 1,2-dichloroethane is sprayed using a coating machine to form film-coated tablets weighing 1198 mg. (One tablet contains 100 mg of sodium valproate) Example 3 300 parts of sodium valproate was dissolved in 140 parts of water,
The mixture was added to 135 parts of magnesium aluminate metasilicate, mixed uniformly, and then dried. Add 60 parts of ethyl cellulose to the dried powder, add 150 parts of 1,2-dichloroethane, and knead uniformly. After drying this mixture, granulate it,
Add 5 parts of magnesium stearate, compression mold,
Tablets are 500 mg in weight and 12 a+m in diameter.

Furthermore, 9 parts of hydroxypropyl methyl cellulose, 2 parts of ethyl cellulose, 2 parts of glycerin fatty acid ester,
A film coating solution consisting of 3 parts of titanium oxide, 150 parts of ethanol, and 150 parts of 1,2-dichloroethane is sprayed using a coating machine to form film-coated tablets weighing 520 mg. (One tablet contains 300mg of sodium valproate)

[Brief explanation of drawings]

Figure 1 shows the change in plasma concentration in Test Example 2 (dog).
represents. Figure 1 Time (hr)

Claims (1)

[Claims] 1. A sustained release tablet of sodium valproate, which contains 100 parts by weight of sodium valproate, 10 to 100 parts by weight of magnesium aluminate metasilicate, and 2 to 80 parts by weight of ethyl cellulose.