JPH0640899A - Sustained release tablet of sodium valproate - Google Patents

Abstract

(57) [Summary] [Object] To provide a sustained release tablet of sodium valproate, which is relatively small in size, stable in elution, and capable of maintaining a stable blood concentration over a long period of time. [Structure] A coating layer obtained by coating the surface of a core tablet containing sodium valproate with a coating agent composed of ethyl cellulose in which silicic acid anhydride is dispersed,
Sustained release tablets of sodium valproate.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to sustained release tablets of sodium valproate.

[0002]

2. Description of the Related Art Sodium valproate is a useful drug generally used for treating epilepsy and preventing seizures, and its effective blood concentration range is generally said to be 50-100 μg / ml. In addition, sodium valproate has a short biological half-life, and 3 days a day is required to maintain effective blood levels.
Single dose is required. However, since such frequent administration is troublesome for patients, efforts have been made to develop sustained-release sodium valproate preparations. However, sodium valproate has a relatively large daily dose of 1200 mg and is highly hygroscopic. Therefore, sustained-release tablets prepared by the prior art contain a large amount of sustained-release agents and the like. In addition, the weight per tablet is large, which is not always satisfactory.

Then, recently, after (a) granules were produced by using ethyl cellulose as a binder in a mixture of sodium valproate and magnesium aluminometasilicate,
A method for producing a sustained release tablet (JP-A-62-81309), or
(B) A method in which valproic acid in which ethyl cellulose is dissolved is added to a mixture of Eudragit (acrylic polymer) and sodium valproate, and the mixture is granulated and tableted (JP-A-60-41610).
Became known. However, although the sustained-release tablet obtained in (a) is said to be sustained-release, the duration of the optimal blood concentration of the drug is not very long, and the blood concentration of the drug significantly decreases 10 hours after administration. Therefore, it cannot be used as a sustained-release tablet that is effective for a long time. Further, the sustained-release tablet obtained in (b) has a drawback that the dissolution rate of the drug is easily influenced by the pH in the digestive tract, and thus the variation in the blood concentration after administration is large.

[0004]

Based on this point of view, the present inventors have conducted extensive studies on a sustained release tablet of sodium valproate, which is relatively small and easy to swallow, and which can be taken once a day. However, a preparation obtained by coating sodium valproate core tablets with ethyl cellulose in which silicic acid is evenly dispersed is excellent in the dissolution rate uniformity without being affected by the pH of the solution even with a relatively small size, and They have found that they have extremely stable and good sustained release properties, and have completed the present invention.

[0005]

DISCLOSURE OF THE INVENTION The present invention has a coating layer (coating) obtained by coating the surface of a core tablet containing sodium valproate with a coating agent composed of ethyl cellulose in which silicic acid anhydride is dispersed. It is a sustained release tablet of sodium. Hereinafter, the present invention will be described in more detail. The sodium valproate core tablet in the present invention is not particularly limited, and the core tablet produced by the conventional technique is used as it is. Such a core tablet is prepared, for example, by adding additives such as an excipient and a binder to sodium valproate and mixing them evenly, and then producing granules according to a granulation method known per se, and then adding a suitable slippery mixture. It is prepared by adding a lubricant and tableting. These additives are used for the purpose of improving moldability during granulation, homogenizing the particle size of granules, and preventing moisture. For example, silicic acid as an excipient, a metal salt of a higher fatty acid (stearic acid, palmitic acid, Metal salts such as calcium and magnesium such as myristic acid), and hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone and the like as a binder are used. Also,
As the lubricant, calcium stearate, magnesium stearate, white carbon, silicic acid anhydride and the like are used.

A sustained-release tablet of sodium valproate is prepared by coating a core tablet containing sodium valproate with an ethylcellulose solution in which silicic acid anhydride is uniformly dispersed by a conventional spray coating method. Hereinafter, if a preferred embodiment in preparing the sustained-release tablet of the present invention is shown, silicic acid anhydride dispersed in ethyl cellulose as a coating agent is insoluble in water and can be dispersed colloidally in water and an organic solvent. used. The coating agent is prepared by dissolving ethyl cellulose in a lower alcohol such as methanol and ethanol in an amount of usually 2 to 10%, preferably 4 to 6% by weight, and then adding anhydrous silicic acid to 1 part by weight of ethylcellulose. .1 to 0.7
Parts by weight, preferably 0.2 to 0.5 parts by weight, mixed and dispersed, are used. The amount of the coating layer (coating amount) is usually 2 to 10% by weight, preferably about 3 to 8% by weight based on the core weight.
Amounts that result in weight percent are desirable.

The sustained-release tablet thus obtained controls the dissolution rate of sodium valproate by changing the compounding ratio of ethyl cellulose and silicic acid anhydride contained in the coating agent and the coating amount of the coating agent. be able to. That is, when the compounding ratio of silicic acid anhydride to ethyl cellulose is large and the coating amount is small, the elution is generally faster. Conversely, when the compounding ratio of silicic acid anhydride is small and the coating amount is large, the elution is entirely. Slow and more sustained release. Furthermore,
In the present invention, a larger amount of silicic acid is used because it is possible to obtain a stable tablet that is not sensitively affected by the coating amount.
This is advantageous in producing tablets. However, if the compounding ratio of silicic acid is too large, a sustained-release tablet cannot be obtained. Therefore, it is desirable that the compounding ratio be within the above range. The formulation technique can also be used for other similar drugs with high water solubility.

[0008]

EXAMPLES Next, the present invention will be described in more detail with reference to Examples, Reference Examples and Test Examples of the present invention.

Example 1 (a) Manufacture of core tablets 1600 g of sodium valproate and 160 g of silicic acid anhydride ("Aerosil-200" manufactured by Nippon Aerosil Co., Ltd.) were thoroughly mixed, and then 608 g of an ethanol solution of 5% by weight hydroxypropyl cellulose was added. Add and knead. The kneaded product was dried with a hot air dryer at 60 ° C., and then sized with a 16 mesh screen. Calcium stearate (1% by weight) was mixed with the granules, and the mixture was compression-molded to give a core tablet (tablet) having a weight of 228.6 mg and a diameter of 8.5 mm. (B) 1000 core tablets obtained in (a) were fluidized by a fluidized bed coating device (Ogawara Seisakusho “Uniglat”),
In addition to this, ethyl cellulose (ethoxy content: 46-51%)
Spray coating a coating agent containing 1% by weight of Aerosil-200 dispersed in a 5% by weight ethanol solution,
Sustained release tablets of sodium valproate (A tablet: weight 236.3m
g, film weight 7.7 mg) was obtained.

Example 2 A core tablet (weight: 226.7 mg, obtained in the same manner as in Example 1 (b))
1,000 tablets (diameter 8.5 mm) were made to flow by a fluidized bed coating device (Uniglat: Okawara Seisakusho), and ethyl cellulose (ethoxy content: 46-51 was used as a coating agent.
%) 1% Aerosil-200 in 5% by weight ethanol solution
~ 1.5 wt% dispersed suspension is spray coated to give sustained release tablets of sodium valproate (E tablets, F tablets,
G tablet) was obtained. The weight% of Aerosil-200 in the coating agent and the characteristic values of the obtained tablets are shown below.

[0011]

Example 3 400 g of sodium valproate and 80 g of Aerosil-200
Is thoroughly mixed, and then 216 g of a 5 wt% hydroxypropylcellulose ethanol solution is added and kneaded. The kneaded product is dried with a hot air dryer at 60 ° C, and then sized with a 16-mesh sieve. After mixing 1% by weight of calcium stearate with the granules, compression molding (tabletting) was performed to weigh 2
It was a core tablet (tablet) with a diameter of 46.2 mg and a diameter of 8.5 mm. This nuclear tablet 1
Sodium valproate was treated in the same manner as in Example 2 by using 000 tablets as a coating agent in which 1.25% by weight of Aerosil-200 was dispersed in an ethanol solution of 5% by weight ethyl cellulose (ethoxy content: 46 to 51%). A sustained release tablet (H tablet: weight 256.4 mg, film weight 10.2 mg) was obtained.

Example 4 After thoroughly mixing 400 g of sodium valproate, 40 g of Aerosil-200 and 10 g of carboxyvinyl polymer,
140 g of an ethanol solution of 5% by weight hydroxypropyl cellulose is added and kneaded. The kneaded product is dried with a hot air dryer at 60 ° C., and then sized with a 16 mesh screen.
1% by weight of magnesium stearate was mixed with the granules, and the mixture was tableted to give a core tablet having a weight of 231.2 mg and a diameter of 8.5 mm. The same treatment as in Example 2 was carried out using 1000 core tablets of this type as a coating agent containing 1 wt% of Aerosil-200 dispersed in an ethanol solution of 5 wt% ethyl cellulose (ethoxy content: 46 to 51%). Thus, sustained release tablets of sodium valproate (I tablet: weight 239.9 mg, film weight 8.7 mg) were obtained.

Example 5 600 g of sodium valproate, Aerosil-200, 120 g
Is thoroughly mixed, and then 348 g of a 5 wt% hydroxypropyl cellulose ethanol solution is added and kneaded. The kneaded product was dried with a hot air dryer at 60 ° C., and then sized with a 16-mesh sieve. After mixing 1% by weight of magnesium stearate with the granules, the mixture is compression molded and weighs 454.6 m.
g and a core tablet with a diameter of 10.5 mm. To 1000 tablets of this nucleating agent, Aerosil-2 was added as a coating agent to an ethanol solution of 5 wt% ethyl cellulose (ethoxy content: 46 to 51%).
Using a liquid in which 1.25% by weight of 00 was dispersed, a sustained-release tablet of sodium valproate (J tablet: weight 47) was prepared in the same manner as in Example 2.
2.9 mg, film weight 18.3 mg) was obtained.

Example 6 Core tablets obtained in the same manner as in Example 1 (a) (weight: 226.8 mg,
Using an automatic film coating machine (Freund Sangyo Co., Ltd., FM2S), 3000 tablets (diameter 8.5 mm) were rotated into 5% by weight ethanol solution of ethyl cellulose (ethoxy content: 46-51%) while rotating the tablets. A coating agent in which 2.5% by weight of Aerosil-200 is dispersed is spray-coated and a sustained release tablet of sodium valproate (K
Tablets: weight 240.1 mg, film weight 13.3 mg) were obtained.

Reference Examples 1 to 3 Sodium valproate was prepared in the same manner as in Example 1 (b) using 1000 tablets of the core tablets obtained in Example 1 (a), using a liquid having the following composition as a coating agent. Made tablets. Reference Example 1 (tablet B): ethyl cellulose (ethoxy content:
46-51%) 5% by weight ethanol solution (weight: 233.1 mg,
Membrane weight: 4.5 mg) Reference Example 2 (C tablet): Ethyl cellulose (ethoxy content:
46-51%) Liquid containing 1% by weight of calcium stearate dispersed in 5% by weight of ethanol solution (weight: 233.0 mg, film weight: 4.4 mg) Reference Example 3 (tablet D): ethyl cellulose (ethoxy content:
46-51%) 5 wt% ethanol solution in which 1 wt% of fatty acid monoglyceride (Eastman Kodak Company, Koyo Shokai "Mybasetto") is dispersed (weight: 234.5 mg,
Membrane weight: 5.9mg)

Test Example 1 (Dissolution test) Test tablets: Tablet A obtained in Example 1 (b) and Reference Examples 1 to 3
The control tablets, B tablets, C tablets and D tablets obtained in 1. were used. Test method: The test was performed according to the second method (paddle method) of the Japanese Pharmacopoeia dissolution test method, twelfth edition. Rotation speed 100 revolutions per minute Test liquid Water (distilled water) and 1st liquid (pH)
1.2) 900 ml After the start of the dissolution test, sampling was carried out over time, and the elution amount of sodium valproate was determined by HPLC analysis. Results: The results of the dissolution test are shown in Table 1 and FIGS.

[0018]

[Table 1]

As a result of the dissolution test, the sustained-release tablet of sodium valproate (A tablet) of the present invention was confirmed to be water and Japanese Pharmacopoeia liquid 1 (p).
H1.2) also shows substantially the same dissolution over a long period of time, which indicates that it is a pH-independent sustained release tablet.
In contrast, when only ethyl cellulose was used as the coating agent (tablet B), when ethyl cellulose and calcium stearate were used (tablet C), or when ethyl cellulose and fatty acid monoglyceride were used (D).
It can be seen that the tablet) elutes earlier in the Japanese Pharmacopoeia 1st solution than in water, and thus it is impossible to prepare a pH-independent sustained-release tablet.

Test Example 2 (dissolution test) Test tablets: sustained release tablets of sodium valproate (E, F, G, H, I, J and K obtained in Examples 2 to 6)
Tablets) were used. Test method: The same as in Test Example 1. Results: The results of the dissolution test are shown in Table 2.

[0021]

[Table 2]

Test Example 3 (human oral administration test) 6 healthy adult males-aged 22 to 29 years old (average 24.2)
Age), and a body weight of 56 to 78 kg (average of 64.4 kg)-, and 4 tablets of sustained release tablets of sodium valproate (A tablet) (containing about 800 mg of sodium valproate) prepared in Example 1 were administered once. After administration, changes in blood concentration were examined. In addition, the test subject was administered 12 hours before the drug administration and 4.5 after the drug administration.
The animals were fasted for an hour and alcohol was prohibited during the test period. Blood samples were collected immediately before administration of the drug and 1, 2, 4, 6, 8, 10, 12, 24, 30, 48 hours after administration, and serum was separated from the collected blood samples, followed by gas chromatography. Quantitation of sodium valproate was performed. The results are shown in Table 3 and FIG.

[0023]

[Table 3]

[0024]

INDUSTRIAL APPLICABILITY The sustained-release tablet of the present invention maintains a stable dissolution rate for a long time without being affected by pH in the dissolution test and causes no decrease in bioavailability in the human oral administration test. , It is possible to maintain a stable blood concentration for a long time.

[0025]

[Brief description of drawings]

FIG. 1 shows the results of a dissolution test of a sustained release tablet (A tablet) of the present invention in Test Example 1.

FIG. 2 shows the results of a dissolution test of a control tablet (B tablet) of Test Example 1.

FIG. 3 shows the results of a dissolution test of a control tablet (C tablet) of Test Example 1.

FIG. 4 shows the results of the dissolution test of the control tablet (D tablet) of Test Example 1.

FIG. 5 shows the results of a human oral administration test of the sustained-release tablet (A tablet) of the present invention in Test Example 3.

Claims (4)

[Claims] 1. A sustained release of sodium valproate, characterized in that it has a coating layer obtained by coating a surface of a core tablet containing sodium valproate with a coating agent composed of ethyl cellulose in which silicic anhydride is dispersed. tablet. 2. The sustained release property of sodium valproate according to claim 1, wherein the ratio of ethyl cellulose and silicic acid anhydride in the coating layer is 0.1 to 0.7 part by weight of silicic acid anhydride to 1 part by weight of ethyl cellulose. tablet. 3. The sustained-release tablet of sodium valproate according to claim 1 or 2, wherein the amount of the coating layer is 2 to 10% by weight based on the core weight. 4. The sustained-release property of sodium valproate according to claim 1, wherein the silicic acid anhydride is insoluble in water and has a property of being dispersed colloidally in water and an organic solvent. tablet.