JPS62178518A - Novel long-acting sulpiride tablet - Google Patents

Abstract

PURPOSE:To obtain the titled tablet by compounding sulpiride used as a principal drug component with two or more kinds of water-soluble hydrogel-forming substances at specific ratios. CONSTITUTION:Sulpiride of formula used as the principals drug component is added with >=2 kinds of water-soluble hydrogel-forming substances (e.g. gelatin, hydroxypropyl cellulose, methylcellulose, etc.) at a weight ratio of 5:1-1:5 (in total), stirred at a high speed, added with extremely small amount of water or ethyl alcohol and stirred and granulated to easily and economically obtain a long-acting tablet. A sufficient effect can be attained by using the water or ethyl alcohol at an amount to give fine granules as major part of the granulated product. The obtained granulated product is dried, mixed with a proper amount of a lubricant such as magnesium stearate, talc, etc., and compression- molded with a tableting machine to obtain the objective tablet having a hardness of 6-10kg. The development of side effect caused by excessive administration can be prevented and effective blood concentration can be maintained over a long period by administering the tablet once a day.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a sulpiride tablet having sustained blood concentration and a method for producing the same. Sulpiride or N-[(1
-ethyl-2-pyrrolidinyl)methyl]-2-methoxy5-sulfamoylbenzamide is represented by the following general formula (1):
It is a well-known compound possessing the following properties and is widely used in clinical practice due to its useful medicinal properties.

015H23N304 S: 341.42 For example,
It is frequently used as an anti-ulcer agent (gastric/duodenal ulcer) at low doses, and as a psychotropic agent (depression, depressive state, schizophrenia) at medium or higher doses.

In particular, unlike previous psychiatric drugs, it has no sedative effect at all, and it has a strong anti-hallucinatory and delusional effect without causing a decline in consciousness, so it has a very good reputation in the field of psychiatry.

However, existing dosage forms of sulpiride such as injectable or oral fine granules, tablets, capsules, etc. have many inconveniences.

For example, since it is necessary to take the drug multiple times a day, the blood concentration rapidly increases continuously and there is a risk of overdosing.

When overdosed, it has the disadvantage of causing tremors of the lips and fingertips, protrusion and tangling of the tongue, flow conditions, galactorrhea, etc.

Furthermore, in the field of psychiatry, it has been pointed out that, especially in the case of outpatient patients, there are many cases where patients do not take their medication as instructed by their doctors, making it impossible to provide accurate and efficient treatment.

Therefore, an object of the present invention is to provide a new formulation of sulpiride that better meets practical needs than conventional formulations, and which prevents the occurrence of side effects due to overdosing after 9181 administrations. , and can maintain an effective blood concentration over a long period of time, preventing patient non-compliance with medication.

[Conventional technology]

Up until now, methods for producing sustained-release tablets have used water-insoluble polymers such as ethylcellulose, higher fatty acids, higher alcohols, and fat-soluble substances such as waxes as release-retarding substances, as well as cellulose acetate phthalate, hydroxyglopyl, etc. A common example is the use of polymers such as methylcellulose phthalate, which dissolve depending on various pH values.

In methods that use water-insoluble polymers, they are only soluble in specific organic solvents, making it difficult to clean the equipment and requiring consideration of environmental pollution issues. This also applies to methods using polymers that dissolve depending on the location, but these methods often require a coating operation, which is disadvantageous in terms of the manufacturing process.

In methods using fat-soluble substances such as waxes, the drugs and excipients are mixed and melted by heating to a temperature above their melting point, so in order to prevent them from solidifying inside the melting pot, piping, spray machine, etc. It is necessary to keep each part at a high temperature.

[Failure to solve the problem]

As a result of intensive research into the production of long-acting tablets of sulpiride, the present inventor found that by mixing and stirring a mixture of two or more hydrogel-forming substances and sulpiride, and adding a very small amount of water or ethyl alcohol to granulate it, It has been found that a long-lasting tablet can be easily and advantageously produced, and that its delayed efflux rate can be represented by a substantially first order curve, ie, a straight line.

Here, the expression "two or more types" also refers to polymer hydrogel-forming substances of the same type but with different physical properties, such as viscosity and average molecular weight.

The hydrogel-forming substance used in the present invention is soluble in water or alcohol and is selected from those that inherently have properties as a binder and a thickener, and specifically, gelatin,
Hydroxypropylcellulose (RPC), methylcellulose (MC), hydroxyglobil methylcellulose (HPMC), bentonite, sodium alginate,
Examples include polyvinylflu:7-/I/ (PVA), flulan (PUL LULAN), chitosan, and the like.

To produce the tablet of the present invention, first, a mixture of two or more hydrogel-forming substances and sulpiride are stirred at high speed,
Add a very small amount of water or ethyl alcohol, stir and granulate. The amount of water or ethyl alcohol is sufficient to make most of the granules into fine particles.After drying the granules thus obtained, mix an appropriate amount of a lubricant such as magnesium stearate or Merck. , compression molded with a tablet machine, hardness 6
~10kQ of product is obtained.

As for the blending weight ratio of the crude drug sulpiride and the hydrogel-forming substance mixture in the tablets of the present invention, as a result of repeated dissolution tests, it was found that the suitable range is 5:1 to 1:5, preferably 3:1 to 1:6. It has been tentatively determined that there is a
It was confirmed that a dissolution rate of 70% to 100% in 12 hours could be obtained with good reproducibility. Furthermore, in the case of a commercially available product without the addition of a hydrogel-forming substance, 100% of sulpiride was observed to elute within just 2 hours; In contrast, when a mixture of L-type HPC and H-type RPC is added at a weight ratio of 2=6, the degree of dissolution of crude drugs is approximately 55% even after 12 hours. (See Figure 1 of the accompanying drawings).

In the present invention, for the purpose of examining a suitable blending weight ratio in the case of mixing two different types of hydrogel-forming substances of the same type, the following formulations of L type and M type f (PC) were prepared as an example. The results of dissolution tests conducted on these three formulation examples are shown in Figure 3 of the attached drawings, and based on these results, the range of weight ratios that can be realized by the present invention for HPO is The ratio of type (6.0~10.0c S) and M type (150~400Cps) is 1:1~1:1
It was determined that the ratio of 0, L type and L type (1,000 to 4,000 cpl> is 10:1 to 1:10, and the ratio of M type and L type is about 3:1 to 1.5) .

Example 1 Sulpiride 200? 20 f of hydroxypropyl cellulose L type (6,0 to 10.Otins) and 301i' of L type (1,000 to 4,000 C#) are added to the mixture, and the mixture is stirred at 600 rpm for 5 minutes using a mixing granulator. Then, under high speed stirring at 3000 rpm, ethanol 5
ml and continue stirring for 10 minutes. After drying the obtained granules in a dryer, the granules were sized to 20 to 48 meshes and were compressed into tablets using a tablet machine at a pressure of 500k (J/P), with a weight of about 250q per tablet. tablets with a hardness of about 8 kQ are obtained.

Example 2 Sulpiride 2002 and pullulan average molecular weight 200.0
00 + 7) 80P and 20y with an average molecular weight of 70,000 were added and treated in the same manner as in Example 1 to obtain tablets with a weight of about 250q per tablet and a hardness of 6 to 8 kQ. obtain. However, 10 ml of water was used instead of 5 ml of ethanol.

Example 3 Sodium alginate 352 and chitosan 15f were added to Sulpiride 2001 and treated in the same manner as in Example 1 to obtain a tablet with a weight of about 250 kg and a weight of 6 to 8 kg.
(obtain tablets with a hardness of j.However, ethanol 5
Water 10a+1 instead of yrl! Use.

Test Example 1 The above Example 1.2 was conducted using the dissolution test method described in the Japanese Pharmacopoeia.
A dissolution test was conducted on commercially available processed products and single-flavored L-type HI'C products as controls for the products of the present invention and No. 5.

That is, one tablet containing 200 Da of sulpiride was placed in a basket and rotated at 100 revolutions per minute in an eluent of 900 tttl at 37°C, and the eluate was collected over time to measure the dissolution rate of sulpiride. Sulpiride was quantified by spectrophotometry. The results are shown in FIG. 1 of the accompanying drawings, which demonstrate that the tablets of the present invention control the dissolution of sulpiride over a long period of time.

Test Example 2 The tablets of the products of the present invention in Examples 1, 2 and 3 described above and the commercially available product as a control were orally administered to pegle dogs to examine changes in the blood concentration of sulpiride. After administering one tablet of each test tablet to each animal, blood was collected over time, and sulpiride in the serum separated from the blood was quantified by high performance liquid chromatography. The results are shown in FIG. 2 of the accompanying drawings, and it was confirmed that the long-acting tablet of the present invention maintains a therapeutically effective blood concentration for a long time when administered orally.

[Brief explanation of drawings]

FIG. 1 is a diagram showing the results of a dissolution test of the tablet of the present invention. FIG. 2 is a diagram showing the change in blood concentration of the tablet of the present invention. 6th
The figure is a diagram showing the results of a dissolution test of tablets containing mixtures of L-type HPC and M-type HPC of the present invention at various weight ratios. 11 ■ and ■ show the results of the products of Examples 1.2 and 3, respectively, I shows the results of the L-type HPC single-compound product, and S shows the results of the commercially available product as a comparative example, respectively. (Patent applicant: Toho Pharmaceutical Co., Ltd.) (Agent: Patent attorney: Yasu Kasuya)

Claims (1)

[Claims] 1. A sulpiride long-lasting product, characterized in that two or more water-soluble hydrogel-forming substances are blended with the main drug sulpiride in a total weight ratio in the range of 5:1 to 1:5. sex pills. 2. A patent claim in which the water-soluble hydrogel-forming substance is a mixture of two or more selected from the group consisting of gelatin, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, bentonite, sodium alginate, polyvinyl alcohol, pullulan, and chitosan. The sulpiride long-acting tablet according to item 1. 3. The water-soluble hydrogel-forming substance is hydroxypropylcellulose, and its viscosity is L-type 6.0-10.
0 cps, 150-400 cps for M type and 1 for H type
000 to 4000 cps, and their weight ratio is 1:1 to 1:10 for L type and M type, 10:1 to 1:10 for L type and H type, and The sulpiride long-acting tablet according to claim 1, wherein the ratio between type M and type H is 3:1 to 1:5. 4. The water-soluble hydrogel-forming substance is pullulan,
Its average molecular weight is 70,000, 100,000, 20
The long-acting tablet of sulpiride according to claim 1, which is a mixture of two or more of 0,000 and 300,000. 5. A long-lasting sulpiride tablet in which the water-soluble hydrogel-forming substance is polyvinyl alcohol and is a mixture of two or more completely saponified and partially saponified products having different viscosities. 6. The water-soluble hydrogel-forming substance is methylcellulose, and its viscosity is 13-18 and 80-120, respectively.
The long-acting sulpiride tablet according to claim 1, which is a mixture of two or more of the following: and 350 to 550 cps. 7. Blend a mixture of two or more of the main drug sulpiride and a water-soluble hydrogel-forming substance at a weight ratio of 5:1 to 1:5, stir this at high speed, and add an appropriate amount of ethyl alcohol or water. A method for producing sulpiride long-acting tablets, which comprises granulation.