JPS6310719A - Slow-releasing capsule drug - Google Patents

Abstract

PURPOSE:To produce a capsule having excellent slow-releasability and residence of drug in stomach, by putting a drug and a gel-forming polymer in a capsule consisting of a water-soluble cap and a water-insoluble or enteric body. CONSTITUTION:A drug and a polymer forming a gel in contact with water (e.g. hydroxypropyl methylcellulose, carboxyvinyl polymer, etc.) are put into a capsule consisting of a cap made of a water-soluble polymer and a body made of a water-insoluble or enteric polymer or a body made of a water-soluble polymer and coated with a water-insoluble or enteric polymer. It is preferable to leave a space in the body view of residence in stomach. Only the cap is dissolved in stomach and the polymer gelled by contacting with gastric juice forms a gel at the opening of the body part. The drug in the body is slowly released by the aid of gastric juice permeated in the body.

Description

Detailed Description of the Invention The present invention provides a capsule consisting of a water-soluble head and a water-insoluble or enteric-coated body. The present invention relates to a capsule which contains a polymer (referred to as a polymer) and which may have a space inside the capsule body.

<Industrial Field of Application> The capsule of the present invention has excellent sustained drug release properties and gastric retention, and is useful as a sustained release capsule.

<Description of the Prior Art> Conventionally, as a sustained release capsule, one in which a drug is made into sustained release granules or pellets and filled into a gelatin capsule is known.

In recent years, various sustained-release capsules have become known due to advances in sustained-release formulation technology. Among these, those disclosed in JP-A-51-11591Q and JP-B-55-12411 are known as sustained-release capsules that remain in the stomach.

<Problems to be Solved by the Invention> The above sustained-release capsules that remain in the stomach have the following drawbacks.

l) In order to obtain a sufficient sustained release effect, it is necessary to increase the blending ratio of additives imparting the sustained release effect, such as gelling polymers, in the formulation.

2) Since the compounding ratio of drugs in the formulation is small, only drugs that are effective in small amounts can be applied.

3) When applying conventional drugs, large capsules must be used, which is inconvenient to administer.

The present inventors completed the present invention as a result of intensive studies to eliminate the above-mentioned drawbacks.

<Configuration of the Invention> The present invention provides a capsule comprising a water-soluble head and a water-insoluble or enteric-coated body, which contains a drug and a gelling polymer, and which may have a space inside the body. Regarding drugs.

A water-soluble capsule head can be manufactured by a known method using a water-soluble polymer. Examples of water-soluble polymers include water-soluble cellulose conductors such as gelatin and methylcellulose, and polyvinyl derivatives such as polyvinyl alcohol. These polymers can be used alone or in combination.

The water-insoluble capsule body may be made of a water-insoluble polymer or a water-soluble polymer coated with a water-insoluble polymer. Examples of water-insoluble polymers include ethyl cellulose, ethyl methacrylate/trimethylammonium ethyl methacrylate copolymer (aminoalkyl methacrylate copolymer R3), shellac, and the like. Capsule bodies can be manufactured using known techniques using these polymers alone or in combination. Alternatively, a capsule body may be formed by adding the above-mentioned water-soluble polymers or a plasticizer such as propylene glycol or triethyl citrate to these water-insoluble polymers. In this case, the blending amount of the above additive is usually 50% or less.

As the enteric-coated capsule body, a capsule body formed of an enteric polymer and a capsule body formed of a water-soluble polymer coated with an enteric polymer can be used. Enteric polymers include cellulose acetate phthalate, hydroxypropyl methyl cellulose fucrate, hydroxypropyl methyl cellulose acetate succinate, methacrylic acid/methyl methacrylate copolymer (methacrylic acid copolymer L or methacrylic acid copolymer S), methacrylic acid Ethyl acrylate copolymer (methacrylic acid copolymer L)
D), carboxymethylethylcellulose, etc. Capsule bodies can be manufactured using these polymers alone or in combination using known methods.

The capsule body may also be formed by adding the above-mentioned water-soluble polymer or plasticizer to these enteric polymers. In this case, the blending amount of the additive is usually 50 or less.

The size of the capsule head and body used is not particularly limited, but a size 4 to 0 capsule head and body are usually sufficient.

The capsule of the present invention, which uses a capsule body with a space inside, is preferable in terms of retention in the stomach. Various methods can be used to provide this space, but a simple method is usually a method in which a capsule head, which is smaller in size than the capsule body, is inserted and fitted into the capsule body. For example, it is desirable to use a No. 1 capsule head for a No. 0 capsule body, a No. 2 capsule head for a No. 1 capsule body, and a No. 3 capsule head for a No. 2 capsule body. . The material for these heads may be water-soluble, water-insoluble or enteric-coated, preferably water-insoluble or enteric-coated. The volume of the space is not particularly limited, but if it is too large, the amount of herbal medicine filled will decrease, so it is usually about 5,096 or less of the volume of the capsule body.

Examples of gelling polymers include hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, carboxyvinyl polymer, polyvinyl alcohol, hydroxyethylcellulose, sodium alginate, gelatin, etc., preferably hydroxypropylmethylcellulose,
Examples include methylcellulose and carboxyvinyl polymer.

The drugs contained in the capsules of the present invention are not particularly limited, and most orally administrable drugs can be applied to the capsules of the present invention. Preferred are drugs that act in the stomach or upper small intestine, and drugs that are acidic and have high solubility and neutral to alkaline and low solubility.

The capsule of the present invention may be produced as follows.

That is, the drug and gelling polymer are mixed uniformly. The capsule of the present invention can be manufactured by filling the mixture into a capsule body using a known technique and fitting the head of the capsule into the body using a known technique.

The gelling polymer in the above mixture is usually 5 to 50% (W/w)
A sufficient sustained release effect can be obtained by containing 10~
By containing 3064 (w/w), an excellent sustained release effect can be obtained.

If necessary, an excipient such as corn starch, a disintegrant such as carboxymethylcellulose calcium, a fluidizing agent such as light silicic anhydride, and a lubricant such as talc may be added to the above mixture.

When filling the capsule body with the obtained mixture, the specific gravity of the filled capsule body may be made smaller than 1 from the viewpoint of retention in the stomach. Therefore, the weight of the capsule after filling with the above mixture is, for example, less than 470 mg in the case of No. 1 capsule, and less than 2
The amount may be less than 370+++ g for capsule No. 3, less than 270 m3 for capsule No. 3, and less than 200 mg for capsule No. 4.

In the capsule of the present invention, the filling amount of the above mixture is usually about 353B for a No. 1 capsule and 278B for a No. 2 capsule when no space is provided in the capsule body.
The amount is approximately 203 mg for a No. 3 capsule and approximately 150 mg for a No. 4 capsule, and in this case, it can be retained in the stomach for a sufficient period of time. In addition, when a space is provided in the capsule body, a sufficient amount of the above-mentioned mixture may be filled into the capsule body. For example, when using a No. 1 capsule body, approximately 212 parts, and in the case of a No. 2 capsule, 1[ 12
mg, approximately 115+ng for a No. 3 capsule, and approximately 86 g for a No. 4 capsule.

In the capsule of the present invention, a sufficient sustained release effect can be obtained even when the specific gravity is 1 or more.

<Effects of the Invention> When the capsule of the present invention is orally administered, only the head of the capsule dissolves in the stomach, and the gelled polymer that comes into contact with gastric juice forms a gel at the opening of the capsule body. Therefore, the drug in the capsule body is released little by little into the gastric fluid through the permeating gastric fluid as the gel forms.

The capsules of the present invention not only have excellent sustained drug release effects, but also use a smaller amount of gelling polymer compared to conventional sustained release preparations, and there is no limit to the number of drugs that can be used. . Therefore, the capsules of the present invention are excellent as sustained release preparations. Furthermore, the capsule of the present invention is a sustained release preparation that remains suspended in the stomach, and also has the characteristics of a gastroretentive preparation.

Furthermore, the capsule of the present invention has an opening area of the capsule body,
It is also possible to control the elution of the drug by changing the size of the capsule, the amount filled, and the amount of gelling polymer blended.

EXAMPLES Hereinafter, the present invention will be further explained in detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

Example 1 Brocainamide hydrochloride 100 parts and hydroxypropyl methylcellulose 2910 (4QOOcps) 30
After uniformly mixing the above mixture, 130 mg per capsule of the above mixture was filled into the body of a No. 3 hard capsule made from hydroxypropyl methyl cellulose acetate succinate (hereinafter referred to as HPMCAS), and the head of a No. 3 gelatin hard capsule was filled. Capsules were obtained by mating.

Example 2 A coating consisting of 10 parts of ethyl cellulose, 50 parts of dichloromethane, and 50 parts of ethanol was coated overnight using the immersion method, except for the inside of the No. 2 gelatin hard capsule body and the part necessary for fitting with the capsule head. , to obtain a water-insoluble capsule body by coating up to 57 mg per capsule. A homogeneous mixture of 100 parts of brocainamide hydrochloride and 30 parts of hydroxypropyl methylcellulose 2910 (4000 cps) was added to the body of the capsule.
Each capsule was filled with 182B, and a No. 2 gelatin hard capsule head was fitted to obtain a capsule.

Example 3 The same procedure as in Example 2 was carried out using a coating solution consisting of 10 parts of ethyl methacrylate/trimethylammonium ethyl methacrylate chloride copolymer, 60 parts of isopropanol, and 40 parts of acetone to obtain 23 mg per 1 capsule. The body of the water-insoluble capsule No. 2 was obtained by coating the capsule body. This capsule body contains 100 parts of procasenamide hydrochloride and 2 parts of hydroxypropyl methylcellulose.
91G (4000 cps) 30 parts of a homogeneous mixture was filled into each capsule in an amount of 195 mg, and the head of a No. 2 gelatin hard capsule was fitted to obtain a capsule.

Example 4 After uniformly mixing 100 parts of procainamide hydrochloride and 30 parts of methyl cellulose (8000 cps), HP
The body of a No. 3 hard capsule made from MCAS was filled with 130 [118] per capsule, and the head of a No. 3 gelatin hard capsule was fitted to obtain a capsule.

Example 5 After uniformly mixing 100 parts of hydrochloric acid pro-inamide, 5 parts of carboxyvinyl polymer, and 20 parts of corn starch, the same procedure as in Example 4 was carried out to form No. 3 capsules by filling each capsule with 125 mg. Obtained.

Example 6 Brocainamide hydrochloride 100 parts and hydroxypropyl methylcellulose 2208 (1500Qcps)
After uniformly mixing 30 parts, the same procedure as in Example 4 was carried out to fill 130 mg per capsule to obtain No. 3 capsules.

Example 7 Brocainamide hydrochloride 100 parts, hydroxypropyl methylcellulose 2910 (4000 cps) 1
After uniformly mixing 0 parts and 30 parts of corn starch, the same procedure as in Example 4 was carried out to obtain 1 part per capsule.
No. 3 capsules were obtained by filling 40 mg.

Example 8 After uniformly mixing 100 parts of procainamide hydrochloride, 5 parts of hydroxypropyl methylcellulose 2910 (4000 cps) and 35 parts of corn starch,
140 per l capsule, operated as in Example 4.
Capsules No. 3 were obtained.

Example 9 A No. 3 gelatin hard capsule head was inserted into a No. 2 capsule body made of ethyl cellulose and fitted. Sodium riboflavin phosphate 900mg, lactose 5181mg, hydroxypropyl methylcellulose 291G (3cps)
450mg, 9tr1g of light anhydrous silicic acid, and 60mg magnesium stearate were uniformly mixed. 220 mg of this mixture was filled into the body of the capsule, and the head of a No. 2 gelatin hard capsule was fitted to obtain a capsule.

Comparative Example 1 The mixed powder prepared in Example 1 was filled into No. 3 gelatin hard capsules in the same amount as in Example 1 to obtain capsules.

Comparative Example 2 The same amount of the mixed powder prepared in Example 1 as in Example 1 was filled into No. 3 hard capsules made of HPMCAS to obtain capsules. This was band sealed using a 5% acetone solution of HPMCAS.

Control Example 3 100 parts of procainamide hydrochloride and 30 parts of corn starch were uniformly mixed, and 130B of the above mixture was filled into the body of a No. 3 hard capsule made of HPMCAS.
The head of a gelatin hard capsule was fitted to obtain a capsule.

Control Example 4 The head of a No. 3 hard gelatin capsule was inserted into the body of a No. 2 hard gelatin capsule and fitted. 220n of the mixture prepared in Example 9
g was filled into the above capsule, and the head of a No. 2 gelatin hard capsule was fitted to obtain a capsule.

Test Example 1 For the samples obtained in Examples 1 to 7 and Control Examples 1 to 3,
The test was conducted according to Japanese Pharmacopoeia General Test Methods, Dissolution Test Method 2 (paddle method). The results are shown in Table 1.

Table 1 Test method: Nippon Pharmacopoeia General Test Method Dissolution Test Method 2 Method (
Paddle method) Test Solution: Japanese Pharmacopoeia 1st solution (put, z
) Paddle rotation speed: 1 GO rpm Sample: One capsule was placed in a sinker of the Japanese Pharmacopoeia, and the test was conducted by submerging it in the test liquid.

Quantification of brocainamide hydrochloride: Absorbance method (wavelength 224n
s) Control example 1 and control example 3 showed relatively fast elution, and control example 2 showed almost no elution.

On the other hand, in all sustained-release capsules of the present invention, the dissolution of brocainamide hydrochloride was sustained.

Test Example 2 A dissolution test was conducted on the capsules obtained in Example 8 and Test Example 4 in the same manner as in Test Example 1. The results are shown in Table 2.

Table 2 Test method 2 days * Pharmacopoeia general test method Dissolution test method 2nd method (paddle method) test Solution: Japanese Pharmacopoeia 1st solution (pH 1, 2)
Paddle rotation speed: 1 (1 Orpm) Sample 2 One capsule was placed in a Japanese Pharmacopoeia sinker, and the test was conducted by submerging it in the test liquid.

Quantification of tuboflavin phosphate: Absorbance method・Wavelength 444n
m) Control Example 4 showed relatively fast elution. On the other hand, in all sustained-release capsules of the present invention, the elution of sodium riboflavin phosphate was sustained.

Claims (1)

[Scope of Claims] 1) A capsule consisting of a water-soluble head and a water-insoluble or enteric-coated body, which contains a drug and a polymer that forms a gel when it comes into contact with water. 2) Claim 1 in which a space is provided in the capsule body
Capsules listed in section