JPH0798742B2 - Sustained release pharmaceutical composition - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] The present invention ensures that when orally administered, it forms a highly viscous gel layer in contact with gastric juice, and further retains air bubbles in this gel layer to ensure long-lasting. The present invention relates to a pharmaceutical composition capable of easily and easily producing a sustained-release preparation which retains in the stomach for a long time and has an improved utilization rate of an active ingredient, and a method for producing the same.

[Prior Art] It is known that the gastrointestinal tract migration rate of orally administered preparations varies greatly among individuals, and that it varies depending on the same person and physiological conditions.

However, when the site of action of the active ingredient is in the stomach and the action of the ingredient is required for a long time, or when absorption of the ingredient is expected in the stomach and upper part of the small intestine, the entire amount is released during retention in the stomach. Not necessarily.

In a sustained-release preparation, when it is necessary to gradually release the active ingredient over a long period of time, the ingredient released after passing through the small intestine, which is the main absorption site of the gastrointestinal tract, is active due to a decrease in absorption rate. It is also known that the utilization rate of ingredients is poor.

JP-A-58-39618 describes a layered tablet using waxes in order to increase the dissolution rate after a certain period of time since the amount of drug absorbed in the lower part of the digestive tract decreases. However, the method of the publication has a drawback that the drug utilization rate is further deteriorated because the drug release amount is large in a portion having a low absorption rate.

For the above reasons, it has been reported that the drug product is retained above the small intestine, which is the main drug absorption site in the digestive tract, that is, in the stomach for a long time.

JP-A-51-115910 describes a hydrodynamically equilibrated gastric floating formulation containing a hydrocolloid. The publication also allows tablets, but it is said that the compression pressure should be controlled and the specific gravity should not be increased, and the buoyancy in the stomach is lacking and the manufacturing method is not practical. Have.

Further, Japanese Patent Publication No. 55-12411 discloses that a hard capsule or a soft capsule remains hollow inside or is filled with a substance having a low density, and a film containing a drug is applied to the gastric suspension. Sexual preparations have been reported. But,
The formulation of the publication has a drawback that the manufacturing method is complicated and the amount of drug to be applied is limited.

[Problems to be Solved by the Invention] Conventional sustained-release preparations with gastroretentive properties have a problem of reliable floating property, or even if the floating property is reliable, the preparation method is very difficult. It had the drawback of being complicated.

The present invention is intended to solve these problems by compression-molding a homogeneous mixture containing a foaming component in a mixture of a highly viscous water-soluble polymer substance and a crosslinked insoluble polyvinylpyrrolidone. .

[Means for Solving the Problem] As a result of various studies on means for achieving the above-mentioned object, the present inventors have found that a compression molded product of a mixture of a highly viscous water-soluble polymer substance and a crosslinked insoluble polyvinylpyrrolidone Surprisingly, they have found that they are surely floating in the dissolution test solution.

Furthermore, when a foaming component was added to these mixtures,
The present invention has been completed by confirming that air bubbles are retained in the gel layer formed on the surface and more reliable floating property is exhibited.

Generally, when the matrix of water-soluble polymer substance is hydrated,
It is well known to form a gel layer on the surface and prevent water from entering the inside.

On the other hand, the present inventors have found that when a water-soluble polymer, particularly a highly viscous water-soluble polymer substance, is hydrated with a matrix containing a cross-linked insoluble polyvinylpyrrolidone, the gel layer formed on the surface is It was found that the thickness and the strength of the gel layer increased more than the gel layer formed by the matrix of the water-soluble polymer.

Furthermore, the crosslinked insoluble polyvinylpyrrolidone is
Due to its low bulk density, the mixed matrix with the water-soluble polymer has a low specific gravity and the volume increase due to the formation of the gel layer, and this matrix has buoyancy even though it is a normal compression molded matrix. did. Also,
Furthermore, when a component that foams when contacted with gastric juice is added to the matrix, bubbles are retained in the formed gel layer, and the buoyancy of the matrix is further ensured.

Usually, in a gel layer composed of a plain water-soluble polymer matrix, the incorporation of a foaming component results in accelerating erosion and dissolution of the gel layer, and a long-term sustained release effect cannot be expected. However, the gel layer made of the matrix of the present invention surely retains the generated bubbles in the gel layer to make the buoyancy more reliable and does not accelerate the erosion or dissolution of the gel layer. These phenomena are not possible with the formulation of other similar additives.

Further, when the preparation of the present invention is produced, it is not necessary to perform treatments such as controlling the compression pressure and adjusting the specific gravity because of the certainty of its buoyancy.

That is, the present invention is a sustained-release preparation, wherein a mixture of an active ingredient, a highly viscous water-soluble polymer substance and a crosslinked insoluble polyvinylpyrrolidone is mixed with a foaming ingredient and then compression-molded for a long time in the stomach. The present invention relates to a composition of a drug product that stays in the soil and a method for producing the same.

Here, as the highly viscous water-soluble polymer substance, a substance that forms a gel layer when hydrated is preferable,
The viscosity of the aqueous solution is 50 centipoises or more, more preferably 100 centipoises or more, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose as a cellulose ether, or polyvinyl alcohol, etc., in the above viscosity conditions. Compatible materials are used alone or in combination.

Crosslinked insoluble polyvinylpyrrolidone can be obtained under the trade name of Kollidon CL (BASF) or Polyplasdone (GAF). The blending amount is 5 to 45% by weight, and more preferably 15 to 35% by weight.

Further, calcium carbonate or precipitated calcium carbonate is preferable as the component that foams when it comes into contact with gastric juice, since it is necessary for the generated bubbles to be retained in the gel layer. Further, in consideration of the case of anoxic acid or hypoxic acid, it is possible to add a small amount of citric acid, fumaric acid, tartaric acid, succinic acid, etc. as a weakly acidic component. The blending amount of these foaming components is preferably 1 to 10% by weight.

Other than these, crystalline cellulose which is a known additive,
Lactose, starch, etc. are added as needed.

As the active ingredient applied to the present invention, antacids, gastric secretion inhibitors, drugs that preferably act for a long time in the stomach such as anti-pepsin, or vitamin agents such as riboflavin, benzodiazepines, etc. Examples include neurotropic agents, ferrous iron salt preparations such as ferrous fumarate, and the like.

Further, the sustained-release preparation preferably has a long-acting effect and may be an orally administrable drug, for example, an agent for circulatory organs such as nifedipine, an antipyretic analgesic / anti-inflammatory agent such as indomethacin, and salbutamol. Antitussives, antibiotics such as cephalexin, anti-neoplastic agents such as 5-FU, etc.

[Action] By applying the formulation of the present invention, a drug that is expected to have a long-term action in the stomach, or a drug that has a limited absorption site and is known to have poor utilization in conventional formulations, With regard to the sustained-release preparation, the dissolution rate is reduced over a long period of time, and the absorption rate is lowered in the lower part of the digestive tract. Therefore, the utilization rate can be improved when the utilization rate is reduced.

In addition, since the formulation of the present invention completely releases the active ingredient contained in the composition in the stomach, the utilization rate does not decrease even if the ingredient is poorly soluble in water.

Furthermore, since the preparation of the present invention can be produced by a known compression method and is not restricted by the specific gravity of the compression-molded product, a sustained-release preparation having reliable gastric retention can be easily and easily obtained. be able to.

[Examples] Examples of the present invention will be described in more detail below.
The invention is in no way limited to these examples.

Example 1 200 g of theophylline were uniformly mixed with 397 g of hydroxypropyl cellulose (HPC-M: Nippon Soda), 240 g of Kollidon CL, 54 g of calcium carbonate, and 9 g of magnesium stearate, and a single punch tableting machine was used to form a flat punch having a diameter of 10 mm. One tablet 450m
Take g (theophylline 100 mg) tablets.

The elution amount of theophylline from the preparation of this example was examined by the paddle method of item 2 of the Japanese Pharmacopoeia (X) dissolution test method.

As the eluent, the Japanese Pharmacopoeia (X) first liquid (pH 1.2) was used, and the following results were obtained.

Dissolution time (Hr) Dissolution rate (%) 1 38.1 2 57.3 3 69.8 4 78.2 5 84.0 6 88.2 7 91.5 8 94.7 The hardness of the preparation of this example was 9 to 12 Kg (Schleuniger hardness meter), and it was added to the eluate. Immediately after that, it floated and was floating during this elution period (8 hours).

Example 2 100 g of theophylline were uniformly mixed with 68 g of corn starch, 135 g of hydroxypropyl cellulose (HPC-H: Nippon Soda), 120 g of Kollidon CL, 22 g of calcium carbonate, and 5 g of magnesium stearate, and a flat tablet having a diameter of 10 mm was formed with a single tableting machine. Use a punch to make a tablet of 450 mg (theophylline 100 mg).

The elution amount of theophylline from the preparation of this example was examined by the same method.

As the eluent, the Japanese Pharmacopoeia (X) first liquid (pH 1.2) was used, and the following results were obtained.

Dissolution time (Hr) Dissolution rate (%) 1 46.4 2 64.2 3 72.1 4 77.8 5 81.7 6 84.2 7 85.6 The hardness of the preparation of this example is 7 to 10 kg, and this preparation is
Immediately after the eluate was added, it floated and remained floating during the elution period (7 hours).

Example 3 Riboflavin butyrate 10 g, methyl cellulose (SM-100: Shin-Etsu Chemical Co., Ltd.) 250 g, Kollidon CL 90 g, crystalline cellulose 120 g, calcium carbonate 24 g, fumaric acid 10 g, magnesium stearate 6 g At the diameter
Make a tablet of 300 mg (riboflavin butyrate 5 mg) with a 9 mm flat punch.

The hardness of the preparation of this example was 11 to 14 kg, and in the disintegration test without the auxiliary plate, the preparation was suspended in the test solution (pH 1.2) for 5 hours.

Example 4 Riboflavin butyrate 20 g, crystalline cellulose 75 g, polyvinyl alcohol (Shin-Etsu Bovar: partially saponified type) 232.5 g, Kollidon CL 130 g, calcium carbonate 20 g, fumaric acid 7.5 g, light anhydrous silicic acid 2.5 g, magnesium stearate 12.5 g The ingredients are mixed uniformly and made into tablets of 250 mg (riboflavin butyrate 10 mg) with a single punch tableting machine using a flat punch with a diameter of 9 mm.

The hardness of the preparation of this example was 6 to 9 kg, and this preparation was suspended in the test solution (purified water) for 7 hours in the disintegration test without the auxiliary plate.

Example 5 Chlorpheniramine maleate 10 g, crystalline cellulose 48
g, Methylcellulose (SM-400: Shin-Etsu Chemical) 70g, Kollidon CL 50g, Calcium carbonate 16g, Fumaric acid 4g, Magnesium stearate 2g are evenly mixed and a single punch tableting machine with a flat punch having a diameter of 9.0mm. One tablet is 200 mg (chlorpheniramine maleate 10 mg).

The dissolution amount of chlorpheniramine maleate from the preparation of this example was examined by the second method paddle method of the Japanese Pharmacopoeia (X) dissolution test method.

Purified water was used as the eluent, and the following results were obtained.

Dissolution time (Hr) Dissolution rate (%) 1 38.0 2 60.2 3 73.8 4 84.6 5 90.8 6 96.2 The hardness of the preparation of this example is 8 to 11 kg, and this preparation is
It was floating in the eluate during the elution period (6 hours).

Example 6 70 g of synthetic hydrotalcite, 10 g of precipitated calcium carbonate, 64 g of hydroxypropyl cellulose (HPC-H: Nippon Soda),
50 g of Kollidon CL and 4 g of magnesium stearate are uniformly mixed, and a single punch tableting machine makes a tablet of 500 mg with a flat punch having a diameter of 10 mm.

The hardness of the preparation of this example was 12 to 15 kg, and the preparation was suspended in the test solution (pH 1.2) for 4 hours in the disintegration test without the auxiliary plate.

Example 7 Precipitated calcium carbonate 30 g, crystalline cellulose 6.5 g, hydroxypropylmethyl cellulose (Metroses 60SH-4000:
Shin-Etsu Chemical) 38 g, Kollidon CL 23 g, light anhydrous silicic acid 0.5 g, and magnesium stearate 2 g are uniformly mixed and made into tablets of 500 mg per tablet with a 10 mm flat punch using a single punch tableting machine.

The hardness of the preparation of this example was 6 to 8 kg, and in the disintegration test excluding the auxiliary plate, the preparation was suspended in the test solution (pH 1.2) for 3 hours.

Example 8 Riboflavin butyrate formulation of the present invention (riboflavin butyrate 5 mg) obtained in Example 3 and, as a control, riboflavin butyrate 5 g, lactose 180 g, crystalline cellulose 108.5 g, light anhydrous silicic acid 1.5 g, plant hydrogenated oil 3.0 g and magnesium stearate 2.0g were evenly mixed, and one tablet 300mg (riboflavin butyrate 5mg) tablets was prepared with a single punch tableting machine using a flat punch with a diameter of 9mm. For comparison.

Crossover was carried out by 2 healthy males in 1 group, and the results were shown as an average of 4 cases. Water for each formulation
Oral administration was performed with 100 ml, and urine was collected every other hour for 10 hours, and the total amount of riboflavin in urine was quantified by the lumiflavin fluorescence method. Some riboflavin is derived from a living body, and urine is collected before administration of the preparation, and the amount of riboflavin in this urine is derived from the living body, and the results are shown below.

From these results, the utilization of the formulation of the present invention was clearly improved, and the usefulness of the present invention was confirmed.

[Effects of the Invention] As described above, the composition of the present invention can stay in the stomach for a long time and improve the utilization rate of the active ingredient, and the effect is superior to the conventional one, Extremely useful.

Claims (5)

[Claims] 1. A sustained-release preparation composition comprising a high-viscosity water-soluble polymeric substance, 5-45% by weight of crosslinked insoluble polyvinylpyrrolidone and a component which foams when contacted with gastric juice, and compression-molded. object. 2. The sustained-release preparation composition according to claim 1), which comprises a weakly acidic component. 3. A highly viscous water-soluble polymer substance is 20 ° C., 2%
Claims 1) or 2) comprising one or more selected from cellulose ethers or polyvinyl alcohol having a water-soluble viscosity of 50 centipoise or more.
The sustained-release pharmaceutical composition according to the above item. 4. The sustained-release preparation composition according to claim 1) or 2), wherein the component that foams when contacted with gastric juice is calcium carbonate or precipitated calcium carbonate. 5. The weak acid component is citric acid, fumaric acid, tartaric acid or succinic acid, as defined in claim 1) or 2).
The sustained-release pharmaceutical composition according to the above item.