JP2001048779A - Intracolic releasing capsuple pharmaceutical preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a capsule pharmaceutical preparation capable of overcoming the weakness in bond strength of a chitosan layer to an enteric layer and specifically releasing a drug in the colon. SOLUTION: This intracolic releasing capsule pharmaceutical preparation is obtained by inserting a solid substance prepared by coating a drug-containing solid substance with a layer consisting essentially of chitosan or the drug- containing solid substance or a drug-containing liquid substance into a chitosan- containing solid container, sealing the resultant solid substance in a capsule and coating the envelope thereof with an enteric film. The method for producing the intracolic releasing capsule pharmaceutical preparation comprises inserting the solid substance prepared by coating the drug-containing solid substance with the layer consisting essentially of the chitosan, the drug-containing solid substance or the drug-containing liquid substance into the chitosan-containing solid container and sealing the resultant solid substance in the capsule and coating the envelope with the enteric film.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to a capsule preparation capable of being released into the large intestine, and more particularly, to a drug which is released orally when administered orally without disintegration in the stomach or small intestine and is released by disintegration in the large intestine. Capsule formulation.

[0002]

2. Description of the Related Art Several chitosan preparations that release a drug specifically in the large intestine have been known.

[0003] For example, Japanese Patent Application Laid-Open No. 4-69333 discloses that a solid drug and a layer composed of chitosan and an enteric coating layer mainly composed of hydroxypropylmethylcellulose acetate succinate or hydroxypropylmethylcellulose hexahydrophthalate are described. ,
A large intestine release solid preparation characterized by being sequentially coated is described.

Japanese Patent Application Laid-Open No. 6-179618 discloses that chitosan having a degree of deacetylation of 60 to 98 mol% is used as a film-forming component and contains 5 to 50% by weight of silica fine particles per capsule weight. A chitosan hard capsule is described.

[0005]

Since chitosan is usually soluble only in an acidic aqueous solution and hardly soluble in an organic solvent, it is not coated at all in the process of producing a solid preparation to be released into the large intestine. In order to coat a solid preparation with chitosan, it is necessary to dissolve chitosan in an aqueous acid solution. However, it is difficult to completely remove the acid contained in this solution after coating, and it is inevitable that the acid remains in the coated chitosan film, so that the acid lowers the water resistance of the chitosan film, The effect of acids on drugs is problematic. In order to solve such a drawback, Japanese Patent Application Laid-Open No. 4-69333 discloses that an enteric coating is formed in advance inside a chitosan layer. In addition, in order to release the drug in the large intestine, a combination with an enteric base is indispensable, and some enteric coating is usually performed on various coating machines, but the affinity with the chitosan layer is not good. , The bonding strength between the chitosan layer and the enteric layer is not sufficient,
Therefore, in mass production, problems such as peeling of the enteric coating have occurred.

[0006]

Means for Solving the Problems The present inventors have conducted various studies on applying an enteric coating to a chitosan layer, and as a result, by interposing a capsule layer between the chitosan layer and the enteric layer, the chitosan layer and the enteric coating were formed. We have found a capsule formulation that overcomes the weak bonding strength of the layers and can release the drug specifically in the large intestine.

[0007] According to the present invention, since a solid comprising a drug-containing solid coated with a layer containing chitosan as a main component or a drug-containing solid or a drug-containing liquid is inserted into a chitosan-containing solid container. A solid body obtained by encapsulating the solid body in a capsule and coating the outer skin with an enteric coating, and a solid body obtained by coating a chitosan-based layer on a drug-containing solid substance or A capsule releaseable into the large intestine characterized in that a solid obtained by inserting a drug-containing solid or a drug-containing liquid into a chitosan-containing solid container is encapsulated in a capsule, and the outer skin is coated with an enteric coating. A manufacturing method is provided.

[0008] "Drug-containing solid material" means a drug or a mixture of a drug and a carrier component for a drug, which is solid or semi-solid, in a form that can be coated or inserted into a solid container. It may be in the form of a powder, granule, pellet, tablet, or any of these semisolids.

The "drug-containing liquid substance" means an oily drug or a mixture of a drug and a liquid or oily carrier component for a pharmaceutical preparation, and may be in the form of an aqueous solution or oil.

[0010] The carrier components for pharmaceutical preparations include solid, liquid or oily preparations usually used in the preparation of excipients, binders, disintegrants, lubricants, fluidizers, diluents, stabilizers and the like. Ingredients are included.

The chitosan used in the present invention is usually about 6
A substance deacetylated by 0% or more is used.
% To about 98% is preferred.

The term "layer containing chitosan as a main component" means a layer containing chitosan in an amount of usually about 50% or more, and can be obtained, for example, by coating chitosan or a mixture of chitosan and other components. The chitosan-containing layer is included in the “layer containing chitosan as a main component” in the present invention.

The "chitosan-containing solid container" may be of any size and form as long as it is a solid container containing chitosan as a main component. Examples of the chitosan-containing solid container include chitosan-containing capsules, and specific examples thereof include silica-containing chitosan hard capsules described in JP-A-6-179618.

[0014] The "solid body" to be inserted into the capsule is a solid body coated with a layer containing chitosan as a main component, for example, a powder, granule, pellet, tablet or solid containing chitosan. One in a state of being sealed in a container, for example, a capsule-like one may be mentioned.

As the enteric polymer for forming the enteric film (hereinafter sometimes referred to as “enteric base”), any of those commonly used in the art can be used. For example, carboxymethylethylcellulose (CMEC) ), Hydroxypropyl methylcellulose acetate succinate [HPMCAS (Shin-Etsu Chemical)], hydroxypropyl methylcellulose phthalate [HPMCP (Shin-Etsu Chemical)], cellulose acetate phthalate, shellac,
Acrylic acid-based copolymer (for example, Eudragit L-1)
One or two or more selected from ethyl methacrylate such as 00 and methyl methacrylate methacrylate such as Eudragit S-100). Preferred enteric bases include hydroxypropyl methylcellulose acetate succinate (HPM
CAS) and hydroxypropyl methylcellulose phthalate (HPMCP).

The capsule to be subjected to enteric coating is not particularly limited in size and type, and may be any material as long as it has a high affinity for the enteric film coated on the outer skin. Is, for example, a gelatin capsule.

The enteric base is usually dissolved in a solvent and coated, and ethanol, water or a mixture thereof is used as the solvent.

Further, talc, magnesium stearate, light anhydrous silicic acid, glyceryl monostearate, etc., which are generally used as a lubricant, a fluidizing agent or an anti-agglomerating agent, are added to the enteric coating. You can also.

The drug used in the present invention may be water-soluble, hardly water-soluble, or any other substance.
Although the type is not particularly limited, for example, 5-aminosalicylic acid (5-ASA), which is effective for irritable colitis, other protein preparations, insulin and the like can be mentioned.

[0020]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Preferred forms include commercially available particles such as granular crystalline cellulose (eg, Selfia (Asahi Kasei)), purified sucrose spherical granules, and sucrose / starch spherical granules (eg, various nonpareils (Freund Corporation)). The substance is charged into a coating apparatus and coated with a drug or a mixture of a drug and a pharmaceutical carrier to form a core component, which is coated with an aqueous chitosan solution, and further encapsulated in a capsule. And a capsule preparation thus obtained.

In the simplest form, a commercially available chitosan capsule enclosing a drug or a mixture of a drug and a pharmaceutical carrier is placed in a one-size-large gelatin capsule, which is coated with an enteric coating, and the capsule preparation thus obtained is obtained. No.

[0022]

The present invention will be described in more detail with reference to the following Examples and Comparative Examples.

Example 1 : Nonpareil 103 (24/3)
45 mesh of acetaminophen is powder-coated on 1450 g of 2 mesh; Freund's industrial product) with an aqueous solution of hydroxypropylmethylcellulose 2910 [TC-5E (Shin-Etsu Chemical)] as a binding solution to produce a drug core. 360% of this drug core is coated with a 0.5% chitosan acetic acid aqueous solution (0.3%) at a solid content of 15% on the core granules to obtain a chitosan-coated preparation. 70 mg of this preparation is encapsulated in a No. 5 gelatin capsule (about 28 mg per capsule), and the capsule (about 98 mg per capsule)
0 g of HPMCAS (Shin-Etsu Chemical) which is an enteric base
Was dissolved in a mixed solution of ethanol / water (8/2), and 1000 g of a coating solution (5 w / w%) was coated in 4 hours to obtain a capsule preparation.

Example 2 : 200 mg of acetaminophen 30-times diluted acetaminophen diluted with lactose was placed in Chitosan No. 3 capsule (1 capsule, about 46 mg; Aicello Chemicals), and this capsule was converted into a No. 2 gelatin capsule (1 capsule, about 65 capsules).
mg), and put this capsule (about 31 per capsule).
1 mg) 250 g of a coating solution (5 w / w%) obtained by dissolving HPMCAS (Shin-Etsu Chemical Co., Ltd.) as an enteric base in a mixture of ethanol / water (8/2) for 100 hours in 4 hours.
0 g was coated to obtain a capsule preparation.

Example 3 200 mg of a 30-fold aqueous solution of acetaminophen was placed in a No. 3 chitosan capsule (about 46 mg per capsule; Icelo Chemical), and this capsule was placed in a No. 2 gelatin capsule (about 65 mg per capsule). (About 311mg per capsule) 2
50 g of an enteric base, HPMCAS (Shin-Etsu Chemical Co., Ltd.) mixed with ethanol / water (8/2) (5 w / w%)
The coating solution (5 w / w%) dissolved in the solution was coated with 1000 g for 4 hours to obtain a capsule preparation.

Comparative Example 1: As a comparative example, Chitosan No. 3 capsule (about 46 mg per capsule; Aicello Chemicals)
Acetaminophen diluted 30 times with lactose 200
mg of this capsule (about 246 per capsule).
mg) 250 g of HPMCAS which is an enteric base directly
(Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixed solution of ethanol / water (8/2), and a coating solution (5 w / w%) was added in 5 hours.
250 g was coated to obtain a capsule preparation.

Dissolution Test Using the capsule preparations of Examples 1 to 3 and Comparative Example 1, the dissolution behavior of the drug in the first solution (pH 1.2) of the dissolution test of the 13th revised Japanese Pharmacopoeia was observed (dissolution). 900 ml of test solution,
37 ° C, paddle speed 100 rpm).

As is clear from FIGS. 1, 2 and 3,
In any of the capsule preparations of Examples 1 to 3, since the dissolution of the drug can be controlled by changing the coating time, it is possible to design a desired capsule release preparation into the large intestine. On the other hand, as is clear from FIG. 4, the capsule preparation of Comparative Example 1 immediately starts elution of the drug regardless of the coating time. Can not.

[0029]

EFFECTS OF THE INVENTION The colon-releasable capsule preparation of the present invention can release a drug specifically in the large intestine by ensuring that the chitosan-containing layer is covered with the enteric layer via the capsule. In addition, the method for producing capsules makes it possible to produce a large intestinal release capsule preparation having the same effect in a large amount by a simple method, instead of coating an enteric film on chitosan, which has been difficult until now. A manufacturing method is provided.

[Brief description of the drawings]

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the dissolution of a drug from the capsule preparation of Example 1 when the coating time was 1 hour, 2 hours, 3 hours, and when the coating was applied for the final 4 hours. Shows the relationship between rate and time.

FIG. 2 is a graph showing the dissolution rate and time of drug in the capsule preparation of Example 2 for the preparation partially removed when the coating time was 2 hours and 3 hours and the preparation for which coating was performed for the final 4 hours. The relationship is shown below.

FIG. 3 shows the dissolution of a drug in the capsule preparation of Example 3 for the preparation partially removed when the coating time was 1 hour, 2 hours, and 3 hours, and the preparation for which coating was performed for the final 4 hours. Shows the relationship between rate and time.

FIG. 4 shows the relationship between the drug dissolution rate and time for the capsule preparation of Comparative Example 1 for a preparation partially removed when the coating time was 4 hours and for a preparation for which coating was performed for the last 5 hours. Is shown.

Claims (5)

[Claims] 1. A solid comprising a drug-containing solid coated with a chitosan-based layer or a solid comprising a drug-containing solid or a drug-containing liquid inserted into a chitosan-containing solid container. A large intestine release capsule preparation which is encapsulated in a capsule and its outer skin is coated with an enteric coating. 2. The preparation according to claim 1, wherein the solid is a granule or a pellet. 3. The preparation according to claim 1, wherein the chitosan-containing solid container is a chitosan-containing capsule. 4. An enteric coating comprising hydroxypropylmethylcellulose acetate succinate or hydroxypropylmethylcellulose phthalate.
The preparation according to any one of the above. 5. A solid obtained by coating a layer containing chitosan as a main component on a drug-containing solid or a solid obtained by inserting a drug-containing solid or a drug-containing liquid into a chitosan-containing solid container. A method for producing a capsule release preparation into the large intestine, wherein the preparation is encapsulated in a capsule and its outer skin is coated with an enteric coating.