JPH0710745A - Oral preparation for release-starting time control type intestinal delivery - Google Patents

Abstract

PURPOSE:To obtain a medicinal preparation for oral administration, capable of efficiently transmitting a medicinal ingredient to a desired target site in an intestine. CONSTITUTION:This medicinal preparation comprises (a) nucleus containing an acidic substance, (b) the first layer which comprises a water-insoluble polymer, may contain a water-soluble substance, and covers the nucleus, (c) the second layer containing a main medicinal ingredient and covering the first layer, (d) the third layer comprising a low pH soluble polymer and covering the second layer, and (e) the fourth layer comprising an enteric polymer and covering the third layer. The oral preparation has an excellent characteristic that the main medicinal ingredient is not released during a gastric retention time and during a constant time required for passing through a small intestine after passed through a stomach, namely during a time required for reaching a target site in the small intestine, and then subsequently rapidly released.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an intestinal delivery oral preparation having a controlled release onset time.

[0002]

2. Description of the Related Art In drug therapy, such as 1) local therapy for inflammatory diseases in the large intestine such as ulcerative colitis, and 2) oral administration of peptide drugs that are susceptible to chemical or enzymatic degradation in the small intestine. In the field, it is desirable to selectively deliver drugs from the lower small intestine to the large intestine. For this reason, various studies have been conducted in recent years on a pharmaceutical preparation for oral administration that selectively delivers a drug from a desired target site in the intestine, for example, from the lower small intestine to the large intestine. It is necessary to design the drug product taking into consideration the physical and physiological environment in the tube and the transit time of the drug in the gastrointestinal tract.

Among such preparations, classical enteric-coated preparations and sustained-release preparations are also included. The former effectively suppresses drug release in the stomach, but releases rapidly in the upper small intestine. Therefore, most of the drug is absorbed or degraded by the time it reaches the large intestine. Further, in the latter, since the drug is continuously released, there is a problem that a considerable amount of the drug is released even during the time when the preparation stays in the stomach and the process of passing through the small intestine. Attempts have been made to suppress the release in the stomach by coating a sustained-release preparation with an enteric coating, but the problem of release during passage through the small intestine has not been completely solved. Further, as a relatively new technique, the use of a technique for controlling the release start time has been attempted (for example, JP-A-4-7241).
7), a satisfactory formulation has not been obtained.

[0004]

DISCLOSURE OF THE INVENTION The present invention provides rapid release of a contained drug at a set time,
It is an object of the present invention to provide an intestinal delivery oral preparation with a controlled onset release time, which can efficiently deliver a drug to a desired target site in the intestine.

[0005]

Means for Solving the Problems As a result of intensive investigations by the present inventors, a main drug layer was formed on a core containing an acidic substance coated with a water-insoluble polymer for release control, and By coating with a low-pH soluble polymer that dissolves and disappears when the acidic substance elutes, and by further coating this with an enteric polymer, the time from gastric emptying to the start of release of the main drug can be controlled and It was found that a formulation capable of rapidly releasing the main drug at a desired target site was obtained, and the present invention was completed.

That is, the preparation of the present invention comprises a core (a) containing an acidic substance, a water-insoluble polymer and may contain a water-soluble substance, a first layer (b) covering the core, a main ingredient And a second layer (c) that covers the first layer, is composed of a low-pH soluble polymer, a third layer (d) that covers the second layer, and an enteric polymer that covers the third layer. An oral preparation comprising the fourth layer (e).

FIG. 1 shows a schematic diagram of the preparation of the present invention in the case of granules.

With this constitution, when the preparation of the present invention is orally administered, in the stomach after passing through the esophagus, the main drug is not released at all in the stomach due to the outermost enteric layer, as in the case of a normal enteric preparation. Next, after moving into the intestinal tract, the pH of the digestive juice rises, the enteric layer dissolves and disappears, and the low pH dissolving layer becomes the outermost layer. At the same time, the digestive juice begins to infiltrate into the preparation, and then the infiltrated digestive fluid dissolves the acidic substance in the nucleus. The dissolved acidic substance is gradually released through the acidic substance release control layer and becomes acidic in the formulation, whereby the low pH dissolution layer is dissolved and disappears, and at the same time, the main drug is rapidly released.

In the preparation of the present invention, as the acidic substance of the nucleus, a solid water-soluble substance other than the main drug, which has a pH of 1 to 5 after being dissolved in water, can be used. Examples of such acidic substances include organic acids such as succinic acid, maleic acid, tartaric acid, citric acid, fumaric acid and malic acid, inorganic acids such as boric acid, and combinations of two or more thereof. . Among these, organic acids such as succinic acid, maleic acid, tartaric acid, citric acid, fumaric acid and malic acid can be preferably used, and succinic acid is particularly preferable.

The water-insoluble polymer used in the first layer may be any film-forming one capable of controlling the release of the above-mentioned acidic substances, and examples thereof include ethyl acrylate / methyl methacrylate / trimethylammonium methacrylate. Water such as ethyl copolymer (eg, Eudragit RS, Eudragit RL (trade name, manufactured by Rohm Pharma)), ethyl acrylate / methyl methacrylate copolymer (eg, Eudragit NE (trade name, manufactured by Rohm Pharma)), etc. Examples thereof include water-insoluble cellulose derivatives such as insoluble acrylic acid-based copolymers, ethyl cellulose and cellulose acetate, water-insoluble vinyl derivatives such as polyvinyl acetate and polyvinyl chloride, and combinations of two or more thereof. Among them, ethyl cellulose, ethyl acrylate / methyl methacrylate / methacrylic acid trimethylammonium ethyl copolymer (Eudragit R
S, Eudragit RL) is preferable, and ethyl cellulose, ethyl acrylate / methyl methacrylate / trimethylammonium ethyl methacrylate (1: 2: 0.1) copolymer (Eudragit RS) is particularly preferable.

Further, the first layer may contain a water-soluble substance together with the above water-insoluble polymer, and such a water-soluble substance is a substance which dissolves in water at room temperature at about 1% (W / V) or more. It suffices if it is present, and examples thereof include a water-soluble polymer satisfying the above conditions, a low-molecular electrolyte, and a saccharide. Examples of the water-soluble polymer substance include water-soluble polysaccharide ethers such as methylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, polyvinylpyrrolidone, water-soluble vinyl derivatives such as polyvinyl alcohol, polysaccharides such as pullulan, and polyethylene glycol. To be Furthermore, examples of the low molecular weight electrolyte include inorganic salts such as sodium chloride, and examples of the saccharide include monosaccharides such as glucose or disaccharides such as sucrose.

These water-soluble substances may be mixed with the water-insoluble polymer, or the water-soluble substance may be dispersed in the water-insoluble polymer. The combination of the water-soluble substance and the water-insoluble polymer is not particularly limited, but a particularly preferable example is a combination of ethyl cellulose and hydroxypropyl cellulose, or a combination of ethyl cellulose and hydroxypropyl methyl cellulose.

In the preparation of the present invention, the main drug to be contained in the second layer is a drug which is desirably released in the intestine (for example, a drug which is efficiently absorbed at a specific site in the intestine or a treatment for intestinal diseases). (Drugs, etc.), and drugs that are desired to have a long-acting effect. Specific examples include peptide / protein drugs, antibacterial drugs, antitumor drugs, antipyretic and anti-inflammatory analgesics, and antitussive and analgesic drugs. , Antidepressant, muscle relaxant, anti-ulcer agent, anti-allergic agent, antihypertensive diuretic, antidiabetic agent, cardiotonic agent, vasodilator, antiarrhythmic agent, anticoagulant, hemostatic agent,
Narcotic antagonists, hormones, immunostimulants, antiepileptic agents,
Examples include antihistamines and diagnostic agents. These main agents can be suitably used regardless of whether they are easily soluble in water or sparingly soluble in water. In the case of a drug that is easily soluble in water, a drug having a pH of 5 or more when dissolved in water is preferable.

In the preparation of the present invention, the low pH-soluble polymer used in the third layer dissolves in the acidic region of pH 1 to 5, but does not dissolve in the neutral to alkaline region of higher pH, That is, a substance usually used as a gastric-soluble polymer in this field can be used. Examples of such a polymer include polyvinyl acetal diethylaminoacetate, methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer (for example, Eudragit E (trade name, manufactured by Rohm Pharma)), polyvinylaminoacetal. Etc., or a combination of two or more thereof. Of these, polyvinyl acetal diethylaminoacetate,
A methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer is preferred.

As the enteric polymer used in the fourth layer, a polymer which does not dissolve in the acidic range but dissolves in the neutral to weakly alkaline range of pH 5 to 8 and higher pH can be used. Examples of such a polymer include hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate,
Cellulose acetate phthalate, cellulose propionate phthalate, cellulose acetate maleate,
Cellulose derivatives such as carboxymethyl ethyl cellulose, methacrylic acid / methyl methacrylic acid copolymers (eg Eudragit L100, Eudragit S (both are trade names, manufactured by Rohm Pharma)), methacrylic acid / ethyl acrylate copolymers (eg Eudragit L100). -55 (trade name, manufactured by Rohm Pharma), etc., methacrylic acid copolymer, styrene-acrylic acid copolymer, polyvinyl alcohol phthalate, polyvinyl acetal phthalate, shellac, etc., or a combination of two or more thereof. There are some. Of these, hydroxypropyl methylcellulose acetate succinate,
Methacrylic acid / methyl methacrylate copolymer (Eudragit L100, Eudragit S), methacrylic acid / ethyl acrylate copolymer (Eudragit L1
00-55) is preferred.

Acidic substance of the nucleus, water-insoluble polymer of the first layer,
The combination of the low-pH soluble polymer in the third layer is as follows: "The acidic substance is an organic acid, the water-insoluble polymer is ethyl acrylate.
Methyl methacrylate / methacrylic acid trimethylammonium ethyl copolymer or ethyl cellulose,
The low-pH soluble polymer is preferably polyvinyl acetal diethylaminoacetate or methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer ”.

In the preparation of the present invention, a drug (which may be the same as the main drug of the second layer, may be added between the third layer and the fourth layer).
May be different) or may have an intermediate layer composed of a water-soluble substance. By providing the intermediate layer made of the drug, the drug can be selectively delivered even in the upper part of the small intestine. Further, when the fourth layer is coated, the characteristics of the coating film of the third layer rarely change, but this may be prevented by providing an intermediate layer made of a water-soluble substance. Examples of the drug that can be used in this intermediate layer include those similar to the main drug in the second layer, and examples of the water-soluble substance include those similar to the above-described water-soluble substance in the first layer.

The core, the first layer, the second layer, the third layer, the fourth layer and the intermediate layer between the third layer and the fourth layer may contain, if necessary, an excipient, a binder and a lubricant. Agents, anti-agglomeration agents, plasticizers for improving coating properties and film forming properties, surfactants, antistatic agents, additives for adjusting light transmission, coloring agents, etc., which are usually used in this field. You may mix | blend various compounding agents.

The specific structure of the formulation of the present invention can be set so that the main drug component is released at a desired target site in the intestine by controlling the release initiation time. For example, as one method, by increasing (decreasing) the coating rate of the first layer that controls the release of the acidic substance and decreasing (increasing) the elution rate of the acidic substance, the time until the release starts is increased ( Can be shortened). Alternatively, as another method, the coating rate of the first layer is kept constant and the coating rate of the third layer composed of the low pH-soluble polymer substance is increased (decreased) to increase the time until the release is started ( It can be shortened).

In the preparation of the present invention, the content of the acidic substance in the nucleus is preferably 5 to 100% by weight. Further, the preferable coating rate of each layer changes depending on the release start time to be set and the combination of each component as described above,
Generally, the first layer is 5 to 100% by weight with respect to the core.
, The second layer is 5 to 20 relative to the core coated with the first layer.
0% by weight, the third layer is 5 to 100% by weight with respect to the core which covers the first layer and the second layer, and the fourth layer is the core which covers the first layer, the second layer and the third layer. On the other hand, it is preferably 5 to 100% by weight.

The dosage form of the preparation of the present invention includes granules, capsules, tablets including dry coated tablets, and the like.

The method for producing the preparation of the present invention may be a general method known to those skilled in the art and is not particularly limited. For example, the core may be prepared by adding an excipient, a binder, a lubricant, etc., to an acidic component, if desired, and mixing the mixture, followed by a conventional method such as a wet granulation method or a dry granulation method. it can.
Alternatively, it can be prepared by coating the acidic component on carrier particles made of sucrose, lactose, starch, crystalline cellulose or the like by a fluidized bed coating method or the like while spraying a binder solution.

The coating of the first layer to the fourth layer is performed by a fluidized granulation coating apparatus, a centrifugal fluidized granulation coating apparatus, a pan coating apparatus or the like using a fluidized granulation coating method or a centrifugal fluidized granulation coating method. Alternatively, it can be performed by a method commonly used in this field such as a pan coating method. In addition, the coating can be applied by any of water-based and non-water-based methods that are usually used in this field.

Examples will be shown below.

[0025]

Example 1 150 g of non-pareil (brand name, manufactured by Freund Sangyo Co., Ltd., component: sucrose) having a particle size of 475 to 655 μm was put in a centrifugal fluidized granulation coating apparatus (CF) and rolled, and a binder was added thereto. While spraying (20% sucrose / 25% ethanol), 400 g of succinic acid was gradually added to obtain 630 g of succinic acid granules. Next, the obtained succinic acid granulated product 150
g against CF, Eudragit RS (trade name, manufactured by Rohm Pharma Co., ingredient: ethyl acrylate
A solution prepared by dissolving methyl methacrylate / trimethylammonium methacrylic acid trimethylammonium ethyl copolymer) in an ethanol-water mixture (1: 2) at a concentration of 15% was sprayed to coat 15 g of Eudragit RS, and the first layer coated granules were prepared. Obtained.

Subsequently, the obtained first-layer coated granules were powder-coated with a powder mixture containing 45 g of theophylline and 155 g of mannitol while spraying a binder (20% sucrose / 25% ethanol), and the main drug layer. 420 g of coated granules were obtained.

Finally, using CF, the Eudragit E was added to 150 g of the obtained main drug layer-coated granules.
(Trade name, manufactured by Rohm Pharma Co., Ltd., component: methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer) was dissolved in an ethanol-water mixture (1: 2) at a concentration of 5% to spray a solution. Then, 60 g of Eudragit E was coated, and hydroxypropylmethylcellulose acetate succinate (hereinafter referred to as HPMCAS) was suspended in water at a concentration of 5%, and triethyl citrate was added as a plasticizer to 1.
Sprayed with 5% added liquid, 42g as HPMCAS
Coating was performed to obtain 250 g of the target granule.

Example 2 150 g of non-pareil having a particle size of 475 to 655 μm was put in a centrifugal fluidized granulation coating apparatus (CF) and rolled,
While spraying a binder (20% sucrose / 25% ethanol) on this, 400 g of succinic acid was gradually added to obtain 630 g of a succinic acid granulated product. Next, with respect to 150 g of the obtained succinic acid granulated product, 6 parts of ethyl cellulose were added using CF.
A solution prepared by dissolving a 5% water-35% ethanol mixed solution at a concentration of 10% was sprayed, and 30 g of ethyl cellulose was coated to obtain a first-layer coated granule. The obtained first-layer coated granules were treated in the same manner as in Example 1 below to obtain target granules.

Example 3 150 g of non-pareil having a particle size of 475 to 655 μm was put in a centrifugal fluidized granulation coating apparatus (CF) and rolled,
While spraying a binder (20% sucrose / 25% ethanol) on this, 400 g of succinic acid was gradually added to obtain 630 g of a succinic acid granulated product. Next, with respect to 150 g of the obtained succinic acid granulated product, 65% of an ethyl cellulose-hydroxypropyl cellulose (9: 1) mixture was added using CF.
A solution obtained by dissolving a 10% concentration in a water-35% ethanol mixed solution was sprayed, and 45 g of ethyl cellulose-hydroxypropyl cellulose was coated to obtain a first-layer coated granule. The obtained first-layer coated granules were treated in the same manner as in Example 1 below to obtain target granules.

Example 4 In the same manner as in Example 1, a main drug layer-coated granule was obtained. Subsequently, using CF, a solution of Eudragit E dissolved in an ethanol-water mixed solution (1: 2) at a concentration of 5% was sprayed onto 150 g of the obtained active ingredient layer-coated granules, and 60 g of Eudragit E was coated. Then, 75 g of sucrose powder was gradually added while spraying a binder (20% sucrose / 25% ethanol) to form a sucrose layer. Further, HPMCAS was suspended in water at a concentration of 5%, and a liquid containing 1.5% of triethyl citrate as a plasticizer was further sprayed to coat 42 g of HPMCAS to obtain 250 g of target granules.

Example 5 150 g of non-pareil having a particle size of 475 to 655 μm was put in a centrifugal fluidized granulation coating apparatus (CF) and rolled,
While spraying a binder (20% sucrose / 25% ethanol) on this, 400 g of succinic acid was gradually added to obtain 630 g of a succinic acid granulated product. Then, using 150 g of the obtained succinic acid granulated product, Eudragit RS- using CF.
Eudragit RL (trade name, manufactured by Rohm Pharma,
Ingredients: Ethyl acrylate / Methyl methacrylate / Trimethylammonium methacrylic acid trimethylammonium ethyl copolymer) (1: 1) A mixture of ethanol and water (1: 2)
Was sprayed with a solution dissolved at a concentration of 15% to coat 30 g of Eudragit RS-Eudragit RL to obtain a first-layer coated granule. Subsequently, theophylline 45 was added to the obtained first-layer coated granules.
g, and 155 g of mannite are mixed powder (20
Powder coating was performed while spraying (% sucrose / 25% ethanol) to obtain 435 g of the active ingredient layer-coated granules.
Finally, using CF, a solution of polyvinyl acetal diethylaminoacetate (hereinafter referred to as AEA) dissolved in ethanol-water mixture (1: 2) at a concentration of 10% was obtained with respect to 150 g of the obtained drug substance-coated granules. Is sprayed to coat 90 g of AEA, and HP
MCAS was suspended in water at a concentration of 5%, and a liquid containing 1.5% of triethyl citrate as a plasticizer was further sprayed to coat 42 g of HPMCAS to obtain 280 g of target granules.

Example 6 150 g of non-pareil having a particle size of 475 to 655 μm was put in a centrifugal fluidized granulation coating apparatus (CF) and rolled,
While spraying a binder (20% sucrose / 25% ethanol) on this, 400 g of succinic acid was gradually added to obtain 630 g of a succinic acid granulated product. Next, a solution of Eudragit RS dissolved in ethanol-water mixture (1: 2) at a concentration of 15% using CF was sprayed onto 150 g of the obtained succinic acid granules to coat 15 g of Eudragit RS. did. Then, to the obtained first layer coated granules, theophylline 45 g and mannitol 155 g
The powder mixture was spray-coated with a binder (20% sucrose / 25% ethanol) to obtain 420 g of the active ingredient layer-coated granules.

Finally, CF was used to spray 150 g of the obtained main drug layer-coated granules with a solution of AEA dissolved in an ethanol-water mixed solution (1: 2) at a concentration of 10% to obtain 90 g of AEA. Coating and further spraying a solution of Eudragit L100 (trade name, manufactured by Rohm Pharma Co., Ltd., component: methacrylic acid / methyl methacrylate copolymer) in an ethanol-water mixture (2: 1) at a concentration of 10%. , As Eudragit L100 3
Coating with 0 g gave 270 g of the target granules.

Example 7 150 g of nonpareil having a particle size of 475 to 655 μm was placed in a centrifugal fluidized granulation coating apparatus (CF) and rolled.
While spraying a binder (20% sucrose / 25% ethanol) on this, 200 g of succinic acid was gradually added to obtain 430 g of succinic acid granules. Next, 150 g of the obtained succinic acid granulated product was sprayed with a solution of Eudragit RS dissolved in an ethanol-water mixed solution (1: 2) at a concentration of 15% using CF to give Eudragit RS 22. 5 g
Coating was carried out to obtain a first layer coated granule. Then, a mixed powder consisting of 100 g of 5-aminosalicylic acid (5-amino-2-hydroxybenzoic acid) and 100 g of mannitol was added to the obtained first-layer coated granules as a binder (20% sucrose / 25% ethanol). ) Is sprayed and powder coated, and the active ingredient layer-coated granules 42
0 g was obtained. The obtained active ingredient layer-coated granules were treated in the same manner as in Example 1 below to obtain target granules.

Example 8 150 g of nonpareil having a particle size of 475 to 655 μm was put in a centrifugal fluidized granulation coating apparatus (CF) and rolled,
While spraying a binder (20% sucrose / 25% ethanol) on this, 200 g of succinic acid was gradually added to obtain 430 g of succinic acid granules. Next, 150 g of the obtained succinic acid granulated product was sprayed with a solution of Eudragit RS dissolved in an ethanol-water mixed solution (1: 2) at a concentration of 15% using CF to give Eudragit RS 22. 5 g
Coating was carried out to obtain a first layer coated granule. Subsequently, the first-layer coated granules thus obtained were powder-coated with a mixed powder consisting of 100 g of 5-aminosalicylic acid and 100 g of mannitol while spraying a binder (20% sucrose / 25% ethanol), and then the main ingredient. 420 g of layer-coated granules were obtained.

Finally, CF was used to spray 150 g of the obtained base layer-coated granules with a solution of Eudragit E dissolved in an ethanol-water mixture (1: 2) at a concentration of 5%, and Eudragit E was sprayed. As a plasticizer, triethyl citrate is added as a plasticizer at a concentration of 1.5%, and HPMCAS is suspended at a concentration of 5% in water.
The added liquid was sprayed and coated with 42 g of HPMCAS to obtain 280 g of target granules.

Example 9 150 g of non-pareil having a particle size of 475 to 655 μm was put into a centrifugal fluidized granulation coating apparatus (CF) and rolled,
While spraying a binder (20% sucrose / 25% ethanol) on this, 200 g of succinic acid was gradually added to obtain 430 g of succinic acid granules. Next, 150 g of the obtained succinic acid granulated product was sprayed with a solution of Eudragit RS dissolved in an ethanol-water mixed solution (1: 2) at a concentration of 15% using CF to give Eudragit RS 22. 5 g
Coating was carried out to obtain a first layer coated granule. Subsequently, the first-layer coated granules thus obtained were coated while spraying a solution prepared by dissolving 50 g of 5-aminosalicylic acid and 150 g of Eudragit E in 1 L of a dichloromethane-ethanol mixed liquid (1: 1), and the main layer-coated granules 370 g were obtained. Next, HPMCAS was suspended in water at a concentration of 5%, and a solution containing 1.5% of triethyl citrate as a plasticizer was further sprayed to give HPMCAS.
42g as coating, 410g of target granules
Got

Experimental Example Target granules were obtained in the same manner as in Example 1. About this granule, Japanese Pharmacopoeia 12th revision, 1st liquid (pH 1.
2) and the second liquid (pH 6.8) were used to carry out the dissolution test. The results are shown in Fig. 2. As is clear from the figure, it is found that the main drug is not released at all in the first liquid for a long time, and the main drug is rapidly released in the second liquid after a lag time of about 4 hours.

[0039]

INDUSTRIAL APPLICABILITY The present invention does not release the main drug during the retention time in the stomach and a certain period of time after gastric emptying and during passage through the small intestine, that is, during the time required to reach the target site in the small intestine, and then promptly. It is intended to provide an oral preparation having an excellent characteristic of releasing the main drug. In the preparation of the present invention, the time until the start of the main drug release is set by the thickness of the first layer composed of a water-insoluble polymer or the third layer composed of a low pH-soluble polymer that controls the release of acidic substances. This allows the release to be initiated at the desired target site in the intestine.
Further, since the third layer that suppresses the release of the main drug dissolves and disappears after the set time, even with the main drug that is poorly soluble in water,
It can be released rapidly after a set time. Due to such characteristics, the preparation of the present invention can efficiently deliver a drug to a desired site in the intestine, and thus is effective when, for example, a peptide drug or a drug for treating inflammatory diseases in colon is the main drug. It becomes an excellent pharmaceutical preparation with high

[Brief description of drawings]

1 is a schematic diagram in the case of granules of the preparation according to the present invention.

FIG. 2 is a graph showing the results of a dissolution test using the first liquid (pH 1.2) and the second liquid (pH 6.8) of the 12th revision of the Japanese Pharmacopoeia in Experimental Examples.

[Explanation of symbols]

1 nucleus containing an acidic substance 2 first layer consisting of a water-insoluble polymer which may contain a water-soluble substance 3 second layer containing a main drug 4 third layer consisting of a low pH soluble polymer 5 high entericity Fourth layer of molecules

Claims (8)

[Claims] 1. A core (a) containing an acidic substance, a first layer (b) consisting of a water-insoluble polymer, which may contain a water-soluble substance, and which covers the core, a first layer containing a main agent. A second layer (c) covering the third layer, a low pH-soluble polymer, a third layer (d) covering the second layer, and an enteric polymer from a fourth layer (e) covering the third layer Oral formulation. 2. The preparation according to claim 1, which has an intermediate layer composed of a water-soluble substance or a drug between the third layer and the fourth layer. 3. The preparation according to claim 1, wherein the acidic substance of the nucleus is an organic acid. 4. The preparation according to claim 1, wherein the water-insoluble polymer in the first layer is ethyl cellulose or ethyl acrylate / methyl methacrylate / trimethylammonium ethyl acrylate copolymer. 5. The preparation according to claim 1, wherein the low pH-soluble polymer in the third layer is polyvinyl acetal diethylaminoacetate or a methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer. 6. The preparation according to claim 1, wherein the enteric polymer in the fourth layer is hydroxypropylmethylcellulose acetate succinate, methacrylic acid / methyl methacrylate copolymer or methacrylic acid / ethyl acrylate copolymer. 7. The preparation according to claim 1, wherein the coating ratios of the first layer and the third layer are set so as to release the main drug at a desired site in the intestine. 8. The preparation according to claim 1, wherein the main drug is a poorly water-soluble drug or a drug having a pH of 5 or more when dissolved in water.