JP3469926B2 - Granules for pharmaceutical release in the large intestine - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND ART In recent years, colorectal cancer, ulcerative colitis, Crohn's disease, and other colorectal diseases are increasing remarkably due to westernization of eating habits and rapid progress of colorectal examination methods, and they are effective against these colorectal diseases. It is desired to establish a drug therapy that is highly effective and has few side effects. For example, in the case of ulcerative colitis, this disease is a nonspecific inflammation of unknown origin that causes erosion or ulceration of the mucosa or submucosa of the large intestine. -Classified as all colitis type, drug therapy by corticosteroid administration plays an important role.

[0002] When this corticoid is orally administered as an uncoated tablet or granule, or as an enteric coated tablet, many drugs are absorbed from the small intestine, and the drug is absorbed through the blood. Since it is delivered systemically, side effects associated with suppression of adrenal function increase in frequency, making long-term administration difficult.

On the other hand, since there is little drug absorption in the large intestine, apart from such a method, a corticosteroid is administered transrectally as an enema preparation, and the systemic effect is small and the drug directly acts on the affected mucous membrane. Enema therapy has also been attempted, but there is a drawback in that when the lesion site extends to the deep large intestine, the drug does not reach the lesion site and a therapeutic effect cannot be expected. In the oral administration of corticosteroids, if a dosage form is developed in which the drug is released only when it reaches the large intestine, which is the site of the disease, it will be a drug therapy with a high therapeutic effect and few side effects.

Further, with regard to drugs such as anti-cancer drugs having a local action, such a dosage form can be expected to have a therapeutic effect on colorectal diseases. Furthermore, since the activity of proteolytic enzymes in the large intestine is lower than that in the small intestine, it is expected that a drug that is decomposed by ordinary oral administration and cannot obtain a medicinal effect will be absorbed in the large intestine, There is a strong demand for development of this type of large intestine release preparation.

The first type conventionally known as a means for releasing a drug in the large intestine is Japanese Patent Publication No. 57-50043.
As shown in Fig. 2, it is a type that attempts to release the drug in the large intestine by taking into account the transit time in the digestive tract until reaching the large intestine. In this type, a drug is coated with a water-insoluble and semipermeable membrane-forming polymer substance such as ethylcellulose, the thickness of this film is adjusted, and after oral administration, the drug is released in the digestive tract. It is to delay the time until it starts. In other words, by setting the time for the drug to reach the large intestine and adjusting the thickness of the coating film, the drug is gradually released through the semipermeable membrane when it reaches the vicinity of the large intestine site. Is. However, this type has many drawbacks because it lacks certainty of drug release control because there are many factors in which the transit time of the drug in the digestive tract varies due to other factors.

The second type is Japanese Patent Publication No. 4-1408.
As shown in Japanese Patent Laid-Open No. 3, a type in which the drug is controlled to be released in the large intestine by utilizing the pH in the digestive tract. In the human digestive tract, the pH of the end of the small intestine is about 7
Since it is the highest as described above, it is a type in which the drug release is controlled in the vicinity of the large intestine by oral administration by coating the drug with a polymer substance which is soluble for the first time at pH 7 or higher, such as methacrylic acid copolymer S. However,
With this type, the pH of the digestive tract varies from individual to individual, so if you want to deliver a drug to the end of the small intestine, you need to make the coating film thick. In some cases, this type of product also has certainty in controlling drug release.For example, if the coating film is too thin, the drug may be released before it reaches the large intestine. Lack.

[0007] The third type is an attempt to release a drug in the large intestine by utilizing intestinal bacteria. Almost no microorganisms exist in the small intestine, but since intestinal bacteria grow in the large intestine, chemical bonds (for example, azo bonds) that can only be decomposed by microorganisms can be added to the drug or coating film to protect the large intestine. After reaching the target, it is a type of releasing the drug or active ingredient in the drug by the action of microorganisms. However, in this type as well, absorption from the small intestine until reaching the large intestine cannot be ignored, and there is a problem in the time until the drug and the active ingredient are released by being decomposed by microorganisms. There is a drawback of lacking certainty in exerting a medicinal effect.

As described above, it is difficult to reliably release the drug in the large intestine by the method based on the simple principle of the migration time in the digestive tract, pH in the digestive tract, conditions such as intestinal microorganisms. Further, finer conditions are required to surely control the release in the large intestine, and various proposals for that have been made so far.

1) According to Japanese Patent Application Laid-Open No. 4-224517, the active ingredient is formulated in a multi-particle multi-dose form, and each particle is coated with at least two layers, one of which has a pH of 5.
It dissolves at 5 or more and other membranes have such p
Formulations have been shown that are insoluble in H, yet permeate intestinal fluid, and release the active ingredient at the end of the ileum and colon.

This formulation is characterized by a combination of a membrane that reaches and dissolves in the small intestine and a membrane that forms a semipermeable membrane due to the transit time in the digestive tract. This is the type of control method. Therefore, although the influence of the gastric emptying time has been taken into consideration, the certainty of achieving the purpose of releasing the drug in the large intestine is uncertain. Further, the method for producing a solid oral dosage form containing the active ingredient shown in the publication is by a usual granulation method, and in the solid oral dosage form containing a poorly water-soluble pharmacologically active substance, the drug is Because of poor solubility of L. and low bioavailability, the expected therapeutic effect cannot be obtained.

2) According to Japanese Patent Publication No. Hei 4-501411, there is described an oral pharmaceutical preparation having a colon-selective accessibility comprising a core containing a therapeutically active substance and an outer coating. . Although this formulation shows that the coating is an inner layer of anionic copolymer soluble at pH above 7.0; an intermediate layer of gelling polymer that readily swells in intestinal fluids of any pH; and insoluble in gastric fluid. 5.
It is a formulation consisting of an outer layer of a gastric resistant polymer which is soluble at pH 5 and above.

[0012] This is basically based on a release control system utilizing the pH in the digestive tract, and even if the digestive tract pH in the small intestine becomes pH 7 or higher due to biological variability, the intermediate layer Although the gelled polymer layer of the above-mentioned gel is designed so that the inner layer is not affected by intestinal fluid within the transit time of the intestinal tract, it still lacks certainty and the preparation contains a pharmacologically active substance that is poorly soluble in water. If it is a substance, the drug is poorly dissolved and bioavailability is low, so that the therapeutic effect cannot be obtained. Further, since the water-soluble gelling polymer is used for the intermediate layer, the coating amount is as large as 10 to 40% of the core weight, and therefore there is a drawback that the production efficiency is poor.

3) JP-A-2-223513 discloses that when a biologically active substance such as a corticosteroid is made into a solid dispersion together with an acid resistant or controlled release substance, water is added before the dispersion is solidified. Mixing with insoluble carrier particles, then
A method for controlling the release in the large intestine, which is characterized by processing by an ordinary granulation method, is shown. In this method, the idea is to increase the bioavailability of a poorly water-soluble drug, but the pH of the human digestive tract differs between individuals, and the time it takes for the drug to reach the large intestine is also different. Due to variability, it is difficult to control with the use of a one-component polymeric material to reliably deliver the drug to the large intestine.

As described above, it is still difficult for the techniques presented to date to alleviate all of the following drawbacks, and it is not possible to meet the expectations demanded as a drug for intracolonic release. I can't. Since a large proportion is dissolved before reaching the large intestine and is absorbed in the small intestine, the effective drug amount does not reach the large intestine. Furthermore, absorption of the drug from the small intestine is likely to cause side effects due to systemic effects. If the coating film is made thicker to allow the drug to reach the large intestine, the drug elution ability in the large intestine also decreases. In the case of a drug which is poorly soluble in water, even if it can be delivered to the large intestine, an effective drug concentration cannot be obtained and a drug effect cannot be obtained.

[0015]

DISCLOSURE OF THE INVENTION The present invention relates to a granular drug for pharmaceutical preparation which can be reliably released into the large intestine by more reliable drug delivery to the large intestine and improvement in bioavailability of a poorly water-soluble drug, and the pharmaceutical. It is an object of the present invention to provide a pharmaceutical preparation containing granules for preparation. The present inventors focused on the high frequency of occurrence of side effects due to adrenal function suppression by systemic action of oral administration of corticosteroids for ulcerative colitis, and by releasing corticosteroids in the large intestine, We examined the controlled release in the large intestine, which enables treatment by action. In general, corticosteroids are poorly soluble in water, and it is difficult to obtain a drug concentration effective for local action in the large intestine even if it can reach the large intestine in the form of a large intestine release preparation in a crystalline form.

The present inventors have investigated a method of increasing the solubility of a poorly soluble drug by a pharmaceutical means without changing its chemical structure, and greatly improving the solubility in water by the method of forming a solid solution by a solid dispersion method. I succeeded in making it. The solid dispersion here is defined as a solid in which one or more drugs are dispersed in a monomolecular form in an inert carrier. In a solid solution in which a drug is dissolved in a solid solvent (carrier), the drug exists as an amorphous substance in the carrier. In the present invention, the present inventors dissolved both a drug and a polymeric substance in an organic solvent that is acceptable for manufacturing pharmaceuticals, and then distilled off the solvent to make it amorphous. Whether or not the drug was amorphized was confirmed by X-ray diffraction.

In the production method of the granular product of the present invention, a pharmacologically acceptable carrier substance is used as a core, and both a pharmacologically active substance which is poorly soluble in water and a gastric insoluble polymer substance are used as a drug in the production of the drug. By spraying and drying a solution dissolved in an acceptable organic solvent on the core particle surface, a mixed layer of amorphous pharmacologically active substance and gastric insoluble polymer substance is formed on the particle surface of the core carrier substance. Is.

The core consisting of the above-mentioned pharmacologically acceptable carrier substance means sucrose, crystalline cellulose and starch,
It is a small spherical particle formed from lactose or a mixture thereof. Examples of the gastric insoluble polymer substance include methacrylic acid copolymer S (see the 1993 edition of the pharmaceutical additive standard), methacrylic acid copolymer L (see the 1993 edition of the pharmaceutical additive standard), hydroxypropylmethylcellulose acetate succinate, and hydroxypropylmethylcellulose. Examples thereof include phthalate and carboxymethylethyl cellulose, or a mixture of two or more kinds.

As the pharmacologically active substance used in the granular material of the present invention, for its purpose, a sparingly soluble pharmacologically active substance having the large intestine as the site of action is preferably used. For example, corticosteroids beclomethasone dipropionate, betamethasone, cortisone acetate, fludrocortisone acetate, hydrocortisone, triamcinolone acetate,
Paramethasone acetate, dexamethasone, triamcinolone, prednisolone, methylprednisolone, amcinonide, prednisolone valerate acetate, diflucortron valerate, dexamethasone valerate, diflorazone acetate, dexamethasone acetate, hydrocortisone acetate, methylprednisolone acetate, diprednisolone acetate Betamethasone dipropionate, triamcinolone acetonide, halcinonide, flumethasone pivalate, budesonide, fluocinonide, fluocinolone acetonide,
Fluorometholone, fludroxycortide, alclomethasone propionate, clobetasol propionate, dexamethasone propionate, deprodone propionate,
Examples include clobetasone butyrate, hydrocortisone butyrate, hydrocortisone butyrate propionate, and the like.

The mixing ratio of the pharmacologically active substance and the above-mentioned gastric insoluble polymer substance is preferably 1: 3 to 1:20 by weight in consideration of amorphization and solubility. Using methanol or ethanol and isopropyl alcohol, acetone or the like, these are used alone or in the form of a mixed solution with water, or chloroform or dichloromethane including the above-mentioned solvent, or a pharmaceutically acceptable organic solvent such as dichloroethane. It is used as a mixed solvent of two or more, and this solution is sprayed and dried on the surface of the particles of the core carrier material using a complex granulator such as a fluidized bed granulator, centrifugal tumbling granulator or spiral flow granulator. , A gastric insoluble polymer film containing an amorphous pharmacologically active substance is formed on the surface of the core carrier substance particles.

Then, a water-insoluble and semipermeable membrane-forming polymer substance is added to the obtained coated particle substance by using methanol, ethanol and isopropyl alcohol, acetone or the like, either alone or with water. As a mixed solution or as a single solvent or a mixed solvent of two or more pharmaceutical-acceptable organic solvents such as the above-mentioned organic solvents such as chloroform and dichloromethane, spraying and drying are continuously performed using the above-mentioned apparatus.

The above-mentioned water-insoluble and semi-permeable polymer substance does not dissolve in an aqueous solution of any pH, and it is possible to gradually permeate water and drugs depending on the thickness of the coating and the residence time of the digestive tract. The above-mentioned polymer substance is used, and for example, aminoalkyl methacrylate copolymer RS (see 1993 edition of drug additive standard) or ethyl cellulose is used alone or as a mixture of two or more kinds. The amount of the water-insoluble and semipermeable membrane-forming polymer substance used is preferably about 5% or less by weight of the coated particles.

Further, on the surface of the coated particle substance, the same gastric insoluble polymer substance as described above is used by suspending it in water, or by using methanol, ethanol and isopropyl alcohol, acetone, etc. Or as a mixed solution with water, or as a single solvent or a mixed solvent of two or more of the above-mentioned organic solvents, such as chloroform, dichloromethane and the like, which are acceptable for pharmaceutical production,
The particles are continuously sprayed and dried using the above-mentioned apparatus to obtain a particulate substance for pharmaceutical preparation for large intestine release preparation.

The individual particle size of the particulate substance for drug production for the large intestine release preparation is preferably 0.1 to 2.0 mm in order to reduce the variation in the digestive tract transit time. Examples of the gastric insoluble polymer substance to be used by suspending in water include methacrylic acid copolymer LD (see 1993 edition of drug additive standard) or hydroxypropylmethylcellulose acetate succinate,
As the gastric insoluble polymer substance to be dissolved and used, methacrylic acid copolymer S, methacrylic acid copolymer L, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, alone or in a mixture of two or more kinds, It is illustrated.

The particulate substance for pharmaceutical preparations for the large intestine release preparation prepared as described above can be directly used as granules, but can also be prepared as capsules or tablets. Examples will be shown below.

[0026]

EXAMPLES Example 1 (1) Methacrylic acid copolymer S (trade name: Eudragit S-100: manufactured by Reem Farm) was used as a gastric insoluble polymer substance, and 30.0 g of the methacrylic acid copolymer S was mixed with 1250 ml of dichloromethane and 1250 ml of ethanol. It was dissolved in a mixed solution, and 3.0 g of beclomethasone dipropionate as a pharmacologically active substance was dissolved therein to prepare a solution for spray coating. The particle size of the carrier core material is 500 to 710
150 μg of spherical refined white sucrose (trade name: Nonpareil 103: made by Freund) of μm was put in a centrifugal tumbling granulator (trade name: CF-360: made by Freund), and the above solution for spray coating was used. Was sprayed and dried to form a film of gastric insoluble polymer containing beclomethasone dipropionate as a solid solution on the particle surface of the carrier core material, and formed into a granular material in a centrifugal tumbling granulator. so,
It was dried with hot air at about 50 ° C. for 15 minutes.

(2) Ethyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.) as a water-insoluble and semipermeable membrane-forming polymer substance.
Using 5 g, this polymer substance was dissolved in a mixed solution of 500 ml of ethanol in which 5.0 g of talc was suspended and 77.5 ml of purified water to prepare a solution for spray coating. By spraying and drying this solution on the granular material obtained in the above (1), a membrane of a water-insoluble and semipermeable membrane-forming polymer substance is formed on the surface of the granular particle, and centrifugal rolling is performed. In a granulator, it was dried with hot air at about 50 ° C. for 30 minutes to obtain granules.

(3) Further, 115.0 g of methacrylic acid copolymer S (trade name: Eudragit S-100: manufactured by Reem Farm) was used as a gastric insoluble polymer substance, and 11.6 g of triethyl citrate and talc were used. Dichloromethane 970 in which 34.8 g was dissolved or suspended
It was dissolved in a mixed liquid of 1 ml of ethanol and 1400 ml of ethanol, and this liquid was sprayed and dried on the granular material obtained in (2) above. The resulting granules were further processed in a centrifugal tumbling granulator for about 50
After drying with hot air at ℃ for 30 minutes, 850μm sieve and 4
After sieving with a 25 μm sieve, about 1436 g of granules for medicated drug in the large intestine in the range of 425 to 850 μm was obtained.

Example 2 (1) Methacrylic acid copolymer L (trade name: Eudragit L-100: manufactured by Reem Farm) was used as a gastric insoluble polymer substance, and 100.0 g thereof was mixed with 833 ml of dichloromethane and 833 ml of ethanol. Dissolve, 10.0 g of betamethasone as a pharmacologically active substance
Was dissolved into a solution for spray coating. As a carrier core substance, spherical purified white sugar having a particle size of 500 to 710 μm (trade name: Nonpareil 103: manufactured by Freund) 890.
Centrifugal rolling granulator (trade name: CF-3
60: made by Freund), and spraying and drying the above solution for spray coating to form a film of a gastric insoluble polymer substance containing betamethasone amorphized as a solid solution on the particle surface of the carrier core substance. The granules were dried in a centrifugal tumbling granulator with hot air at about 50 ° C for 15 minutes.

(2) Ethyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.) as a water-insoluble and semipermeable membrane-forming polymer substance.
Using 2 g, this polymer substance was dissolved in a mixed solution of 320 ml of ethanol in which 3.2 g of talc was suspended and 50 ml of purified water to prepare a solution for spray coating. By spraying and drying this solution on the granular material obtained in the above (1), a membrane of a water-insoluble and semipermeable membrane-forming polymer substance is formed on the surface of the granular particle, and centrifugal rolling is performed. In a granulator, it was dried with hot air at about 50 ° C. for 30 minutes to obtain granules.

(3) Furthermore, 76.5 g of methacrylic acid copolymer L (trade name: Eudragit L-100: manufactured by Reem Farm) was used as a gastric insoluble polymer substance, and 7.7 g of triethyl citrate, Talc 2
640m of dichloromethane dissolved or suspended in 3.0g
It was dissolved in a mixed liquid of 1 and 935 ml of ethanol, and this liquid was sprayed and dried on the granular material obtained in (2) above. The obtained granules were further dried in a centrifugal tumbling granulator with hot air at about 50 ° C. for 30 minutes, and then 850 μm sieve and 425 μm.
After sieving with a μm sieve, about 972 g of granules for large intestine release-type pharmaceutical preparation in the range of 425 to 850 μm was obtained.

Example 3 (1) Methacrylic acid copolymer S (trade name: Eudragit S-100: manufactured by Reem Farm) was used as a gastric insoluble polymer substance, and 100.1 g thereof was mixed with 833 ml of dichloromethane and 833 ml of ethanol. And betamethasone 10.0 as a pharmacologically active substance.
g was dissolved to give a solution for spray coating. Spherical purified sucrose having a particle diameter of 500 to 710 μm (trade name: Nonpareil 103: manufactured by Freund) as a carrier core substance 89
Centrifugal rolling granulator (trade name: CF
-360: manufactured by Freund), the solution for spray coating is sprayed and dried to form a film of a gastric insoluble polymer substance containing betamethasone amorphized as a solid solution on the particle surface of the carrier core substance. The granules were dried in a centrifugal tumbling granulator with hot air at about 50 ° C. for 15 minutes.

(2) Next, 11.2 g of ethyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.) was used as a water-insoluble and semipermeable membrane-forming polymer substance.
320 ml of ethanol in which 2 g was suspended and 50 m of purified water
It was dissolved in a mixed solution with 1 to prepare a solution for spray coating. By spraying and drying this solution on the granular material obtained in the above (1), a membrane of a water-insoluble and semipermeable membrane-forming polymer substance is formed on the surface of the granular particle, and centrifugal rolling is performed. In a granulator, it was dried with hot air at about 50 ° C. for 30 minutes to obtain granules.

(3) Further, 76.5 g of methacrylic acid copolymer S (trade name: Eudragit S-100: manufactured by Reem Farm) was used as a gastric insoluble polymer substance, and 7.7 g of triethyl citrate and talc were used. Two
640m of dichloromethane dissolved or suspended in 3.0g
It was dissolved in a mixed solution of 1 and 935 ml of ethanol, and this solution was sprayed and dried on the granular material obtained in (2) above. The obtained granules were further dried in a centrifugal tumbling granulator with hot air at about 50 ° C. for 30 minutes, and then a 850 μm sieve and 42
After sieving with a 5 μm sieve, about 981 g of granules for large intestine release type pharmaceutical preparation in the range of 425 to 850 μm was obtained.

Experimental Example 1 Using the granules for large intestine release type pharmaceutical preparation obtained in (3) of Example 1, a dissolution test was conducted by the Japanese Pharmacopoeia Dissolution Test Method 2. 1.5 mg as beclomethasone dipropionate
Weigh an amount of the above-mentioned pharmaceutical granules corresponding to
0 ml of purified water and phosphate buffer solution of various pH (p
H6.4, 6.8, 7.2, 7.4), 37
Rotate the paddle at 100 ° C at 100 ° C and use a spectrometer equipped with a continuous flow sampling system for 244n
Absorbance at m was measured for 8 hours. The result is shown in FIG. Purified water, pH 6.4 phosphate buffer solution and pH
In the test example of the phosphate buffer solution of 6.8, the dissolution of the drug was suppressed for a long time, so it was judged that this granular substance hardly released the drug while passing through the stomach and small intestine. To be done.

Further, in the test examples of the pH 7.2 phosphate buffer solution and the pH 7.4 phosphate buffer solution, the drug was rapidly eluted from the particulate matter, so that the particulate matter reached the end of the small intestine. It is considered that the drug is released when the digestive tract pH is maximized, and the drug is efficiently delivered to the large intestine. Further, when the above-mentioned dissolution test was carried out in a pH 7.2 phosphate buffer solution for a mixture of beclomethasone dipropionate and lactose which had not been made amorphous, it was confirmed that the dissolution was poor as shown in FIG. Was given.

Experimental Example 2 For each of the four cases (A) to (D) below, gelatin capsules were filled with the following granules in an amount corresponding to 3 mg as betamethasone, and each was added to a beagle dog (3 in 1 group).
The blood concentration was measured. Specimen (A) ... Granules for large intestine release type pharmaceutical preparation obtained in (2) of Example 2 Specimen (B): Granules for large intestine release type pharmaceutical preparation obtained in (3) of Example 3 Specimen (C) ... Powdered specimen (D) in which betamethasone was evenly dispersed with lactose ... During the administration of the particulate matter obtained in (1) of Example 3, salicylazosulfapyridine was co-administered to the large intestine. The time required for the sulfapyridine formed in the blood to appear in the blood after the azo bond in the molecule was cleaved by the intestinal bacterium was used as a guide for reaching the large intestine.

Before administration to beagle dogs, 2
Fasted for 4 hours, before administration, 0.5, 1 after administration,
2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48
Blood was collected at 14 points each time. The drug parameters as shown in Table 1 were obtained, and it was determined that most of the drugs were absorbed after reaching the vicinity of the large intestine.

[Table 1] Further, in order to investigate the influence of diet, feeding was performed 30 minutes before administration, and after administration of the drug, blood collection was performed under the same test conditions as above. From the obtained results, the drug parameters as shown in Table 2 were obtained, which shows that there is no influence of diet.

[Table 2] The granules for intestinal release-type pharmaceutical preparation according to the present invention can be made into various drug dosage forms by a conventional method, for example, tablets or capsules and the like which can be easily taken.

Formulation Example 1 100 g of the granule for pharmaceutical preparation for large intestine release obtained in (3) of Example 1 above, 27 g of microcrystalline cellulose, 7 g of low-substituted hydroxypropylcellulose, 1.5 g of talc, magnesium stearate 0 0.7g were mixed and compressed,
Tablets having a tablet diameter of 11 mm and 8.0 mm were obtained. The disintegration time of each of these tablets was within 2 minutes.

Formulation Example 2 Granules for large intestine release type pharmaceutical preparation obtained in (2) of Example 2 above and excipients such as lactose, microcrystalline cellulose and starch, and lubricants such as talc and magnesium stearate. The mixture was mixed with the agent and filled in a gelatin capsule to prepare a capsule agent.

[Brief description of drawings]

FIG. 1 shows the dissolution rate and dissolution time of various granular materials obtained in one example of the present invention in various dissolution tests.
It is a graph which shows the result measured in the environment.

FIG. 2 shows the dissolution rate and dissolution time obtained in the environment of pH = 7.2 in the same dissolution test as in FIG. 1 for the control particles for comparison with the granules obtained in the example of the present invention. It is a graph which shows the measured result.

─────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-61-227524 (JP, A) JP-A-4-224517 (JP, A) JP-A-2-223513 (JP, A) Chem. Pharm. Bull. , 33 (4), 1615-1619 (58) Fields surveyed (Int.Cl. ⁷ , DB name) A61K 47/32 A61K 47/38 A61K 9/14

Claims (4)

(57) [Claims] 1. A granule for intestinal release-type pharmaceutical preparation comprising a core particle which is a pharmaceutically acceptable carrier substance and a coating layer coating the surface of the core particle, wherein the coating layer comprises (A) An amorphous corticosteroid-based pharmacologically active substance formed on the surface of a core particle, and a gastric insoluble polymer substance selected from methacrylic acid copolymer S, methacrylic acid copolymer L and carboxymethylethylcellulose A mixed layer composed of (b) a layer composed of ethyl cellulose which is a water-insoluble and semipermeable membrane-forming polymer substance formed on the surface of the mixed layer, and (c) a surface of the layer (b) above. The granule for pharmaceutical preparation for intestinal release, comprising the formed layer composed of the insoluble polymer substance in the stomach. 2. The granule for intestinal release-type pharmaceutical preparation according to claim 1, wherein the pharmacologically active substance is beclomethasone propionate or budesonide. 3. The core particles have a particle size of 0.1 to 2.0 mm.
The granules for large intestine release-type pharmaceutical preparation according to claim 1 or 2, wherein 4. A pharmaceutical preparation comprising the granules for large intestine release-type pharmaceutical preparation according to claim 1.