JP7336187B2 - Particulate pharmaceutical composition having multilayer structure - Google Patents

Description

The present invention relates to an enteric coated granule having a multi-layered structure, which has an elution control layer containing a cationic polymer and an enteric layer containing an anionic polymer, and has a structure in which these layers are continuous. and a tablet containing the same, particularly an orally disintegrating tablet.

Enteric-coated formulations are formulations that are devised so that they do not dissolve in the stomach, but only enter the intestines before eluting, such as for drugs that decompose in the stomach, drugs that cause gastric disorders, or drugs that are intended to pass into the intestine. , Solid preparations for internal use that are coated with a coating that dissolves in alkaline intestinal juices but do not dissolve in acidic gastric juices, or that are made enteric-coated, such as fine granules, granules, pills, tablets, capsules, and microcapsules. It has been reported that Enteric-coated formulations are formulations devised so that they do not dissolve in the stomach but only after they move to the intestine, and therefore active ingredients that are decomposed by gastric acid require sufficient acid resistance. Moreover, since the enteric base is acidic, decomposition of the active ingredient by the enteric base is also a problem.

On the other hand, orally disintegrating tablets are characterized by the fact that they do not require water at the time of administration and can be taken as they are by disintegrating the tablets in the oral cavity. It is possible to improve the compliance of patients such as children. However, when the active ingredient has an unpleasant taste such as bitterness, there is a problem that the active ingredient released in the oral cavity gives strong discomfort to the patient and significantly lowers compliance with administration. In order to solve this problem, it is necessary to suppress the release of the active ingredient in the oral cavity for a certain period of time in the oral particulate pharmaceutical composition. In addition, it is desired that the time (lag time) for suppressing the release of the active ingredient and the subsequent dissolution rate can be appropriately controlled according to the properties of the active ingredient.
Therefore, when designing an orally disintegrating tablet containing enteric coated granules containing a drug with low acid stability as a main ingredient, it is necessary to design the formulation in consideration of the above problems.

As prior art related to these, for example, Patent Document 1 discloses (i) a core particle containing a drug having an unpleasant taste in the center of a particulate pharmaceutical composition, and (ii) two kinds of aqueous solutions in an intermediate layer. A layer containing an insolubilization accelerator and an insolubilizing substance, which are sexual components, and (iii) a water infiltration control layer that controls the rate of water infiltration into the outermost layer. A time-release particulate pharmaceutical composition for oral administration is disclosed. And, as an example of the layer (ii) containing the insolubilization accelerator and the insolubilizing substance, an acid-type insolubilizing accelerator (citric acid, malic acid, tartaric acid, etc.) and an acid-insolubilizing substance (methacrylic acid copolymer L, LD, S etc.), and as specific examples of the water infiltration amount control layer (iii), ethyl cellulose, aminoalkyl methacrylate copolymers RS, RL, E, methacrylic acid copolymers L, LD, S, etc. are disclosed. . However, this disclosed composition uses a production process using an environmentally harmful organic solvent, and small particles that cause little foreign body sensation in the oral cavity are not sufficient for rapid drug release after a sufficient lag time. There are still issues to be addressed.

Japanese Patent No. 4277904

The present invention relates to an enteric coated granule having a multi-layered structure, which has an elution control layer containing a cationic polymer and an enteric layer containing an anionic polymer, and has a structure in which these layers are continuous. and a tablet containing the same, particularly an orally disintegrating tablet.

The present inventors have found that enteric granules having a multi-layer structure have an elution control layer containing a cationic polymer and an enteric layer containing an anionic polymer, and have a structure in which these layers are continuous. In soluble granules and orally disintegrating tablets containing the same, it was found that the time to suppress the release of the active ingredient (lag time) and the subsequent dissolution rate are controlled, and the stability of the drug is maintained. Completed.

That is, the present invention
(1) Enteric-coated granules having a multi-layered structure, comprising an elution-controlling layer containing a cationic polymer and an enteric-coated layer containing an anionic polymer, wherein these layers are continuous. It is.
(2) The present invention also relates to enteric granules according to (1) above, wherein the cationic polymer according to (1) above is selected from aminoalkyl methacrylate copolymer E and ammonioalkyl methacrylate copolymer, or a combination thereof. is.
(3) The present invention also relates to the enteric granules described in (1) or (2) above, wherein the cationic polymer described in (1) or (2) is an ammonioalkyl methacrylate copolymer.
(4) Further, in the present invention, the anionic polymer described in (1) is selected or combined from methacrylic acid copolymer L, methacrylic acid copolymer S, methacrylic acid copolymer LD and methyl acrylate/methyl methacrylate/methacrylic acid copolymer. The present invention relates to the enteric coated granules described in (1) to (3) above, which are composed of a mixture.
(5) The present invention also relates to the enteric coated granules described in (1) to (4) above, wherein the anionic polymer described in (1) or (4) is methacrylic acid copolymer LD.
(6) The present invention also relates to the enteric granules described in (1) to (5), which contain an acid-labile drug in the enteric granules described in (1) to (5).
(7) The present invention also relates to the enteric granules according to (6) above, wherein the acid-labile drug according to (6) above is a proton pump inhibitor.
(8) The present invention also relates to solid preparations containing the enteric coated granules described in (1) to (7) above.
(9) The present invention also relates to the solid preparation according to (8) above, wherein the solid preparation is a tablet.
(10) The present invention also relates to the solid preparation according to (8) or (9) above, wherein the tablet is an orally disintegrating tablet.

The enteric-coated granules having a multilayer structure of the present invention have an elution-controlling layer containing a cationic polymer and an enteric-coating layer containing an anionic polymer, the enteric granules having a structure in which these layers are continuous; Orally disintegrating tablets containing this compound can control the time to suppress the release of the active ingredient (lag time) and the dissolution rate after that, so that the bitterness at the time of administration is reduced, and it is unstable to acids. Since the drug can be stably present in the granules and formulation, it is useful for the production of tablets containing enteric-coated granules, especially orally disintegrating tablets.

1 is a diagram showing the dissolution rate of Example 1 granules at pH 6.8/50 rpm. FIG. 1 is a diagram showing the dissolution rate of Comparative Example 1 granules at pH 6.8/50 rpm. FIG. FIG. 2 is a diagram showing the dissolution rate of Example 2 granules at pH 6.8/50 rpm. FIG. 2 is a diagram showing the dissolution rate of granules of Comparative Example 2 at pH 6.8/50 rpm.

The present invention will be described in more detail below.
Examples of the cationic polymer constituting the elution control layer used in the present invention include aminoalkyl methacrylate copolymer E (e.g., Eudragit (registered trademark) E100, Eudragit (registered trademark) EPO, manufactured by Evonik), and ammonioalkyl methacrylate copolymer. (For example, Eudragit (registered trademark) RL100/RLPO/RL30D, Eudragit (registered trademark) RS100/RSPO/RS30D, manufactured by Evonik) and other polymers containing methacrylic acid derivatives, preferably ammonioalkyl methacrylate copolymers. can be done.

In addition to the cationic polymer described above, the elution control layer may optionally contain other additives such as lubricants, plasticizers and surfactants. can be blended in an amount of 50 to 95% by mass, preferably 60 to 90% by mass, more preferably 70 to 85% by mass.
The film thickness of the coating of the elution control layer is not particularly limited, but if it is too thin, the effects of the present invention cannot be sufficiently exhibited, and if it is too thick, the particle size of the granules will increase and tablet hardness will decrease. In the case of a decrease or an orally disintegrating tablet, when disintegrated in the oral cavity, there is a possibility that discomfort may occur due to roughness. ~20 μm.

Examples of the anionic polymer constituting the enteric layer used in the present invention include methacrylic acid copolymer L, methacrylic acid copolymer S (e.g., Eudragit (registered trademark) L100, Eudragit (registered trademark) S100, manufactured by Evonik), and methacrylic. acid copolymer LD (e.g. Eudragit L100-55, Eudragit L30D-55, manufactured by Evonik), methyl acrylate-methyl methacrylate-methacrylic acid copolymer (e.g. Eudragit FS30D, (manufactured by Evonik) and the like, and preferably methacrylic acid copolymer LD and the like can be used.

Additives such as other lubricants, plasticizers and surfactants can be blended in the enteric layer, in addition to the anionic polymer, if necessary. can be blended in an amount of 30 to 80% by mass, preferably 40 to 70% by mass, more preferably 45 to 65% by mass.
The film thickness of the enteric layer is not particularly limited. In the case of a decrease or an orally disintegrating tablet, when it is disintegrated in the oral cavity, there is a possibility that discomfort may occur due to roughness. ˜80 μm.

The enteric-coated granules and solid preparations of the present invention may optionally contain additives such as commonly known binders, disintegrants, plasticizers, lubricants, excipients, coating bases, surfactants, and flavoring agents. Agents, coloring agents, perfumes and the like can be appropriately combined and blended in necessary amounts.

Binders that can be used in the present invention include methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, gelatin, agar, alginic acid, sodium alginate, partially saponified polyvinyl alcohol, pullulan, partially pregelatinized starch, dextrin, and xanthan gum. , gum arabic powder and the like. Preferred are hydroxypropylcellulose, hypromellose and polyvinylpyrrolidone. These may be used alone or as a mixture of two or more.

Disintegrants that can be used in the present invention include, for example, crystalline cellulose, carboxymethylcellulose (carmellose), croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, crospovidone, hydroxypropyl starch, starch, partial α modified starch, sodium starch glycolate, calcium carbonate, precipitated calcium carbonate, calcium citrate, light anhydrous silicic acid, synthetic aluminum silicate, etc., preferably croscarmellose sodium, sodium starch glycolate, crospovidone, Crospovidone is more preferred. Further, the crospovidone used in the present invention includes Polyplasdone (registered trademark) XL, Polyplasdone (registered trademark) XL-10, Polyplasdone (registered trademark) INF-10 (manufactured by Ashland), and Kollidon. (registered trademark) CL, Kollidon (registered trademark) CL-F, Kollidon (registered trademark) CL-SF, Kollidon (registered trademark) CL-M and the like, preferably Kollidon CL, Kollidon CL-F, Kollidon CL- SF and Kollidon CL-M (manufactured by BASF Japan Ltd.), and Kollidon CL-F is particularly preferred. The amount of the disintegrant used is preferably 5 to 30% by mass, more preferably 5 to 15% by mass in the core particles. In addition, when blended in an orally disintegrating tablet, it is preferably 1 to 10% by mass, more preferably 2 to 6% by mass in the solid preparation.

Plasticizers that can be used in the present invention include polyethylene glycol (e.g., polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 6000, etc.), triethyl citrate, glycerin, castor oil, poloxyethylene hydrogenated castor oil, polysorbate 80, Macrogol, lauromacrogol, triacetin, etc., preferably polyethylene glycol and triethyl citrate.

Lubricants that can be used in the present invention include glycerin fatty acid ester, hydrogenated oil, sucrose fatty acid ester, stearyl alcohol, stearic acid, magnesium stearate, calcium stearate, talc, precipitated calcium carbonate, fumaric acid, and stearyl fumarate. Examples include sodium, macrogol and glyceryl monostearate, preferably talc and magnesium stearate.

Excipients that can be used in the present invention include, for example, celluloses such as crystalline cellulose, ethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose (hypromellose etc.), corn starch, potato starch, wheat starch, Starches such as rice starch, partially pregelatinized starch, and hydroxypropyl starch, sugars such as glucose, lactose, sucrose, refined sucrose, powdered sugar, trehalose, dextran, and dextrin, sugars such as D-mannitol, xylitol, sorbitol, and erythritol Inorganic salts such as alcohols, glycerin fatty acid esters, magnesium aluminometasilicate, synthetic hydrotalcite, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium hydrogen phosphate hydrate, and sodium hydrogen carbonate. Formulations can be blended at 10 to 70% by mass in solid preparations.

Surfactants that can be used in the present invention include cationic surfactants such as bis-(2-ethylhexyl) sodium sulfosuccinate (docusate sodium), alkyltrimethylammonium bromide (eg cetyltrimethylammonium bromide (cetrimide)). agents, especially non-ionic agents such as polyoxyethylene sorbitan (e.g. Tween ^™ 20, 40, 60, 80 or 85), and other sorbitans (e.g. Span ^™ 20, 40, 60, 80 or 85). ).

Examples of flavoring agents that can be used in the present invention include sugar alcohols, aspartame, stevia, saccharin sodium, dipotassium glycyrrhizinate, thaumatin, acesulfame potassium, sucralose and the like. These may be used alone or as a mixture of two or more.

Coloring agents that can be used in the present invention include Food Blue No. 1, Food Blue No. 2, Food Yellow No. 4, Food Yellow No. 5, Food Red No. 2, Food Red No. 3, Food Red No. 102 and Food Blue No. 1. No. 2 Aluminum Lake, Food Blue No. 2 Aluminum Lake, Food Yellow No. 4 Aluminum Lake, Food Yellow No. 5 Aluminum Lake, Food Red No. 2 Aluminum Lake, Food Red No. 3 Aluminum Lake, Food Red No. 102 Aluminum Lake, Ferric Oxide ( red), titanium oxide, yellow ferric oxide, orange essence, caramel, talc, green tea powder, and the like. These may be used alone or as a mixture of two or more.

Flavors that can be used in the present invention include mint, lemon flavor, orange cortone, pineapple flavor, l-menthol, black tea micron and the like. These may be used alone or as a mixture of two or more.

In the present invention, the ingredients to be incorporated into the drug layer are not particularly limited. Preferred ingredients include proton pump inhibitors (omeprazole, lansoprazole, esomeprazole, etc.), analgesics (aspirin, etc.), medicines such as salazosulfapyridine, health foods such as fish oil, garlic, lactic acid bacteria, bifidobacteria, etc. preferably include proton pump inhibitors, more preferably esomeprazole.

The enteric-coated granules having a multi-layered structure in the present invention comprise, for example, a core containing crystalline cellulose or lactose, (1) a drug layer containing an active ingredient, a continuous (2) enteric-coated layer containing an anionic polymer and ( 3) Enteric coated granules having at least an elution control layer containing a cationic polymer. In addition, the term "multilayered structure" as used in the present invention means an enteric coated granule comprising at least three layers (1) to (3) above, and if necessary, a drug layer containing a different drug, an elution control It can be coated with layers, an enteric layer, or a barrier layer separating each layer. Also, the enteric layer and the elution control layer must be continuous, but either one may be located outside the other in the enteric granules. Production can be carried out by generally known methods, for example, fluid granulation methods such as tumbling fluidized bed granulation and fluid granulation, tumbling granulation methods such as centrifugal tumbling granulation, stirring granulation, and the like. can be manufactured by

The enteric-coated granules of the present invention can be used by being contained in an enteric-coated preparation, and solid preparations are particularly preferred. mentioned. Tablets are preferred in terms of ease of handling. Among tablets, orally disintegrating tablets are particularly preferred. In addition, these solid preparations can be coated using a generally used coating base, if necessary.

The orally disintegrating tablet of the present invention can be produced by a generally known method, for example, by mixing the enteric coated granules of the present invention and additives (excipients, disintegrants, etc.) in the presence or absence of a solvent, molding, and optionally It can be produced by drying with Mixing can be performed using a device such as a V-type mixer, a universal kneader, a fluid bed granulator, a tumbler mixer, and the like.
When the solid preparation of the present invention is a tablet or an orally disintegrating tablet, it can be formed by tableting using, for example, a rotary tableting machine.
Drying may be performed by any method commonly used for drying pharmaceuticals, such as vacuum drying and fluidized bed drying.

The enteric-coated granules and enteric-coated preparations of the present invention can be produced, for example, by the following steps.
(Process 1: Layering/classification process)
Microcrystalline cellulose is placed in a tumbling fluidized bed granulator, and drug suspension (purified water, drug, hypromellose and polysorbate 80) is sprayed for layering. Then, after drying, it is classified by passing through a sieve.
(Step 2: Intermediate layer coating/classification step)
The classified product produced in the first step is placed in a tumbling fluidized bed granulator, and an intermediate layer coating liquid (purified water, hydroxypropyl cellulose, talc, magnesium stearate) is sprayed to carry out intermediate layer coating. Subsequently, after drying, classify by passing through a sieve (Step 3: Dissolution control layer/classifying step)
The classified product produced in the second step is placed in a tumbling fluidized bed granulator and coated with a coating liquid (purified water, cationic polymer (ammonioalkyl methacrylate copolymer, etc.), triethyl citrate, polysorbate 80, glycerin monostearate, etc.). additive) is sprayed and coated. Then, after drying, it is classified by passing through a sieve.
(Step 4: Enteric coating/classification step)
The classified product produced in the third step is placed in a tumbling fluidized bed granulator and coated with an enteric coating liquid (purified water, anionic polymer (methacrylic acid copolymer LD, etc.), polyethylene glycol, polysorbate 80, glyceryl monostearate, etc.). additives) and enteric coating. Then, after drying, it is classified by passing through a sieve.
(Step 5:)
The classified product produced in the fourth step is placed in a V-type mixer, and additives such as D-mannitol, crystalline cellulose, crospovidone, magnesium aluminometasilicate and aspartame are added and mixed. Then add magnesium stearate and mix further.
(Step 6: tableting step)
Compress the mixed granules produced in the fifth step using a rotary tableting machine.

EXAMPLES The present invention will be described in more detail with reference to Examples, Comparative Examples and Test Examples below, but the present invention is not limited to these.

(Example 1)
Spherical crystalline cellulose is placed in a tumbling fluid bed granulator (manufactured by Freund Corporation, SFC-MINI) and coated while spraying a liquid obtained by dissolving and dispersing esomeprazole magnesium hydrate, hypromellose and polysorbate 80 in water. did. The resulting drug layer-coated particles were dried and then coated with a liquid in which hypromellose, talc and D-mannitol were dissolved and dispersed in water while being sprayed. After drying the resulting intermediate layer-coated particles, they are coated while spraying a solution prepared by dissolving and dispersing ammonioalkyl methacrylate copolymer dispersion (solid content 30%), triethyl citrate, glyceryl monostearate and polysorbate 80 in water. did. After drying the obtained elution control layer-coated particles, methacrylic acid copolymer LD (solid content 30%), ethyl acrylate/methyl methacrylate copolymer dispersion (solid content 30%), triethyl citrate, glyceryl monostearate, polysorbate 80, sodium hydroxide, citric acid monohydrate and iron sesquioxide dissolved and dispersed in water while spraying. The obtained enteric layer-coated particles were dried and classified to obtain coated microparticles having an average particle size of 300 μm.

(Example 2)
Spherical crystalline cellulose is placed in a tumbling fluidized bed granulator (manufactured by Freund Corporation, SFC-MINI), and esomeprazole magnesium hydrate, hypromellose, low-substituted hydroxypropyl cellulose and polysorbate 80 are dissolved and dispersed in water. The liquid was sprayed while coating. After drying the obtained drug layer-coated particles, they were coated while being sprayed with a liquid in which hypromellose, talc, low-substituted hydroxypropylcellulose and D-mannitol were dissolved and dispersed in water. The resulting intermediate layer-coated particles were dried and then coated with a solution of methacrylic acid copolymer LD (solid content: 30%), polyethylene glycol 6000, glyceryl monostearate and polysorbate 80 dissolved and dispersed in water while being sprayed. After drying the obtained enteric layer-coated particles, ammonioalkyl methacrylate copolymer dispersion (solid content 30%), triethyl citrate, glyceryl monostearate and polysorbate 80 dissolved and dispersed in water while spraying. coated. After drying the obtained elution control layer-coated particles, methacrylic acid copolymer LD (solid content 30%), ethyl acrylate/methyl methacrylate copolymer dispersion (solid content 30%), triethyl citrate, glyceryl monostearate and polysorbate 80 was dissolved and dispersed in water while being sprayed. The obtained enteric layer-coated particles were dried and classified to obtain coated microparticles having an average particle size of 350 μm.

(Comparative example 1)
Granules were obtained in the same manner as in Example 1 except that the ammonioalkyl methacrylate copolymer dispersion (solid content: 30%), triethyl citrate, glyceryl monostearate and polysorbate 80, which are elution control layers, were not coated.

(Comparative example 2)
Spherical crystalline cellulose is placed in a tumbling fluidized bed granulator (manufactured by Freund Corporation, SFC-MINI), and esomeprazole magnesium hydrate, hypromellose, low-substituted hydroxypropyl cellulose and polysorbate 80 are dissolved and dispersed in water. The liquid was sprayed while coating. After drying the obtained drug layer-coated particles, they were coated while being sprayed with a liquid obtained by dissolving and dispersing hydroxypropylcellulose, magnesium stearate and talc in water. The resulting intermediate layer-coated particles were dried and then coated with a solution of methacrylic acid copolymer LD (solid content: 30%), polyethylene glycol 6000, glyceryl monostearate and polysorbate 80 dissolved and dispersed in water while being sprayed. After drying the obtained enteric layer-coated particles, methacrylic acid copolymer LD (solid content 30%), ethyl acrylate/methyl methacrylate copolymer dispersion (solid content 30%), triethyl citrate, glyceryl monostearate and polysorbate 80 was dissolved and dispersed in water while being sprayed. The obtained enteric layer-coated particles were dried and classified to obtain coated microparticles having an average particle size of 350 μm.

(Test example 1)
As the first solution for the dissolution test, coated microparticles equivalent to 20 mg of esomeprazole are taken, and 900 mL of the test solution is used, and the test is performed by the paddle method at 50 revolutions per minute. After starting the dissolution test, withdraw 20 mL or more of the eluate at a specified time and filter through a membrane filter with a pore size of 0.45 μm or less. Remove the first 5 mL of the filtrate and use the next filtrate as the sample solution. Separately, weigh precisely about 25 mg of esomeprazole magnesium hydrate for quantitative use and dissolve in methanol to make exactly 50 mL. Accurately measure 1 mL of this solution, add the test solution to make exactly 20 mL, and use it as a standard solution. The test solution is used as a control for the sample solution and the standard solution, and the test is performed by the ultraviolet-visible absorbance measurement method.
As the second fluid for the dissolution test, coated microparticles equivalent to 20 mg of esomeprazole are used, and 900 mL of the test fluid is used. After starting the dissolution test, take 20 mL of the eluate at predetermined intervals, and immediately add 20 mL of the test solution heated to 37±0.5° C. carefully. The eluate is filtered through a membrane filter with a pore size of 0.45 µm or less. Remove the first 5 mL of the filtrate, measure the next 5 mL of the filtrate, and add exactly 1 mL of sodium hydroxide solution (1→100) to obtain the sample solution. Separately, weigh precisely about 21 mg of esomeprazole magnesium hydrate for quantitative use, dissolve in methanol, and make exactly 50 mL. Accurately measure 1 mL of this solution, add test solution/sodium hydroxide solution (1→100) mixture (5:1) to make exactly 20 mL, and use it as a standard solution. Accurately take 10 μL each of the sample solution and the standard solution, and perform the test by liquid chromatography.
For the purity test, take coated microparticles equivalent to 80 mg of esomeprazole, add 20 mL of methanol, and shake well. Add 40 mL of diluted pH 12 phosphate buffer (1→10) to this solution, shake and mix, sonicate for 5 minutes, and add water to make 200 mL. This liquid is filtered through a membrane filter with a pore size of 0.45 μm or less, and the filtrate is used as a sample solution. Accurately measure 1 mL of this solution, add diluted pH 12 phosphate buffer (1→50) to make exactly 100 mL, and use it as a standard solution. Accurately take 20 μL each of the sample solution and the standard solution, and perform the test by liquid chromatography.
The granules obtained in Example 1 and Comparative Example 1 were subjected to dissolution rate and purity tests at pH 1.2 and pH 6.8, and the results are shown in tables and figures (Tables 4 and 5, Figures 1 and 2).

Example 1 coated with an elution control layer had improved acid resistance compared to Comparative Example 1. 1 and 2, Example 1, in which the elution control layer was coated, had a longer lag time than Comparative Example 1, and the results of gradual elution of the active ingredient were shown.

(Test example 2)
The granules obtained in Example 2 and Comparative Example 2 were subjected to a dissolution test at pH 6.8, and the results are shown in Table and Figure.

Example 2, in which the elution control layer was coated, had a longer lag time than Comparative Example 2, and the active ingredient was gradually eluted.

(Test example 3)
The stability of the enteric granules of Example 1 and Comparative Example 1 after one week under accelerated test conditions (40° C.±2° C./75% RH±5%) was examined. By-products of esomeprazole magnesium hydrate, (1) thiol, (2) N-oxide, (3) sulfone, (4) demethoxy, (5) sulfide, and (6) In addition, it was evaluated by the production amount under the test.

The results in Table 7 indicate that Example 1, in which the elution control layer was coated, suppressed the increase in related substances compared to Comparative Example 1.

Claims (10)

An enteric coated granule having a multi-layered structure, comprising an elution control layer containing a cationic polymer and an enteric coated layer containing an anionic polymer, wherein these layers are continuous. Enteric-coated granules having two same or different enteric layers sandwiching an elution control layer outside the drug layer of the enteric-coated granules, wherein the anionic polymer is the same in the two enteric layers. soluble granules . 2. Enteric coated granules according to claim 1, wherein the cationic polymer according to claim 1 is selected from aminoalkyl methacrylate copolymer E, ammonioalkyl methacrylate copolymer, or consists of a combination thereof. 3. Enteric coated granules according to claim 1 or 2, wherein the cationic polymer according to claim 1 or 2 is an ammonioalkyl methacrylate copolymer. 1. The anionic polymer of claim 1 is selected from or consists of a methacrylic acid copolymer L, a methacrylic acid copolymer S, a methacrylic acid copolymer LD and a methyl acrylate/methyl methacrylate/methacrylic acid copolymer. Enteric coated granules according to any one of claims 1 to 3. Enteric coated granules according to any one of claims 1 to 4, wherein the anionic polymer according to claims 1 or 4 is methacrylic acid copolymer LD. The enteric granules according to any one of claims 1 to 5, which contain an acid-labile drug in the enteric granules according to any one of claims 1 to 5. 7. Enteric coated granules according to claim 6, wherein the acid-labile drug according to claim 6 is a proton pump inhibitor. A solid preparation containing the enteric coated granules according to any one of claims 1 to 7. The solid preparation according to claim 8, wherein the solid preparation is a tablet. The solid preparation according to claim 9, wherein the tablet is an orally disintegrating tablet.