JPH04338324A - Multi-reservoir-type sustained release granule and its preparation - Google Patents

Abstract

PURPOSE:To separately control the release of plural pharmacologicall active components contained in a granule. CONSTITUTION:The objective sustained release preparation for plural pharmacologically active components is composed of a core substance and a multilayer structure formed on the surface of the core substance, wherein the constituent unit of each layer of the multilayer structure is composed of a powdery coating pharmaceutical layer containing a pharmaceutically active component and a water-insoluble film layer covering the powdery coating pharmaceutical layer. A plural kinds of pharmacologically active components can be filled in one granule and the releasing rate of each active component can be controlled at an arbitrary level.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention provides that the constituent units of each layer of a multilayer structure consist of a powder-coated drug layer containing a pharmaceutically active ingredient and a water-insoluble film layer covering the powder-coated drug layer. Provided are sustained-release granules and a method for producing the same. Therefore, the present invention can be applied to preparations that contain a plurality of pharmaceutically active ingredients and require individual release control, such as sustained-release general cold preparations.

0002

[Prior Art] Many sustained release techniques for effectively controlling the elution and absorption of pharmaceutically active ingredients have been disclosed, including matrix formation methods, diaphragm separation methods, use of chemical adsorption, and use of water-soluble gel matrices. However, all of these are aimed at sustained release of a single pharmaceutically active ingredient, and no attempt has been made to individually control the release of multiple types of pharmaceutically active ingredients.

[0003]Also, several techniques regarding sustained release granules having a multilayer structure have been disclosed, including a technique for making the dissolution curve zero-order (Japanese Patent Application Laid-Open No. 63-27424), and There is a description of a technique for a multilayer structure preparation combining a sustained release part and an immediate release part (Japanese Unexamined Patent Publication No. 60-4120), which describes a sustained release technology that can individually control the elution characteristics of multiple types of pharmaceutically active ingredients. can not see.

0004

[Problems to be Solved by the Invention] In the sustained release granules containing multiple types of pharmaceutically active ingredients prepared based on the above-mentioned prior art, due to differences in solubility, blending amount, dissolution rate, etc. between the pharmaceutically active ingredients, Each pharmaceutically active ingredient often exhibits different elution behavior, and it is extremely difficult to simultaneously provide desired elution characteristics to all pharmaceutically active ingredients. On the other hand, when sustained-release granules are prepared individually for each pharmaceutically active ingredient and used as a single preparation by mixing them, as is well known, segregation during mixing may cause the amount of the pharmaceutically active ingredient in the desired preparation to be mixed. It is difficult to precisely control and manage the content, elution characteristics, etc.

[0005]

[Means for Solving the Problems] In view of the above points, the present inventors installed a plurality of drug layers capable of storing pharmaceutically active ingredients in one granule, and further, each drug layer was formed with a water-insoluble film layer. The present invention was completed based on the discovery that the release rate of each pharmaceutically active ingredient can be arbitrarily controlled by separating it into a multilayer structure. More specifically, the present invention provides a powder-coated drug layer (hereinafter also simply referred to as drug layer) in which the constituent units of each layer of a multilayer structure contain a pharmaceutically active ingredient, and a water-insoluble drug layer covering the powder-coated drug layer. The present invention provides a sustained release granule comprising a film layer (hereinafter also simply referred to as a film layer), each drug layer forming a reservoir isolated by the film layer.

[0006] The method for producing this preparation will be explained below. This preparation can be manufactured by performing the following two steps multiple times as one unit. Step a: Powder coating step of powder containing a pharmaceutically active ingredient Step b: Subsequent water-insoluble film coating step Each step will be explained below.

(Step a) In this step, in the presence of a binder, a powder containing a pharmaceutically active ingredient is coated on the core material or on the surface of the particles obtained after completion of Step b of the present manufacturing method using a powder coating method. This step is to form a drug layer.

A wide variety of binders can be used as long as they are water-insoluble or poorly soluble, as long as they do not adversely affect the pharmaceutically active ingredients and their dissolution properties, such as methylcellulose, ethylcellulose, hydroxy Examples include ethyl cellulose, hydroxypropyl cellulose, and xanthan gum.

[0009] As the core substance, any substance can be used as long as it is pharmacologically inactive and has no interaction with the pharmaceutically active ingredients used, such as sugars such as sucrose, lactose, mannitol, fructose, etc. Examples include celluloses, starches, sugar fatty acid esters, etc., and these may be used alone, as crystals, or as a mixture. However, when coating with a water-insoluble film base using a water-based spray, the core material swells and disintegrates easily, so crystalline cellulose particles, etc., which do not disintegrate due to swelling, are used. It is preferable to do so. The amount used can be arbitrarily selected depending on the desired size of the granules.

Powder containing a pharmaceutically active ingredient is a mixed powder of the pharmaceutically active ingredient and suitable excipients and other additives for improving the operability of coating.

The pharmaceutically active ingredients are not particularly limited as long as they are water-soluble, but examples include chlorpheniramine maleate, chlorpheniramine d-maleate, clemastine fumarate, carbinoxamine maleate, promethazine hydrochloride, diphenhydramine, Antihistamines such as terfenadine, antipyretic analgesics or analgesics such as aspirin, salicylamide, ethenzamide, acetaminophen, diclofenac sodium, dihydrocodeine phosphate, morphine sulfate, morphine hydrochloride, codeine phosphate, and bronchodilators such as bitolterol mesylate. , dextromethorphan hydrobromide, cloperastine hydrochloride, phenylpropanolamine hydrochloride, methylephedrine, potassium cresol sulfate, antitussive expectorants such as belladonna total alkaloids, anti-ulcer agents such as cetraxate, ranitidine, famotidine, pindro Circulatory system drugs such as alcohol, propranolol, alprenolol, oxypurinol, diltiazem, pinacidil, antitumor agents such as 5-fluorouracil and tegafur, antibacterial agents such as cinoxacin, enoxacin, lomefloxacin, cephalexin, Examples include antibiotics such as cefaclor. The excipient is not particularly limited, and a wide variety of commonly used excipients can be used, such as organic substances such as lactose and cornstarch, and inorganic substances such as calcium phosphate. Although the amount used is not necessarily limited, it is preferable to reduce the amount used as much as possible for pharmaceutical active ingredients that are blended in small amounts and have high solubility, that is, pharmaceutical active ingredients that are blended near the center.

[0012] As additives, thickeners, lubricants, water retention agents, etc. are used. Examples of the lubricant include magnesium stearate and glycerin fatty acid ester. Examples of water retention agents include corn starch, crystalline cellulose, and partially pregelatinized starch. However, in the case of both additives, they are used to improve the operability of powder coating of powders containing pharmaceutically active ingredients;
The type and amount used are not necessarily limited.

(Step b) This step is a step of coating the surface of the particles obtained in step a (hereinafter referred to as elementary granules) with a water-insoluble film coating base to form a film layer. . If desired, additives such as an enteric coating base, a water-soluble coating base, a lubricant, a filler, a plasticizer, and the like may be added.

Water-insoluble film coating bases that can be used in this step include ethyl cellulose, ethyl methacrylate/trimethylammonium methacrylate copolymer, and ethyl acrylate/methyl methacrylate copolymer. emulsion (Eudragit NE30D, 30
% water emulsion, Higuchi Shokai Co., Ltd., shellac, highly polymerized polyvinyl alcohol, water-insoluble polyvinylpyrrolidone, polyvinyl chloride, cellulose acetate, polyurethane, tetrafluoroethylene, polystyrene, polypropylene, lactic acid polymer, Examples include hydroxyethyl methacrylate, glycolic acid polymer, polyethylene terephthalate, polyethylene, polyamide, polyacrylonitrile, polycarboxylic acid, and cyanoacrylate polymer.

In the present invention, a thin and dense film with particularly high water permeability is required, so the Eudragit NE30D, which is rich in plasticity, can be easily made seamless, and has high water permeability, is preferred. Additionally, additives may be added to the water-insoluble film coating base if necessary.
For the above reasons, it is preferable to reduce the amount used as much as possible without adversely affecting film forming properties and water permeability.

[0016] The amount of water-insoluble film coating base coated varies depending on the type of base, the amount of pharmaceutically active ingredient in the drug layer, solubility, surface area of bare granules, desired elution characteristics, etc. Although it cannot be absolutely defined, the weight increase is generally 1 to 50% compared to the elementary granules, preferably 1 to 50%.
The range is 20% weight increase. Above the upper limit, it will have a significant negative effect on the release control of the pharmaceutically active ingredient contained in the drug layer near the center, and below the lower limit, the film layer will not be effective as a release control membrane, and the sustained release of the contained pharmaceutical active ingredient will not be achieved. Not enough is achieved. Note that it is desirable to proceed to the next step after slightly drying the particles obtained in each step.

Hydroxypropylmethylcellulose phthalate (HPMCP) is used as the enteric coating base.
, hydroxypropylmethylcellulose acetate succinate (HPMC-AS), methacrylic acid/methyl methacrylate copolymer, cellulose acetate phthalate (CAP), and the like. Examples of water-soluble coating bases include methylcellulose (MC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), gelatin, and hydroxypropylmethylcellulose (HPMC). )
, polycarboxylic acid, starch, sodium alginate, etc. Examples of the lubricant include magnesium stearate and stearic acid. Examples of the filler include talc, calcium carbonate, and the like. Examples of the plasticizer include triacetin and triethyl citrate.

The preparation of the present invention can be produced by performing the above two steps as one unit (hereinafter simply referred to as coating operation) multiple times. Therefore, for example, a formulation with a two-layer structure can be manufactured by performing the coating operation twice, a formulation with a three-layer structure can be manufactured by performing the coating operation three times, and formulations with a four-layer or five-layer structure can also be manufactured. It can be manufactured by a similar method. That is, by repeating the coating operation depending on the desired number of drug layers, it is possible to produce a preparation having a multilayer structure.

[0019] The formulation of the present invention allows for individual controlled release of a plurality of pharmaceutically active ingredients. This mechanism of action is explained as follows. After the administered preparation reaches the stomach, the water in the stomach passes through the outermost film layer and penetrates into the inside.
Fill each drug layer. The water filled in the drug layer dissolves a portion of each pharmaceutically active ingredient in the drug layer and is then released while diffusing through each film layer.

At this time, the rate-determining steps for elution are the dissolution of the pharmaceutically active ingredient and its diffusion through the film layer. Therefore, by controlling the dissolution rate and the diffusion permeation rate, the pharmaceutically active ingredient can be given desired elution characteristics. The dissolution rate can be determined by changing the volume of the drug layer of each pharmaceutical active ingredient, and the diffusive permeation rate can be determined by changing the volume of the drug layer of each pharmaceutical active ingredient.
Each can be controlled by changing the composition and thickness of the film layer.

[0021] Generally, it is known that in order to achieve sustained release of a pharmaceutically active ingredient by dissolution rate limiting, it is desirable to increase the compounding density of the pharmaceutically active ingredient in the reservoir. Therefore, it is preferable that the higher the solubility of the pharmaceutically active ingredient and the smaller the amount of the pharmaceutically active ingredient to be blended, the closer to the center of the granule it is and the smaller the volume of the drug layer.For this purpose, the amount of additives other than the pharmaceutically active ingredient should be reduced as much as possible. It is preferable.

[0022] Furthermore, it is preferable that the elution characteristics of each pharmaceutically active ingredient depend only on the film layer directly covering each drug layer, and are not substantially influenced by film layers outside this. For this purpose, it is preferable that each film layer be as thin as possible, dense, and have good water permeability, so it is preferable not to add an extender such as talc to the water-insoluble film coating base.

According to the present invention, the elution characteristics of each pharmaceutically active ingredient can be individually and arbitrarily controlled depending on the desired sustained release. Furthermore, if the solubility or blending amount of the pharmaceutically active ingredients is considered, it is possible, for example, to make the elution characteristics of each pharmaceutically active ingredient almost the same. It should be noted that the pharmaceutical active ingredients in each drug layer do not necessarily all have to be of different types, and depending on the purpose of the sustained release agent, some or all of them may be of the same type without causing any inconvenience. .

Examples and reference examples are shown below to explain the present invention in more detail, but these are not intended to limit the present invention in any way.

(General method for preparing the preparation of the present invention) Using a centrifugal rolling granulator (CF-360, Freund Sangyo Co., Ltd.), the steps a and b are carried out as follows without stopping the rolling. Repeat the coating operation.

Step a: Powder coating step 50% Crystalline cellulose grains (Avicel SP, Asahi Kasei Corporation) having an average particle diameter of 320 μmφ or particles obtained after completion of step b are used as a material that can serve as the central core. While spraying the binder spray liquid, the mixed powder forming the powder coating drug nth layer (hereinafter simply referred to as drug nth layer, n represents an integer of 1 or more) is mixed with a substance that can serve as a core. Coat the surface. Next, air is blown at about 50° C. and about 300 NL/min from the bottom for about 15 minutes to dry it slightly.

Step b: Water-insoluble film coating step The elementary granules obtained in step a are heated at about 40°C and about 200℃.
Ethyl acrylate while blowing air at NL/min.
Methyl methacrylate copolymer emulsion (Eudragit NE30D, 30% water emulsion, Higuchi Shokai Co., Ltd.)
A predetermined amount of is coated at a rate of about 10 g/min. Then, sprinkle a small amount of talc to form a water-insoluble film.
After forming a layer (hereinafter simply referred to as the n-th film layer, n represents an integer of 1 or more), about 50°C and about 300NL
Blow air at a rate of /min for some drying.

For example, when producing a preparation of the present invention having a three-layer structure, the following six steps are carried out. First step: Formation of drug first layer Using the crystalline cellulose grains as a core material, step a is performed to form a drug first layer. Second step: Formation of first layer of film The elementary granules obtained in the first step are subjected to step b to form a first layer of film.

Third step: Formation of second drug layer The particles obtained in the second step are subjected to step a to form a second drug layer. Fourth step: Formation of second film layer The elementary granules obtained in the third step are subjected to step b to form a second film layer.

Fifth step: Formation of third drug layer The particles obtained in the fourth step are subjected to step a to form a third drug layer. Sixth step: Formation of third layer of film After performing step b on the elementary granules obtained in the fifth step to form a third layer of film, rolling is stopped and the resulting particles are taken out.

[0031] The particles obtained in the final step were dried at about 50°C for about 1 hour in a fluidized dryer (WSG5 type, Glatt Co., Ltd.).
By drying, the desired multi-reservoir sustained release granules are obtained. Next, Table 1 shows the water solubility of each pharmaceutical active ingredient used.

[Table 1]

Example 1 Granules having a two-layer structure were prepared according to a general preparation method by the following steps. First step: As the core material for forming the drug first layer,
1000 g of crystalline cellulose grains (Avicel SP, Asahi Kasei Corporation) with a 50% average particle diameter of 320 μmΦ were used, and 2% methylcellulose 25% was applied as a binder on the surface.
A mixed powder consisting of 88.8 g of dextromethorphan hydrobromide and 4.4 g of magnesium stearate is powder coated while spraying 340 g of a 15% cps ethanol aqueous solution to form a first drug layer. Next, air is blown at about 50° C. and about 300 NL/min from the bottom for about 15 minutes to dry it slightly.

Second step: Formation of second film layer The elementary granules obtained in the first step are heated at about 40° C. and about 200 NL/m.
Eudragit NE30D while blowing air inside
A predetermined amount of 740 g is coated at a rate of about 10 g/min. Next, 74 g of talc is sprinkled to form a second film layer, and then air is blown at about 50° C. and about 300 NL/min to perform some drying.

Third step: Formation of drug second layer. 2% methylcellulose 25cps 15% ethanol aqueous solution 61 as a binder is applied to the surface of the particles obtained in the second step.
A mixed powder consisting of 1665 g of acetaminophen, 10.0 g of magnesium stearate, and 14.0 g of 25 cps of methylcellulose is powder coated while spraying 6 g of the drug to form a second drug layer. Next, air is blown at about 50° C. and about 300 NL/min from the bottom for about 15 minutes to dry it slightly.

Fourth step: Formation of second layer of film The elementary granules obtained in the third step are heated at about 40° C. and about 200 NL/m.
Eudragit NE30D while blowing air inside
A predetermined amount of 1000 g is coated at a rate of about 10 g/min. Next, 110 g of talc was sprinkled to form a second film layer, and then heated at about 50°C and about 300 NL/mi.
Slight drying is performed by blowing n air.

[0036] The rolling was stopped, and the obtained particles were taken out and dried at about 50°C in a fluidized fluid dryer (WSG5 type, Glatt Co., Ltd.).
Let dry for about 1 hour. In this way, one dose unit
Dextromethorphan hydrobromide 2 in 1038mg
Contains 4mg, acetaminophen 450mg, 50
Granules with a % average particle diameter of about 620 μmφ are obtained.

Examples 2 to 3 and Reference Examples 1 to 5 Each step was prepared based on the amounts shown in Table 2 according to the general preparation method described above.

[Table 2] Examples 2 to 3 are granules with a two-layer structure similar to Example 1, and Reference Examples 1 to 5 are ordinary diaphragm-separated granules (hereinafter referred to as
(referred to as single reservoir type granules). In both cases, the core material contains 1000 of the crystalline cellulose grains.
g was used.

[0038] Each substance used may also be represented by the following abbreviations. Crystalline cellulose grains: a, dextromethorphan hydrobromide: b, acetaminophen: c, ethenzamide: d, magnesium stearate: e, methylcellulose 25cps: f, 2% methylcellulose 25
cps 15% ethanol aqueous solution: g, Eudragit NE30D: h, talc: i

Table 3 shows the composition of the pharmaceutically active ingredient in each granule obtained in each Example and each Reference Example.

[Table 3] Table 4 shows the particle size distribution, yield, and yield of each granule obtained in each example.

[Table 4]

Examples 4 to 7 Films were prepared by varying the coating amount of Eudragit NE30D (h) used as the water-insoluble film coating base in the fourth step of Example 1, as shown in Table 5.

[Table 5]

Examples 8 to 11 The coating amount of Eudragit NE30D (h) used as the water-insoluble film coating base in the fourth step of Example 2 was varied as shown in Table 6.

[Table 6]

(Dissolution test) Test method The test was conducted using the paddle method (100 rpm) in accordance with the 11th revised Japanese Pharmacopoeia, General Test Methods, Dissolution Test section.
The test liquid includes the first liquid (Fluid) and the second liquid (Fluid).
), or using water.

Experimental Example 1 The above dissolution test was conducted on the multi-reservoir sustained release granules of Example 1. The test liquid includes the first liquid (Flui
d), a second liquid (Fluid) was used, and the granules used were equivalent to 24 mg of dextromethorphan hydrobromide (b) and 450 mg of acetaminophen (c). The results are shown in Figure 1. All pharmaceutical active ingredients showed approximately the same elution characteristics, and almost no pH dependence was observed.

Experimental Example 2 The above dissolution test was conducted on the multi-reservoir sustained release granules of Example 2. The test solutions used were the first and second solutions, and the granules used were equivalent to 125 mg of acetaminophen and 375 mg of ethenzamide. The results are shown in Figure 2. All pharmaceutical active ingredients showed approximately the same elution characteristics, and almost no pH dependence was observed.

Experimental Example 3 The above dissolution test was conducted on the multi-reservoir sustained release granules of Example 3. Water was used as the test solution, and granules were used in amounts equivalent to 24 mg of dextromethorphan hydrobromide, 125 mg of acetaminophen, and 375 mg of ethenzamide. The results are shown in Figure 3. All pharmaceutical active ingredients showed approximately the same elution characteristics.

Experimental Example 4 The above dissolution test was conducted on the single reservoir type granules of Reference Examples 1, 2, and 4. Water is used as the test liquid,
The granules are dextromethorphan hydrobromide 24mg,
An amount equivalent to 450 mg of acetaminophen was used. The results are shown in Figure 4. In the case of the granules of Reference Examples 1 and 2 containing a single pharmaceutically active ingredient in a single reservoir,
The desired elution characteristics were obtained for each. On the contrary,
In the case of Reference Example 4, in which a single reservoir contains two types of pharmaceutically active ingredients with approximately the same level of solubility but greatly different amounts, each of them exhibits completely different elution behavior, resulting in individual elution. Control could not be achieved.

Experimental Example 5 The above dissolution test was conducted on the single reservoir type granules of Reference Examples 2, 3, and 5. Water is used as the test liquid,
The granules used were equivalent to 125 mg of acetaminophen and 375 mg of ethenzamide. The results are shown in Figure 5. In the case of the granules of Reference Examples 2 and 3 containing a single pharmaceutically active ingredient in a single reservoir, appropriate elution characteristics were obtained. In contrast, single reservoir
In the case of Reference Example 5, which contained two types of pharmaceutically active ingredients with different solubility and blending amounts, each exhibited completely different elution behavior, and individual elution control could not be achieved.

Experimental Example 6 The multi-reservoir sustained release granules of Examples 1, 4, 5, 6, and 7 were subjected to the dissolution test described above, and the dissolution rate after about 3 hours was determined. The influence of the coverage rate was investigated. Water was used as the test solution, and the granules contained 24 mg of dextromethorphan hydrobromide and 4 mg of acetaminophen.
An amount equivalent to 50 mg was used. The results are shown in FIG. As the coverage of the second layer of the film increases, the dissolution rate of acetaminophen blended into the second drug layer (hereinafter also referred to as outer layer) smoothly decreases. On the other hand, the elution rate of dextromethorphan hydrobromide blended in the drug first layer (hereinafter also referred to as inner layer) is controlled by the first film layer when the coverage is 10.9% or less. However, when the value exceeds the same value, it shows a decreasing tendency. Therefore, by arbitrarily changing the coverage of the second layer of the film between 0 and 10.9%, the acetate in the outer layer can be reduced without affecting the elution characteristics of dextromethorphan hydrobromide in the inner layer. Aminophen elution can be controlled.

Experimental Example 7 The multi-reservoir sustained release granules of Examples 2, 8, 9, 10, and 11 were subjected to the dissolution test described above, and the dissolution rate after about 3 hours was determined. The influence of the coverage rate was investigated. Water was used as the test liquid, and granules were used in amounts equivalent to 125 mg of acetaminophen and 375 mg of ethenzamide. The results are shown in FIG. As the coverage of the second layer of the film increases, the elution rate of ethenzamide blended into the outer layer decreases smoothly. On the other hand, the elution rate of acetaminophen blended into the inner layer is 10.
When it is 8% or less, it shows a value almost equal to the value controlled by the first layer of the film, but when it exceeds the same value, it shows a decreasing tendency. Therefore, the coverage rate of the second layer of the film is 0 to 10.8.
By arbitrarily changing the amount between % and %, the elution of ethenzamide in the outer layer can be controlled without affecting the elution characteristics of acetaminophen in the inner layer.

[0050]

According to the present invention, it is possible to contain a plurality of pharmaceutically active ingredients in a single granule and to arbitrarily control the release rate of each active ingredient. Therefore, this preparation is suitable for sustained-release granules that require sustained release of multiple types of pharmaceutically active ingredients, such as sustained-release general cold preparations. In addition, since this formulation uses a water-insoluble film coating base as a sustained release agent, it exhibits pH-independent dissolution characteristics, making it suitable for the elderly, hypoacidemia, and achlorhydria. , the same sustained release as when administered to normal healthy individuals is expected.

[Brief explanation of drawings]

FIG. 1 shows the results of a dissolution test of the pharmaceutically active ingredient contained in the granules obtained in Example 1. The vertical axis represents dissolution rate (%), and the horizontal axis represents time (hr).

FIG. 2 shows the results of a dissolution test of the pharmaceutically active ingredient contained in the granules obtained in Example 2. The vertical axis represents dissolution rate (%), and the horizontal axis represents time (hr).

FIG. 3 shows the results of a dissolution test of the pharmaceutically active ingredient contained in the granules obtained in Example 3. The vertical axis represents dissolution rate (%), and the horizontal axis represents time (hr).

FIG. 4 shows the results of a dissolution test of pharmaceutically active ingredients contained in the granules obtained from Reference Examples 1, 2, and 4. The vertical axis represents dissolution rate (%), and the horizontal axis represents time (hr).

FIG. 5 shows the results of a dissolution test of the pharmaceutically active ingredients contained in the granules obtained from Reference Examples 2, 3, and 5. The vertical axis represents dissolution rate (%), and the horizontal axis represents time (hr).

FIG. 6 shows the results of a dissolution test of the pharmaceutically active ingredients contained in the granules obtained in Examples 1, 4, 5, 6, and 7. The vertical axis represents the elution rate (%), and the horizontal axis represents the coverage rate (%) of the second layer of the water-insoluble film.

FIG. 7 shows the results of a dissolution test of the pharmaceutically active ingredients contained in the granules obtained in Examples 2, 7, 8, 9, and 10. The vertical axis represents the elution rate (%), and the horizontal axis represents the coverage rate (%) of the second layer of the water-insoluble film.

Claims (6)

[Claims] [Claim 1] A sustained release drug characterized in that the constituent units of each layer of the multilayer structure are a powder-coated drug layer containing a pharmaceutically active ingredient and a water-insoluble film layer covering the powder-coated drug layer. Granules. 2. The sustained release granule according to claim 1, wherein the multilayer structure is a two-layer structure. 3. The sustained release granule according to claim 1, wherein the multilayer structure is a three-layer structure. 4. Claims 1 to 3 in which the water-insoluble film layer comprises an ethyl acrylate/methyl methacrylate copolymer.
The sustained release granule according to any one of the above. 5. A method for producing sustained release granules, which comprises performing the following two steps multiple times as one unit. Step a: Powder coating step of powder containing pharmaceutically active ingredients Step b: Subsequent water-insoluble film coating step 6. The method according to claim 5, wherein in step b, an ethyl acrylate/methyl methacrylate copolymer is used as a water-insoluble film coating base.