Enteric-coated preparations

Abstract

To provide an enteric preparation that prevents breakage of an enteric layer in the enteric preparation when tableting.SOLUTION: An enteric preparation has enteric granules containing agents and other additional components that are sugar alcohol and / or disaccharides, which can prevent breakage of an enteric layer.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an enteric preparation in which damage to the enteric layer during tableting is prevented. [Background technology]

[0002] Enteric-coated preparations are preparations designed to not dissolve in the stomach but only dissolve after they have been transferred to the intestines, for example, when a drug is to be transferred to the intestines or when a drug is to be decomposed in the stomach or causes stomach disorders. Technically, these are solid preparations for internal use that are coated with a film that does not dissolve in acidic gastric juice but dissolves in alkaline intestinal juice, or the capsules themselves are made enteric-coated, and fine granules, granules, pills, tablets, capsules, and microcapsules have been reported.

[0003] Enteric preparations used for such purposes are applied to various drugs because of their usefulness, but on the other hand, they have some problems. For example, in the production of enteric granules coated with an enteric coating, the enteric layer is damaged during tableting, and as a result, the content ingredients leak out from the granules or the preparation containing the granules, resulting in problems such as a decrease in the content ingredients or tableting problems during formulation. Therefore, since a high tableting pressure cannot be applied during tableting, the hardness of the obtained tablets is not sufficient, and there is a concern that the tablets may break during transportation. In addition, in the case of drugs that decompose in the stomach, if the enteric coating is damaged, the main drug will decompose in gastric juice when taken, and the expected medicinal effect may be insufficient. Therefore, there is a demand for the development of a stable enteric preparation in which damage to the enteric layer during the production of such preparations is suppressed.

[0004] As a related prior art, it has been disclosed that a tablet produced by compressing a mixed powder obtained by mixing coated granules containing duloxetine hydrochloride coated with an enteric coating agent and starch or a derivative thereof has an acid resistance effect. Furthermore, Patent Document 2 discloses a coating composition containing D-mannitol and polyethylene glycol as a coating composition for preventing damage to an enteric layer. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] JP 2017-222645 A

[0006] [Patent Document 2] JP 2018-118936 A Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide an enteric preparation in which damage to the enteric layer during tableting is prevented. [Means for solving the problem]

[0008] The present inventors have conducted various investigations into techniques for preventing damage to the enteric layer in enteric preparations, and as a result have found that damage to the enteric layer during tableting can be prevented in enteric granules containing a drug and in enteric preparations containing a sugar alcohol and / or a disaccharide in the rear end portion, thereby completing the present invention.

[0009] That is, the present invention relates to (1) a solid preparation which comprises enteric granules containing a drug and a sugar alcohol and / or a disaccharide in the distal portion. (2) The present invention also relates to the solid preparation according to the above (1), wherein the sugar alcohol is any one of mannitol, xylitol, sorbitol and erythritol. (3) The present invention also relates to the solid preparation according to the above (1) or (2), wherein the sugar alcohol is mannitol. (4) The present invention also relates to the solid preparation according to any one of (1) to (3) above, wherein the disaccharide is any one of sucrose, lactose, maltose and trehalose. (5) The present invention also relates to the solid preparation according to any one of (1) to (4) above, wherein the disaccharide is lactose. (6) The present invention also relates to the solid preparation according to any one of (1) to (5) above, wherein the sugar alcohol and / or disaccharide is contained in the distal portion of the solid preparation in an amount of 40% by weight to 80% by weight. (7) The present invention also relates to the solid preparation according to any one of (1) to (6) above, wherein the enteric granules are coated with an enteric polymer. (8) The present invention also relates to the solid preparation according to any one of (1) to (7) above, wherein the enteric granules are coated with an enteric coating comprising an enteric polymer and an ethyl acrylate-methyl methacrylate copolymer. (9) The present invention also relates to the solid preparation according to any one of (1) to (8) above, wherein the enteric polymer is one or more selected from the group consisting of enteric methacrylic acid copolymers, enteric cellulose-based polymers, and enteric vinyl alcohol-based polymers. (10) The present invention also relates to the solid preparation according to any one of (1) to (9) above, wherein the solid preparation is a tablet. (11) The present invention also relates to the solid preparation according to the above (10), wherein the tablet is an orally disintegrating tablet. (12) The present invention also relates to the solid preparation according to any one of (1) to (11) above, wherein the drug is an acid-labile drug. (13) The present invention also relates to the solid preparation according to the above (12), wherein the acid-labile drug is a proton pump inhibitor. Effect of the Invention

[0010] A solid preparation containing the enteric coated granules of the present invention is useful for producing enteric coated preparations since it improves problems such as a decrease in the content of the active ingredient due to breakage of the enteric layer and tableting problems. [Brief description of the drawings]

[0011] [Figure 1] FIG. 2 shows the results of observing enteric granules in the tablet of Example 1-2 under a scanning electron microscope (SEM). [Diagram 2] FIG. 2 shows the results of observing enteric granules in the tablet of Example 1-3 under a scanning electron microscope (SEM). [Diagram 3] FIG. 1 shows the results of observing enteric granules in a tablet of Comparative Example 1-1 under a scanning electron microscope (SEM). [Figure 4] FIG. 2 is a diagram showing the results of observation of enteric granules in the tablet of Comparative Example 1-2 under a scanning electron microscope (SEM). BEST MODE FOR CARRYING OUT THEINVENTION

[0012] The present invention will now be described in further detail. In the present invention, the term "powders" refers to the additive portion other than the enteric coated granules in the tablet. The sugar alcohol used in the present invention refers to a type of sugar generated by reduction of the carbonyl group of a commonly known aldose or ketose, and examples thereof include sorbitol, mannitol, maltitol, lactitol, xylitol, erythritol, threitol, threitol, arabinitol, iditol, galactitol, volemitol, perseitol, D-erythro-D-galactoctitol, inositol, quercitol, glycerin, fatty acid esters, etc., but for example, those in a solid state at room temperature are preferred, and among such sugar alcohols, preferred are sorbitol, mannitol, erythritol, glycerin, fatty acid esters, and particularly preferred are sorbitol, mannitol, and erythritol. These sugar alcohols exist in D- and L-forms, and either can be used, but the D-form is preferred.

[0013] The disaccharides used in the present invention refer to compounds in which two commonly known monosaccharides are bonded together, such as sucrose, lactose, maltose, trehalose, and derivatives thereof having substituent groups. Of these, preferred are sucrose, lactose, maltose, and trehalose, and particularly preferred is lactose.

[0014] The sugar alcohol and / or disaccharide used in the present invention can be incorporated into the tablet powder in an amount of 40% to 80% by weight, preferably 40% to 70% by weight, more preferably 45% to 65% by weight, and even more preferably 50% to 65% by weight.

[0015] The enteric granules and solid preparations of the present invention may contain, as necessary, appropriate combinations of required amounts of binders, disintegrants, excipients, coating bases, formulation auxiliaries such as surfactants, flavorings, colorants, fragrances, etc.

[0016] Examples of 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, xanthan gum, and powdered gum arabic. Hydroxypropylcellulose, hypromellose, and polyvinylpyrrolidone are preferred. These may be used alone or in combination of two or more.

[0017] Examples of disintegrants that can be used in the present invention include crystalline cellulose, carboxymethylcellulose (carmellose), croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, crospovidone, hydroxypropyl starch, starch, partially pregelatinized starch, sodium starch glycolate, calcium carbonate, precipitated calcium carbonate, calcium citrate, light anhydrous silicic acid, synthetic aluminum silicate, and the like. Preferred are croscarmellose sodium, sodium starch glycolate, and crospovidone, and more preferred is crospovidone. Further, examples of the crospovidone used in the present invention include Polyplasdone (registered trademark) XL, Polyplasdone (registered trademark) XL-10, Polyplasdone (registered trademark) INF-10 (all manufactured by Ashland), Kollidon (registered trademark) CL, Kollidon (registered trademark) CL-F, Kollidon (registered trademark) CL-SF, Kollidon (registered trademark) CL-M, etc., preferably Kollidon CL, Kollidon CL-F, Kollidon CL-SF, Kollidon CL-M (all manufactured by BASF Japan), and particularly preferably Kollidon CL-F. The amount of the disintegrant used is preferably 5 to 30% by mass in the core particles, more preferably 5 to 15% by mass. When incorporated into an orally disintegrating tablet, it is preferably 1 to 10% by mass in the powder, more preferably 2 to 6% by mass.

[0018] In the present invention, excipients other than the sugar alcohols and disaccharides described in the claims can be used in combination in the powder, for example, celluloses such as crystalline cellulose, ethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose, etc.), starches such as corn starch, potato starch, wheat starch, rice starch, partially gelatinized starch, hydroxypropyl starch, etc., glycerin fatty acid esters, magnesium aluminometasilicate, synthetic hydrotalcite, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium hydrogen phosphate hydrate, sodium hydrogen carbonate, etc. The excipients can be blended in an amount of 10 to 70% by mass in the solid preparation.

[0019] The enteric polymers 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), methacrylic acid copolymer LD (e.g., Eudragit (registered trademark) Examples of the coating base include enteric methacrylic acid copolymers such as Eudragit L100-55, Eudragit L30D-55, manufactured by Evonik, methyl acrylate-methyl methacrylate-methacrylic acid copolymer (e.g., Eudragit FS30D, manufactured by Evonik), enteric cellulose polymers such as hydroxypropyl methylcellulose phthalate (manufactured by Shin-Etsu Chemical Co., Ltd.), hydroxypropyl methylcellulose acetate succinate (manufactured by Shin-Etsu Chemical Co., Ltd.) and carboxymethylethylcellulose (manufactured by Freund Corporation), and enteric vinyl alcohol polymers such as polyvinyl alcohol acetate phthalate (manufactured by Colorcon Co., Ltd.), and preferably methacrylic acid copolymers, among which methacrylic acid copolymer L, methacrylic acid copolymer S and methacrylic acid copolymer LD are preferred. These coating bases can be used in combination of one or more types. These enteric polymers may be used in combination of one or more types, but preferably one type. Furthermore, from the viewpoint of preventing damage to the enteric coating, an enteric coating containing an enteric polymer and an ethyl acrylate-methyl methacrylate copolymer is more preferable. The ethyl acrylate-methyl methacrylate copolymer used in the present invention may be a commercially available product, for example, Eudragit (registered trademark) NE30D (manufactured by Evonik). The blending ratio of the enteric polymer to the ethyl acrylate-methyl methacrylate copolymer may be within the range of 6:1 to 1:1 by mass, preferably 5:1 to 1:1, more preferably 4:1 to 1:1. The content of the enteric coating is about 30 to about 80% by weight, preferably about 40 to about 70% by weight, more preferably about 45 to about 65% by weight, based on the weight of the polymer solid content in the coating layer.

[0020] Surfactants that may be used in the present invention include cationic agents such as sodium bis-(2-ethylhexyl) sulfosuccinate (docusate sodium), alkyltrimethylammonium bromides (e.g., cetyltrimethylammonium bromide (cetrimide)), and in particular polyoxyethylene sorbitan (e.g., Tween TM 20, 40, 60, 80 or 85), and other sorbitans (e.g., Span TM 20, 40, 60, 80 or 85).

[0021] Examples of flavoring agents that can be used in the present invention include sugar alcohols, aspartame, stevia, sodium saccharin, dipotassium glycyrrhizinate, thaumatin, acesulfame potassium, sucralose, etc. These may be used alone or in combination of two or more kinds.

[0022] Examples of colorants 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, Food Blue No. 1 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, etc. These may be used alone or in a mixture of two or more kinds.

[0023] The flavors that can be used in the present invention include mint, lemon flavor, orange courtney, pineapple flavor, l-menthol, black tea micron, etc. These may be used alone or in combination of two or more kinds.

[0024] In the present invention, the components to be incorporated in the drug layer are not particularly limited, but include components that are preferably broken down in the stomach or that impart damage or burden to the stomach, and are released through disintegration in the intestines. Examples of such components include pharmaceuticals such as proton pump inhibitors (omeprazole, lansoprazole, etc.), analgesics (aspirin, etc.), duloxetine hydrochloride, salazosulfapyridine, and components used in health foods such as fish oil, garlic, lactic acid bacteria, and bifidobacteria.

[0025] The enteric granules of the present invention may have a two-layer structure consisting of a core containing at least crystalline cellulose or lactose, (1) a drug layer containing a drug, etc., and (2) an enteric layer containing an enteric polymer or an enteric polymer and an ethyl acrylate-methyl methacrylate copolymer, but may also have a multilayer structure containing a drug layer containing a different drug, etc., a dissolution control layer, or a barrier layer that blocks the spaces between the layers, if necessary. The enteric coating is preferably applied to the outermost layer in the multilayer structure. The enteric granules of the present invention can be produced by a generally known method, for example, by producing granules by a fluidized bed granulation method such as tumbling fluidized bed granulation or fluidized bed granulation, a rolling granulation method such as centrifugal rolling granulation, or an agitation granulation method, and then coating the granules with an enteric coating liquid and drying them. The enteric coating solution used in the present invention can be prepared by adding an enteric polymer or an enteric polymer and an ethyl acrylate-methyl methacrylate copolymer to a solvent and removing the solvent as necessary. The solvent used can be water, alcoholic solvents such as methyl alcohol and ethyl alcohol, or a mixture of these. If necessary, additives such as binders, plasticizers, coating bases, surfactants, excipients, etc. can be appropriately blended. The amount of the solvent is not particularly limited, but it can be used in an amount 3 to 10 times the total amount of the dissolved material (enteric polymer, ethyl acrylate-methyl methacrylate copolymer, and additives). There are no particular limitations on the film thickness of the enteric coating of the present invention, but if it is too thin, the effects of the present invention cannot be fully exhibited, and if it is thicker than necessary, the particle size of the granules will become large, which may reduce tablet hardness and cause an unpleasant sensation as roughness when disintegrated in the oral cavity. Therefore, the suitable film thickness is 10 to 100 μm, preferably 45 to 90 μm, and more preferably 50 to 80 μm.

[0026] The enteric preparation of the present invention may be, for example, a solid preparation such as a tablet, an orally disintegrating tablet, a granule, a fine granule, or a capsule, or a liquid preparation such as a suspension. From the viewpoint of ease of handling, tablets and orally disintegrating tablets are preferred. Furthermore, these solid preparations may be coated as necessary.

[0027] The orally disintegrating tablet of the present invention can be produced by a generally known method, for example, by mixing the enteric granule of the present invention and additives (filler, disintegrant, etc.) in the presence or absence of a solvent, molding, and drying as necessary. Mixing can be performed using an apparatus such as a V-type mixer, a universal kneader, a fluidized bed granulator, or a tumbler mixer. The solid preparation of the present invention can be formed into tablets or orally disintegrating tablets by tableting using, for example, a rotary tableting machine. Drying may be carried out by any method generally used for drying pharmaceutical preparations, such as vacuum drying or fluidized bed drying.

[0028] The enteric coated granules and enteric coated preparations of the present invention can be produced, for example, by the following steps. (Step 1: Granule coating steps 1 and 2) Microcrystalline cellulose is placed in a tumbling fluidized bed granulator, and esomeprazole suspension (purified water, esomeprazole magnesium trihydrate, hypromellose, and polysorbate 80) is sprayed onto it for layering. This is followed by drying. After that, coating liquid (purified water, hypromellose, D-mannitol, and talc) is sprayed onto it for coating. This is followed by drying. (Process 2: Granule coating 3 / classification process) The granules produced in step 1 are placed in a tumbling fluidized bed granulator and coated with a coating liquid (purified water, ammonioalkyl methacrylate copolymer, triethyl citrate, polysorbate 80, and glycerin monostearate). After drying, the granules are passed through a sieve for classification. (Process 3: Granule coating 4 / classification process) The classified product produced in step 2 is placed in a tumbling fluidized bed granulator and coated with a coating liquid (purified water, methacrylic acid copolymer LD, ethyl acrylate-methyl methacrylate copolymer, triethyl citrate, ferric oxide, sodium hydroxide, anhydrous citric acid, polysorbate 80, and glycerin monostearate).The product is then dried and classified through a sieve. (Step 4: Mixing step) The classified product produced in step 3 is placed in a V-type blender, and D-mannitol, crospovidone, magnesium aluminometasilicate, and aspartame are added and mixed therein. Then, magnesium stearate is added and mixed. (Process 5: Tableting process) The mixed granules produced in step 4 are compressed into tablets using a rotary tablet press. EXAMPLES

[0029] The present invention will be described in more detail below with reference to examples, comparative examples and test examples, but the present invention is not limited to these.

[0030] (Example 1-1) Process: Manufacturing of enteric coated granules Spherical crystalline cellulose was placed in a tumbling fluidized bed granulator (Freund Corporation, SFC-MINI) and coated with a solution of esomeprazole magnesium trihydrate, hypromellose, and polysorbate 80 dissolved and dispersed in water while spraying. The obtained drug layer-coated particles were dried and then coated with a solution of hypromellose, talc, and D-mannitol dissolved and dispersed in water while spraying. The obtained intermediate layer-coated particles were dried and then coated with a solution of ammonioalkyl methacrylate copolymer dispersion (30% solids), triethyl citrate, glycerin monostearate, and polysorbate 80 dissolved and dispersed in water while spraying. The resulting particles coated with the dissolution control layer were dried and then sprayed with a solution of methacrylic acid copolymer LD (30% solids), ethyl acrylate-methyl methacrylate copolymer dispersion (30% solids), triethyl citrate, glyceryl monostearate, polysorbate 80, sodium hydroxide, anhydrous citric acid, and ferric oxide dissolved and dispersed in water. The resulting enteric layer-coated particles were dried and classified to obtain coated microparticles with an average particle size of 300 μm. The formulation is summarized in Table 1.

[0031] [Table 1]

[0032] (Example 1-2) Process: Tablet manufacturing D-mannitol, crospovidone, magnesium aluminometasilicate, aspartame and magnesium stearate were added as post-powders to the enteric granules obtained in Example 1-1, and mixed to obtain a powder for tableting. The mixture was tableted with a rotary tableting machine (VELA5) at a tableting pressure of 12 kN to obtain tablets with a diameter of 8.0 mm.

[0033] (Examples 1-3) Process: Tablet manufacturing The enteric granules obtained in Example 1-1 were mixed with lactose, crospovidone, magnesium aluminometasilicate, aspartame and magnesium stearate as powders to obtain a powder for tableting. The mixture was compressed with a rotary tableting machine (VELA5) at a compression pressure of 12 kN to obtain tablets with a diameter of 8.0 mm.

[0034] In order to confirm the effect of the present invention, tablets were prepared using crystalline cellulose and anhydrous calcium hydrogen phosphate, which are commonly used as powders. (Comparative Example 1-1) Process: Tablet manufacturing The enteric granules obtained in Example 1-1 were mixed with crystalline cellulose, crospovidone, magnesium aluminometasilicate, aspartame and magnesium stearate as post-powders to obtain a powder for tableting. The mixture was compressed with a rotary tableting machine (VELA5) at a compression pressure of 12 kN to obtain tablets with a diameter of 8.0 mm.

[0035] (Comparative Example 1-2) Process: Tablet manufacturing Anhydrous calcium hydrogen phosphate, crospovidone, magnesium aluminometasilicate, aspartame and magnesium stearate were added as post-powders to the enteric granules obtained in (Example 1-1) and mixed to obtain a powder for tableting. The mixture was tableted with a rotary tableting machine (VELA5) at a tableting pressure of 12 kN to obtain tablets with a diameter of 8.0 mm.

[0036] The formulations of the tablets of (Example 1-2), (Example 1-3), (Comparative Example 1-1) and (Comparative Example 1-2) are summarized in Table 2.

[0037] [Table 2]

[0038] (Test Example 1) The tablets obtained in Example 1-2, Example 1-3, Comparative Example 1-1, and Comparative Example 1-2 were examined for dissolution properties using the first dissolution test fluid (pH 1.2). The results are shown in Table 3.

[0039] [Table 3]

[0040] In the case where D-mannitol was added (Example 1-2) and in the case where lactose was added (Example 1-3), good acid resistance was obtained, and it was found that damage to the enteric coating due to tableting could be reduced. In contrast, in the case where crystalline cellulose was added (Comparative Example 1-1) and in the case where anhydrous calcium hydrogen phosphate was added (Comparative Example 1-2), 10% or more was dissolved, and damage to the enteric coating due to tableting was predicted.

[0041] (Test Example 2) For the tablets obtained in (Example 1-2), (Example 1-3), (Comparative Example 1-1) and (Comparative Example 1-2), the enteric granules in the tablets were observed by a scanning electron microscope (SEM). The results are shown in Figures 1 to 4.

[0042] When D-mannitol was added (Example 1-2) and lactose was added (Example 1-3), no breakage of the enteric granules was observed. In contrast, when crystalline cellulose was added (Comparative Example 1-1) and anhydrous calcium hydrogen phosphate was added (Comparative Example 1-2), breakage of the enteric granules was confirmed.

[0043] From the above results, it was found that damage to the enteric layer was prevented in enteric granules containing a drug and in enteric preparations containing sugar alcohol and / or disaccharide in the rear end.

Claims

1. A solid preparation comprising enteric granules containing a drug and a sugar alcohol and / or disaccharide in a rear end portion, the enteric granules being coated with an enteric coating containing an enteric polymer and an ethyl acrylate-methyl methacrylate copolymer, and the sugar alcohol and / or disaccharide in the rear end portion being contained in an amount of 40% by weight to 80% by weight based on the weight of the solid preparation, the solid preparation being in the form of a tablet.

2. 2. The solid formulation according to claim 1, wherein the sugar alcohol is any one of mannitol, xylitol, sorbitol and erythritol.

3. 3. The solid formulation according to claim 1 or 2, wherein the sugar alcohol is mannitol.

4. The solid formulation according to any one of claims 1 to 3, wherein the disaccharide is any one of sucrose, lactose, maltose and trehalose.

5. The solid formulation according to any one of claims 1 to 4, wherein the disaccharide is lactose.

6. The solid preparation according to any one of claims 1 to 5, wherein the enteric polymer is one or more selected from the group consisting of enteric methacrylic acid copolymers, enteric cellulose-based polymers, and enteric vinyl alcohol-based polymers.

7. The solid formulation described in claim 6, wherein the tablet is an orally disintegrating tablet.

8. A solid formulation described in any one of claims 1 to 7, wherein the drug is an acid-labile drug.

9. The solid formulation described in claim 8, wherein the acid-labile drug is a proton pump inhibitor.

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