Water-insoluble polymer-coated granules, preparations containing the same, orally disintegrating tablets, and methods for producing the same

Abstract

To provide water-insoluble polymer-coated granules suppressing the lowering of the elution rate, which is designed based on a novel indicator, to provide formulations containing the same, and to provide methods for manufacturing the same.SOLUTION: According to one embodiment of the present invention, provided is a water-insoluble polymer coated granule, which contains a drug-containing granule and a water-insoluble polymer coating layer that coats the drug-containing granule, 65% or more of the drug-containing granule having a circularity of 0.7 or more, and the angle of repose of the drug-containing granule being 52° or less.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a water-insoluble polymer-coated granule, a preparation containing the same, and a method for producing the same. [Background technology]

[0002] In pharmaceutical formulations, the dissolution rate of the drug often decreases over time during storage after production. Creating a formulation that maintains the same quality as immediately after production over time is a major challenge in formulation research.

[0003] For example, Patent Document 1 discloses a method for producing a solid formulation containing aripiprazole, in which a suspension of aripiprazole powder in an aqueous solution of a water-soluble polymer is sprayed onto a powdered excipient and wet granulated, thereby suppressing a decrease in dissolution rate during long-term storage.

[0004] Furthermore, Patent Document 2 discloses a solid preparation of pyrrolecarboxamide in which a decrease in dissolution rate is prevented by mixing lactose hydrate with the preparation and having an average particle size in the range of 5 to 50 μm. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent No. 6183979 [Patent Document 2] International Publication No. 2016 / 121664 Summary of the Invention [Problem to be solved by the invention]

[0006] As such, various combinations of additives and combinations of additives and manufacturing methods have been investigated as means of suppressing the decline in dissolution rate of formulations after storage. However, the investigation of additives requires the consideration of a huge number of combinations, including the type and grade of additives, making it difficult to develop formulations that suppress the decline in dissolution rate.

[0007] The present invention aims to solve the above-mentioned problems in formulation development, and one of its objects is to provide water-insoluble polymer-coated granules that are designed based on new indicators and suppress a decrease in dissolution rate, a formulation containing the same, and a method for producing the same. [Means for solving the problem]

[0008] According to one embodiment of the present invention, there is provided water-insoluble polymer-coated granules comprising drug-containing granules and a water-insoluble polymer coating layer covering the drug-containing granules, wherein 65% or more of the drug-containing granules have a circularity of 0.7 or more, and the angle of repose of the drug-containing granules is 52° or less.

[0009] The drug-containing granules may contain memantine hydrochloride, fexofenadine hydrochloride, or irbesartan.

[0010] According to one embodiment of the present invention, there is provided a formulation comprising the above-described water-insoluble polymer-coated granules and one or more pharmaceutically acceptable additives.

[0011] According to one embodiment of the present invention, there is provided an orally disintegrating tablet comprising the above-mentioned water-insoluble polymer-coated granules and one or more pharmaceutically acceptable additives.

[0012] According to one embodiment of the present invention, there is provided a method for producing water-insoluble polymer-coated granules, comprising: granulating a drug and one or more pharmaceutically acceptable additives by a granulation method that applies centrifugal force to obtain drug-containing granules; and coating the obtained drug-containing granules with a water-insoluble polymer, wherein 65% or more of the obtained drug-containing granules have a circularity of 0.7 or more and the angle of repose of the drug-containing granules is 52° or less.

[0013] The drug-containing granules may contain memantine hydrochloride, fexofenadine hydrochloride, or irbesartan.

[0014] According to one embodiment of the present invention, there is provided a method for producing a formulation, which comprises mixing the above-mentioned water-insoluble polymer-coated granules with one or more pharmaceutically acceptable additives, and compressing or encapsulating the resulting mixture.

[0015] According to one embodiment of the present invention, there is provided a method for producing an orally disintegrating tablet, which comprises mixing the above-mentioned water-insoluble polymer-coated granules with one or more pharmaceutically acceptable additives, and compressing the resulting mixture into tablets. [Effects of the Invention]

[0016] According to one embodiment of the present invention, there are provided water-insoluble polymer-coated granules that are designed based on new indicators and suppress the decrease in dissolution rate, a formulation containing the same, and a method for producing the same. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1(a) is a schematic diagram showing a water-insoluble polymer-coated granule according to one embodiment of the present invention, and FIG. 1(b) is a schematic diagram showing a formulation according to one embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0018] The water-insoluble polymer-coated granules, a formulation containing the same, and a method for producing the same according to the present invention are described in detail below. However, the water-insoluble polymer-coated granules, a formulation containing the same, and a method for producing the same according to the present invention should not be construed as being limited to the description of the following embodiments and examples.

[0019] As a result of investigations, the present inventors have found that in a formulation containing drug-containing granules coated with a water-insoluble polymer, the decrease in the drug dissolution rate over time can be reduced by making the shape of the drug-containing granules closer to spherical. Generally, water-insoluble polymer coatings are applied to drug-containing granules for the purposes of masking the bitterness or odor of the drug or preventing contact between the drug and other additives. However, the present invention is a method for suppressing the decrease in the drug dissolution rate over time by applying a water-insoluble polymer coating to drug-containing granules, and is therefore different from conventional water-insoluble polymer coating techniques for masking or preventing contact.

[0020] [Water-insoluble polymer coated granules] FIG. 1(a) is a schematic diagram showing a water-insoluble polymer-coated granule 10 according to one embodiment of the present invention. The water-insoluble polymer-coated granule 10 according to the present invention comprises drug-containing granules 11 and a water-insoluble polymer coating layer 13 covering the drug-containing granules 11. More than 65% of the drug-containing granules 11 have a circularity of 0.7 or greater, and the angle of repose of the drug-containing granules 11 is 52° or less. Preferably, in the water-insoluble polymer-coated granules 10 according to the present invention, more than 70% of the drug-containing granules 11 have a circularity of 0.7 or greater, and the angle of repose of the drug-containing granules 11 is 50° or less. It has not been previously reported that the circularity distribution and angle of repose of the drug-containing granules 11 before coating are related to the dissolution rate of the formulation 100, and this is a new finding in the present application.

[0021] In this specification, the circularity of the drug-containing granules 11 is measured using a particle image analyzer (Malvern Panalytical, Morphologi 4-ID). Furthermore, the phrase "65% or more of the drug-containing granules have a circularity of 0.7 or greater" defines the structural characteristics calculated using the particle image analyzer (Malvern Panalytical, Morphologi 4-ID). Particles with a circle-equivalent diameter of <4.00, a perimeter envelopment ratio of <0.800, and an area envelopment ratio of <0.800 are filtered out for analysis.

[0022] In this specification, the angle of repose of drug-containing granules 11 is measured using a repose angle measuring device (ABD Powder Property Measuring Device, manufactured by Tsutsui Scientific Instruments Co., Ltd.).

[0023] The drug contained in drug-containing granules 11 is not particularly limited. For example, drug-containing granules 11 may contain an unpleasant-tasting drug substance as the drug. In one embodiment, drug-containing granules 11 may contain a drug or a salt thereof selected from, but not limited to, memantine, fexofenadine, angiotensin II receptor antagonists such as irbesartan, candesartan, and valsartan, DPP-IV inhibitors such as teneligliptin and linagliptin, clarithromycin, and donepezil.

[0024] Drug-containing granules 11 may also contain one or more pharmaceutically acceptable additives, such as, but not limited to, excipients, binders, and disintegrants.

[0025] The excipient may be selected from, for example, sugars, sugar alcohols, starches, celluloses, carmelloses, gum arabic, dextran, pullulan, silicates, phosphates, carbonates, sulfates, etc. Examples of sugars include lactose, sucrose, glucose, trehalose, maltose, etc. Examples of sugar alcohols include mannitol, erythritol, xylitol, sorbitol, isomalt, etc. Examples of starches include corn starch, potato starch, pregelatinized starch, partially pregelatinized starch, dextrin, etc. Examples of celluloses include crystalline cellulose, low-substituted hydroxypropyl cellulose, etc. Examples of carmelloses include carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, etc. Examples of silicates include light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium aluminometasilicate, etc. Examples of phosphates include calcium hydrogen phosphate, etc. Examples of carbonates include calcium carbonate, magnesium carbonate, etc. Examples of sulfates include calcium sulfate, etc. These excipients can be used alone or in combination of two or more.

[0026] The binder can be selected from, for example, celluloses such as crystalline cellulose, hydroxypropyl cellulose, hypromellose, hydroxyethylmethyl cellulose, ethyl cellulose, and methyl cellulose; vinyl polymers such as povidone, polyvinyl acetal diethylaminoacetate, fully saponified polyvinyl alcohol, partially saponified polyvinyl alcohol, carboxyvinyl polymer, and polyvinyl chloride; acrylic polymers such as aminoalkyl methacrylate copolymers (E, RS), methacrylic acid copolymers (L, S, LD), and ethyl acrylate-methyl methacrylate copolymer dispersions; stearyl alcohol, gelatin, dextrin, gum arabic, pullulan, macrogol, starch, and the like.

[0027] The disintegrant can be selected from, for example, celluloses such as carmellose, carmellose calcium, low-substituted hydroxypropyl cellulose, croscarmellose sodium and methylcellulose; starches such as partially pregelatinized starch and corn starch; crospovidone; and the like.

[0028] The water-insoluble polymer-coated granules according to the present invention can be designed based on a new index, thereby suppressing the decrease in dissolution rate.

[0029] [formulation] FIG. 1(b) is a schematic diagram showing a formulation 100 according to one embodiment of the present invention. The formulation 100 according to the present invention comprises water-insoluble polymer-coated granules 10 and one or more pharmaceutically acceptable additives 101. In one embodiment, the formulation 100 may be in the form of tablets such as regular tablets, sublingual tablets, or orally disintegrating tablets; capsules such as soft capsules or microcapsules; granules; fine granules; powders; pills; chewable tablets, or lozenges. In one embodiment, the water-insoluble polymer-coated granules 10 are suitable for use in orally disintegrating tablets.

[0030] Examples of additives 101 contained in formulation 100 include, but are not limited to, excipients, binders, disintegrants, emulsifiers, lubricants, stabilizers, flavoring agents, and coloring agents. The excipients, binders, and disintegrants can be selected from the additives described above.

[0031] The emulsifier can be selected from, for example, colloidal clays such as bentonite or veegum, metal hydroxides such as magnesium hydroxide or aluminum hydroxide, anionic surfactants such as sodium lauryl sulfate or calcium stearate, cationic surfactants such as benzalkonium chloride, or nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, or sucrose fatty acid esters. These emulsifiers can be used alone or in combination of two or more.

[0032] The lubricant can be selected from, for example, hydrous silicon dioxide, light anhydrous silicic acid, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, talc, leucine, and the like.

[0033] The stabilizer can be selected from, for example, ascorbic acid, sodium ascorbate, aspartic acid, sodium aspartate, arginine, sodium edetate, anhydrous citric acid, citric acid hydrate, sodium citrate hydrate, sodium hydroxide, magnesium hydroxide, stearic acid, potassium carbonate, potassium bicarbonate, sodium bicarbonate, magnesium carbonate, etc. These stabilizers can be used alone or in combination of two or more.

[0034] The flavoring agent can be selected from, for example, ascorbic acid, aspartic acid, sodium aspartate, aspartame, caramel, reduced maltose syrup, glycyrrhizic acid, saccharin, saccharin sodium, sucralose, purified stevia extract, refined white sugar, citric acid, malic acid, tartaric acid, menthol, etc.

[0035] The colorant can be selected from, for example, iron oxides (iron sesquioxide, etc.), titanium oxide, tar dyes, lake dyes, and the like.

[0036] The formulation according to the present invention can suppress the decrease in dissolution rate by including water-insoluble polymer-coated granules designed based on new indicators.

[0037] [Method for producing water-insoluble polymer-coated granules] The water-insoluble polymer-coated granules according to the present invention can be produced by granulating a drug and one or more pharmaceutically acceptable additives by a centrifugal granulation method. Examples of "centrifugal granulation methods" include tumbling fluidized bed granulation and stirring / kneading granulation.

[0038] Known coating methods can be used to coat drug-containing granules with water-insoluble polymers, such as, but not limited to, one or more selected from the group consisting of aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, and ethyl cellulose.

[0039] [Manufacturing method of the formulation] The above-described formulation according to the present invention can be produced by mixing the water-insoluble polymer-coated granules with one or more pharmaceutically acceptable additives and tableting or encapsulating the resulting mixture. The mixture may be tableted using a known tablet press, or may be encapsulated in a capsule or packaging material. [Example]

[0040] The water-insoluble polymer-coated granules according to the present invention and preparations containing the same will now be described in detail with reference to specific examples and test results.

[0041] [Example 1] Drug-containing granules containing memantine hydrochloride as the drug were produced by agitation granulation. Memantine hydrochloride is a drug described as slightly soluble in water in the Memary® Tablet Pharmaceutical Interview Form, 18th Edition. 60.0 g of memantine hydrochloride, 121.2 g of D-mannitol (Rocket Co., Ltd., Pearitol 25C), 24.0 g of crystalline cellulose (Asahi Kasei Corporation, Ceolus® PH101), 13.2 g of carmellose calcium (Gotoku Pharmaceutical Co., Ltd., ECG®-505), and 7.2 g of hydroxypropyl cellulose (Nippon Soda Co., Ltd., HPC-L(FP)) were mixed using a high-speed mixer (Fukae Powtec Co., Ltd., LFS-GS-2J). 90.4 g of purified water was added to the high-speed mixer and kneaded to obtain a granule. The granules were sieved through a No. 22 sieve to produce the drug-containing granules of Example 1.

[0042] A coating solution was prepared by dispersing 325 g of methacrylic acid copolymer LD (Higuchi Shokai Co., Ltd., Eudragit L30D-55), 9.8 g of triethyl citrate (Morimura Shoji Co., Ltd., Citroflex® 2), and 48.8 g of talc (Fuji Talc Industrial Co., Ltd., talc) in 243.8 g of purified water. 244.4 g of the drug-containing granules of Example 1 were placed in a fluidized bed granulator (Powrex Corporation, MP01), and the coating solution was added to form a water-insoluble polymer coating layer. This yielded the water-insoluble polymer-coated granules of Example 1.

[0043] 336.0 g of D-mannitol (Mannit P, Mitsubishi Corporation Foodtech Co., Ltd.) and 152.0 g of crystalline cellulose (CEOLUS® KG-1000, Asahi Kasei Corporation) were mixed in a fluidized bed granulator (Powrex Corporation, MP01), and a granulation liquid prepared by dissolving 30.0 g of pregelatinized starch (SWELSTAR® PD-1, Asahi Kasei Corporation) in 344.4 g of purified water was added to produce granules containing no active pharmaceutical ingredient.

[0044] The water-insoluble polymer-coated granules of Example 1, active ingredient-free granules, 25.2 g of crospovidone (BASF, Kollidon CL-F), 15.0 g of aspartame (Ajinomoto Co., Inc., Aspartame), and 0.3 g of flavoring (Sanei Gen FFI, Sunfix Natural Strawberry) were mixed together, and 4.2 g of magnesium stearate (Taihei Chemical Industry Co., Ltd., Plant) was added and further mixed, followed by tableting to produce the orally disintegrating tablet of Example 1.

[0045] [Comparative Example 1] Water-insoluble polymer-coated granules containing memantine hydrochloride as a drug were prepared by fluidized bed granulation. 110.0 g of memantine hydrochloride, 222.0 g of D-mannitol (Mannit P, Mitsubishi Corporation Foodtech Co., Ltd.), 44.0 g of microcrystalline cellulose (Ceolas® PH101, Asahi Kasei Corporation), and 24.2 g of carmellose calcium (ECG®-505, Gotoku Pharmaceutical Co., Ltd.) were mixed using a fluidized bed granulator (Powrex Corporation MP01). A granulation solution prepared by dissolving 13.2 g of hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd.) in 206.3 g of purified water was added to the fluidized bed granulator and granulated to obtain a granule. The granules were sieved through a No. 22 sieve to produce the drug-containing granules of Comparative Example 1.

[0046] The water-insoluble polymer-coated granules of Comparative Example 1 were obtained in the same manner as in Example 1, except that the drug-containing granules of Comparative Example 1 were used. The orally disintegrating tablet of Comparative Example 1 was produced in the same manner as in Example 1, except that the water-insoluble polymer-coated granules of Comparative Example 1 were used.

[0047] [Dissolution] The orally disintegrating tablets of Example 1 and Comparative Example 1 were stored under accelerated conditions (40°C, 75% RH, open state) for 2 weeks. Using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.), in accordance with Dissolution Test Method 2 (paddle method, 50 rpm) of the Japanese Pharmacopoeia, Seventeenth Edition, 900 mL of Dissolution Test Fluid 1 of the Japanese Pharmacopoeia, Seventeenth Edition, was used as the test fluid to conduct dissolution tests on the orally disintegrating tablets of Example 1 and Comparative Example 1 before and after storage. The dissolution tests were conducted three times using one orally disintegrating tablet from each of Example 1 and Comparative Example 1 as a sample, and the average values ​​measured at 5, 10, and 15 minutes after the start of the test were used to represent the dissolution rates of memantine hydrochloride from the orally disintegrating tablets of Example 1 and Comparative Example 1. Table 1 also shows the percentage change (%) in the dissolution rate of memantine hydrochloride from the orally disintegrating tablets after storage relative to the dissolution rate of memantine hydrochloride from the orally disintegrating tablets before storage.

[0048] [Table 1]

[0049] The results in Table 1 show that when orally disintegrating tablets containing the water-insoluble polymer-coated granules of Comparative Example 1 granulated by fluidized bed granulation were stored under accelerated conditions (40°C, 75% RH, open state), a significant delay in dissolution of memantine hydrochloride was observed compared to the orally disintegrating tablets before storage. On the other hand, when orally disintegrating tablets containing the water-insoluble polymer-coated granules of Example 1 granulated by agitation granulation were stored under accelerated conditions (40°C, 75% RH, open state), the delay in dissolution was suppressed.

[0050] [Example 2] In Example 2, drug-containing granules with an average circularity of 0.75 were produced by agitation granulation. 220.0 g of memantine hydrochloride, 112.2 g of D-mannitol (Mannit C, Mitsubishi Corporation Foodtech Co., Ltd.), 44.0 g of crystalline cellulose (Ceolas® PH101, Asahi Kasei Corporation), 24.2 g of carmellose calcium (ECG®-505, Gotoku Pharmaceutical Co., Ltd.), and 13.2 g of hydroxypropyl cellulose (HPC-L(FP), Nippon Soda Co., Ltd.) were mixed using a high-speed mixer (LFS-GS-5J, Fukae Powtec Co., Ltd.). 64.8 g of purified water was added to the high-speed mixer and kneaded to obtain a granule. The granules were sieved through a No. 22 sieve to produce the drug-containing granules of Example 2.

[0051] A coating solution was prepared by dispersing 135.0 g of methacrylic acid copolymer LD (Higuchi Shokai Co., Ltd., Eudragit L30D-55), 4.1 g of triethyl citrate (Morimura Shoji Co., Ltd., Citroflex® 2), and 20.3 g of talc (Fuji Talc Industrial Co., Ltd., talc) in 50.6 g of purified water. 101.5 g of the drug-containing granules of Example 2 were placed in a fluidized bed granulator (Powrex Corporation, MP01), and the coating solution was added by top spray to form a water-insoluble polymer coating layer. The coated granules were sieved through a No. 22 sieve to obtain the water-insoluble polymer-coated granules of Example 2.

[0052] 73.9 g of the water-insoluble polymer-coated granules of Example 2, 88.2 g of D-mannitol (ROQUETTE, Pearitol 200SD), 5.0 g of crospovidone (BASF, Kollidon CL-F), and 0.8 g of magnesium stearate (Taihei Chemical Industry Co., Ltd., Plant) were mixed together and compressed into tablets to produce the orally disintegrating tablets of Example 2.

[0053] [Examples 3 to 4] Using the same manufacturing method as in Example 2, drug-containing granules having an average circularity of 0.77 were produced as Example 3, except that the purified water used during kneading was changed to 78.0 g. Furthermore, using the same manufacturing method as in Example 2, drug-containing granules having an average circularity of 0.79 were produced as Example 4, except that the purified water used during kneading was changed to 71.7 g. Water-insoluble polymer-coated granules of Examples 3 to 4 were obtained using the same manufacturing method as in Example 2. Orally disintegrating tablets of Examples 3 to 4 were obtained using the water-insoluble polymer-coated granules of Examples 3 to 4, using the same manufacturing method as in Example 2.

[0054] Comparative Example 2 Drug-containing granules with an average circularity of 0.72 were produced using the same manufacturing method as in Example 2, except that the amount of purified water used during kneading was changed to 28.4 g, and water-insoluble polymer-coated granules of Comparative Example 2 were obtained using the same manufacturing method as in Example 2. Orally disintegrating tablets of Comparative Example 2 were obtained using the water-insoluble polymer-coated granules of Comparative Example 2 using the same manufacturing method as in Example 2.

[0055] Circularity The drug-containing granules were measured using a particle image analyzer (Malvern Panalytical, Morphologi 4-ID). The proportion of particles with a circularity of 0.7 or greater was also calculated using the particle image analyzer (Malvern Panalytical, Morphologi 4-ID). Particles with a circular equivalent diameter of <4.00, a perimeter envelopment ratio of <0.800, and an area envelopment ratio of <0.800 were filtered out for analysis.

[0056] Aspect Ratio The drug-containing granules were measured using a particle image analyzer (Malvern Panalytical, Morphologi 4-ID). The proportion of particles with an aspect ratio of 0.5 or greater was also calculated using the particle image analyzer (Malvern Panalytical, Morphologi 4-ID). Particles with a circular equivalent diameter of <4.00, a perimeter envelopment ratio of <0.800, and an area envelopment ratio of <0.800 were filtered out for analysis.

[0057] [Angle of repose] The angle of repose of the drug-containing granules was measured using a repose angle measuring device (Tsutsui Scientific Instruments Co., Ltd., ABD Powder Property Measuring Device).

[0058] The circularity, aspect ratio, and angle of repose of the drug-containing granules of Examples 2 to 4 and Comparative Example 2 are shown in Table 2. [Table 2]

[0059] [Dissolution] The orally disintegrating tablets of Examples 2 to 4 and Comparative Example 2 were stored under accelerated conditions (40°C, 75% RH, open state) for 2 weeks. Using the same method as in Example 1, dissolution tests were conducted on the orally disintegrating tablets of Examples 2 to 4 and Comparative Example 2 before and after storage. The dissolution tests were conducted three times using one orally disintegrating tablet from each of Examples 2 to 4 and Comparative Example 2 as a sample, and the average dissolution rate at 60 minutes after the start of the dissolution test was recorded as the dissolution rate (%) of the orally disintegrating tablets of Examples 2 to 4 and Comparative Example 2. The results of the dissolution rate measurements are shown in Table 3. Table 3 also shows the rate of change (%) of the dissolution rate of memantine hydrochloride from the orally disintegrating tablets after storage relative to the dissolution rate of memantine hydrochloride from the orally disintegrating tablets before storage.

[0060] [Table 3]

[0061] The results in Table 3 show that for the orally disintegrating tablets of Examples 2 to 4, which used drug-containing granules with average circularity of 0.75, 0.77, and 0.79, respectively, the decrease in dissolution rate at 60 minutes was within 15%, assuming the drug dissolution rate of the orally disintegrating tablet before storage to be 100%. Furthermore, for the orally disintegrating tablets of Examples 3 and 4, which used drug-containing granules with average circularity of 0.77 and 0.79, the decrease in dissolution rate at 60 minutes was within 10%. On the other hand, for the orally disintegrating tablet of Comparative Example 2, which used drug-containing granules with an average circularity of 0.72, the decrease in dissolution rate at 60 minutes was 15% or more.

[0062] Referring to Table 2, the drug-containing granules of Examples 2 to 4 had a circularity of 0.7 or more and an angle of repose of 52° or less, accounting for 65% or more of the total drug-containing granules. It was demonstrated that a decrease in the drug dissolution rate can be significantly suppressed in a preparation in which drug-containing granules having such structural characteristics are used as water-insoluble polymer-coated granules.

[0063] Comparative Example 3 In Comparative Example 3, fexofenadine hydrochloride was used as the drug, and drug-containing granules with an average circularity of 0.75 were produced. Note that fexofenadine hydrochloride is a drug listed as sparingly soluble in water in the 17th edition of the Japanese Pharmacopoeia. 150.0 g of fexofenadine hydrochloride, 303.0 g of D-mannitol (Mannit C, Mitsubishi Corporation Foodtech Co., Ltd.), 60.0 g of crystalline cellulose (Ceolas® PH101, Asahi Kasei Corporation), 33.0 g of carmellose calcium (ECG®-505, Gotoku Pharmaceutical Co., Ltd.), and 18.0 g of hydroxypropyl cellulose (HPC-L(FP), Nippon Soda Co., Ltd.) were mixed using a high-speed mixer (LFS-GS-5J, Fukae Powtec Co., Ltd.). 48.5 g of purified water was added to the high-speed mixer and kneaded to obtain a granule. The granules were sieved through a No. 22 sieve to produce drug-containing granules of Comparative Example 3.

[0064] A coating solution was prepared by dispersing 160.0 g of methacrylic acid copolymer LD (Higuchi Shokai Co., Ltd., Eudragit L30D-55), 4.8 g of triethyl citrate (Morimura Shoji Co., Ltd., Citroflex® 2), and 24.0 g of talc (Fuji Talc Industrial Co., Ltd., talc) in 60.0 g of purified water. 120.3 g of the drug-containing granules of Comparative Example 3 were placed in a fluidized bed granulator (Powrex Corporation, MP01), and the coating solution was added by top spray to form a water-insoluble polymer coating layer. The coated granules were sieved through a No. 22 sieve to obtain the water-insoluble polymer-coated granules of Comparative Example 3.

[0065] 61.6 g of the water-insoluble polymer-coated granules of Comparative Example 3, 73.5 g of D-mannitol (ROQUETTE, Pearitol 200SD), 4.2 g of crospovidone (BASF, Kollidon CL-F), and 0.7 g of magnesium stearate (Taihei Chemical Industry Co., Ltd., Plant) were mixed together and compressed into tablets to produce the orally disintegrating tablets of Comparative Example 3.

[0066] [Example 5] Using the same manufacturing method as in Comparative Example 3, drug-containing granules with an average circularity of 0.81 were produced, except that the amount of purified water used during kneading was changed to 160.0 g, and the water-insoluble polymer-coated granules of Example 5 were obtained using the same manufacturing method as in Comparative Example 3. The orally disintegrating tablets of Example 5 were obtained using the water-insoluble polymer-coated granules of Example 5 using the same manufacturing method as in Comparative Example 3.

[0067] The measurement results of the circularity, aspect ratio, and angle of repose for the drug-containing granules of Example 5 and Comparative Example 3 are shown in Table 4. [Table 4]

[0068] [Dissolution] The orally disintegrating tablets of Example 5 and Comparative Example 3 were stored under accelerated conditions (40°C, 75% RH, open state) for 2 weeks. Using the same method as in Example 1, dissolution tests were performed on the orally disintegrating tablets of Example 5 and Comparative Example 3 before and after storage. The dissolution test was performed three times using one orally disintegrating tablet from each of Example 5 and Comparative Example 3 as a sample, and the average value at 360 minutes after the start of the test was taken as the dissolution rate of the orally disintegrating tablets of Example 5 and Comparative Example 3. The dissolution rate measurement results are shown in Table 5.

[0069] [Table 5]

[0070] The results in Table 5 show that, when the drug dissolution rate of the orally disintegrating tablet at the time of manufacture was taken as 100%, the orally disintegrating tablet of Comparative Example 3, which used drug-containing granules with an average circularity of 0.75, had a dissolution rate at 360 minutes that was reduced by 60% or more. However, the orally disintegrating tablet of Example 5, which used drug-containing granules with an average circularity of 0.81, had a reduction in dissolution rate at 360 minutes that was within 10%.

[0071] Referring to Table 4, the drug-containing granules of Example 5 had a circularity of 0.7 or more and an angle of repose of 52° or less, accounting for 65% or more of the total drug-containing granules. It was demonstrated that a formulation in which drug-containing granules having such structural characteristics were used as water-insoluble polymer-coated granules could significantly suppress a decrease in the drug dissolution rate.

[0072] Comparative Example 4 In Comparative Example 4, drug-containing granules with an average circularity of 0.82 were prepared using irbesartan. Irbesartan is a drug listed as practically insoluble in water in the 17th revised Japanese Pharmacopoeia. 240.0 g of irbesartan, 484.8 g of D-mannitol (Mannit C, Mitsubishi Corporation Foodtech Co., Ltd.), 96.0 g of crystalline cellulose (Ceolas® PH101, Asahi Kasei Corporation), 52.8 g of carmellose calcium (ECG®-505, Gotoku Pharmaceutical Co., Ltd.), and 28.8 g of hydroxypropyl cellulose (HPC-L(FP), Nippon Soda Co., Ltd.) were mixed using a high-speed mixer (LFS-GS-5J, Fukae Powtec Co., Ltd.). 129.7 g of purified water was added to the high-speed mixer and kneaded to obtain a granule. The granule was sieved through a No. 22 sieve to produce the drug-containing granules of Comparative Example 4.

[0073] A coating solution was prepared by dispersing 160.0 g of methacrylic acid copolymer LD (Higuchi Shokai Co., Ltd., Eudragit L30D-55), 4.8 g of triethyl citrate (Morimura Shoji Co., Ltd., Citroflex® 2), and 24.0 g of talc (Fuji Talc Industrial Co., Ltd., talc) in 60.0 g of purified water. 120.3 g of the drug-containing granules of Comparative Example 4 were placed in a fluidized bed granulator (Powrex Corporation, MP01), and the coating solution was added by top spray to form a water-insoluble polymer coating layer. The coated granules were sieved through a No. 22 sieve to obtain the water-insoluble polymer-coated granules of Comparative Example 4.

[0074] 61.6 g of the water-insoluble polymer-coated granules of Comparative Example 4, 73.5 g of D-mannitol (ROQUETTE, Pearitol 200SD), 4.2 g of crospovidone (BASF, Kollidon CL-F), and 0.7 g of magnesium stearate (Taihei Chemical Industry Co., Ltd., Plant) were mixed together and compressed into tablets to produce the orally disintegrating tablets of Comparative Example 4.

[0075] [Example 6] Using the same manufacturing method as in Comparative Example 4, drug-containing granules with an average circularity of 0.85 were produced, except that the amount of purified water used during kneading was changed to 227.5 g, and the water-insoluble polymer-coated granules of Example 6 were obtained using the same manufacturing method as in Comparative Example 4. The orally disintegrating tablets of Example 6 were obtained using the water-insoluble polymer-coated granules of Example 6 using the same manufacturing method as in Comparative Example 4.

[0076] [Example 7] Using the same manufacturing method as in Comparative Example 4, drug-containing granules with an average circularity of 0.81 were produced, except that the amount of purified water used during kneading was changed to 310.9 g, and the water-insoluble polymer-coated granules of Example 7 were obtained using the same manufacturing method as in Comparative Example 4. The orally disintegrating tablets of Example 7 were obtained using the water-insoluble polymer-coated granules of Example 7 using the same manufacturing method as in Comparative Example 4.

[0077] Table 6 shows the measurement results of the circularity, aspect ratio, and angle of repose for the drug-containing granules of Examples 6 to 7 and Comparative Example 4. [Table 6]

[0078] [Dissolution] The orally disintegrating tablets of Examples 6 to 7 and Comparative Example 4 were stored under accelerated conditions (40°C, 75% RH, open state) for 2 weeks. Using the same method as in Example 1, dissolution tests were conducted on the orally disintegrating tablets of Examples 6 to 7 and Comparative Example 4 before and after storage. The dissolution tests were conducted three times using one orally disintegrating tablet from each of Examples 6 to 7 and Comparative Example 4 as a sample, and the average value at 60 minutes after the start of the test was taken as the dissolution rate of the orally disintegrating tablets of Examples 6 to 7 and Comparative Example 4. The dissolution rate measurement results are shown in Table 7.

[0079] [Table 7]

[0080] The results in Table 7 show that, when the drug dissolution rate of the orally disintegrating tablet at the time of manufacture was taken as 100%, the orally disintegrating tablet of Comparative Example 4, which used drug-containing granules with an average circularity of 0.82, showed a decrease in dissolution rate of 30% or more at 60 minutes. However, the orally disintegrating tablets of Example 6, which used drug-containing granules with an average circularity of 0.85, and Example 7, which used drug-containing granules with an average circularity of 0.81, showed a decrease in dissolution rate of within 15% at 60 minutes.

[0081] Referring to the results in Table 6, the drug-containing granules of Example 6 had a circularity of 0.7 or more and an angle of repose of 52° or less, accounting for 89% or more of the total drug-containing granules. The drug-containing granules of Example 7 had a circularity of 0.7 or more and an angle of repose of 52° or less, accounting for 80% or more of the total drug-containing granules. It was demonstrated that a formulation in which drug-containing granules having such structural characteristics were converted into water-insoluble polymer-coated granules significantly suppressed a decrease in the drug dissolution rate, even when irbesartan, a drug with low solubility, was used. [Explanation of symbols]

[0082] 10 water-insoluble polymer coated granules, 11 drug-containing granules, 13 water-insoluble polymer coating layer, 100 formulation, 101 additives

Claims

1. drug-containing granules containing a mixture of a drug, D-mannitol, crystalline cellulose, carmellose calcium, and hydroxypropyl cellulose; a water-insoluble polymer coating layer covering the drug-containing granules, the polymer coating layer comprising methacrylic acid copolymer LD, triethyl citrate, and talc; Including, A water-insoluble polymer-coated granule, characterized in that 65% or more of the drug-containing granules have a circularity of 0.7 or more, and the angle of repose of the drug-containing granules is 52° or less.

2. 2. The water-insoluble polymer-coated granule according to claim 1, wherein the drug-containing granule contains memantine hydrochloride, fexofenadine hydrochloride, or irbesartan.

3. The water-insoluble polymer-coated granules according to claim 1 or 2, one or more pharmaceutically acceptable excipients; A formulation comprising:

4. The water-insoluble polymer-coated granules according to claim 1 or 2, one or more pharmaceutically acceptable excipients; An orally disintegrating tablet comprising:

5. A drug, D-mannitol, crystalline cellulose, carmellose calcium, and hydroxypropyl cellulose are granulated by a granulation method using centrifugal force to obtain drug-containing granules; coating the obtained drug-containing granules with a coating liquid containing methacrylic acid copolymer LD, triethyl citrate, and talc; A method for producing water-insoluble polymer-coated granules, characterized in that more than 65% of the obtained drug-containing granules have a circularity of 0.7 or more, and the angle of repose of the drug-containing granules is 52° or less.

6. 6. The method for producing water-insoluble polymer-coated granules according to claim 5, wherein the drug-containing granules contain memantine hydrochloride, fexofenadine hydrochloride, or irbesartan.

7. 3. A method for producing a pharmaceutical composition comprising: mixing the water-insoluble polymer-coated granules according to claim 1 or 2 with one or more pharmaceutically acceptable additives; A method for producing a formulation, comprising compressing the obtained mixture into tablets or encapsulating the tablets.

8. 3. A method for producing a pharmaceutical composition comprising: mixing the water-insoluble polymer-coated granules according to claim 1 or 2 with one or more pharmaceutically acceptable additives; A method for producing an orally disintegrating tablet, comprising tableting the obtained mixture.

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