Manufacturing method of orally disintegrating tablets

Abstract

To provide methods for producing an orally disintegrating tablet that has sufficient hardness to prevent the tablet from cracking during transportation and the handling by healthcare professionals and patients while maintaining rapid disintegration.SOLUTION: The method for producing an orally disintegrating tablet according to an embodiment of the present invention comprises a fluidized bed granulation by spraying or dropping onto an additive a liquid containing hydroxypropyl cellulose having a viscosity of 150 mPa s or more and 400 mPa s or less in a 2% aqueous solution at 20°C. The liquid containing hydroxypropyl cellulose may also be sprayed or dropped onto the additive so that the content of hydroxypropyl cellulose is 0.2 wt.% or more and 5 wt.% or less when the orally disintegrating tablet is 100 wt.%.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a method for producing orally disintegrating tablets and orally disintegrating tablets produced thereby. In particular, the present invention relates to a method for producing orally disintegrating tablets that combine rapid disintegrability with sufficient hardness. [Background technology]

[0002] Orally disintegrating tablets are tablets that disintegrate easily in the oral cavity and are particularly useful for elderly people and young children with poor swallowing ability. Orally disintegrating tablets are required to disintegrate quickly in the oral cavity; for example, disintegration within 30 seconds is desirable. On the other hand, solid tablets in general, including orally disintegrating tablets, require a certain degree of hardness to prevent cracking during transportation or handling by medical professionals or patients. Therefore, the development of orally disintegrating tablets faces a major challenge: imparting the contradictory properties of rapid disintegration and high tablet hardness to orally disintegrating tablets.

[0003] For example, Patent Document 1 describes an orally disintegrating granular preparation containing (1) a medicinal ingredient, (2) a sugar alcohol selected from the group consisting of erythritol, xylitol, and sorbitol, and (3) polyvinylpyrrolidone having a number-average molecular weight of 20,000 to 50,000, and having a water activity value of 15 or less. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Patent No. 3274416 Summary of the Invention [Problem to be solved by the invention]

[0005] Provided is a method for producing an orally disintegrating tablet that maintains rapid disintegrability while having sufficient hardness to prevent the tablet from cracking during transportation or handling by medical professionals or patients. [Means for solving the problem]

[0006] According to one embodiment of the present invention, there is provided a method for producing an orally disintegrating tablet, which comprises spraying or dropping a liquid containing hydroxypropyl cellulose, the viscosity of which as a 2% aqueous solution at 20°C is 150 mPa s or more and 400 mPa s or less, onto an excipient, followed by fluidized bed granulation.

[0007] The liquid containing the hydroxypropyl cellulose may be sprayed or dropped onto the additive so that the content of the hydroxypropyl cellulose is 0.2% by weight or more and 5% by weight or less, based on 100% by weight of the orally disintegrating tablet.

[0008] The liquid containing the hydroxypropyl cellulose may be sprayed or dropped onto the additive so that the content of the hydroxypropyl cellulose is 0.2% by weight or more and 2% by weight or less, based on 100% by weight of the orally disintegrating tablet.

[0009] The liquid containing hydroxypropyl cellulose may be prepared by dissolving hydroxypropyl cellulose and a sweetener, and the additive may be prepared by mixing an excipient and a disintegrant.

[0010] The pharmaceutically active ingredient may be dissolved or dispersed in the liquid containing the hydroxypropyl cellulose, or the pharmaceutically active ingredient may be mixed with the additive.

[0011] According to one embodiment of the present invention, a hydroxypropyl cellulose-containing particle having a viscosity of 150 mPa·s or more and 400 mPa·s or less in a 2% aqueous solution at 20°C is provided, and the particle has a bulk density of 0.40 g / cm. 3 An orally disintegrating tablet is provided, characterized in that:

[0012] The content of the hydroxypropyl cellulose may be 0.2% by weight or more and 5% by weight or less, based on 100% by weight of the orally disintegrating tablet.

[0013] The content of the hydroxypropyl cellulose may be 0.2% by weight or more and 2% by weight or less, relative to 100% by weight of the orally disintegrating tablet. [Effects of the Invention]

[0014] According to one embodiment of the present invention, there is provided a method for producing an orally disintegrating tablet that maintains rapid disintegrability while having sufficient hardness to prevent the tablet from cracking during transportation or handling by medical professionals or patients. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 is a flow chart illustrating a method for producing an orally disintegrating tablet according to one embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0016] The method for producing an orally disintegrating tablet and the orally disintegrating tablet according to the present invention will be described below. However, the method for producing an orally disintegrating tablet and the orally disintegrating tablet according to the present invention should not be construed as being limited to the description of the following embodiments and examples.

[0017] As a result of investigations, the present inventors have found that by performing fluidized bed granulation using a granulation liquid containing a specific grade of hydroxypropyl cellulose, it is possible to produce orally disintegrating tablets that maintain rapid disintegrability while having sufficient hardness to prevent the tablets from cracking during transportation or when handled by medical professionals or patients.

[0018] [Manufacturing method of orally disintegrating tablets] The orally disintegrating tablet according to the present invention can be produced by spraying or dropping a liquid containing hydroxypropyl cellulose (hereinafter also referred to as HPC), which has a viscosity of 150 mPa·s or more and 400 mPa·s or less in a 2% aqueous solution at 20°C, onto an additive, followed by fluidized bed granulation. Figure 1 is a flow diagram illustrating a method for producing an orally disintegrating tablet according to one embodiment of the present invention.

[0019] When using HPC as a binder in the manufacture of orally disintegrating tablets, it is common to use low-viscosity grades of HPC to prevent a decrease in disintegration. Commercially available low-viscosity grades of HPC include Nippon Soda's SSL (viscosity of 2 mPa·s to 2.9 mPa·s in a 2% aqueous solution at 20°C, average molecular weight 40,000), SL (viscosity of 3 mPa·s to 5.9 mPa·s in a 2% aqueous solution at 20°C, average molecular weight 100,000), and L (viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C, average molecular weight 140,000). However, even with these low-viscosity grades of HPC, it is difficult to achieve sufficient tablet hardness to prevent cracking during transportation and handling by healthcare professionals and patients. Commercially available examples of high-viscosity grade HPCs with a viscosity of more than 400 mPa·s in a 2% aqueous solution at 20°C include Nippon Soda's H (viscosity of 1000 mPa·s to 4000 mPa·s in a 2% aqueous solution at 20°C, average molecular weight of 1,000,000) and VH (viscosity of 4001 mPa·s to 6000 mPa·s in a 2% aqueous solution at 20°C, average molecular weight of 2,500,000). However, these high-viscosity grade HPCs are not preferred because they have high viscosity when prepared as a granulation solution, making them less manufacturable. The average molecular weight is measured by gel permeation chromatography (GPC).

[0020] As an HPC having a viscosity of 150 mPa·s or more and 400 mPa·s or less in a 2% aqueous solution at 20° C., for example, M manufactured by Nippon Soda Co., Ltd. can be used. The average molecular weight is 700,000.

[0021] In one embodiment, any known pharmaceutically acceptable solvent capable of dissolving HPC can be used as the solvent used to prepare a solution containing HPC, the viscosity of which as a 2% aqueous solution at 20° C. is 150 mPa·s or more and 400 mPa·s or less. Examples of solvents that can be used include, but are not limited to, purified water, organic solvents such as methanol, ethanol, isopropanol, propylene glycol, and methylene chloride, and mixtures of purified water with these organic solvents.

[0022] In one embodiment, a liquid containing HPC, which has a viscosity of 150 mPa s to 400 mPa s in a 2% aqueous solution at 20°C, is sprayed or dropped onto the additive so that the content of HPC, relative to 100% by weight of the orally disintegrating tablet, is 0.2% by weight to 5% by weight. In another embodiment, a liquid containing HPC may be sprayed or dropped onto the additive so that the content of HPC, relative to 100% by weight of the orally disintegrating tablet, is 0.2% by weight to 2% by weight.

[0023] In one embodiment, the liquid containing HPC may contain a sweetener, which may be any known pharmaceutically acceptable additive that is soluble in the above-mentioned solvent. Examples of sweeteners include aspartame, hyacinth, hyacinth powder, liquid sugar, fructose, high-fructose corn syrup, reduced maltose starch syrup, licorice, licorice extract, crude licorice extract, licorice powder, xylitol, glycine, glycerin, dipotassium glycyrrhizinate, disodium glycyrrhizinate, monoammonium glycyrrhizinate, brown sugar, high-fructose corn syrup, high-glucose corn syrup, saccharin, saccharin sodium hydrate, sucralose, stevia extract, purified stevia extract, refined white sugar, refined white sugar spheres, refined honey, D-sorbitol, D-sorbitol liquid, simple syrup, lactose hydrate, concentrated glycerin, white sugar, honey, glucose, glucose-fructose corn syrup, powdered reduced maltose starch syrup, maltitol, maltitol liquid, maltose hydrate, D-mannitol, and starch syrup, but are not limited to these. There is no particular limitation on the amount of sweetener added, but it is sufficient to add a small amount that can mask the bitterness of other additives.

[0024] HPC, which has a viscosity of 150 mPa·s or more and 400 mPa·s or less in a 2% aqueous solution at 20°C, and a sweetener are dissolved in a solvent to prepare a granulation liquid containing HPC (S101).

[0025] Examples of additives (first additives) used in fluidized bed granulation include excipients and disintegrants. Known additives added to orally disintegrating tablets can be used as excipients and disintegrants. Examples of excipients include, but are not limited to, lactose, crystalline cellulose, D-mannitol, erythritol, xylitol, sorbitol, isomalt, maltitol, sucrose, sucrose, glucose, and partially pregelatinized starch. One or more of these additives can be used as excipients. The excipient is preferably contained in an amount of 50.0% by weight to 97.0% by weight relative to 100% by weight of the orally disintegrating tablet.

[0026] Examples of disintegrants include, but are not limited to, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, hydroxypropyl starch, carboxymethyl starch sodium, crospovidone, powdered agar, and partially pregelatinized starch. One or more of these additives can be used as the disintegrant.

[0027] The excipient and disintegrant are fed into a fluidized bed granulator, and the granulation liquid is sprayed or dropped to perform fluidized bed granulation (S103). The granulated product is dried (S105).

[0028] In one embodiment, a pharmaceutically active ingredient may be dissolved or dispersed in a liquid containing HPC. Alternatively, a pharmaceutically active ingredient may be mixed with an additive for fluidized bed granulation. The pharmaceutically active ingredient contained in the orally disintegrating tablet is not particularly limited, and known ingredients can be used to produce the orally disintegrating tablet.

[0029] The dried granules are sieved and sized (S107). The sized powder is mixed with other additives (second additives) to obtain a powder before tableting (S109).

[0030] Examples of other additives include disintegrants, glidants, and lubricants. The disintegrant can be one or more selected from the disintegrants described above. The total amount of disintegrants added to the first additive and the second additive is preferably 1.0% by weight or more and 40.0% by weight or less, based on 100% by weight of the orally disintegrating tablet.

[0031] As the fluidizer and lubricant, known additives added to orally disintegrating tablets can be used. Examples of fluidizers include, but are not limited to, magnesium aluminometasilicate, hydrous silicon dioxide, light anhydrous silicic acid, and calcium silicate. One or more of these additives can be used as the fluidizer. The fluidizer is preferably contained in an amount of 0.1% by weight to 5.0% by weight based on 100% by weight of the orally disintegrating tablet. Examples of lubricants include, but are not limited to, light anhydrous silicic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, and hydrogenated oil. One or more of these additives can be used as the lubricant. The lubricant is preferably contained in an amount of 0.1% by weight to 5.0% by weight based on 100% by weight of the orally disintegrating tablet.

[0032] The powder before tableting is fed to a tablet press and tableted (S111). In this way, orally disintegrating tablets can be produced. The produced orally disintegrating tablets are then packaged appropriately (S113).

[0033] [Oru-disintegrating tablet] The orally disintegrating tablet produced by the production method of the present invention contains particles containing HPC, the viscosity of which in a 2% aqueous solution at 20°C is 150 mPa s or more and 400 mPa s or less, and the bulk density of the particles is 0.40 g / cm. 3The particle size is as follows. Here, the particle refers to a particle constituting the sieved powder. The sieved powder contains HPC with such viscosity and has such a low bulk density, so that the tablet can maintain rapid disintegration while having sufficient hardness to prevent cracking during transportation or handling by medical professionals or patients. [Example]

[0034] [Example 1] In Example 1, an orally disintegrating tablet containing 0.02% by weight of HPC was prepared, based on 100% by weight of the orally disintegrating tablet. 0.06 g of hydroxypropyl cellulose (HPC-M, Nippon Soda Co., Ltd.) and 3 g of sucralose (Sanei, now F.F.I. Co., Ltd.) were dissolved in purified water to prepare 276 g of granulation liquid. 243 g of D-mannitol (Mannit P, Mitsubishi Shoji Foodtech Co., Ltd.), 18 g of low-substituted hydroxypropyl cellulose (L-HPC (NBD-22), Shin-Etsu Chemical Co., Ltd.), and 18 g of carmellose (NS-300®, Nichirin Chemical Industry Co., Ltd.) were fed into a fluidized bed granulator (Powrex Corporation, Model: MP-01) and mixed. The granulation liquid was sprayed onto the mixed powder, and fluidized bed granulation was performed. The granulated product was dried at 70°C. The dried granules were sieved through a No. 22 sieve to obtain a sieved powder. The sieved powder was mixed with 6 g of crospovidone (Kollidon (registered trademark) CL-F, BASF), 9 g of magnesium aluminometasilicate (Neusilin (registered trademark) UFL2, Fuji Chemical Industry Co., Ltd.), and 3 g of magnesium stearate (Taihei Chemical Industry Co., Ltd.) to obtain a powder before tableting. The powder before tableting was compressed into tablets weighing 100 mg using a tablet press (VELA5, Kikusui Seisakusho Co., Ltd.) to obtain the orally disintegrating tablet of Example 1 having a thickness of 2.10 mm.

[0035] [Example 2] In Example 2, the amount of HPC-M added was changed to 0.6 g, and the amount of D-mannitol added was changed to 242.4 g, and an orally disintegrating tablet with an HPC-M content of 0.2 wt % was produced.

[0036] [Example 3] In Example 3, the amount of HPC-M added was changed to 1.5 g, and the amount of D-mannitol added was changed to 241.5 g, and an orally disintegrating tablet with an HPC-M content of 0.5 wt % was produced.

[0037] [Example 4] In Example 4, the amount of HPC-M added was changed to 3.0 g, and the amount of D-mannitol added was changed to 240.0 g, and an orally disintegrating tablet with an HPC-M content of 1.0 wt % was produced.

[0038] [Example 5] In Example 5, the amount of HPC-M added was changed to 6.0 g, the amount of purified water was increased to prepare 402 g of granulation liquid, and the amount of D-mannitol added was changed to 237.0 g, producing an orally disintegrating tablet with an HPC-M content of 2.0 wt%.

[0039] [Comparative Example 1] In Comparative Example 1, the grade of HPC was changed to HPC-SSL, and an orally disintegrating tablet with an HPC content of 0.02 wt% was produced. The orally disintegrating tablet of Comparative Example 1 having a thickness of 2.10 mm was obtained by the same production method as in Example 1, except that 0.06 g of HPC-SSL (Nippon Soda Co., Ltd.) was used instead of HPC-M.

[0040] Comparative Example 2 In Comparative Example 2, the amount of HPC-SSL added was changed to 0.6 g, the amount of D-mannitol added was changed to 242.4 g, and an orally disintegrating tablet with an HPC-SSL content of 0.2 wt % was produced.

[0041] Comparative Example 3 In Comparative Example 3, the amount of HPC-SSL added was changed to 3.0 g, the amount of D-mannitol added was changed to 240.0 g, and an orally disintegrating tablet with an HPC-SSL content of 1.0 wt % was produced.

[0042] Comparative Example 4 In Comparative Example 4, the amount of HPC-SSL added was changed to 6.0 g, the amount of D-mannitol added was changed to 237.0 g, and an orally disintegrating tablet with an HPC-SSL content of 2.0 wt % was produced.

[0043] Comparative Example 5 In Comparative Example 5, the grade of HPC was changed to HPC-L, and an orally disintegrating tablet with an HPC content of 0.5 wt% was produced. The orally disintegrating tablet of Comparative Example 5 having a thickness of 2.10 mm was obtained by the same production method as in Example 3, except that 1.5 g of HPC-L (Nippon Soda Co., Ltd.) was used instead of HPC-M.

[0044] Comparative Example 6 In Comparative Example 6, an orally disintegrating tablet containing 1.0 wt % HPC-L was produced by the same production method as in Example 4, except that HPC-L was used instead.

[0045] Comparative Example 7 In Comparative Example 7, the grade of HPC was changed to HPC-H, and an orally disintegrating tablet with an HPC content of 1.0 wt% was produced. The orally disintegrating tablet of Comparative Example 7 having a thickness of 2.10 mm was obtained by the same production method as in Example 4, except that 3.0 g of HPC-H (Nippon Soda Co., Ltd.) was used instead of HPC-M.

[0046] [hardness] The hardness of three orally disintegrating tablets from each of Examples 1 to 5 and Comparative Examples 1 to 7 was measured using a Schleuniger tablet hardness tester (MODEL 6D, Schleuniger), and the average value was taken as the hardness of each orally disintegrating tablet. The hardness measurement results are shown in Table 1. [Table 1] *Hardness is measured in N.

[0047] [Collapse time] The disintegration times of the orally disintegrating tablets of Examples 1 to 5 and Comparative Examples 1 to 7 were measured by a sensory test conducted by two subjects, and the average value was taken as the disintegration time of each orally disintegrating tablet. The disintegration time measurement results are shown in Table 2. [Table 2] *The unit of collapse time is seconds.

[0048] The results in Tables 1 and 2 demonstrate that in Examples 1 to 5, which were produced by fluidized bed granulation using HPC with a viscosity of 150 mPa·s or more and 400 mPa·s or less in a 2% aqueous solution at 20°C, both high tablet hardness and rapid disintegration time were achieved. On the other hand, in Comparative Examples 1 to 7, which used other grades of HPC, sufficient tablet hardness was not obtained and disintegration time was delayed. Furthermore, in Comparative Example 7, which used HPC-H, the viscosity of the granulation liquid was high, resulting in significantly coarse granules and a long production time.

[0049] [Example 6] Hypromellose (hereinafter also referred to as HPMC) was investigated as a binder other than HPC. In Example 6 using HPC, a pre-tabletting powder was prepared by the same manufacturing method as in Example 3, and the pre-tabletting powder was compressed to a weight of 100 mg to obtain an orally disintegrating tablet having a thickness of 2.20 mm and an HPC-M content of 0.5 wt%.

[0050] [Comparative Example 8] In Comparative Example 8, a powder before tableting was prepared using the same formulation as in Comparative Example 5, and the powder before tableting was compressed to a weight of 100 mg to obtain an orally disintegrating tablet having a thickness of 2.20 mm and an HPC-L content of 0.5 wt %.

[0051] Comparative Example 9 In Comparative Example 9, an orally disintegrating tablet containing 0.5% by weight of HPMC was produced by changing from HPC-M to HPMC, which has a viscosity similar to that of HPC-M. Except for using 1.5 g of HPMC (METOLOSE (registered trademark) 65SH400, Shin-Etsu Chemical Co., Ltd., viscosity of 400 mPa s in a 2% aqueous solution at 20°C) instead of HPC-M, a pre-tabletting powder was prepared by the same production method as in Example 3, and the pre-tabletting powder was compressed to a weight of 100 mg to obtain an orally disintegrating tablet of Comparative Example 9 having a thickness of 2.20 mm.

[0052] [Comparative Example 10] An orally disintegrating tablet containing 0.5 wt% HPMC was produced as Comparative Example 10. Except for using 1.5 g of HPMC (TC-5 (registered trademark) R, Shin-Etsu Chemical Co., Ltd., viscosity of 5.2 mPa s or more and 7 mPa s or less in a 2% aqueous solution at 20°C) instead of HPC-L, a pre-tabletting powder was prepared by the same production method as in Example 3, and compressed to a weight of 100 mg to obtain an orally disintegrating tablet of Comparative Example 10 having a thickness of 2.20 mm.

[0053] The hardness and disintegration time were measured by the above-mentioned measuring methods for the orally disintegrating tablets of Example 6 and Comparative Examples 8 to 10. Table 3 shows the measurement results. [Table 3]

[0054] The results in Table 3 clearly show that when HPMC is used, a significant delay in disintegration time occurs. Furthermore, the disintegration times in Comparative Examples 9 and 10 also reveal that when HPMC is used, the delay in disintegration time becomes more pronounced as the viscosity of HPMC increases. Therefore, it was revealed that the relationship between the viscosity of HPC and the disintegration time of orally disintegrating tablets behaves differently from the relationship between the viscosity of HPMC and the disintegration time of orally disintegrating tablets.

[0055] [Example 7] The effects of disintegrants added to orally disintegrating tablets on hardness and disintegration time were investigated. In Example 7, a pre-tabletting powder was prepared using the same manufacturing method as in Example 5, and compressed into tablets weighing 100 mg to produce orally disintegrating tablets with a thickness of 2.20 mm and an HPC-M content of 2.0 wt %.

[0056] [Example 8] The orally disintegrating tablets of Example 8 were produced using only HPC-M and L-HPC as a disintegrant. The HPC content was 2.0% by weight, based on 100% by weight of the orally disintegrating tablet. Specifically, 6 g of HPC-M (Nippon Soda Co., Ltd.) and 1 g of sucralose (Sanei, now F.F.I. Co., Ltd.) were dissolved in 279 ml of purified water to prepare a granulation liquid. 249 g of D-mannitol (Mannit P, Mitsubishi Shoji Foodtech Co., Ltd.) and 10 g of low-substituted hydroxypropyl cellulose (L-HPC (NBD-22), Shin-Etsu Chemical Co., Ltd.) were fed into a fluidized-bed granulator (Powrex Corporation, Model: MP-01) and mixed. The granulation liquid was sprayed onto the mixed powder, followed by fluidized-bed granulation. The granules were dried at 70°C. The dried granules were sieved through a No. 22 sieve to obtain a sieved powder. The sized powder was mixed with 9 g of magnesium aluminometasilicate (Neusilin (registered trademark) UFL2, Fuji Chemical Industry Co., Ltd.) and 3 g of magnesium stearate (Taihei Chemical Industry Co., Ltd.) to obtain a powder before tableting. The powder before tableting was compressed into tablets weighing 100 mg using a tableting machine (VELA5, Kikusui Seisakusho Co., Ltd.) to obtain orally disintegrating tablets of Example 8 having a thickness of 2.10 mm.

[0057] [Example 9] In Example 9, a powder before tableting was prepared using the same formulation as in Example 8, and the powder before tableting was compressed to a weight of 100 mg to obtain an orally disintegrating tablet having a thickness of 2.20 mm and an HPC-M content of 2.0 wt %.

[0058] [Example 10] The orally disintegrating tablets of Example 10 were produced using only HPC-M and crospovidone as a disintegrant. The HPC content was 2.0% by weight, based on 100% by weight of the orally disintegrating tablet. Specifically, 6 g of HPC-M (Nippon Soda Co., Ltd.) and 3 g of sucralose (Sanei F.F.I. Co., Ltd.) were dissolved in 279 ml of purified water to prepare a granulation liquid. 267 g of D-mannitol (Mannit P, Mitsubishi Shoji Foodtech Co., Ltd.) and 6 g of crospovidone (Kollidon® CL-F, BASF) were added to a fluidized-bed granulator (Powrex Corporation, Model: MP-01) and mixed. The granulation liquid was sprayed onto the mixed powder, followed by fluidized-bed granulation. The granules were dried at 70°C. The dried granules were sieved through a No. 22 sieve to obtain a sieved powder. The sized powder was mixed with 6 g of crospovidone (Kollidon® CL-F, BASF), 9 g of magnesium aluminometasilicate (Neusilin® UFL2, Fuji Chemical Industry Co., Ltd.), and 3 g of magnesium stearate (Taihei Chemical Industry Co., Ltd.) to obtain a powder before tableting. The powder before tableting was compressed into tablets weighing 100 mg using a tablet press (VELA5, Kikusui Seisakusho Co., Ltd.) to obtain the orally disintegrating tablet of Example 10 having a thickness of 2.10 mm.

[0059] [Example 11] In Example 11, a powder before tableting was prepared using the same formulation as in Example 10, and the powder before tableting was compressed to a weight of 100 mg to obtain an orally disintegrating tablet having a thickness of 2.20 mm and an HPC-M content of 2.0 wt %.

[0060] [Comparative Example 11] In Comparative Example 11, a pre-tabletting powder was prepared using the same manufacturing method as in Comparative Example 4, and the pre-tabletting powder was compressed to a weight of 100 mg to produce an orally disintegrating tablet having a thickness of 2.20 mm and an HPC-SSL content of 2.0 wt%.

[0061] [Comparative Example 12] In Comparative Example 12, an orally disintegrating tablet was produced using only HPC-SSL and L-HPC as a disintegrant, with the HPC content being 2.0% by weight, based on 100% by weight of the orally disintegrating tablet. The pre-tabletting powder was compressed to a weight of 100 mg using the same production method as in Example 8, except that 6 g of HPC-SSL (Nippon Soda Co., Ltd.) was used instead of HPC-M, to obtain an orally disintegrating tablet of Comparative Example 12 having a thickness of 2.10 mm.

[0062] [Comparative Example 13] In Comparative Example 13, a pre-tabletting powder was prepared using the same formulation as in Comparative Example 12, and compressed to a weight of 100 mg to obtain an orally disintegrating tablet having a thickness of 2.20 mm and an HPC-SSL content of 2.0 wt%.

[0063] [Comparative Example 14] In Comparative Example 14, an orally disintegrating tablet was produced using only HPC-SSL and crospovidone as a disintegrant, with the HPC content being 2.0% by weight relative to 100% by weight of the orally disintegrating tablet. The pre-tabletting powder was compressed to a weight of 100 mg using the same production method as in Example 10, except that 6 g of HPC-SSL (Nippon Soda Co., Ltd.) was used instead of HPC-M, to obtain the orally disintegrating tablet of Comparative Example 14 having a thickness of 2.10 mm.

[0064] [Comparative Example 15] In Comparative Example 15, a pre-tabletting powder was prepared using the same formulation as in Comparative Example 14, and the pre-tabletting powder was compressed to a weight of 100 mg to obtain an orally disintegrating tablet having a thickness of 2.20 mm and an HPC-SSL content of 2.0 wt%.

[0065] The hardness and disintegration time were measured by the above-mentioned measurement methods for the orally disintegrating tablets of Examples 7 to 11 and Comparative Examples 11 to 15. The measurement results for Examples 8, 10 and Comparative Examples 12 and 14, which are orally disintegrating tablets with a thickness of 2.10 mm, are shown in Table 4, along with the results for Example 5 and Comparative Example 4. The measurement results for Examples 7, 9, and 11 and Comparative Examples 11, 13, and 15, which are orally disintegrating tablets with a thickness of 2.20 mm, are shown in Table 5. [Table 4] [Table 5]

[0066] The results in Tables 4 and 5 demonstrate that the Examples using HPC-M were able to obtain higher hardness and more rapid disintegration than the Comparative Examples using HPC-SSL, even when the disintegrant was changed. Furthermore, the Examples using HPC-M were able to obtain higher hardness and more rapid disintegration than the Comparative Examples using HPC-SSL, even when the tablet thickness was changed. Therefore, it became clear that the binder added to the granulation liquid used in fluidized bed granulation has a greater effect than the disintegrant in order to obtain high hardness and rapid disintegration in an orally disintegrating tablet.

[0067] [Comparative Example 16] The effects of differences in manufacturing methods, particularly granulation methods, on hardness and disintegration time were investigated. In Comparative Example 16, HPC-M was added as a powder during fluidized-bed granulation to produce orally disintegrating tablets with an HPC content of 2.0% by weight, based on 100% by weight of the orally disintegrating tablet. Specifically, 3 g of sucralose (now San-ei F.F.I. Co., Ltd.) was dissolved in 276 ml of purified water to prepare a granulation liquid. 6 g of HPC-M (Nippon Soda Co., Ltd.), 237 g of D-mannitol (Mannit P, Mitsubishi Shoji Foodtech Co., Ltd.), and 18 g of low-substituted hydroxypropyl cellulose (L-HPC (NBD-22), Shin-Etsu Chemical Co., Ltd.) were fed into a fluidized-bed granulator (Powrex Corporation, Model: MP-01) and mixed. The granulation liquid was sprayed onto the mixed powder, followed by fluidized-bed granulation. The granules were dried at 70°C. The dried granules were sieved through a No. 22 sieve to obtain a sieved powder. The sieved powder was mixed with 6 g of crospovidone (Kollidon (registered trademark) CL-F, BASF), 9 g of magnesium aluminometasilicate (Neusilin (registered trademark) UFL2, Fuji Chemical Industry Co., Ltd.), and 3 g of magnesium stearate (Taihei Chemical Industry Co., Ltd.) to obtain a powder before tableting. The powder before tableting was compressed into tablets weighing 100 mg using a tablet press (VELA5, Kikusui Seisakusho Co., Ltd.) to obtain orally disintegrating tablets of Comparative Example 16 having a thickness of 2.10 mm.

[0068] [Comparative Example 17] In Comparative Example 17, an orally disintegrating tablet with an HPC content of 2.0% by weight, based on 100% by weight of the orally disintegrating tablet, was produced using HPC-SSL by the same production method as in Comparative Example 16. Except for using 6 g of HPC-SSL (Nippon Soda Co., Ltd.) instead of HPC-M, the pre-tabletting powder was compressed to a weight of 100 mg using the same production method as in Comparative Example 16, to obtain the orally disintegrating tablet of Comparative Example 17 with a thickness of 2.10 mm.

[0069] [Comparative Example 18] In Comparative Example 18, an orally disintegrating tablet was produced by direct compression using HPC-M, with the content of HPC being 2.0% by weight based on 100% by weight of the orally disintegrating tablet. 79 g of FRERES, 6 g of low-substituted hydroxypropyl cellulose (L-HPC (NBD-22), Shin-Etsu Chemical Co., Ltd.), 2 g of HPC-M (Nippon Soda Co., Ltd.), 1 g of sucralose (Sanei, now F.F.I. Co., Ltd.), 6 g of carmellose (NS-300®), 2 g of crospovidone (Kollidon® CL-F, BASF), and 3 g of magnesium aluminometasilicate (Neusilin® UFL2, Fuji Chemical Industry Co., Ltd.) were mixed in a plastic bag and sieved through a No. 30 sieve. 1 g of magnesium stearate (Taihei Chemical Industry Co., Ltd.) was mixed with the mixed powder to obtain a powder before tableting. The powder before tableting was compressed into tablets weighing 100 mg using a tablet press (VELA5, Kikusui Seisakusho Co., Ltd.) to obtain orally disintegrating tablets of Comparative Example 18 having a thickness of 2.10 mm.

[0070] Comparative Example 19 In Comparative Example 19, an orally disintegrating tablet with an HPC content of 2.0% by weight, based on 100% by weight of the orally disintegrating tablet, was produced using HPC-SSL by the same production method as in Comparative Example 18. Except for using 2 g of HPC-SSL (Nippon Soda Co., Ltd.) instead of HPC-M, the pre-tabletting powder was compressed to a weight of 100 mg using the same production method as in Comparative Example 18, to obtain the orally disintegrating tablet of Comparative Example 19 with a thickness of 2.10 mm.

[0071] [Comparative Example 20] In Comparative Example 20, an orally disintegrating tablet containing 2.0% HPC by weight (based on 100% by weight of the orally disintegrating tablet) was produced by kneading HPC-M. Specifically, 237 g of D-mannitol (Mannit P, Mitsubishi Shoji Foodtech Co., Ltd.), 18 g of low-substituted hydroxypropyl cellulose (L-HPC (NBD-22), Shin-Etsu Chemical Co., Ltd.), 3 g of sucralose (Sanei, now F.F.I. Co., Ltd.), and 18 g of HPC-M (Nippon Soda Co., Ltd.) were mixed in a plastic bag and sieved through a No. 30 sieve. 41.8 ml of purified water was added to the sieved mixed powder, and the mixture was kneaded using a high-speed mixer (LFS-GS-2J, Earth Technica Co., Ltd.). The resulting mixture was heated at 70°C for 3 hours in a mini-jet oven (Fujimac Co., Ltd.) and dried. The dried mixture was granulated using a power mill φ1 mm (Dalton Co., Ltd.). The sized powder was mixed with 6 g of crospovidone (Kollidon® CL-F, BASF), 9 g of magnesium aluminometasilicate (Neusilin® UFL2, Fuji Chemical Industry Co., Ltd.), and 3 g of magnesium stearate (Taihei Chemical Industry Co., Ltd.) to obtain a powder before tableting. The powder before tableting was compressed into tablets weighing 100 mg using a tablet press (VELA5, Kikusui Seisakusho Co., Ltd.), yielding an orally disintegrating tablet of Comparative Example 20 having a thickness of 2.10 mm.

[0072] [Comparative Example 21] In Comparative Example 21, an orally disintegrating tablet with an HPC content of 2.0% by weight, based on 100% by weight of the orally disintegrating tablet, was produced using HPC-SSL by the same production method as in Comparative Example 20. Except for using 6 g of HPC-SSL (Nippon Soda Co., Ltd.) instead of HPC-M and changing the amount of purified water to 57.7 ml, the pre-tabletting powder was compressed to a weight of 100 mg using the same production method as in Comparative Example 20, to obtain an orally disintegrating tablet of Comparative Example 21 with a thickness of 2.10 mm.

[0073] The hardness and disintegration time were measured by the above-mentioned measuring methods for the orally disintegrating tablets of Comparative Examples 16 to 21. The measurement results of Comparative Examples 16 to 21 are shown in Table 6 together with the results of Example 5 and Comparative Example 4. [Table 6]

[0074] The results in Table 6 clearly show that orally disintegrating tablets made with HPC-M have a shorter oral disintegration time than orally disintegrating tablets made with HPC-SSL, regardless of the manufacturing method. Meanwhile, the only orally disintegrating tablets that showed a higher hardness than orally disintegrating tablets made with HPC-SSL were those made with fluidized bed granulation using HPC-M as a liquid. Therefore, it was revealed that by adding HPC-M to a liquid and performing fluidized bed granulation, higher hardness and more rapid disintegration can be achieved than orally disintegrating tablets made with HPC-SSL.

[0075] [Bulk density of granulated powder] The sized powders before tableting in Example 5, Comparative Example 4, and Comparative Examples 16 to 21 were filled into a 100 ml container without tapping, and the mass was measured to calculate the bulk density. The measured bulk densities are shown in Table 7. [Table 7]

[0076] From the bulk density in Table 7, the sized powder of Example 5, which was fluidized using HPC-M as the granulation liquid, had a bulk density of 0.40 g / cm 3 The bulk density of the sieved powders granulated using a granulation liquid containing HPC, whose viscosity in a 2% aqueous solution at 20°C is 150 mPa s or more and 400 mPa s or less, was found to be lower than that of the sieved powders produced by other manufacturing methods. 3 It is presumed that by having the following bulk density, it is possible to maintain rapid disintegrability while providing sufficient hardness to prevent the tablet from breaking during transportation or when handled by medical professionals or patients.

Claims

1. A method for producing an orally disintegrating tablet, comprising spraying or dropping a liquid containing hydroxypropyl cellulose, the viscosity of which in a 2% aqueous solution at 20°C is 150 mPa s or more and 400 mPa s or less, onto an excipient (excluding spherical D-mannitol having a particle size range of 75 μm to 150 μm) and an additive containing a disintegrant, and performing fluidized bed granulation.

2. 2. The method for producing an orally disintegrating tablet according to claim 1, wherein the liquid containing hydroxypropyl cellulose is sprayed or dropped onto the additive so that the content of hydroxypropyl cellulose is 0.2% by weight or more and 5% by weight or less, based on 100% by weight of the orally disintegrating tablet.

3. 2. The method for producing an orally disintegrating tablet according to claim 1, wherein the liquid containing hydroxypropyl cellulose is sprayed or dropped onto the additive so that the content of hydroxypropyl cellulose is 0.2% by weight or more and 2% by weight or less, based on 100% by weight of the orally disintegrating tablet.

4. 4. The method for producing an orally disintegrating tablet according to claim 1, wherein the liquid containing hydroxypropyl cellulose is prepared by dissolving hydroxypropyl cellulose and a sweetener, and the additive is prepared by mixing the excipient and the disintegrant.

5. 5. The method for producing an orally disintegrating tablet according to claim 1, wherein a pharmaceutically active ingredient is dissolved or dispersed in a liquid containing hydroxypropyl cellulose, or the pharmaceutically active ingredient is mixed with the additive.

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