JP2018199674A - Orally disintegrable tablet containing dementia therapeutic agent - Google Patents

Abstract

To provide a compounding agent that is easily taken by an elderly person or a subject of aphagia, and shows biologically the same effects as in the combined use of a single agent of memantine hydrochloride and a single agent of donepezil hydrochloride.SOLUTION: An orally disintegrable tablet contains (a) memantine or pharmaceutically acceptable salt thereof, (b) donepezil or pharmaceutically acceptable salt thereof, (c) carmellose sodium of 0.5-3.0 wt.% relative to the total weight of the tablet and (d) hydroxypropyl cellulose.SELECTED DRAWING: None

Description

  The present invention relates to an orally disintegrating tablet containing a therapeutic agent for dementia that is excellent in dosing, dissolution, and stability.

  Memantine hydrochloride is a therapeutic agent for Alzheimer-type dementia, whose mechanism of action is N-methyl-D-aspartate (NMDA) receptor antagonism, one of the glutamate receptor subtypes. Donepezil hydrochloride is a therapeutic agent for Alzheimer-type dementia that has acetylcholinesterase inhibition as a mechanism of action. Since memantine hydrochloride and donepezil hydrochloride have different mechanisms of action, they are often used in combination, and the development of a combination drug is desired.

  So far, preparations containing memantine hydrochloride and donepezil hydrochloride have been provided with sustained-release part controlled by water-insoluble polymer and enteric polymer, and memantine hydrochloride is contained in the sustained-release part ( Patent Document 1), a preparation (Patent Document 2) in which pellets with controlled release of memantine and donepezil are prepared and filled in one capsule is known.

  On the other hand, many Alzheimer-type dementia patients are elderly and people who have difficulty swallowing, so it is desirable that the preparation be easy to take in order to improve medication adherence and reduce the burden on caregivers managing medication. Moreover, since there is a possibility that the compliance with medication may be reduced if bitterness remains in the mouth, it is required that the bitterness at the time of medication is reduced in addition to being easy to take. Orally disintegrating tablets disintegrate rapidly in the oral cavity and are a dosage form that can be taken without water, so they are preferred as preparations for the treatment of dementia. In Japan, donepezil hydrochloride orally disintegrating tablets in 2004 In 2013, orally disintegrating tablets of memantine hydrochloride were approved and sold. Patent Document 3 describes memantine hydrochloride orally disintegrating tablets together with its production method, and also describes donepezil hydrochloride as an example of a drug to which the technique of orally disintegrating tablets of the document can be applied. .

  However, an orally disintegrating tablet containing these two drugs has not been developed.

International Publication WO2006 / 118265 Pamphlet International Publication WO2006 / 121560 Pamphlet International publication WO2013 / 161823 pamphlet

  In order to blend memantine hydrochloride and donepezil hydrochloride into an orally disintegrating tablet, it is a combination drug that can be expected to have the same therapeutic effect as a single drug combination. Since all have a peculiar bitter taste, it is necessary that the bitter taste in the mouth is reduced. An object of the present invention is to provide a compound which is easy to take even for elderly people and patients who have difficulty swallowing and which is biologically equivalent to a combination of memantine hydrochloride and donepezil hydrochloride alone. .

  In order to make a drug having a bitter taste into an orally disintegrating tablet, the present inventors first form a drug and a disintegrant into granules using a binder, coat the granules with a coating agent, and then perform compression molding. Tried method. As a result, it was found that the dissolution properties of the manufactured tablets may be reduced depending on the type of disintegrant in the drug-containing granule. Therefore, as a result of intensive investigations to solve these problems, the present inventors used 0.5 to 3.0% by weight of carmellose sodium as the disintegrant and the use of hydroxypropylcellulose as the binder. The present inventors have found that good elution characteristics can be obtained, and that the use of specific fragrances has the effect of maintaining good dosing even after long-term storage, thus completing the present invention.

That is, the present invention relates to the following (1) to (14).
(1) (a) memantine or a pharmaceutically acceptable salt thereof, (b) donepezil or a pharmaceutically acceptable salt thereof, (c) 0.5 to 3.0% by weight of carmellose sodium and (d ) Orally disintegrating tablets containing hydroxypropylcellulose.
(2) The tablet according to (1), wherein the content of (c) carmellose sodium is 0.8 to 2.5% by weight based on the total weight of the tablet.
(3) The tablet according to (1) or (2), wherein the content of (d) hydroxypropylcellulose is 0.2 to 1.2% by weight based on the total weight of the tablet.
(4) The tablet according to any one of (1) to (3), further comprising (e) one or more polymers selected from methacrylic acid copolymer LD, methacrylic acid copolymer L, and methacrylic acid copolymer S.
(5) The tablet according to (4), wherein the content of the polymer (e) is 3 to 15% by weight based on the total weight of the tablet.
(6) The tablet according to any one of (1) to (5), further comprising (f) a fragrance.
(7) The tablet according to (6), wherein the fragrance is a butter, strawberry, kyoho, lemon, perilla or cocoa powder.
(8) Any one of (1) to (7), wherein (a) memantine or a pharmaceutically acceptable salt thereof, (c) carmellose sodium and (d) hydroxypropylcellulose are contained in the drug-containing granules. The tablet according to item.
(9) A drug-containing granule comprising (a) memantine or a pharmaceutically acceptable salt thereof, (c) sodium carmellose and (d) hydroxypropylcellulose is obtained by (e) methacrylic acid copolymer LD, methacrylic acid copolymer L and methacrylic acid The tablet according to (8), which is coated with one or more polymers selected from the acid copolymer S.
(10) The tablet according to (8) or (9), wherein (b) donepezil or a pharmaceutically acceptable salt thereof is contained in the drug-containing granule.
(11) Compression molding a drug-containing granule containing (a) memantine or a pharmaceutically acceptable salt thereof, (b) donepezil or a pharmaceutically acceptable salt thereof, (c) carmellose sodium and (d) hydroxypropylcellulose The manufacturing method of the orally disintegrating tablet of any one of (1)-(10) including the process to do.
(12) (a) memantine or a pharmaceutically acceptable salt thereof, (c) a drug-containing granule containing carmellose sodium and (d) hydroxypropylcellulose, and (b) donepezil or a pharmaceutically acceptable salt thereof The method for producing an orally disintegrating tablet according to any one of (1) to (10), comprising a step of compression molding powder or granule.
(13) The method further comprises the step of coating the drug-containing granules with one or more methacrylic acid polymers selected from (e) methacrylic acid copolymer LD, methacrylic acid copolymer L, and methacrylic acid copolymer S. The manufacturing method of the tablet of description.
(14) The method for producing a tablet according to any one of (11) to (13), further comprising a step of mixing the drug-containing granules and (f) a fragrance.

  The orally disintegrating tablet of the present invention has dissolution characteristics similar to those of conventional memantine hydrochloride and donepezil hydrochloride tablets, and is bioequivalent and has a reduced specific bitterness. Excellent in properties. In addition, it has storage stability as a preparation and sufficient hardness that does not cause cracking even during transportation or use of an automatic packaging machine, and can reduce the burden on medication management of medical staff and caregivers.

  Hereinafter, the orally disintegrating tablet of the present invention and the production method thereof will be described in detail.

  In the present invention, the orally disintegrating tablet is a compression-molded product that has rapid disintegration and solubility when contained in the mouth or in water. Specifically, it means a tablet that disintegrates in the oral cavity mainly in about 5 to 120 seconds, preferably 5 to 60 seconds, more preferably about 5 to 40 seconds in a disintegration test using saliva or a disintegration test using a device.

Memantine has the chemical name 3,5-Dimethyltricyclo [3.3.1.1 ^3,7 ] dec-1-ylamine. Examples of the pharmaceutically acceptable salt of memantine in the present invention include memantine hydrochloride. When memantine hydrochloride is used, the content in the tablet is preferably 5 to 20 mg.

  Donepezil has the chemical name (2RS) -2-[(1-Benzylpiperidin-4-yl) methyl] -5,6-dimethoxy-2,3-dihydro-1H-inden-1-one. In the present invention, the pharmaceutically acceptable salt of donepezil includes donepezil hydrochloride. When donepezil hydrochloride is used, the content in the tablet is preferably 3 to 10 mg.

  Carmellose sodium has a chemical name of sodium carboxymethylcellulose and is listed in the 16th revised Japanese Pharmacopoeia. In the present invention, carmellose sodium is used in an amount of 0.5 to 3.0% by weight based on the total weight of the tablet. The preferred content is 0.8 to 2.5% by weight, most preferably 1.0 to 1.8% by weight, based on the total tablet weight. Carmellose sodium functions as a disintegrant in the granules containing the drug.

  Hydroxypropyl cellulose is also known as hypromellose and is listed in the 16th revised Japanese Pharmacopoeia. In the present invention, the preferred content of hydroxypropylcellulose is 0.2 to 1.2% by weight, more preferably 0.4 to 0.8% by weight, based on the total weight of the tablet. Hydroxypropylcellulose functions as a binder within the granules containing the drug.

  Methacrylic acid copolymer LD is an emulsion of a copolymer of methacrylic acid and ethyl acrylate obtained in an aqueous solution of polysorbate 80 (JP) and sodium lauryl sulfate (JP) (Pharmaceutical Additive Standard 2013). . The methacrylic acid copolymer LD is commercially available. For example, Eudragit (registered trademark) L100-55 (Evonik), Kollicoat (registered trademark) MAE 100-55 (BASF) and the like can be used.

The methacrylic acid copolymer L is a powder obtained by drying an emulsion of a copolymer resin obtained by polymerizing methacrylic acid and methyl methacrylate in an aqueous solution using sodium lauryl sulfate (JP) as an emulsifier. When the dried product is quantified, it contains 38.0 to 52.0% of a copolymer component methacrylic acid (C ₄ H ₆ O ₂ : 86.09) (Pharmaceutical Additive Standard 2013). The methacrylic acid copolymer L is commercially available. For example, Eudragit (registered trademark) L100 (Evonik) can be used.

Methacrylic acid copolymer S is a powder obtained by drying an emulsion of copolymer resin obtained by polymerizing methacrylic acid and methyl methacrylate in an aqueous solution using sodium lauryl sulfate (JP) as an emulsifier. When the dried product is quantified, it contains 25.0 to 34.05% of the copolymer constituent methacrylic acid (C ₄ H ₆ O ₂ : 86.09) (Pharmaceutical Additive Standard 2013). The methacrylic acid copolymer S is commercially available. For example, Eudragit (registered trademark) S100 (Evonik) can be used.

  In the present invention, the content of one or more polymers selected from methacrylic acid copolymer LD, methacrylic acid copolymer L and methacrylic acid copolymer S is preferably 3 to 15% by weight, more preferably 5%, based on the total weight of the tablet. ~ 12% by weight. The polymer is preferably used as a coating agent for drug-containing granules. The polymer may be mixed with drugs and other additives to form granules. In the present invention, the most preferred polymer is methacrylic acid copolymer LD.

  When a polymer is used as a coating agent, it is desirable to use a plasticizer together. Examples of the plasticizer include one or a combination of two or more selected from diethyl sebacate, dibutyl sebacate, triethyl citrate, stearic acid, polyethylene glycol, and triacetin.

  In the tablet of this invention, it is preferable to use a fragrance | flavor for the improvement of taking property. Since fragrances may be gradually attenuated during the quality assurance period of pharmaceutical products, the sustainability of the effect is also an issue. In the orally disintegrating tablet of the present invention, a strawberry-based, kyoho-based, lemon-based, perilla-based, cocoa-based or butter-based powder fragrance is preferable from the viewpoint of sustained effect and overall odor. Spray dry type (spray dry type) fragrances, which are common powder fragrances, are, for example, fragrances such as oil-soluble natural essential oils, oleoresin, formulated fragrances in aqueous solutions such as dextrin, starches, gum arabic, gelatin, and casein. Are mixed, and then homogenized to prepare an O / W emulsion, which is atomized by spraying droplets, and evaporated to dry powder to produce a dry powder. Powdered fragrances are commercially available, and strawberry micron, kyo micron, lemon micron, perilla micron, cocoa micron or butter micron (all Takasago flavors) can be used. Particularly preferred are strawberry-based, koji-based and lemon-based powder flavors. The blending amount of the fragrance is 0.05 to 0.2% by weight, preferably about 0.08 to 0.12% by weight, based on the total weight of the tablet when using the powder fragrance.

  The orally disintegrating tablet of the present invention can also contain various additives generally used for tablet production as long as the effect of the invention is not hindered. Examples of the additive include a disintegrant, an excipient, a binder, a lubricant, a coloring agent, a sweetener, a corrigent, a fluidizing agent, a foaming agent, and a surfactant.

  Examples of disintegrants include crospovidone (for example, compliant products with pharmaceutical additives), carmellose calcium (for example, compliant with Japanese Pharmacopoeia), carmellose (for example, compliant with Japanese Pharmacopoeia), low-substituted hydroxypropylcellulose (For example, Japanese Pharmacopoeia compatible product), croscarmellose sodium (for example, pharmaceutical additive standard compliant product), and pregelatinized starch (for example, pharmaceutical additive standard compliant product) Particularly preferred are crospovidone, carmellose calcium and pregelatinized starch.

  Examples of the excipient include organic excipients selected from sugars, sugar alcohols, starches, and celluloses, and inorganic excipients. Examples of the saccharide include one or a combination of two or more selected from lactose, sucrose, fructooligosaccharide, glucose, palatinose, maltose, reduced maltose, powdered sugar, powdered koji, fructose, isomerized lactose and honey sugar. be able to. Examples of the sugar alcohol include D-mannitol, erythritol, xylitol, maltitol, sorbitol and the like. Examples of the starches include one or a combination of two or more selected from corn starch, potato starch, rice starch, partially pregelatinized starch, and pregelatinized starch. Examples of celluloses include, in addition to crystalline cellulose, one or a combination of two or more selected from powdered cellulose, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, and croscarmellose sodium. Examples of the inorganic excipient include one or a combination of two or more selected from synthetic hydrotalcite, precipitated calcium carbonate, hydrous silicon dioxide, light anhydrous silicic acid, magnesium aluminate silicate and magnesium hydroxide. be able to.

  As the binder, for example, selected from gum arabic, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, sodium polyacrylate, pullulan, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone and macrogol One or a combination of two or more may be mentioned.

  Examples of lubricants include magnesium stearate (e.g., Japanese Pharmacopoeia), calcium stearate (e.g., Japanese Pharmacopoeia), sodium stearyl fumarate (e.g., pharmaceutical additive standards) and talc ( For example, one type or a combination of two or more types selected from Japanese Pharmacopoeia) can be mentioned, and magnesium stearate is particularly preferable.

  The blending amount of the lubricant is usually 0.1 to 3.0% by weight, preferably 0.5 to 1.5% by weight, based on the total weight of the tablet.

  The colorant is selected from, for example, edible dyes such as edible yellow No. 5, edible red No. 2 and edible blue No. 2; edible lake dyes, yellow ferric oxide, ferric oxide, titanium oxide, β-carotene and riboflavin One or a combination of two or more can be mentioned.

  Examples of the sweetener include one or a combination of two or more selected from saccharin sodium, saccharin, aspartame, acesulfame potassium, dipotassium glycyrrhizinate, sucralose stevia, and thaumatin.

  Examples of the corrigent include one or a combination of two or more selected from sodium chloride, magnesium chloride, disodium inosinate, sodium L-glutamate, and honey.

  Examples of the surfactant include one or a combination of two or more selected from polyoxyl 40 stearate, sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polysorbate, glyceryl monostearate and sodium lauryl sulfate. it can.

  Examples of the foaming agent include tartaric acid and / or anhydrous citric acid.

  Examples of the fluidizing agent include one or a combination of two or more selected from hydrous silicon dioxide, light silicic anhydride, and talc.

The method for producing the orally disintegrating tablet of the present invention is as follows.
Manufacturing method A)
Memantine hydrochloride, donepezil hydrochloride, carmellose sodium and hydroxypropylcellulose are granulated and compression-molded with other excipients as necessary to obtain orally disintegrating tablets. The granulation can be performed using a conventional extrusion granulation method, a mixed stirring granulation method, a high speed stirring granulation method, a fluidized bed granulation method, a rolling granulation method, or the like. For example, when using the fluidized bed granulation method, memantine hydrochloride, donepezil hydrochloride, carmellose sodium and, if necessary, excipients are added and mixed uniformly, and the fluidized bed is sprayed while spraying the hydroxypropylcellulose solution. After granulation, the granulated product obtained is dried and then sized. The obtained granules can be coated with (e) one or more polymers selected from methacrylic acid copolymer LD, methacrylic acid copolymer L, and methacrylic acid copolymer S. The polymer can also be incorporated into the granules. Optionally, other excipients, disintegrants, fluidizing agents, flavoring agents, fragrances, and the like can be added to the obtained granules and compression molded to obtain orally disintegrating tablets. When the above polymer is used, it is preferable to add a fragrance.

Manufacturing method B)
Memantine hydrochloride, carmellose sodium and hydroxypropylcellulose are granulated and compression-molded with donevezil hydrochloride and other excipients as needed to form an orally disintegrating tablet. The granulation can be performed using a conventional extrusion granulation method, a mixed stirring granulation method, a high speed stirring granulation method, a fluidized bed granulation method, a rolling granulation method, or the like. For example, when using a fluidized bed granulation method, memantine hydrochloride, carmellose sodium and, if desired, excipients are added and mixed uniformly, and fluidized bed granulation while spraying a solution of hydroxypropylcellulose, The obtained granulated product is dried and then sized. The obtained granules can be coated with (e) one or more polymers selected from methacrylic acid copolymer LD, methacrylic acid copolymer L, and methacrylic acid copolymer S. The polymer can also be incorporated into the granules. To the obtained granules, donepezil hydrochloride and optionally other excipients, disintegrating agents, fluidizing agents, corrigents, fragrances and the like can be added and compression molded to obtain orally disintegrating tablets. When the above polymer is used, it is preferable to add a fragrance.

  The following examples are for illustrative purposes and are not intended to limit the invention to these examples.

1. Comparison of dissolution characteristics by disintegrant type [Example 1] Preparation of carmellose sodium-containing preparation [Step 1]
D-mannitol (Roquette, Pearlitol 50C) 88,200 g, crystalline cellulose (Asahi Kasei Chemicals, Theolas KG-1000, bulk density 0.10-0.15 g / cm ³ ) 39,900 g fluidized bed granulator (Pauleck, WSG-120 ), Sprayed with a solution in which 5,250 g of pregelatinized starch (manufactured by Asahi Kasei Chemicals Co., Ltd., Swelstar PD-1) in 60,380 g of purified water was sprayed and dried to obtain fast disintegrating granules.

[Step 2]
According to the formulation shown in Table 1, memantine hydrochloride (Mertz) 1,200 g, donepezil hydrochloride (Teva API) 300 g, D-mannitol (Roquette, Pearlitol 50C) 2,100 g, crystalline cellulose (Asahi Kasei Chemicals, Theolas PH101 ) 480 g and carmellose sodium (Serogen PM-250L, manufactured by Gotoku Pharmaceutical Co., Ltd.) 270 g were mixed to obtain a mixed powder.
The obtained mixed powder was put into a fluidized bed granulator (Freund, FLO-5 type), after spraying a binding solution in which 150 g of hydroxypropylcellulose (Nippon Soda, HPC-L) was dissolved in 2,350 g of purified water. The drug-containing granulated product was obtained by drying.
3,000 g of the resulting drug-containing granulated product was charged into a fluidized bed granulator (Freund, FLO-5 type), coating liquid 7,720 g (methacrylic acid copolymer LD (Evonik, Eudragit L30-D55) 51.8%, After spraying triethyl citrate (Morimura Shoji 1.6%), talc (Matsumura Sangyo 7.8%, purified water 38.8%) and drying, drug-containing coated granules were obtained.

[Step 3]
After mixing 2,460 g of drug-containing coated granules obtained in Step 2, 2,540 g of fast disintegrating granules prepared in Step 1, 344 g of crospovidone (BASF, Kollidon CL-F), 200 g of aspartame (Ajinomoto Co.), Add 56 g of magnesium stearate (manufactured by Marinckrod) and perform tableting with a tableting pressure of 8 kN using a rotary tableting machine to produce an orally disintegrating tablet (tablet diameter 9 mmφ, mass 280 mg). Obtained.

[Comparative Examples 1 to 4] Preparation of preparations with different types of disintegrants According to the formulation shown in Table 1, instead of carmellose sodium used in Step 2 of Example 1, carmellose calcium (Comparative Example 1) , Carmellose (Comparative Example 2), crospovidone (Comparative Example 3) and croscarmellose sodium (Comparative Example 4) were used in the same manner as in Steps 1 to 3 of Example 1 to produce tablets. In Comparative Example 4, tableting was performed after mixing ferric oxide, yellow ferric oxide, and strawberry micron in Step 3.

[Test Example 1] Dissolution evaluation results According to the Japanese Pharmacopoeia Dissolution Test Method Paddle Method, test solution: JP 1 dissolution solution, 2nd solution, rotation speed: 50 rpm, test solution volume: 900 mL, n The dissolution test was performed using = 3. The dissolution rates of donepezil hydrochloride for each preparation are shown in Tables 2 and 3, and the dissolution rates of memantine hydrochloride are shown in Tables 4 and 5, respectively.

  The formulation of Example 1 was good in both the dissolution property of donepezil hydrochloride and the dissolution property of memantine hydrochloride. However, although the preparations of Comparative Examples 1 to 4 had good dissolution of memantine hydrochloride, the dissolution of donepezil hydrochloride was inferior to that of Example 1.

2. Comparison of dissolution and disintegration due to differences in the amount of sodium carmellose As shown in Table 6, three types of preparations (Examples 2 and 3 and Comparative Example 5) with different amounts of sodium carmellose were prepared and dissolved. And disintegration was evaluated. The amount of memantine hydrochloride / donepezil hydrochloride was 20 mg / 10 mg.

Example 2 Preparation of Formulation of Carmellose Sodium 4.5 mg (1.6 wt%) According to the formulation shown in Table 6, memantine hydrochloride (Mertz) 1,200 g, donepezil hydrochloride (Teva API) 600 g, D-mannitol ( Roquette, Pearlitol 50C (1,800 g), crystalline cellulose (Asahi Kasei Chemicals, Theolas PH101) 480 g, carmellose sodium (Gotoku Pharmaceutical, Cellogen PM-250L) 270 g were mixed to obtain a mixed powder.
The obtained mixed powder was put into a fluidized bed granulator (Freund, FLO-5 type), after spraying a binding solution in which 150 g of hydroxypropylcellulose (Nippon Soda, HPC-L) was dissolved in 2,350 g of purified water. The drug-containing granulated product was obtained by drying.
3,000 g of the resulting drug-containing granulated product was charged into a fluidized bed granulator (Freund, FLO-5 type), coating liquid 7,720 g (methacrylic acid copolymer LD (Evonik, Eudragit L30-D55) 51.8%, After spraying triethyl citrate (Morimura Shoji 1.6%), talc (Matsumura Sangyo 7.8%, purified water 38.8%) and drying, drug-containing coated granules were obtained.
Drug-containing coated granules 2,460 g, fast disintegrating granules 2,540 g prepared by the method described in Step 1 of Example 1, crospovidone (BASF, Kollidon CL-F) 344 g, aspartame (Ajinomoto Co.) 183.2 g, three 5.6 g of iron dioxide (manufactured by Kasei Kasei), 5.6 g of yellow ferric oxide (manufactured by Kasei Kasei), 5.6 g of strawberry micron (manufactured by Takasago Flavor H-81280), and then 56 g of magnesium stearate (manufactured by Marinck Rod) Additional mixing was performed, and tableting was performed at a tableting pressure of 8 kN, 10 kN, or 12 kN using a rotary tableting machine to obtain an orally disintegrating tablet (tablet diameter 9 mmφ, mass 280 mg).

[Example 3] Preparation of formulation containing 6.75 mg (2.4% by weight) of carmellose sodium [Step 1] Preparation of fast disintegrating granules
D-mannitol (Roquette, Pearlitol 50C) 70,560 g, crystalline cellulose (Asahi Kasei Chemicals, Theolas KG-1000, bulk density 0.10-0.15 g / cm ³ ) 31,921 g fluidized bed granulator (Pauleck, WSG-120 ), Sprayed with a dispersion of 4,199 g of pregelatinized starch (manufactured by Asahi Kasei Chemicals Co., Ltd., Swelstar PD-1) in 48,288 g of purified water, and dried to obtain fast disintegrating granules.

[Step 2] Preparation of 6.75 mg carmellose sodium formulation A sample was prepared according to the formulation shown in Table 6. Memantine hydrochloride (Mertz) 1,200 g, donepezil hydrochloride (Teva API) 600 g, D-mannitol (Roquette, Pearlitol 50C) 1,665 g, crystalline cellulose (Asahi Kasei Chemicals, Theolas PH101) 480 g, carmellose sodium 405 g (Serogen PM-250L, manufactured by Gotoku Pharmaceutical Co., Ltd.) was mixed to obtain a mixed powder.
The obtained mixed powder was put into a fluidized bed granulator (Freund, FLO-5 type), after spraying a binding solution in which 150 g of hydroxypropylcellulose (Nippon Soda, HPC-L) was dissolved in 2,350 g of purified water. The drug-containing granulated product was obtained by drying.
3,000 g of the resulting drug-containing granulated product was charged into a fluidized bed granulator (Freund, FLO-5 type), coating liquid 7,720 g (methacrylic acid copolymer LD (Evonik, Eudragit L30-D55) 51.8%, Triethyl citrate (manufactured by Morimura Corporation, Citroflex) 1.6%, talc (manufactured by Matsumura Sangyo) 7.8%, purified water 38.8%) was sprayed and dried to obtain drug-containing coated granules.

[Step 3]
Drug-containing coated granules 2,460 g, fast disintegrating granules obtained in Step 1, 2,540 g, crospovidone (BASF, Kollidon CL-F) 344 g, aspartame (Ajinomoto) 183.2 g, iron sesquioxide (manufactured by Kasei Chemical) 5.6 g, yellow iron sesquioxide (manufactured by Kasei Kasei) 5.6 g After mixing 5.6 g of strawberry micron, add 56 g of magnesium stearate (manufactured by Marinck Rod) and mix with a rotary tableting machine. Tableting was performed at 10 kN or 12 kN to obtain an orally disintegrating tablet (tablet diameter 9 mmφ, mass 280 mg).

[Comparative Example 5] Preparation of 9 mg (3.2 wt%) carmellose sodium formulation In accordance with the formulation shown in Table 6, the amount of D-mannitol (Roquette, Pearlitol 50C) in Step 2 of Example 3 was changed to 1,530 g. Tablets were produced in the same manner as in Steps 1 to 3 of Example 3 except that the amount of carmellose sodium (Serogen PM-250L, manufactured by Gotoku Pharmaceutical Co., Ltd.) was changed to 540 g.

[Test Example 2] Quality evaluation results A disintegration test was performed on the preparations prepared in Examples 2, 3 and 5 according to the Japanese Pharmacopoeia disintegration test method (n = 6). Table 7 shows the average and minimum and maximum results of the disintegration time (seconds) of 6 tablets in each group. The preparations of Examples 2 and 3 showed rapid disintegration, but the preparation of Comparative Example 5 delayed the disintegration time as the tableting pressure increased.
In addition, the dissolution property in the second solution of the JP dissolution test was evaluated using a dissolution tester (manufactured by Varian, Inc.). Table 7 shows the average dissolution rate of donepezil hydrochloride and memantine hydrochloride (after 15 minutes) of 3 tablets in each group. The preparations of Examples 2 and 3 showed rapid dissolution of 85% or more in 15 minutes at any tableting pressure, whereas the preparation of Comparative Example 5 had a dissolution rate of donepezil hydrochloride at a tableting pressure of 12 kN. Decreased.

3. Effect on sensory evaluation by addition of fragrance [Formulation Examples 1 to 6] Preparation of fragrance added preparation [Step 1] Preparation of fast disintegrating granules
D-mannitol (Roquette, Pearlitol 50C) 88,200 g, crystalline cellulose (Asahi Kasei Chemicals, Theolas KG-1000, bulk density 0.10-0.15 g / cm ³ ) 39,900 g fluidized bed granulator (Pauleck, WSG-120 ), Sprayed with a solution in which 5,250 g of pregelatinized starch (manufactured by Asahi Kasei Chemicals Co., Ltd., Swelstar PD-1) in 60,380 g of purified water was sprayed and dried to obtain fast disintegrating granules.

[Step 2] Preparation of drug-containing coated granules
According to the formulation shown in Table 8, memantine hydrochloride (Mertz) 6,000 g, D-mannitol (Roquette, Pearlitol 50C) 12,000 g, crystalline cellulose (Asahi Kasei Chemicals, Theolas PH101) 2,400 g, carmellose sodium (manufactured by Gotoku Pharmaceutical) , Serogen PM-250L) 1,350 g was mixed to obtain a mixed powder.
The obtained mixed powder was put into a fluidized bed granulator (manufactured by Paulec, GPCG-30), and after spraying a binding solution in which 750 g of hydroxypropylcellulose (Nippon Soda, HPC-L) was dissolved in 11,750 g of purified water, A drug-containing granulated product was obtained by drying.
The obtained drug-containing granulated product (21,000 g) was charged into a fluidized bed granulator (Pauleck, GPCG-30), and coating liquid 54,040 g (methacrylic acid copolymer LD (Evonik, Eudragit L30-D55) 51.8%, After spraying triethyl acid (manufactured by Morimura Shoji) 1.6%, talc (manufactured by Matsumura Sangyo) 7.8%, purified water 38.8%), drug-containing coated granules were obtained by drying.

[Step 3] Preparation of Donepezil hydrochloride mixed powder Donepezil hydrochloride (Teva API) 1,250 g, Crospovidone (BASF, Kollidon CL-F) 4,300 g, Aspartame (Ajinomoto Co.) 2,170 g The mixture was put into Paulec's FM-VG-50) and mixed to obtain donepezil hydrochloride mixed powder.

[Step 4] Preparation of a fragrance-added preparation 22,140 g of drug-containing coated granules prepared by the method described in [Step 2], 5,558.4 g of Donepezil hydrochloride mixed powder prepared by the method described in [Step 3], [Step 1] After mixing 21,945.6 g of fast disintegrating granules prepared by the method described in 1. above, 756 g of magnesium stearate (manufactured by Marin Rod) was further mixed to obtain mixed granules.
201.6 g of the obtained mixed granule and strawberry micron (formulation example 1), lemon micron (formulation example 2), kyo micron (formulation example 3), cocoa micron (formulation example 4), shisomicron (formulation) described in Table 9 Example 5), Buttermicron (Formulation Example 6) 1 Fragrance of 0.2016 g was mixed and tableted with a tableting pressure of 8 kN using a rotary tableting machine. Orally disintegrating tablets (tablet diameter 9 mmφ) , Mass 280.28 mg).

[Preparation Example 7] Preparation of a fragrance-free preparation According to the formulation shown in Table 8, in the same manner as in Steps 1 to 3 of Preparation Examples 1 to 6, drug-containing coated granules, Donevezil hydrochloride mixed powder, and fast disintegrating granules Prepared. The resulting drug-containing coated granules 22,140 g, donepezil hydrochloride mixed powder 5,558.4 g, fast disintegrating granules 21,945.6 g were mixed, and then magnesium stearate (manufactured by Marinckrod) 756 g was added and mixed in a rotary tableting machine. Tableting was performed at a tableting pressure of 8 kN to obtain an orally disintegrating tablet (tablet diameter 9 mmφ, mass 280 mg).

[Test Example 3] Odor sensory evaluation For the preparations of Preparation Examples 1 to 7, 5 tablets were filled in a glass bottle and stored at 60 ° C for 2 weeks to obtain a sample for sensory evaluation. For the stored products, according to the sensory evaluation criteria shown in Table 9, the odor of the fragrance and the overall odor were evaluated by 6 subjects.
The results are shown in Table 10. For any of the preparations of Preparation Examples 1 to 6, the evaluation of the odor of the fragrance showed a score of 1 (feeling a slight slight odor), confirming that the effect was sustained. As a result of comprehensive odor evaluation, the score of Formulation Example 6 (Buttermicron-added formulation) was slightly low, but the score of the other fragrance-added formulation was 2 (normal) or higher. In particular, Formulation Examples 1 to 3 showed good results.

  As described above, it was shown that the orally disintegrating tablet of the present invention has a reduced bitterness of the drug, a good scent, and good dosage.

Claims (14)

  (A) memantine or a pharmaceutically acceptable salt thereof, (b) donepezil or a pharmaceutically acceptable salt thereof, (c) 0.5 to 3.0% by weight of carmellose sodium and (d) hydroxypropyl based on the total weight of the tablet An orally disintegrating tablet containing cellulose.   The tablet according to claim 1, wherein the content of (c) carmellose sodium is 0.8 to 2.5% by weight based on the total weight of the tablet.   The tablet according to claim 1 or 2, wherein the content of (d) hydroxypropylcellulose is 0.2 to 1.2% by weight based on the total weight of the tablet.   The tablet according to any one of claims 1 to 3, further comprising (e) one or more polymers selected from methacrylic acid copolymer LD, methacrylic acid copolymer L, and methacrylic acid copolymer S.   The tablet according to claim 4, wherein the content of the polymer (e) is 3 to 15% by weight based on the total weight of the tablet.   Furthermore, the tablet of any one of Claims 1-5 containing (f) fragrance | flavor.   (F) The tablet according to claim 6, wherein the fragrance is a butter, strawberry, kyoho, lemon, perilla or cocoa powder.   The tablet according to any one of claims 1 to 7, wherein (a) memantine or a pharmaceutically acceptable salt thereof, (c) carmellose sodium and (d) hydroxypropylcellulose are contained in the drug-containing granule. .   A drug-containing granule comprising (a) memantine or a pharmaceutically acceptable salt thereof, (c) sodium carmellose and (d) hydroxypropylcellulose is obtained by (e) methacrylic acid copolymer LD, methacrylic acid copolymer L and methacrylic acid copolymer S. The tablet of Claim 8 coat | covered with 1 or more types of polymers chosen from these.   The tablet according to claim 8 or 9, wherein (b) donepezil or a pharmaceutically acceptable salt thereof is contained in the drug-containing granule.   A step of compression-molding a drug-containing granule comprising (a) memantine or a pharmaceutically acceptable salt thereof, (b) donepezil or a pharmaceutically acceptable salt thereof, (c) carmellose sodium and (d) hydroxypropylcellulose. The manufacturing method of the orally disintegrating tablet of any one of Claims 1-10 containing.   (A) memantine or a pharmaceutically acceptable salt thereof, (c) a drug-containing granule containing carmellose sodium and (d) hydroxypropylcellulose, and (b) a powder or granule containing donepezil or a pharmaceutically acceptable salt thereof. The manufacturing method of the orally disintegrating tablet of any one of Claims 1-10 including the process of compressing.   The tablet production according to claim 11 or 12, further comprising the step of coating the drug-containing granules with one or more methacrylic acid polymers selected from (e) methacrylic acid copolymer LD, methacrylic acid copolymer L and methacrylic acid copolymer S. Method.   Furthermore, the manufacturing method of the tablet of any one of Claims 11-13 including the process of mixing a drug containing granule and (f) fragrance | flavor.