JP5656258B2 - Orally disintegrating tablets containing galantamine - Google Patents

Description

  The present invention relates to an orally disintegrating tablet of galantamine, which is a therapeutic agent for Alzheimer's disease. More specifically, the present invention relates to an orally disintegrating tablet containing galantamine or a salt thereof and sodium carboxymethyl starch.

で示される。ガランタミンの化学名は［４ａＳ−（４ａα，６β，８ａＲ＊）］−４ａ，５，９，１０，１１，１２−ヘキサヒドロ−３−メトキシ−１１−メチル−６Ｈ−ベンゾフロ［３−ａ，３，２−ｅｆ］［２］ベンゾアゼピン−６−オールである。ガランタミン臭化水素酸塩の水溶解度は２０℃で約３３ｍｇ／ｍLである。このような水溶解度の高い薬物の場合、溶出率のばらつきが大きくなる恐れがある。 Alzheimer's disease is a type of dementia whose main symptoms are cognitive decline and personality change, and gradually progressing cognitive impairment (memory disorder, disorientation, learning disorder, attention disorder, spatial cognitive function and problem solving Disability, etc.).
Galantamine has attracted attention as a drug that suppresses the progression of Alzheimer's disease. Galantamine has an acetylcholinesterase inhibitory action, and its hydrobromide has the following formula:

Indicated by The chemical name of galantamine is [4aS- (4aα, 6β, 8aR *)]-4a, 5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro [3-a, 3 2-ef] [2] benzoazepin-6-ol. The water solubility of galantamine hydrobromide is about 33 mg / mL at 20 ° C. In the case of such a drug with high water solubility, there is a risk that the variation in dissolution rate will increase.

  Many patients with Alzheimer's disease dementia are elderly and have low swallowing ability, making it difficult to take tablets. Development of an orally disintegrating tablet that rapidly disintegrates in the oral cavity and has improved dissolution properties is desired in order to allow such elderly people to easily take tablets and to obtain sufficient medicinal effects. Yes. As preparations related to galantamine, a spray-dried mixture of lactose-hydrate and microcrystalline cellulose (75:25) and a tablet containing a disintegrant are known (Patent Document 1). There is no mention of inward disintegrating tablets.

The following literature is mentioned regarding an orally disintegrating tablet.
Patent Document 2 describes an orally disintegrating tablet containing an active ingredient, crystalline cellulose, an inorganic excipient, and carmellose.
Patent Document 3 describes an orally disintegrating tablet containing an antipsychotic drug, risperidone, crystalline cellulose, an inorganic excipient, and carmellose.
Patent Document 4 describes an orally disintegrating tablet containing methylprednisolone and 10% by weight or more of sodium carboxymethyl starch.
Non-Patent Document 1 describes an orally disintegrating tablet containing crystalline cellulose, anhydrous calcium hydrogen phosphate, carmellose and magnesium stearate which is a lubricant.
However, even tablets with good disintegration may not improve the dissolution properties depending on the drug, and the dissolution rate may increase when multiple dissolution tests are performed. There is no mention of drug dissolution rate or improvement in dissolution rate variation.

On the other hand, the following literature is mentioned regarding the formulation which improved the elution rate.
Patent Document 5 describes that the elution rate of nefiracetam was improved by increasing the particle size of nefiracetam.
Patent Document 6 describes the main drug (N-hydroxy-4-5- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) phenoxy] bentoxy-benzamidine), sodium carboxymethyl starch and An oral preparation containing calcium hydrogen phosphate is described, which describes that the dissolution of the active ingredient has been improved.
However, the above document does not describe that the tablet disintegrates in the oral cavity.

Special table 2000-511918 WO2007 / 018192 WO2008 / 081774 1-501934 JP 2002-104966 A Special table 2008-520655 Brochure of Kyowa Chemical Industry Co., Ltd. (Excipient for direct hitting, anhydrous calcium hydrogen phosphate GS)

  Accordingly, there has been a demand for the development of orally disintegrating tablets with high dissolution rate and small variation in dissolution rate for galantamine.

  The present inventors have intensively studied and found that carboxymethyl starch sodium is useful as an additive for forming an orally disintegrating tablet with improved dissolution of galantamine. In particular, if the content of sodium carboxymethyl starch is 1 to 30% by weight, preferably 3 to 15% by weight, more preferably 5 to 10% by weight, based on the total weight of the tablet, the effect is remarkable. Hereinafter, the content of galantamine and additives is expressed as a content relative to the total weight of the tablet. As the additive in the present specification, for example, those described in the Pharmaceutical Additives Encyclopedia 2007 (2007, published by Yakuji Nippo Co., Ltd.), the Japanese Pharmacopoeia, or those usually used in medicine can be used.

That is, the present invention
(1) An orally disintegrating tablet comprising galantamine or a salt thereof, and sodium carboxymethyl starch,
(2) The orally disintegrating tablet according to (1) above, containing 1 to 30% by weight of sodium carboxymethyl starch,
(3) The orally disintegrating tablet according to (1) above, containing 5 to 10% by weight of sodium carboxymethyl starch,
(4) The orally disintegrating tablet according to any one of (1) to (3), which contains an inorganic excipient,
(5) The orally disintegrating tablet according to the above (4), wherein the inorganic excipient is anhydrous calcium hydrogen phosphate,
(6) The orally disintegrating tablet according to any one of (1) to (5), comprising celluloses;
(7) The orally disintegrating tablet according to (6) above, wherein the cellulose is crystalline cellulose and / or carmellose,
(8) The orally disintegrating tablet according to (7) above, containing 5 to 10% by weight sodium carboxymethyl starch and 1 to 5% by weight carmellose,
(9) The orally disintegrating tablet according to any one of (1) to (8) above, which contains a lubricant,
(10) The orally disintegrating tablet according to (9), wherein the lubricant is magnesium stearate,
(11) The orally disintegrating tablet according to (9) or (10) above, containing 0.001 to 0.8% by weight of a lubricant,
(12) The orally disintegrating tablet according to any one of (9) to (11), wherein the method of adding the lubricant is an external lubricant method,
(13) The orally disintegrating tablet according to any one of (1) to (12), comprising a sweetener,
(14) The orally disintegrating tablet according to the above (13), wherein the sweetener is aspartame,
(15) The orally disintegrating tablet according to any one of (1) to (14) above, which contains galantamine or a salt thereof, sodium carboxymethyl starch, anhydrous calcium hydrogen phosphate, crystalline cellulose, aspartame and magnesium stearate,
(16) An orally disintegrating tablet according to the above (15), comprising galantamine or a salt thereof, sodium carboxymethyl starch, anhydrous calcium hydrogen phosphate, crystalline cellulose, carmellose, aspartame, and magnesium stearate,
(17) 1 to 20% by weight of galantamine or a salt thereof, 1 to 30% by weight of sodium carboxymethyl starch, 10 to 60% by weight of anhydrous calcium hydrogen phosphate, 10 to 50% by weight of crystalline cellulose, An orally disintegrating tablet according to (16), comprising 10 wt. Carmellose and 0.001-0.8 wt. Magnesium stearate;
(18) 3 to 10% by weight galantamine or a salt thereof, 5 to 10% by weight sodium carboxymethyl starch, 30 to 50% by weight anhydrous calcium hydrogen phosphate, 20 to 40% by weight crystalline cellulose, 1 to 5% by weight Orally disintegrating tablet according to the above (16), comprising 1% carmellose, 0.5 to 7.5% by weight aspartame and 0.1 to 0.5% by weight magnesium stearate,
(19) In the dissolution test method of the Japanese Pharmacopoeia, the orally disintegrating tablet according to any one of (1) to (18), wherein the dissolution rate of galantamine 15 minutes after the start of the test is 85% or more,
(20) The orally disintegrating tablet according to any one of (1) to (19) above, wherein in the dissolution test method of the Japanese Pharmacopoeia, the variation in dissolution rate of galantamine 15 minutes after the start of the test is within 8.5% ,
(21) The oral cavity according to the above (19), which contains galantamine or a salt thereof and sodium carboxymethyl starch and has a dissolution rate of galantamine of 85% or more 15 minutes after the start of the test in the Japanese Pharmacopoeia dissolution test method Disintegrating tablets,
(22) The galantamine or a salt thereof and carboxymethyl starch sodium, and in the dissolution test method of the Japanese Pharmacopoeia, the dispersion of the dissolution rate of galantamine within 15 minutes after the start of the test is within 8.5% (20) Orally disintegrating tablets,
(23) In the disintegration test method of the Japanese Pharmacopoeia, the orally disintegrating tablet according to any one of (1) to (22), wherein the disintegration time is 1 to 60 seconds,
(24) The orally disintegrating tablet according to any one of (1) to (23), having a hardness of 10 to 200 N,
(25) The orally disintegrating tablet according to any one of (1) to (24), wherein the salt of galantamine is galantamine hydrobromide,
(26) A method for controlling the dissolution rate of galantamine in an orally disintegrating tablet, comprising sodium carboxymethyl starch,
(27) In the dissolution test method of the Japanese Pharmacopoeia, the method according to (26) above, wherein the dissolution rate of galantamine 15 minutes after the start of the test is controlled to 85% or more,
(28) The method according to (26) above, wherein in the dissolution test method of the Japanese Pharmacopoeia, the dispersion of the dissolution rate of galantamine 15 minutes after the start of the test is controlled within 8.5%,
About.

  The galantamine-containing orally disintegrating tablet of the present invention (hereinafter referred to as “the present preparation”) exhibits good dissolution and disintegration. Also, the hardness of the tablet is at a level that can withstand practicality. This preparation preferably has a dissolution rate of 85% or more 15 minutes after the start of the dissolution test in the dissolution test method of the Japanese Pharmacopoeia, and the variation in dissolution rate is within 8.5%.

Dissolution behavior of galantamine when the disintegrant is changed Dissolution behavior of galantamine when the content of sodium carboxymethyl starch is changed

  As the salt of galantamine, a pharmaceutically acceptable salt is preferably used. Examples of the “pharmaceutically acceptable salt” include salts of inorganic acids such as hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid, and organic acids such as paratoluenesulfonic acid, methanesulfonic acid, oxalic acid or citric acid. And salts of organic bases such as ammonium, trimethylammonium and triethylammonium, alkali metal salts such as sodium and potassium, and alkaline earth metal salts such as calcium and magnesium. More preferred is galantamine hydrobromide. The content of galantamine or a salt thereof is 1 to 20% by weight, preferably 2 to 15% by weight, more preferably 3 to 10% by weight. If it is less than these contents, the disintegration time of the tablet may be relatively shortened, and if it is more, the disintegration time of the tablet may be delayed.

  Sodium carboxymethyl starch is a sodium salt of carboxymethyl ether of starch, also called sodium starch glycolate. Specifically, Papill No. 50 (Nippon Chemical Industry), Exprotab (Kimura Sangyo), Primogel (Matsutani Chemical Industry), Bontab (Nippon Chemical Industry) and the like. In this preparation, sodium carboxymethyl starch is mainly used for the purpose of improving disintegration, but may be used for the purpose of improving dissolution.

  The content of sodium carboxymethyl starch is 1 to 30% by weight, preferably 3 to 15% by weight, more preferably 5 to 10% by weight. If it is less than these contents, the disintegration time cannot be shortened, and the dissolution rate may be lowered, or the dispersion of dissolution may be increased. If it is more, the hardness of the tablet may be reduced. There is.

  The formulation may contain an inorganic excipient. Specifically, anhydrous calcium hydrogen phosphate, magnesium aluminate metasilicate, synthetic hydrotalcite, precipitated calcium carbonate, magnesium carbonate, particularly preferably anhydrous calcium hydrogen phosphate (bulk density: 0.71-1.0 g) / ML). As anhydrous calcium hydrogen phosphate, specifically, anhydrous calcium hydrogen phosphate GS (manufactured by Kyowa Chemical Industry Co., Ltd.), Fujicalin (Fuji Chemical Industry Co., Ltd.), light anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry Co., Ltd.) And anhydrous calcium hydrogen phosphate heavy (manufactured by Kyowa Chemical Industry Co., Ltd.). These inorganic excipients may be used alone or in combination of two or more.

  The content of the inorganic excipient is 10 to 60% by weight, preferably 20 to 55% by weight, more preferably 30 to 50% by weight. If the content is less than these, the hardness of the tablet may be lowered, and if it is more, the dissolution may not be improved.

  The bulk density of the inorganic excipient is usually 0.30 to 1.0 g / mL, preferably 0.5 to 1.0 g / mL, more preferably 0.6 to 1.0 g / mL. If it is outside the range of this bulk density, there is a possibility that the hardness of the tablet is lowered and the disintegration time is delayed.

  This preparation may contain celluloses. Specific examples include crystalline cellulose, carmellose, carmellose sodium, carmellose calcium, hydroxypropylcellulose, hypromellose, carboxymethylethylcellulose and the like. Preferably, crystalline cellulose and carmellose are used. These celluloses promote the disintegration of tablets and may be used alone or in combination of two or more.

  The cellulose content is 0.1 to 50% by weight, preferably 0.5 to 45% by weight, more preferably 1 to 40% by weight. If it is less than these contents, the hardness of the tablet may be lowered or the disintegration time may be prolonged, and if it is more, the tablet may become large and the dosage may be deteriorated.

  Specific examples of the crystalline cellulose include Theola PH-101, Theola PH-102, Theola PH-200, Theola PH-301, Theola PH-302, Avicel PH-F20JP, Theola KG-802, Theola KG-1000, Theola. UF-702, Theolas UF-711 (manufactured by Asahi Kasei Kogyo Co., Ltd.), VIVAPUR (grade 105, 101, 103, 301, 102, 112), ARBOCEL (grade M80, P290, A300), Prosolv SMCC50, Prosolv SMCC90 (JRS) PHARMA). The average particle size of the crystalline cellulose is 10 to 200 μm, preferably 30 to 130 μm, more preferably 40 to 120 μm. Specifically, Theolas PH102 (Asahi Kasei Kogyo Co., Ltd., average particle size of about 100 μm) is used. If the average particle size is outside this range, the hardness of the tablet may be reduced, and the disintegration time may be delayed.

  The content of crystalline cellulose is 10 to 50% by weight, preferably 15 to 45% by weight, more preferably 20 to 40% by weight. If it is less than these contents, the hardness of the tablet may be lowered or the disintegration time may be prolonged, and if it is more, the tablet may become large and the dosage may be deteriorated.

  The blending ratio of the inorganic excipient of this preparation, particularly anhydrous calcium hydrogen phosphate and celluloses, particularly crystalline cellulose, can be determined as appropriate, but is 8: 2 to 2: 8, preferably 3: 7 to 5: 5. More preferably, the ratio is about 6: 4. If the blending ratio of the cellulose is higher than this, the texture may be lowered due to the roughness of the cellulose. On the other hand, if the blending ratio of cellulose is lower than this, the tablet hardness may be lowered.

  Carmellose is also known as carboxymethyl cellulose, and specific examples thereof include NS-300 (Gotoku Pharmaceutical Co., Ltd.). If carmellose is contained in the tablet, the disintegration delay of the tablet can be suppressed even when stored over time.

  The content of carmellose is 0.1 to 10% by weight, preferably 0.5 to 7.5% by weight, more preferably 1 to 5% by weight. If it is less than these contents, the disintegration time of the tablet may be prolonged, and if it is more, the hardness of the tablet may be reduced, or the dissolution rate may vary.

  The preparation may contain a lubricant. Specific examples include metal stearate, sucrose fatty acid ester, talc, hydrous silicon dioxide, and the like, but metal stearate is preferred. Examples of the metal stearate include magnesium stearate and calcium stearate, and magnesium stearate is preferable.

  The content of the lubricant is 0.001 to 0.8% by weight, preferably 0.01 to 0.65% by weight, more preferably 0.1 to 0.5% by weight. If the content is less than these, tableting may not be possible, and if it is more, the disintegration time of the tablet may be delayed.

  The preparation may contain a sweetening agent. The sweetener is preferably a substance that feels strong sweetness in a small amount as compared with sugars and sugar alcohols, and non-saccharide natural sweeteners and synthetic sweeteners are preferred. Specifically, when the sweetness of sucrose is 1, the sweetener has a sweetness of 50 times or more. Examples include aspartame, acesulfame potassium, saccharin or a salt thereof, glycyrrhizic acid or a salt thereof, stevia or a salt thereof, sucralose, thaumatin and the like.

  The content of the sweetener is 0.1 to 10% by weight, preferably 0.25 to 9% by weight, and more preferably 0.5 to 8% by weight. If it is less than these contents, sweetness may not be produced, and if it is more, the hardness of the tablet may be lowered.

The preparation is more preferably characterized by being substantially free of sugars as an excipient. Specific examples of the saccharide include sucrose, glucose, fructose, starch syrup, lactose, and sucrose. When these saccharides are used, the disintegration time of the tablet becomes longer, and the hardness of the tablet may decrease. Here, “saccharides” mean monosaccharides and disaccharides according to the nutrition labeling standards of the Ministry of Health, Labor and Welfare. Further, “substantially free of saccharide” means that the saccharide content is less than 0.5 wt%, preferably less than 0.25 wt%, more preferably less than 0.1 wt%.
In addition, the preparation is more preferably characterized by being substantially free of sugar alcohol as an excipient. Specific examples of the sugar alcohols include erythritol, D-sorbitol, xylitol, D-mannitol, maltitol and the like. When these sugar alcohols are used, there is a possibility that the disintegration time of the tablet becomes long and the hardness of the tablet decreases. Here, “sugar alcohol” refers to a polyhydric alcohol obtained by reducing a carbonyl group of a saccharide molecule. Further, “substantially free of sugar alcohol” means that the sugar alcohol content is less than 0.5 wt%, preferably less than 0.25 wt%, more preferably less than 0.1 wt%. .

  The formulation may contain a fluidizing agent. The fluidizing agent is for increasing the fluidity of the powder before tableting. Specific examples include light anhydrous silicic acid, hydrous silicon dioxide, heavy anhydrous silicic acid, titanium oxide and the like, and light anhydrous silicic acid is preferred.

  The content of the fluidizing agent is 0.01 to 10% by weight, preferably 0.05 to 5% by weight, more preferably 0.1 to 2.5% by weight. If it is less than these contents, the fluidity of the mixed powder before tableting may be lowered, and if it is more, the disintegration time of the tablet may be delayed.

If necessary, this preparation may contain additives other than those mentioned above used for tablet production. These additives may be used alone or in a mixture at any ratio. Examples of additives other than those mentioned above include disintegrants, colorants, flavoring agents, fragrances, binders, and coating agents.
Specific examples of the disintegrant include carmellose calcium, crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose, and corn starch.
Specific examples of the colorant include yellow sesquioxide, sesquioxide, edible red No. 3, edible yellow No. 5, edible blue No. 1, etc., brown iron oxide, black iron oxide, copper chlorophyll, copper chlorophyllin. Sodium, riboflavin, powdered green tea powder, etc. are mentioned.
As a corrigent, specifically, ascorbic acid and its salt, glycine, sodium chloride, magnesium chloride, hydrochloric acid, dilute hydrochloric acid, citric acid and its salt, anhydrous citric acid, L-glutamic acid and its salt, succinic acid and its salt, Examples include acetic acid, tartaric acid and its salt, sodium hydrogen carbonate, fumaric acid and its salt, malic acid and its salt, glacial acetic acid, disodium inosinate, honey and the like.
Perfumes include what are called flavoring agents, specifically orange essence, orange oil, caramel, camphor, cinnamon oil, spearmint oil, strawberry essence, chocolate essence, cherry flavor, spruce oil, pine oil, mint oil. , Vanilla flavor, bitter essence, fruit flavor, peppermint essence, mixed flavor, mint flavor, menthol, lemon powder, lemon oil, rose oil and the like.
Specific examples of binders include gum arabic, gum arabic powder, partially pregelatinized starch, gelatin, agar, dextrin, pullulan, povidone, polyvinyl alcohol, ethyl cellulose, carboxymethyl ethyl cellulose, carmellose, carmellose sodium, hydroxyethyl cellulose, hydroxy Examples include ethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and the like.
Specific coating agents include polyvinyl alcohol, ethyl cellulose, carboxymethyl ethyl cellulose, carmellose, carmellose sodium, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, PVA copolymer, ethyl acrylate / methyl methacrylate copolymer Dispersion, aminoalkyl methacrylate copolymer, Opadry, carnauba wax, carboxyvinyl polymer, dry methacrylic acid copolymer, dimethylaminoethyl methacrylate / methyl methacrylate copolymer, stearyl alcohol, shellac, cetanol, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methyl ester Loin phthalate, fumaric acid-stearic acid-polyvinylacetal diethylaminoacetate-hydroxypropylmethylcellulose mixture, polyvinylacetal diethylamino acetate, polyvinyl alcohol, methacrylic acid copolymer, 2-methyl-5-vinylpyridine methylacrylate-methacrylic acid copolymer, and the like.

  These additives can usually be used alone or in admixture, as long as they do not impair the dissolution property, disintegration property, and moldability in the present preparation. Preferred drug and additive combinations are: 1) Galantamine or its salt / sodium carboxymethyl starch / anhydrous calcium hydrogen phosphate / crystalline cellulose / magnesium stearate, 2) Galantamine or its salt / sodium carboxymethyl starch / anhydrous hydrogen phosphate Calcium / crystalline cellulose / aspartame / magnesium stearate, 3) Galantamine or its salt / sodium carboxymethyl starch / anhydrous calcium hydrogen phosphate / crystalline cellulose / aspartame / light anhydrous silicic acid / magnesium stearate, 4) Galantamine or its salt / Sodium carboxymethyl starch / anhydrous calcium hydrogen phosphate / crystalline cellulose / carmellose / magnesium stearate, 5) Galantamine or its salt / carboxyme Lustach sodium / anhydrous calcium hydrogen phosphate / crystalline cellulose / carmellose / aspartame / magnesium stearate, and 6) galantamine or its salt / sodium carboxymethyl starch / anhydrous calcium hydrogen phosphate / crystalline cellulose / carmellose / aspartame / light anhydrous silica Acid / magnesium stearate.

  In the combination of galantamine or a salt thereof / sodium carboxymethyl starch / anhydrous calcium hydrogen phosphate / crystalline cellulose / magnesium stearate, each content is 1 to 20% by weight of galantamine or a salt thereof, and 1 to 1 of carboxymethyl starch sodium. 30% by weight, anhydrous calcium hydrogen phosphate is 10 to 60% by weight, crystalline cellulose is 10 to 50% by weight, and magnesium stearate is 0.001 to 0.8% by weight. Preferably, galantamine or a salt thereof is 2 to 15% by weight, sodium carboxymethyl starch is 3 to 15% by weight, anhydrous calcium hydrogen phosphate is 20 to 55% by weight, crystalline cellulose is 15 to 45% by weight, and magnesium stearate 0.01 to 0.65% by weight. More preferably, galantamine or a salt thereof is 3 to 10% by weight, sodium carboxymethyl starch is 5 to 10% by weight, anhydrous calcium hydrogen phosphate is 30 to 50% by weight, crystalline cellulose is 20 to 40% by weight, and magnesium stearate. Is 0.1 to 0.5% by weight.

  In a combination of galantamine or a salt thereof / sodium carboxymethyl starch / anhydrous calcium hydrogen phosphate / crystalline cellulose / aspartame / magnesium stearate, each content is 1 to 20% by weight of galantamine or a salt thereof, and sodium carboxymethyl starch 1-30 wt%, anhydrous calcium hydrogen phosphate 10-60 wt%, crystalline cellulose 10-50 wt%, aspartame 0.1-10 wt% and magnesium stearate 0.001-0.8 wt% It is. Preferably, galantamine or a salt thereof is 2 to 15% by weight, sodium carboxymethyl starch is 3 to 15% by weight, anhydrous calcium hydrogen phosphate is 20 to 55% by weight, crystalline cellulose is 15 to 45% by weight, and aspartame is 0.1% by weight. 25 to 9% by weight and 0.01 to 0.65% by weight of magnesium stearate. More preferably, galantamine or a salt thereof is 3 to 10% by weight, sodium carboxymethyl starch is 5 to 10% by weight, anhydrous calcium hydrogen phosphate is 30 to 50% by weight, crystalline cellulose is 20 to 40% by weight, and aspartame is 0%. 0.5 to 8 wt% and magnesium stearate 0.1 to 0.5 wt%.

  In the combination of galantamine or a salt thereof / sodium carboxymethyl starch / anhydrous calcium hydrogen phosphate / crystalline cellulose / aspartame / light anhydrous silicic acid / magnesium stearate, each content is 1 to 20% by weight of galantamine or a salt thereof, 1 to 30% by weight of sodium carboxymethyl starch, 10 to 60% by weight of anhydrous calcium hydrogen phosphate, 10 to 50% by weight of crystalline cellulose, 0.1 to 10% by weight of aspartame, and 0.01 to light anhydrous silicic acid -10 wt% and magnesium stearate 0.001-0.8 wt%. Preferably, galantamine or a salt thereof is 2 to 15% by weight, sodium carboxymethyl starch is 3 to 15% by weight, anhydrous calcium hydrogen phosphate is 20 to 55% by weight, crystalline cellulose is 15 to 45% by weight, and aspartame is 0.1% by weight. 25 to 9% by weight, light anhydrous silicic acid is 0.05 to 5% by weight, and magnesium stearate is 0.01 to 0.65% by weight. More preferably, galantamine or a salt thereof is 3 to 10% by weight, sodium carboxymethyl starch is 5 to 10% by weight, anhydrous calcium hydrogen phosphate is 30 to 50% by weight, crystalline cellulose is 20 to 40% by weight, and aspartame is 0%. 0.5 to 8 wt%, light anhydrous silicic acid is 0.1 to 2.5 wt%, and magnesium stearate is 0.1 to 0.5 wt%.

  In the combination of galantamine or a salt thereof / sodium carboxymethyl starch / anhydrous calcium hydrogen phosphate / crystalline cellulose / carmellose / magnesium stearate, each content is 1 to 20% by weight of galantamine or a salt thereof, and sodium carboxymethyl starch 1-30 wt%, anhydrous calcium hydrogen phosphate 10-60 wt%, crystalline cellulose 10-50 wt%, carmellose 0.1-10 wt% and magnesium stearate 0.001-0.8 wt% It is. Preferably, galantamine or a salt thereof is 2 to 15% by weight, sodium carboxymethyl starch is 3 to 15% by weight, anhydrous calcium hydrogen phosphate is 20 to 55% by weight, crystalline cellulose is 15 to 45% by weight, and carmellose is 0.1% by weight. 5 to 7.5 wt% and magnesium stearate is 0.01 to 0.65 wt%. More preferably, galantamine or a salt thereof is 3 to 10% by weight, carboxymethyl starch sodium is 5 to 10% by weight, anhydrous calcium hydrogen phosphate is 30 to 50% by weight, crystalline cellulose is 20 to 40% by weight, and carmellose is 1%. ~ 5 wt% and magnesium stearate is 0.1 to 0.5 wt%.

  In a combination of galantamine or a salt thereof / sodium carboxymethyl starch / anhydrous calcium hydrogen phosphate / crystalline cellulose / carmellose / aspartame / magnesium stearate, each content is 1 to 20% by weight of galantamine or a salt thereof, carboxymethyl starch 1-30 wt% sodium, 10-60 wt% anhydrous calcium hydrogen phosphate, 10-50 wt% crystalline cellulose, 0.1-10 wt% carmellose, 0.1-10 wt% aspartame and stearin Magnesium acid is 0.001 to 0.8% by weight. Preferably, galantamine or a salt thereof is 2 to 15% by weight, sodium carboxymethyl starch is 3 to 15% by weight, anhydrous calcium hydrogen phosphate is 20 to 55% by weight, crystalline cellulose is 15 to 45% by weight, and carmellose is 0.1% by weight. 5 to 7.5% by weight, aspartame is 0.25 to 9% by weight, and magnesium stearate is 0.01 to 0.65% by weight. More preferably, galantamine or a salt thereof is 3 to 10% by weight, carboxymethyl starch sodium is 5 to 10% by weight, anhydrous calcium hydrogen phosphate is 30 to 50% by weight, crystalline cellulose is 20 to 40% by weight, and carmellose is 1%. ~ 5 wt%, aspartame 0.5-8 wt% and magnesium stearate 0.1-0.5 wt%.

  In the combination of galantamine or a salt thereof / sodium carboxymethyl starch / anhydrous calcium hydrogen phosphate / crystalline cellulose / carmellose / aspartame / light anhydrous silicic acid / magnesium stearate, each content is 1 to 20 weights of galantamine or a salt thereof. %, Sodium carboxymethyl starch 1-30% by weight, anhydrous calcium hydrogen phosphate 10-60% by weight, crystalline cellulose 10-50% by weight, aspartame 0.1-10% by weight, light anhydrous silicic acid 0 0.01 to 10 wt% and magnesium stearate is 0.001 to 0.8 wt%. Preferably, galantamine or a salt thereof is 2 to 15% by weight, sodium carboxymethyl starch is 3 to 15% by weight, anhydrous calcium hydrogen phosphate is 20 to 55% by weight, crystalline cellulose is 15 to 45% by weight, and aspartame is 0.1% by weight. 25 to 9% by weight, light anhydrous silicic acid is 0.05 to 5% by weight, and magnesium stearate is 0.01 to 0.65% by weight. More preferably, galantamine or a salt thereof is 3 to 10% by weight, sodium carboxymethyl starch is 5 to 10% by weight, anhydrous calcium hydrogen phosphate is 30 to 50% by weight, crystalline cellulose is 20 to 40% by weight, and aspartame is 0%. 0.5 to 8 wt%, light anhydrous silicic acid is 0.1 to 2.5 wt%, and magnesium stearate is 0.1 to 0.5 wt%.

  This preparation is a tablet that rapidly disintegrates in the oral cavity by saliva. The disintegration time of this preparation is 1 to 60 seconds, preferably 1 to 40 seconds, more preferably 1 to 30 seconds, and the mouth dissolution time in the oral cavity is 1 to 60 seconds, preferably in the disintegration test method according to the Japanese Pharmacopoeia. Is 1 to 40 seconds, more preferably 1 to 30 seconds. This preparation can be taken smoothly without leaving roughness even after the tablet disintegrates in the oral cavity.

  Further, this preparation exhibits good dissolution properties, and the dissolution rate of galantamine 15 minutes after the start of the test is 80% or more, preferably 85% or more, more preferably 87.5% in the dissolution test method by the Japanese Pharmacopoeia. Above, especially preferably 90% or more. If the dissolution test is performed multiple times, the dissolution rate should be the average value.

  In this preparation, when the dissolution rate variation in the dissolution test method by the Japanese Pharmacopoeia, that is, when the dissolution test was performed multiple times, the difference between the maximum value and the minimum value of the dissolution rate of galantamine 15 minutes after the start of the test was 9.0. %, Preferably within 8.5%, more preferably within 5.0%, even more preferably within 2.5%, particularly preferably within 1.0%.

  The hardness of this preparation is about 10 to 200 N, preferably about 20 to 150 N, and more preferably about 30 to 100 N when measured with a tablet hardness meter. If it is lower than this hardness, the tablet may be damaged during storage or when the tablet is taken out from the PTP package, and if it is higher, the disintegration time of the tablet may be delayed.

  The dosage of this preparation depends on the severity and age of the patient, but the daily dosage for an adult is about 8 to 24 mg as an active ingredient. In addition, this preparation can be taken without being disintegrated in the oral cavity or taken together with water.

For the preparation of this preparation, a conventional tablet production method can be used. That is, the preparation is prepared by a direct powder compression method (direct compression method or direct compression method) in which the powder is mixed and directly compressed and compressed, or a granule compression method in which the powder is granulated and the granules are compressed. Can be manufactured. Hereinafter, the manufacturing method of this formulation is demonstrated concretely.
For example, a mixed powder for tablets obtained by mixing galantamine or a salt thereof and an additive with a suitable mixer such as a V-type mixer is produced by direct compression and compression using a tableting machine described later. The mixed powder for tablets is a method of strongly mixing with a stirring granulator, a method of mixing and pulverizing with a pulverizer, a method of compressing and granulating with a dry granulator, water with a binder dispersed or dissolved as necessary, acetone , Ethyl alcohol, propyl alcohol, or a mixture thereof, and the like. When producing a mixed powder for tablets, a binder, a corrigent, a fluidizing agent, a lubricant, a fragrance, a sweetener, a coloring agent, and the like may be mixed as necessary. In the present invention, the particle size of galantamine or a salt thereof and an additive is not particularly limited.

  The mixed powder for tablets obtained in this way can be compression-molded at a tableting pressure of 2 kN to 15 kN using, for example, a single-punch tableting machine or a rotary tableting machine to produce tablets. If the pressure is lower than this, the tablet hardness is insufficient and sufficient hardness for handling cannot be secured, and if the pressure is high, disintegration is delayed, which is not preferable.

  In addition, tablets can be produced by an external lubricant tableting method in which a lubricant is attached to a mortar and pestle for tableting. As an apparatus for performing the external lubricant tableting method, there is ELSP1-type III manufactured by Kikusui Seisakusho Co., Ltd. If it is an external lubrication tableting method, even a small amount of lubricants can be tableted. With a small amount of lubricant, the disintegration time of the tablet can be shortened and the stability of the drug can be increased.

  Any shape can be adopted for the molding of this preparation, for example, a round shape, an oval shape, a spherical shape, a rod shape, a donut shape, a laminated tablet, a dry-coated tablet, etc. It can also be coated by a coating. Also, marks for improving the identification, characters, etc., and dividing lines for division may be attached.

  In this invention, after manufacturing the bitterness suppression preparation (for example, powder and granule) containing galantamine beforehand, the said additive is mixed with these preparations, and a tablet can also be manufactured. In this case, it is possible to produce an orally disintegrating tablet with suppressed bitterness.

EXAMPLES Hereinafter, although an Example, a comparative example, and a reference example are given and this invention is demonstrated in detail, this invention is not restrict | limited by these.
The manufactured tablets were measured for dissolution rate, tablet hardness and disintegration time by the following test methods.
(1) Dissolution Test Method Dissolution test method of the 15th revised Japanese Pharmacopoeia General Test Method The second method (paddle method) was applied mutatis mutandis and tested at 50 revolutions per minute. The test solution is purified water specified by the Japanese Pharmacopoeia, the eluate is sampled 5, 10, 15, 30 minutes after the start of the dissolution test, and the 15th revised Japanese Pharmacopoeia General Test Method UV-Vis Absorbance Measurement Method is applied mutatis mutandis. The absorbance of galantamine at an analysis wavelength of 289 nm was measured, and the elution rate was calculated. The dissolution rate of the same prescription tablet was measured 3 times, and the average value was calculated. Hereinafter, the average value may be referred to as an elution rate. Further, the difference between the maximum value and the minimum value of the dissolution rate 15 minutes after the start of the dissolution test was taken as the variation in dissolution rate.
(2) Hardness test method The hardness was measured using a tablet hardness tester (manufactured by ERWEKA International AG). The test is performed with 3 tablets, and the average value is shown. (30N or more as the standard of practicality)
(3) Disintegration test method Fifteenth revision of the Japanese Pharmacopoeia Disintegration Test Method shall apply mutatis mutandis, and the test solution shall use the purified water specified by the Japanese Pharmacopoeia, measure the disintegration time of 2 tablets without an auxiliary board, and determine the maximum value. Show. (The standard of practicality is within 30 seconds)

(Tablet manufacturing method)
A predetermined amount of galantamine hydrobromide, disintegrant, anhydrous calcium hydrogen phosphate, crystalline cellulose, aspartame, and light anhydrous silicic acid was weighed and mixed in a plastic bag to obtain a mixed powder. After applying a lubricant to the pestle and die, these mixed powders were weighed so as to be about 140 mg per tablet, filled into a mortar, and tableted with a compression tester. At this time, the shape of the ridge was round, and the diameter was 7 mm.

(Examination of disintegrant)
(Example 1, Comparative Examples 1-3)
In order to examine the disintegrant, powders having the formulations shown in Table 1 were mixed and directly compressed into tablets, and the hardness, disintegration time, and dissolution rate 15 minutes after the start of the dissolution test were measured. Galantamine hydrobromide is manufactured by Janssen Pharma Co., Ltd., disintegrators are carboxymethyl starch sodium, extractprotab (manufactured by Kimura Sangyo Co., Ltd.), carmellose NS-300 (manufactured by Gotoku Pharmaceutical Co., Ltd.), carme ECG505 (manufactured by Gotoku Pharmaceutical Co., Ltd.) was used as roast calcium, and polyplastidone XL-10 (manufactured by ISP Technologies) was used as crospovidone. In addition, Theolas PH-102 (produced by Asahi Kasei Chemicals Corporation) as crystalline cellulose, anhydrous calcium hydrogen phosphate GS (produced by Kyowa Chemical Co., Ltd.) as anhydrous calcium hydrogen phosphate, PAL SWEET DIET (produced by Ajinomoto Co., Inc.) as light aspartame, light AEROSIL200 (manufactured by Nippon Aerosil Co., Ltd.) was used as silicic anhydride, and magnesium stearate NF (vegetable) (manufactured by Mallinckrodt) was used as magnesium stearate. The tableting pressure was 4 kN.
(Experimental result)
The experimental results are shown in Table 1, and the elution behavior is shown in FIG. In any tablet, the tablet hardness was 30 N or more, which was a practical level, and the disintegration time was as fast as 10 seconds or less. However, as shown in Comparative Examples 1 and 2, when carmellose or carmellose calcium was used as the disintegrant, the dissolution rate was 80% or more, but the variation was 17.3% and 9.8%. It was. Moreover, as shown in Comparative Example 3, when crospovidone was used, the elution rate after 15 minutes did not reach 80% or more, and the variation was about 10%. On the other hand, as shown in Example 1, when carboxymethyl starch sodium was used as the disintegrant, the dissolution rate was 90% or more, and the variation was very small, within 1%.

(Examination of content of sodium carboxymethyl starch)
(Examples 1 and 2 and Comparative Example 4)
In order to examine the optimum content of sodium carboxymethyl starch, tablets were prepared with the content of sodium carboxymethyl starch being 2% by weight, 5% by weight, and 10% by weight. The tablet hardness, disintegration time, and dissolution rate 15 minutes after the start of the dissolution test were evaluated. The tableting pressure was about 4 kN.
(Experimental result)
The experimental results are shown in Table 2, and the elution behavior is shown in FIG. In each tablet, the disintegration time was very fast, within 10 seconds. The hardness of the tablets was practical level of 30 N or more, but it tended to decrease as the amount of sodium carboxymethyl starch increased. As shown in Comparative Example 4, the dissolution rate was about 80% when the content of sodium carboxymethyl starch was 2% by weight, and the variation was about 6%. On the other hand, as shown in Examples 1 and 2, when the content of sodium carboxymethyl starch was 5% by weight and 10% by weight, the dissolution rate was 90% or more, and the variation was within 1%. It was.

(Examination of dissolution when sodium carboxymethyl starch and carmellose are used in combination)
(Examples 2 and 3, Reference Example 1)
As a disintegrant other than sodium carboxymethyl starch, dissolution rate, disintegration property, and tablet hardness when carmellose was used in combination were evaluated. The content of sodium carboxymethyl starch was 5%, and the content of carmellose was 5% by weight and 10% by weight. The tableting pressure in Example 2 and Reference Example 1 was about 4 kN, the tablet mass was 140 mg, the tableting pressure in Example 3 was about 5 kN, and the tablet mass was 210 mg.
(Experimental result)
The experimental results are shown in Table 3, and the elution behavior is shown in FIG. In any tablet, the tablet hardness was 30 N or more, which was a practical level, and the disintegration time was very fast, within 10 seconds. Moreover, the elution rates of Examples 2 and 3 were 90% or more, and the variation was within 1%.

(Examination of galantamine content)
(Examples 3 and 4)
The dissolution rate, disintegration, and tablet hardness when the content of galantamine was changed were evaluated. The content of galantamine was 3.7% by weight, and the tableting pressure was about 4 kN.
(Experimental result)
The experimental results are shown in Table 4. In any tablet, the tablet hardness was 30 N or more, which was a practical level, and the disintegration time was very fast, within 10 seconds. Further, the elution rate of Example 4 was 90% or more, and the variation thereof was within 2.5%, and even when the content of galantamine was changed, the elution rate and the variation thereof were hardly changed.

  Since this preparation disintegrates rapidly in the oral cavity and galantamine elutes rapidly in the digestive tract, it is also useful for Alzheimer patients who have difficulty in swallowing and can obtain sufficient medicinal effects.

Claims (17)

An orally disintegrating tablet comprising galantamine or a salt thereof, sodium carboxymethyl starch and carmellose , comprising 5 to 10% by weight sodium carboxymethyl starch and 1 to 5% by weight carmellose Disintegrating tablets. Orally disintegrating tablet of claim 1 wherein the inorganic excipient. The orally disintegrating tablet according to claim 2 , wherein the inorganic excipient is anhydrous calcium hydrogen phosphate. The orally disintegrating tablet according to any one of claims 1 to 3, comprising crystalline cellulose. The orally disintegrating tablet according to any one of claims 1 to 4 , comprising a lubricant. The orally disintegrating tablet according to claim 5 , wherein the lubricant is magnesium stearate. The orally disintegrating tablet according to claim 5 or 6, comprising 0.001 to 0.8% by weight of a lubricant. The orally disintegrating tablet according to any one of claims 5 to 7 , wherein the lubricant is added by an external lubricant method. The orally disintegrating tablet according to any one of claims 1 to 8 , comprising a sweetening agent. The orally disintegrating tablet according to claim 9 , wherein the sweetening agent is aspartame. An orally disintegrating tablet comprising galantamine or a salt thereof, sodium carboxymethyl starch, anhydrous calcium hydrogen phosphate, crystalline cellulose, carmellose, aspartame and magnesium stearate , comprising 5 to 10% by weight sodium carboxymethyl starch and 1 to The orally disintegrating tablet according to any one of claims 1 to 10, comprising 5% by weight of carmellose . 3-10% by weight galantamine or salt thereof, 5-10% by weight sodium carboxymethyl starch, 30-50% by weight anhydrous calcium hydrogen phosphate, 20-40% by weight crystalline cellulose, 1-5% by weight carmellose The orally disintegrating tablet according to claim 11 , comprising 0.5 to 7.5% by weight of aspartame and 0.001 to 0.8% by weight of magnesium stearate. The orally disintegrating tablet according to any one of claims 1 to 12 , wherein in the dissolution test method of the Japanese Pharmacopoeia, the dispersion of the dissolution rate of galantamine 15 minutes after the start of the test is within 8.5%. Galantamine or a salt thereof, and contain sodium carboxymethyl starch and carmellose, in the elution test method of the Japanese Pharmacopoeia, the dissolution rate of galantamine after the test started 15 minutes variation according to claim 13, wherein is within 8.5% Orally disintegrating tablets. The orally disintegrating tablet according to any one of claims 1 to 14 , which has a disintegration time of 1 to 60 seconds in the disintegration test method of the Japanese Pharmacopoeia. Orally disintegrating tablet according to any one of claims 1 to 15 hardness of 10～200N. The orally disintegrating tablet according to any one of claims 1 to 16 , wherein the salt of galantamine is galantamine hydrobromide.

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