TW201818928A - Pharmaceutical composition containing memantine or pharmaceutically acceptable salt thereof - Google Patents

Abstract

A medicinal composition which is in the form of granules, a powder or a preparation for syrup comprising memantine or a pharmaceutically acceptable salt thereof and an enteric polymer, said composition being easy to ingest even for aged people or patients having difficulty in swallowing and showing a reduced bitterness at administration. In particular, granules or a granular preparation for syrup wherein memantine or a pharmaceutically acceptable salt thereof and an enteric polymer are mixed together in granules.

Description

   Pharmaceutical composition containing memantine or a pharmaceutically acceptable salt thereof   

The present invention relates to a medicinal composition, which is a granule, powder or syrup containing memantine or a pharmaceutically acceptable salt thereof, which is excellent in ingestibility, dissolution and stability.

Memantine hydrochloride is a therapeutic agent for Alzheimer's dementia. It is based on the N-methyl-D-aspartic acid of one of the glutamate receptor subtypes. (NMDA) receptor antagonism as a mechanism of action. This drug was recognized by the European Medicines Agency (EMA) in 2002 and the US Food and Drug Administration (FDA) in 2003 as an indication for Alzheimer's dementia. The performance and effect of the progress of dementia symptoms of high and high Alzheimer-type dementia have been sold as "MEMARY (registered trademark) tablets".

Since most patients with Alzheimer's type of dementia are elderly or have difficulty swallowing, in order to improve the adherence of the medication and reduce the burden on the caregiver who manages the medication, an easy-to-take preparation is desired. In addition, because memantine has a unique bitter taste, if there is a bitter taste remaining in the mouth, the compliance of the medicine may be reduced. Therefore, in the development of formulations containing memantine hydrochloride, in addition to being easy to take, it is also required to reduce the bitterness when taking the drug.

So far, in the preparation of memantine hydrochloride, attempts have been made to apply the technique of intraoral disintegration. For example, in Patent Document 1, an orally disintegrating tablet or an intraorally disintegrating film containing memantine hydrochloride is described. As a method for reducing the bitterness of memantine, granules of memantine hydrochloride have been proposed. Then, the method is coated with methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer (Eudragit EPO); or memantine hydrochloride is prepared with hydroxypropyl β- Method of a cyclodextrin complex (Patent Document 1). In addition, Patent Document 2 describes a case where an instant composition of memantine is produced, and the composition itself is taste-masked with an acrylate-based or cellulose-based polymer (Patent Document 2).

In Patent Document 3, it has been described in a case where an orally disintegrating tablet containing memantine hydrochloride is produced, and the particles containing memantine hydrochloride are composed of methacrylic acid copolymer LD, triethyl citrate, and talc. The coating liquid is applied, and granulated products containing D-mannitol, crystalline cellulose, and α-starch, crospovidone, aspartame, and the like are mixed to form tablets.

Because the intraoral disintegration tablet or intraoral disintegration film quickly disintegrates in the oral cavity, it is a dosage form that can be taken even without water, and is preferably used as a preparation for the treatment of Alzheimer's dementia. Oral disintegration tablets of memantine hydrochloride have been recognized in 2013 and have been sold. However, due to dislike of taking tablets, or difficulty in taking tablets due to swallowing difficulties, the actual situation may have to give up taking memantine hydrochloride.

On the other hand, granules, powders, and dry syrups are known as dosage forms of pharmaceutical products other than lozenges. In particular, dry syrup has the advantage of being easy to take for elderly people, young children, and patients who have difficulty swallowing because it is dissolved or suspended in water during use. However, granules, powders, and dry syrups of bitter memantine hydrochloride have not been developed so far.

    [Prior technical literature]         [Patent Literature]    

[Patent Document 1] International Publication WO2008 / 005534

[Patent Document 2] International Publication WO2009 / 004440

[Patent Document 3] International Publication WO2013 / 161823

An object of the present invention is to provide a novel medicinal composition, particularly a granule, a powder, and a dry syrup, which is easy to take even in an elderly person or a patient with difficulty in swallowing, and has a reduced bitterness when taking the drug, or a pharmaceutically acceptable salt thereof. Agent.

Another object of the present invention is to provide a method for easily producing granules, powders, and dry syrups with reduced bitterness.

In order to suppress the bitterness, granules, powders, or syrups (also called dry syrups) containing the original medicine with a bitter taste are generally used to coat the particles with a coating agent. Suspension stability after water, and agglomeration of particles when stored in an environment with high water content. As a result of intensive research in order to solve these problems, the inventors have found that by incorporating an enteric polymer having a carboxyl group into memantine or a pharmacologically acceptable salt thereof, the pharmaceutical composition is specifically, The pharmaceutical composition is blended with two ingredients, or the granules are blended with the granules, which can reduce the bitterness of memantine or its pharmaceutically acceptable salt without the coating step of the granules, dissolution, suspension stability, and suspension liquid The uniformity of the content of the main drug in the product is good, and aggregation of powders or particles during storage in a high-humidity environment can be suppressed. In addition, it was found that a pharmaceutical composition such as granules, powders, or dry syrups having the same dissolution characteristics (quick solubility) as the conventional memantine hydrochloride lozenges can be prepared, and the present invention has been completed.

That is, this invention relates to the following (1)-(21).

(1) A pharmaceutical composition comprising memantine or a pharmaceutically acceptable salt thereof and an enteric polymer, and the dosage form is granules, powders, or syrups.

(2) The pharmaceutical composition according to (1), wherein the medicinal composition is a granule or a granular syrup, wherein the intra-granular memantine or a pharmaceutically acceptable salt thereof and the enteric polymer are mixed.

(3) The medicinal composition according to (1) or (2), wherein memantine or a pharmaceutically acceptable salt thereof and the enteric polymer are substantially homogeneous and mixed.

(4) The pharmaceutical composition according to any one of (1) to (3), wherein memantine or a pharmaceutically acceptable salt thereof is memantine hydrochloride.

(5) The pharmaceutical composition according to any one of (1) to (4), wherein the enteric polymer is selected from the group consisting of dry methacrylic acid copolymer LD, methacrylic acid copolymer L, and methacrylic acid copolymer One or more groups of S.

(6) The pharmaceutical composition according to any one of (1) to (4), wherein the enteric polymer is a dry methacrylic acid copolymer LD.

(7) The pharmaceutical composition according to any one of (1) to (6), wherein the blending amount of the enteric polymer is 0.5 to 15 parts by weight relative to 1 part by weight of memantine or a pharmaceutically acceptable salt thereof. .

(8) The pharmaceutical composition according to any one of (1) to (6), wherein the amount of the enteric polymer is 2 to 10 parts by weight based on 1 part by weight of memantine or a pharmaceutically acceptable salt thereof. .

(9) The pharmaceutical composition according to any one of (1) to (8), further comprising a compound selected from the group consisting of aspartame, sodium saccharin hydrate, glycerin, and vanillin , Dextrin, and sucralose 1 or 2 or more flavoring agents.

(10) The pharmaceutical composition according to (9), wherein the flavoring agent is aspartame.

(11) The pharmaceutical composition according to (9) or (10), wherein the blending amount of the flavoring agent is 0.05 to 5 parts by weight relative to 1 part by weight of the enteric polymer.

(12) The pharmaceutical composition according to (9) or (10), wherein the blending amount of the flavoring agent is 1 to 3 parts by weight relative to 1 part by weight of memantine or a pharmaceutically acceptable salt thereof.

(13) The pharmaceutical composition according to any one of (1) to (12), further comprising one or more additives selected from the group consisting of a sugar alcohol, a dispersant, a binder, and a fluidizing agent.

(14) The pharmaceutical composition according to (13), wherein the sugar alcohol is D-mannitol.

(15) The pharmaceutical composition according to (13) or (14), wherein the dispersing agent is selected from the group consisting of crospovidone, carmellose calcium, carmellose, One or two or more types of croscarmellose sodium, low-substituted hydroxypropyl cellulose, corn starch, and sodium starch glycolate.

(16) The pharmaceutical composition according to any one of (13) to (15), wherein the adhesive is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone One or more of them.

(17) The pharmaceutical composition according to any one of (13) to (16), wherein the fluidizing agent is selected from the group consisting of light anhydrous silicic acid, hydrous silicon dioxide, titanium oxide, stearic acid, and talc One or more groups.

(18) The pharmaceutical composition according to any one of (1) to (17), which is a paddle method of the dissolution test in the Japanese Pharmacopoeia (test liquid: water; number of paddle plate rotation: 50 rpm; test liquid Amount: 900mL), the dissolution rate of memantine or its pharmaceutically acceptable salt is 85% or more in 15 minutes.

(19) The medicinal composition according to any one of (1) to (18), in the following test, memantine or a pharmaceutically acceptable salt thereof as the main drug contained in the upper layer of the test solution after 30 minutes The content is more than 80% of the theoretical content.

Test for the uniformity of the content of the main drug in the test solution suspended in water: using a 50mL self-standing centrifuge tube with a diameter of 3cm, add 4g of the pharmaceutical composition to 37mL of water and shake it for 1 minute to suspend it, then let it stand; After the prescribed time, the content of the main drug in the upper layer of the test solution was 20 mL, and the theoretical content of the main drug in the upper layer of the uniform test solution immediately after the suspension was set to 100%.

(20) A method for producing a pharmaceutical composition according to any one of (1) to (19), comprising a step of homogeneously mixing memantine or a pharmaceutically acceptable salt thereof with an enteric polymer .

(21) A method for producing the pharmaceutical composition according to any one of (1) to (19), wherein the dosage form is a granule or a granular syrup, and includes the following steps 1 to 3 Step: Step 1: A step of homogeneously mixing memantine or a pharmaceutically acceptable salt thereof, an enteric polymer, and optionally a flavoring agent and / or other additives; a step 2: a step of granulating the obtained mixture And step 3: a step of mixing the granulated material obtained with an optional flavoring agent and / or other additives.

The present invention relates to the following (1a) to (20a).

(1a) A pharmaceutical composition containing memantine hydrochloride and a dry methacrylic acid copolymer LD.

(2a) The pharmaceutical composition according to (1a), which is a pharmaceutical composition containing memantine hydrochloride and dry methacrylic acid copolymer LD, wherein memantine hydrochloride and dry methacrylic acid copolymer LD are essentially It is mixed homogeneously.

(3a) The pharmaceutical composition according to (1a) or (2a), which is a pharmaceutical composition containing memantine hydrochloride and dry methacrylic acid copolymer LD, wherein memantine hydrochloride is copolymerized with dry methacrylic acid The LD system is homogeneously present in the pharmaceutical composition.

(4a) The pharmaceutical composition according to any one of (1a) to (3a), wherein the blending amount of the dry methacrylic acid copolymer LD is 0.5 to 15 parts by weight relative to 1 part by weight of memantine hydrochloride. .

(5a) The pharmaceutical composition according to any one of (1a) to (3a), wherein the blending amount of the dry methacrylic acid copolymer LD is 2 to 10 parts by weight relative to 1 part by weight of memantine hydrochloride. .

(6a) The pharmaceutical composition according to any one of (1a) to (5a), further comprising a compound selected from the group consisting of aspartame, sodium saccharin hydrate, glycerin, vanillin, dextrin, and sucralose One or more flavoring agents in the group.

(7a) The pharmaceutical composition according to (6a), wherein the flavoring agent is aspartame.

(8a) The pharmaceutical composition according to (6a) or (7a), wherein the blending amount of the flavoring agent is 0.05 to 5 parts by weight (preferably 0.1 to 1.5) relative to 1 part by weight of the dry methacrylic acid copolymer LD. Parts by weight).

(9a) The pharmaceutical composition according to any one of (1a) to (8a), further comprising one or more selected from the group consisting of a sugar alcohol, a dispersant, a binder, and a fluidizing agent.

(10a) The pharmaceutical composition according to (9a), wherein the sugar alcohol is D-mannitol.

(11a) The pharmaceutical composition according to (9a) or (10a), wherein the dispersant is selected from the group consisting of crospovidone, carboxymethyl cellulose calcium, carboxymethyl cellulose, and croscarmellose One or more of sodium, low-substituted hydroxypropyl cellulose, corn starch, and sodium starch glycolate.

(12a) The pharmaceutical composition according to any one of (9a) to (11a), wherein the adhesive is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone One or more of them.

(13a) The pharmaceutical composition according to any one of (9a) to (12a), wherein the fluidizing agent is selected from the group consisting of light anhydrous silicic acid, hydrous silicon dioxide, titanium oxide, stearic acid, and talc One or more groups.

(14a) The pharmaceutical composition according to any one of (1a) to (13a), wherein the pharmaceutical composition is a granule, a powder, or a syrup.

(15a) The medicinal composition according to any one of (1a) to (14a), the dissolution rate of memantine hydrochloride in the case of using water in the dissolution test of the Japanese Pharmacopoeia is 15% or more 85% .

(16a) A method for producing a pharmaceutical composition according to any one of (1a) to (15a), comprising a step of homogeneously mixing dry memantine hydrochloride and methacrylic acid copolymer LD .

(17a) A method for reducing the bitterness of memantine hydrochloride, comprising the step of homogeneously mixing memantine hydrochloride and dry methacrylic acid copolymer LD.

(18a) A particle containing memantine hydrochloride and a dry methacrylic acid copolymer LD.

(19a) A granule comprising memantine hydrochloride and a dry methacrylic acid copolymer LD, wherein the memantine hydrochloride and the dry methacrylic acid copolymer LD are homogeneously mixed.

(20a) A particle comprising particles of memantine hydrochloride and dry methacrylic acid copolymer LD, wherein memantine hydrochloride and dry methacrylic acid copolymer LD are homogeneously present in the particles.

The medicinal composition (granule, powder, or dry syrup) containing memantine or a pharmaceutically acceptable salt thereof and an enteric polymer of the present invention has the same dissolution characteristics as conventional lozenges, except that it is biologically equivalent In the case of taking with water or in the case of suspending in water, it reduces the bitterness peculiar to memantine and has excellent applicability. In addition, the stability of the preparation and the dispersion in the case of suspension in water or the uniformity of the content of the main drug in the liquid after a certain period of time are also excellent, which can also reduce the medical management of medical practitioners and nursing staff. burden.

In addition, the method for producing a pharmaceutical composition of the present invention only needs to include a step of mixing memantine or a pharmaceutically acceptable salt thereof with an enteric polymer, and does not require complicated equipment and procedures, and thus has an advantage in manufacturing a preparation.

    [Form of Implementing Invention]    

Hereinafter, the "medical composition containing memantine or a pharmaceutically acceptable salt thereof and an enteric polymer in a dosage form of granules, powders, or syrups" (hereinafter, only referred to as "this" "Inventive pharmaceutical composition") and its manufacturing method.

Memantine as the main drug, its chemical name is 3,5-dimethyltricyclo [3.3.1.1 ^3,7 ] dec-1-ylamine (3,5-Dimethyltricyclo [3.3.1.1 ^3,7 ] dec- 1-ylamine). The pharmaceutically acceptable salt may be any of an inorganic acid salt and an organic acid salt, and examples thereof include hydrochloride, hydrobromic acid, sulfate, acetate, succinate, and tartrate; or Acid addition salts of butenedioic acid, maleic acid, citric acid or phosphoric acid. Among them, memantine hydrochloride (chemical name: 3,5-dimethyltricyclo [3.3.1.1 ^3,7 ] dec-1-ylamine monohydrochloride (3, 5-Dimethyltricyclo [3.3.1.1 ^3,7 ] dec-1-ylamine monohydrochloride)).

Hereinafter, in this specification, "memantine or a pharmaceutically acceptable salt thereof" may be referred to as "main medicine".

The enteric polymer is generally used as a coating base for release in the intestine, but in the present invention, it is an additive that exerts the effect of reducing bitterness in fast-dissolving granules, powders, or dry syrups. The enteric polymer of the present invention may have a carboxyl group, and examples thereof include one or two or more members selected from the group consisting of a dry methacrylic copolymer LD, a methacrylic copolymer L, and a methacrylic copolymer S. The combination.

The dry methacrylic acid copolymer LD is obtained by drying the methacrylic acid copolymer LD into a powder, and has been disclosed in Japanese Pharmaceutical Excipients 2013. Also, it has been disclosed as a methacrylic acid and ethyl acrylate copolymer in the United States Pharmacopeia (USP / NF), and has been disclosed as a methacrylic acid-ethyl acrylate copolymer (Ph.Eur.). ) Type A. In addition, methacrylic acid copolymer LD is an emulsion of a copolymer of methacrylic acid and ethyl acrylate in polysorbate 80 (Japanese Pharmacopoeia) and sodium lauryl sulfate (Japanese Pharmacopoeia) aqueous solution (medicine) Addendum 2013). The dry 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.

Either the methacrylic acid copolymer L or the methacrylic acid copolymer S is a copolymer resin obtained by using sodium lauryl sulfate as an emulsifier to polymerize methacrylic acid and methyl methacrylate in an aqueous solution. The emulsion is dried and powdered. The methacrylic acid copolymer L contains 38.0 to 52.0% of methacrylic acid as a constituent component of the copolymer, and the methacrylic acid copolymer S contains 11.5 to 15.5% of methacrylic acid as a constituent component of the copolymer (Pharmaceutical Additives 2013). Examples of the commercially available methacrylic copolymer L include Eudragit (registered trademark) L100 (Evonik), and examples of the methacrylic copolymer S include Eudragit (registered trademark) S100 (Evonik).

In the pharmaceutical composition of the present invention, the blending amount of the enteric polymer is preferably 0.5 to 15 parts by weight, and more preferably 2 to 10 parts by weight relative to 1 part by weight of the main drug. The enteric polymer can be mixed with the main medicine and used directly as a powder or a powder-like dry syrup; or it can be granulated into a granule or a granulated dry syrup.

In the present invention, the main drug system is mixed with the enteric polymer, that is, the total amount of the main drug in the pharmaceutical composition is mixed with the enteric polymer, and the effect is exhibited. When the main medicine is directly in a powder state or after the granules containing the main medicine are obtained, they are dried by coating with an enteric polymer (aqueous suspension), and the two components exist separately and do not become mixed. The way the state exists. In order to obtain a pharmaceutical composition in which the main drug system and the enteric polymer are mixed, as long as the main drug (the total amount in the composition) in the powder state and the enteric polymer in the powder state are included, a common fluid bed is included. A mixing step such as a dry granulator or an agitation mixing device is sufficient. In addition, an enteric polymer (aqueous suspension) is added to the powder containing the additive of the main drug by using a common fluidized bed granulator or agitation mixing device, etc. (the aqueous suspension is sprayed homogeneously, or the aqueous suspension is added. Mixing, etc.), and then drying, thereby obtaining the pharmaceutical composition of the present invention. The pharmaceutical composition system containing the main drug and the enteric polymer of the present invention can be used in a state where the content of each of the above components in any part of the composition is consistent (that is, "the homogeneous existence exists in a mixed manner"). However, even if the content ratios are not completely the same, a state of converging within a certain narrow range (that is, "substantially homogeneous in a mixed manner") may be adopted.

The flavoring agent used in the present invention is one or two or more selected from the group consisting of aspartame, sodium saccharin hydrate, glycerin, vanillin, dextrin, and sucralose. Aspartame is preferred.

In the present invention, the chemical name of aspartame is α-L-aspartyl-L-phenylalanine methyl ester, which is disclosed in the Japan Pharmaceutical Additives Code 2013. Aspartame is commercially available, and examples include Ajinomoto Co., Ltd. (Ajinomoto Healthy Supply Co., Ltd.) and the like.

In the pharmaceutical composition of the present invention, the blending amount of the flavoring agent (for example, aspartame) is generally 0.05 to 5 parts by weight relative to 1 part by weight of the enteric polymer (for example, dry methacrylic copolymer LD). More preferably, it is 0.1 to 1.5 parts by weight. The flavoring agent can be mixed with the main medicine and the enteric polymer and used directly as a powder; or a part or all of the blended flavoring agent can be mixed with the main medicine and the enteric polymer to be granulated and used in the pharmaceutical composition. Manufacturing. In the case of granulation, it is preferred that the amount of flavor correction in the particles is 0.03 to 0.5 and the amount of flavor correction outside the particles is 0.07 to 1 part by weight relative to 1 part by weight of the enteric polymer.

The blending amount of the flavoring agent in the entire pharmaceutical composition is preferably 1 to 3 parts by weight based on 1 part by weight of the main drug.

The pharmaceutical composition of the present invention may further contain one or more selected from the group consisting of a sugar alcohol, a disintegrating agent, a binder, and a fluidizing agent.

Examples of the sugar alcohol used in the present invention include D-mannitol, erythritol, xylitol, maltitol, and sorbitol. D-mannitol is preferred. D-mannitol can usually be used in Pharmacopoeia suitable for Japan, Europe and the United States. The crystal form, particle size, and specific surface area of the blended D-mannitol are not particularly limited. The crystal form may be any of α-type, β-type, δ-type, and amorphous, and the particle size is preferably 10 μm or more. 250μm or less, more preferably 20μm or more to 150μm or less, preferably a specific surface area of 0.1m ² / g or more 4m ² / g or less, more preferably 0.1m ² / g or more 2m ² / g or less, crystalline form, particle size and the specific The surface area can be measured by, for example, an X-ray diffraction method, a laser diffraction particle size measurement method, or a BET specific surface area measurement method (multipoint method). For the marketer, for example, D-mannitol such as Merck, Roquette, Towa Kasei, Kao, etc. can be cited.

The amount of the sugar alcohol to be blended can be appropriately determined according to the dosage form of the intended pharmaceutical composition, such as granules, powders, or syrups. Generally, it is 10 to 90% by weight, preferably 40 to 80% by weight, relative to the total amount of the pharmaceutical composition.

In the present invention, when the main medicine and the enteric polymer are granulated to form a pharmaceutical composition, it is preferred to disperse a dispersant and / or a binder in the granules, and it is more preferable to blend a fluidizing agent outside the granules.

Examples of the dispersing agent used in the present invention include a member selected from the group consisting of crospovidone (for example, a pharmacopoeia suitable product), carboxymethyl cellulose calcium (for example, a pharmacopoeia suitable product), Carboxymethyl cellulose (e.g., a suitable product of the Japanese Pharmacopoeia), croscarmellose sodium (e.g., a suitable product of the Japanese Pharmacopoeia), low-substituted hydroxypropyl cellulose (e.g., a suitable product of the Japanese Pharmacopoeia), corn starch (For example, a suitable product of the Japanese Pharmacopoeia), or one or two or more combinations of sodium starch glycolate (for example, a suitable product of the Japanese Pharmacopoeia), particularly preferably crospovidone, calcium carboxymethyl cellulose, and a low degree of substitution Hydroxypropyl cellulose.

The blending amount of the disintegrating agent can be appropriately determined depending on the dosage form of the intended pharmaceutical composition, for example, granules or syrups (granular). Generally, it is 1 to 10% by weight, and preferably 3 to 8% by weight, with respect to the total amount of the pharmaceutical composition.

Examples of the binder used in the present invention include, for example, selected from acacia gum, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, sodium polyacrylate, and pullulan. , Or a combination of one or more of methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, and macrogol, particularly preferably Hydroxypropyl cellulose.

The blending amount of the binder can be appropriately determined according to the dosage form of the intended pharmaceutical composition, such as granules or syrups (granular), and is generally 1 to 10 relative to the total amount of the pharmaceutical composition. % By weight, preferably 2 to 7% by weight.

Examples of the fluidizing agent used in the present invention include one or a combination of two or more selected from the group consisting of light anhydrous silicic acid, hydrous silicon dioxide, titanium oxide, stearic acid, and talc. Light anhydrous silicic acid and talc (for example, a suitable product of the Japanese Pharmacopoeia) are preferred.

The blending amount of the fluidizing agent is usually 0.1 to 1% by weight relative to the total amount of the pharmaceutical composition.

As long as the pharmaceutical composition of the present invention does not hinder the effects of the invention, it may contain various additives generally used in the manufacture of pharmaceutical compositions.

Examples of the additives include an excipient, a binder, a coloring agent, a flavoring agent, a sweetener, a flavoring agent, a fluidizing agent, a foaming agent, and a surfactant.

Examples of the excipient include organic excipients selected from sugars, sugar alcohols, starches, and celluloses, and inorganic excipients. Examples of the saccharides include lactose, sucrose, fructooligosaccharide, glucose, palatinose, maltose, reduced maltose, powdered sugar, powdered tincture, fructose, isomerized lactose, and honey One or more types of sugar. Examples of the sugar alcohol include D-mannitol, erythritol, xylitol, maltitol, and sorbitol. Examples of starches include one or a combination of two or more selected from corn starch, potato starch, rice starch, partially alpha starch, and alpha starch. As for celluloses, in addition to crystalline cellulose, for example, powdery cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, and cross-linked carboxymethyl fiber can be listed. One or a combination of two or more sodium sulphate. Examples of the inorganic excipient include one or two selected from the group consisting of synthetic hydrotalcite, precipitated calcium carbonate, hydrous silica, light anhydrous silicic acid, magnesium aluminosilicate, and magnesium hydroxide. A combination of the above.

Examples of the binder include, for example, a gum selected from acacia, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, sodium polyacrylate, polytriglucose, methyl cellulose, and hydroxypropyl cellulose. Or a combination of one or more of hydroxypropyl methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, and polyethylene glycol.

As the colorant, for example, food colorants selected from edible yellow No. 5, edible red No. 2, and edible blue No. 2; edible lake pigments, yellow iron sesquioxide, and three One or more combinations of ferric oxide, titanium oxide, β-carotene, and riboflavin.

Examples of the fragrance include one or a combination of two or more kinds selected from orange, lemon, strawberry, mint, menthol, Menthol Micron, and various flavors.

Examples of sweeteners include 1 selected from the group consisting of saccharin sodium, saccharin, aspartame, acesulfame potassium, dipotassium glycyrrhizinate, sucralose, stevia, and thumatin. One or a combination of two or more.

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

Examples of the surfactant include polyoxyl 40 stearate, sorbitan fatty acid ester, polyoxyethylene hardened castor oil, and polysorbate. One or more types of alcohol ester, glycerol monostearate, and sodium lauryl sulfate.

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

Examples of the fluidizing agent include one type or a combination of two or more types selected from the group consisting of hydrous silica, light anhydrous silicic acid, and talc.

The pharmaceutical composition of the present invention is a granule, powder or syrup.

Granules are granulated into granules for oral administration. Among them, the following can be referred to as fine granules: When the particle size test of the Japanese Pharmacopoeia is performed, the entire amount passes through a No. 18 (850 μm) sieve, and No. 30 (500 μm) sieve residue is 10% or less.

Powder is a powdered preparation.

Syrup preparations are also called dry syrup preparations, which are a kind of granular or powder preparations. When water is added, they become sweet syrup preparations. The dry syrup can be taken by suspending or dissolving in water during use, or it can be taken directly with water, which is particularly preferred as the dosage form of the present invention.

When the pharmaceutical composition of the present invention is a powder or a powdery syrup, the main medicine and the enteric polymer can be uniformly mixed to form a pharmaceutical composition. If necessary, flavoring agents, sugar alcohols, and other additives can also be added.

When the pharmaceutical composition of the present invention is a granule or a granular syrup, the main medicine and the enteric polymer can be uniformly mixed and then granulated to prepare a pharmaceutical composition. The granulation system can be carried out using a conventional extrusion granulation method, a mixing stirring granulation method, a high-speed stirring granulation method, a fluidized bed granulation method, a rotary granulation method, and the like. For example, when using the fluidized bed granulation method, add the main drug and enteric polymer, and if necessary, other additives (flavoring agent, sugar alcohol, disintegrating agent, and binder) and mix uniformly, and spray water or the binder solution The fluidized bed granulation is performed while the obtained granulated material is dried and then granulated, and a fluidizer, a flavoring agent and the like are optionally added to obtain granules or granulated syrup preparations.

The pharmaceutical composition of the present invention is preferably a fast-dissolving one. The instant solubility can be confirmed by, for example, a dissolution test of the Japanese Pharmacopoeia paddle plate method (test liquid: water, paddle plate rotation number: 50 rpm, test liquid volume: 900 mL). The dissolution rate of the main drug may be 85% or more in 30 minutes, and preferably 85% or more in 15 minutes.

The pharmaceutical composition of the present invention is also excellent in storage stability during manufacturing steps and distribution processes, and during storage under high temperature and high humidity. Moreover, among the pharmaceutical compositions of the present invention, particularly, granules or granulated syrup preparations have so-called excellent storage stability in which the particles do not aggregate with each other even when stored in an environment with high water content. Moreover, since it is excellent in suspension stability, it is a preparation which is easy to handle for a patient or a caregiver when it is taken as a syrup preparation in water.

    [Example]    

The following examples are for the purpose of illustration and are not intended to limit the invention to these examples.

The dry methacrylic acid copolymer LD is a powder obtained by drying a "methacrylic acid copolymer LD" which is a 30% aqueous dispersion, and the solid content is completely the same. In the comparative example in which the coating of the particles was performed, the methacrylic acid copolymer LD that was easily prepared by using the coating liquid was used. In the example in which the coating of the particles was not performed, the dry methacrylic acid copolymer LD was used.

[Comparative Example 1]

30 g of memantine hydrochloride, 1122 g of D-mannitol (manufactured by Roquette), 102 g of calcium carboxymethyl cellulose (manufactured by Goto Pharmaceutical Co., Ltd.), and 15 g of aspartame (manufactured by Ajinomoto Healthy Supply) were mixed in a sample mill ( Sample mill (KIIWG-1)) was sieved, and further mixed to obtain a mixture. 846 g of the obtained mixture was put into a fluid bed granulator (Freund, FLO-2 type), and a liquid in which 40 g of hydroxypropyl cellulose (Japan Soda) was dispersed in 666.7 g of pure water was sprayed and then dried. And granulated particles are obtained. 708.8 g of the obtained granulated granules were put into a granulator (QC U-5 manufactured by Powrex), and then 257.3 g of a coating solution (composition: methacrylic acid) was sprayed on a fluid bed granulator (Freund, FLO-2 type) Copolymer LD (manufactured by Evonik, Eudragit L30D-55) 51.8%, triethyl citrate (Morimura Corporation, Citroflex) 1.6%, talc (Matsumura Industrial Co., Ltd.) 7.8%, pure water (38.8%)) by drying Thus, coated particles were obtained. 193.2 g of the obtained coated particles were passed through a No. 18 sieve, and then mixed with 0.8 g of light anhydrous silicic acid (manufactured by YKF) and 6 g of aspartame (manufactured by Ajinomoto Healthy Supply) to obtain a granular pharmaceutical composition.

[Comparative Example 2]

40 g of memantine hydrochloride, 1016 g of D-mannitol (manufactured by Roquette), 136 g of calcium carboxymethyl cellulose (manufactured by Goto Pharmaceutical Co., Ltd.), and 20 g of aspartame (manufactured by Ajinomoto Healthy Supply) were mixed in a sample grinder (KIIWG -1) After sieving, the mixture is obtained by further mixing. 727.2 g of the obtained mixture was put into a fluid bed granulator (manufactured by Powrex, GPCG-1 type), and a liquid in which 40 g of hydroxypropyl cellulose (Japan Soda) was dispersed in 666.7 g of pure water was sprayed, and Dry to obtain granulated particles. 775.2 g of the obtained granulated granules were put into a granulator (QC U-5, manufactured by Powrex), and then 1158 g of a coating solution (composition: methacrylic acid copolymerization) was sprayed on a fluid bed granulator (made by Powrex, GPCG-1) LD (manufactured by Evonik, Eudragit L30D-55) 51.8%, triethyl citrate (Morimura Corporation, Citroflex) 1.6%, talc (Matsumura Industrial Co., Ltd.) 7.8%, pure water (38.8%)), dried by Coated particles were obtained. 193.2 g of the obtained coated particles were passed through a No. 18 sieve, and then mixed with 0.8 g of light anhydrous silicic acid (manufactured by YKF) and 6 g of aspartame (manufactured by Ajinomoto Healthy Supply) to obtain a granular pharmaceutical composition.

The points of Comparative Examples 1 and 2 are shown in Table 1.

[Example 1]

Mixed memantine hydrochloride 40 g, D-mannitol (manufactured by Roquette) 1556 g, carboxymethyl cellulose calcium (manufactured by Goto Pharmaceutical Co., Ltd.) 136 g, aspartame (manufactured by Ajinomoto Healthy Supply) 20 g, dry methacrylic acid copolymer 100 g of LD (manufactured by Evonik, Eudragit L100-55) was sieved in a sample mill (KIIWG-1), and further mixed to obtain a mixture. 926 g of the obtained mixture was put into a fluidized bed granulator (GPCG-1 manufactured by Powrex), and a liquid in which 40 g of hydroxypropyl cellulose (Japan Soda) was dispersed in 666.7 g of pure water was sprayed, and dried to Granulated granules were obtained. 193.2 g of the obtained granulated granules were put into a granulator (QC U-5, manufactured by Powrex), and then 0.8 g of light anhydrous silicic acid (manufactured by YKF) and 6 g of aspartame (manufactured by Ajinomoto Healthy Supply) Mix to obtain a granular pharmaceutical composition.

[Example 2]

30 g of memantine hydrochloride, 1092 g of D-mannitol (manufactured by Roquette), 102 g of calcium carboxymethyl cellulose (manufactured by Goto Pharmaceutical), 15 g of aspartame (manufactured by Ajinomoto Healthy Supply), and dry methacrylic acid copolymer 150 g of LD (manufactured by Evonik, Eudragit L100-55) was sieved in a sample grinder (KIIWG-1), and further mixed to obtain a mixture. 926 g of the obtained mixture was put into a fluidized bed granulator (GPCG-1 manufactured by Powrex), and a liquid in which 40 g of hydroxypropyl cellulose (Japan Soda) was dispersed in 666.7 g of pure water was sprayed, and then dried to dry Granulated granules were obtained. 193.2 g of the obtained granulated granules were put into a granulator (QC U-5, manufactured by Powrex), and then 0.8 g of light anhydrous silicic acid (manufactured by YKF) and 6 g of aspartame (manufactured by Ajinomoto Healthy Supply) Mix to obtain a granular pharmaceutical composition.

[Example 3]

30 g of memantine hydrochloride, 942 g of D-mannitol (manufactured by Roquette), 102 g of calcium carboxymethyl cellulose (manufactured by Goto Pharmaceutical Co., Ltd.), 15 g of aspartame (manufactured by Ajinomoto Healthy Supply), and dried methacrylic acid copolymer 300 g of LD (manufactured by Evonik, Eudragit L100-55) was sieved in a sample grinder (KIIWG-1), and further mixed to obtain a mixture. 926 g of the obtained mixture was put into a fluidized bed granulator (GPCG-1 manufactured by Powrex), and a liquid in which 40 g of hydroxypropyl cellulose (Japan Soda) was dispersed in 666.7 g of pure water was sprayed, and then dried to dry Granulated granules were obtained. 193.2 g of the obtained granulated granules were put into a granulator (QC U-5, manufactured by Powrex), and then 0.8 g of light anhydrous silicic acid (manufactured by YKF) and 6 g of aspartame (manufactured by Ajinomoto Healthy Supply) Mix to obtain a granular pharmaceutical composition.

Tables of Examples 1 to 3 are shown in Table 2.

[Test Example 1]

The granular pharmaceutical composition of Comparative Example 1, Comparative Example 2, Example 1, Example 2, and Example 3 was used as a sample to evaluate the agglutinability. Under 40 ° C and 75% RH open conditions, the degree of agglomeration when stored for 2 days was evaluated in three stages. The results are shown in Table 3.

Degree of agglutination

++: Severe agglutination, +: Slight agglutination,-: Not agglutinated

As a result of evaluating the agglutination property, memantine hydrochloride and the dry methacrylic acid copolymer LD are the pharmaceutical composition of Example 1, Example 2, and Example 3 of the pharmaceutical composition in a mixed manner in the particles. Confirm that there is no agglutination.

[Test Example 2]

The granular pharmaceutical composition of Comparative Example 1, Comparative Example 2, Example 1, Example 2, and Example 3 was used as a sample to evaluate suspension stability. Using a 50 mL self-standing centrifuge tube with a diameter of 3 cm, 30 mL of water was added to 6 g of the particles, and the mixture was shaken for 1 minute to suspend it, and then left for 30 minutes. Suspension stability is evaluated by the ratio of the volume of the precipitate after 30 minutes of suspension when the volume of 6 g of the granular pharmaceutical composition before suspension is set to 1. The results are shown in Table 4.

As a result of evaluating suspension stability, memantine hydrochloride and the dry methacrylic acid copolymer LD are mixed in the granules of the pharmaceutical composition in Examples 1, 1, 2 and 3, compared with coating. Comparative Examples 1 and 2 of the granular pharmaceutical composition of the methacrylic acid copolymer LD had a relatively small amount of precipitates after being suspended for 30 minutes with respect to the volume of the particles before the suspension, and it was confirmed that the suspension stability was excellent. The small amount of precipitation means that when the pharmaceutical composition of the present invention is suspended in water, the particles quickly disintegrate and disperse in water. This is also related to the results of Test Example 4 described later, which shows that the main drug dissolves rapidly and the uniformity of the main drug content in the liquid is excellent. Based on this characteristic, the granular pharmaceutical composition of the present invention has excellent characteristics as a syrup preparation prepared as a syrup in suspension in water.

[Test Example 3]

The dissolution test was performed using the granular pharmaceutical composition of Comparative Example 1, Comparative Example 2, Example 1, Example 2, and Example 3 as a sample. The conditions of the dissolution test are the paddle method of the dissolution test method of the Japanese Pharmacopoeia, using a test solution: water, number of revolutions: 50 rpm, and test solution volume: 900 mL. The results are shown in Table 5.

As a result of the dissolution test, the 15-minute dissolution rate of the commercially available MEMARY tablets was more than 85%, and the memantine hydrochloride and the dry methacrylic acid copolymer LD were examples of a medicinal composition that was mixed in the particles 1. The dissolution rate of Example 2 and Example 3 was 85% or more in 15 minutes, and showed a rapid dissolution property similar to a commercially available MEMARY ingot.

[Test Example 4]

Using the granular pharmaceutical composition of Example 1 as a sample, a functional test was performed on 22 subjects. The evaluation item of the sensory test is set to be bitter, and its degree is evaluated in three stages. In addition, the administration method was evaluated by two methods of administration with water and two methods of administration by suspending in water. The results are shown in Table 6.

Bitterness

++: Strong bitterness, do not want to take it if you can

+: Somewhat bitter, but no problem with medication

-: No bitterness is noticed

As a result of the functional test, it was found that, with regard to memantine hydrochloride having a unique bitterness, the granular pharmaceutical composition of Example 1 can suppress the bitterness by any method of administration.

[Test Example 5]

The granular pharmaceutical composition of Comparative Example 1, Comparative Example 2, Example 1, and Example 3 was used as a sample to evaluate the uniformity of the content of the main drug in the test solution suspended in water. Using a 50 mL self-standing centrifuge tube with a diameter of 3 cm, 4 g of particles were added to 37 mL of water, shaken for 1 minute to suspend, and then allowed to stand. The uniformity of the content of the main drug in the test solution was evaluated by measuring the content of memantine hydrochloride by 20 mL of the upper layer of the test solution after a predetermined period of time. The theoretical content of memantine hydrochloride contained in the upper layer of the homogeneous test solution immediately after suspension (i.e., 2 g of particles in 20 mL due to the volume of the test solution being 40 mL, in the case of memantine hydrochloride) The content at 40 mg) was set to 100%. The results are shown in Table 7.

The results of evaluating the uniformity of the main drug content in the test solution after a predetermined time (15 minutes, 30 minutes, 60 minutes) after suspension, memantine hydrochloride and dry methacrylic acid copolymer LD were mixed in the particles to mix Example 1 and Example 3 of the granular pharmaceutical composition existing in the same manner, compared with Comparative Example 1 and Comparative Example 2 of the granular pharmaceutical composition coated with the methacrylic acid copolymer LD, the test after suspension The content of the main drug in the upper layer of the liquid was closer to 100%, and a correlation with the amount of precipitation in [Test Example 2] was also observed, and it was confirmed that the uniformity of the content of the main drug in the test solution was excellent. From these results, it was shown that the granular pharmaceutical composition of the present invention has excellent characteristics as a syrup preparation prepared as a syrup by suspending in water.

Claims (17)

    A pharmaceutical composition comprising memantine or a pharmaceutically acceptable salt thereof and an enteric polymer, and the dosage form is a granule, a powder or a syrup.         The pharmaceutical composition according to claim 1, wherein the medicinal composition is a granule or a granular syrup, wherein the intra-granular memantine or a pharmaceutically acceptable salt thereof and the enteric polymer are mixed.         The medicinal composition according to claim 1 or 2, wherein memantine or a pharmaceutically acceptable salt thereof and the enteric polymer are substantially homogeneously mixed in a mixed manner.         The pharmaceutical composition according to any one of claims 1 to 3, wherein memantine or a pharmaceutically acceptable salt thereof is memantine hydrochloride.         The pharmaceutical composition according to any one of claims 1 to 4, wherein the enteric polymer is one selected from the group consisting of a dry methacrylic copolymer LD, a methacrylic copolymer L, and a methacrylic copolymer S One or two or more.         The pharmaceutical composition according to any one of claims 1 to 4, wherein the enteric polymer is a dry methacrylic copolymer LD.         The pharmaceutical composition according to any one of claims 1 to 6, wherein the blending amount of the enteric polymer is 0.5 to 15 parts by weight relative to 1 part by weight of memantine or a pharmaceutically acceptable salt thereof.         The pharmaceutical composition according to any one of claims 1 to 6, wherein the blending amount of the enteric polymer is 2 to 10 parts by weight relative to 1 part by weight of memantine or a pharmaceutically acceptable salt thereof.         The pharmaceutical composition according to any one of claims 1 to 8, further blending selected from the group consisting of aspartame, saccharin sodium hydrate, glycerin, vanillin, dextrin and sucralose (sucralose) one or two or more flavoring agents.         The pharmaceutical composition according to claim 9, wherein the flavoring agent is aspartame.         For example, the pharmaceutical composition of claim 9 or 10, wherein the blending amount of the flavoring agent is 0.05 to 5 parts by weight relative to 1 part by weight of the enteric polymer.         For example, the pharmaceutical composition of claim 9 or 10, wherein the blending amount of the flavoring agent is 1 to 3 parts by weight relative to 1 part by weight of memantine or a pharmaceutically acceptable salt thereof.         The pharmaceutical composition according to any one of claims 1 to 12, further comprising one or more additives selected from the group consisting of a sugar alcohol, a dispersant, a binder, and a fluidizer.         For example, the pharmaceutical composition of any one of claims 1 to 13, in the dissolution test paddle method (test solution: water; paddle plate rotation number: 50 rpm; test solution volume: 900 mL) of the Japanese Pharmacopoeia, The dissolution rate of memantine or its pharmaceutically acceptable salt is 85% or more in 15 minutes.         For example, the pharmaceutical composition of any one of claims 1 to 14, in the following test, the content of memantine or its pharmaceutically acceptable salt of the main drug contained in the upper layer of the test solution after 30 minutes is the theoretical content 80% or more; Uniformity test of the content of the main drug in the test solution suspended in water: Using a 50mL self-standing centrifuge tube with a diameter of 3cm, add 4g of the pharmaceutical composition to 37mL of water and shake it for 1 minute to suspend it. The content of the main drug is determined by taking 20 mL of the upper layer of the test solution after a predetermined time has elapsed; the theoretical content of the main drug contained in the 20 mL of the upper layer of the uniform test solution immediately after suspension is set to 100%.         A method for producing a pharmaceutical composition according to any one of claims 1 to 15, comprising the step of homogeneously mixing memantine or a pharmaceutically acceptable salt thereof with an enteric polymer.         A method, which is the method for manufacturing a pharmaceutical composition according to any one of claims 1 to 15, wherein the dosage form is a granule or a granulated syrup, and includes the following steps 1 to 3: Step 1: A step of homogeneously mixing memantine or a pharmaceutically acceptable salt thereof, an enteric polymer, and optionally a flavoring agent and / or other additives; step 2: a step of granulating the obtained mixture; and step 3: A step of mixing the obtained granules with an optional flavoring agent and / or other additives.