JP7009288B2 - Wet tablet manufacturing method and wet tablet quality improvement method - Google Patents

Description

The present invention relates to a method for producing a wet tablet and a method for improving the quality of the wet tablet.

Wet tablets are produced by kneading a powder containing a drug with a water-containing organic solvent, compression-molding the obtained wet powder, and then drying the tablets. The wet tablet can be an orally disintegrating tablet having excellent disintegration property (see, for example, Patent Document 1).

In addition, as a technique for masking the bitterness of a drug exhibiting a bitter taste, a technique of coating granules containing the drug with a sustained release polymer or an enteric polymer (hereinafter, may be referred to as "coating base") is general-purpose. (See, for example, Patent Document 2).

However, in wet tablets, since the solvent used for kneading contains an organic solvent, the coating base is dissolved, the disintegration of the tablets is delayed, the masking effect of bitterness is reduced, and the effect is reduced. When the coated granules become large, a line is formed in the tablet in the grinding process, which is one of the manufacturing processes of the wet tablet, and the appearance is deteriorated. It is said that it cannot be used.

Therefore, there is a strong demand for the rapid development of a technology capable of producing a wet tablet with reduced bitterness while maintaining the orally disintegrating property required for an orally disintegrating tablet without spoiling the appearance. Is the current situation.

Japanese Unexamined Patent Publication No. 6-218028 Japanese Unexamined Patent Publication No. 2014-028804

An object of the present invention is to solve the above-mentioned problems in the prior art and to achieve the following objects. That is, the present invention is a method for producing a wet tablet and a method for producing a wet tablet, which can produce a wet tablet having a reduced bitterness while maintaining the orally disintegrating property required for an orally disintegrating tablet without impairing the appearance. It is an object of the present invention to provide a method for improving the quality of tablet making.

The means for solving the above problems are as follows. That is,
<1> A coating step of coating a drug-containing substance with a coating base to obtain a coated drug-containing substance, and
A wet powder preparation step of adding a water-containing organic solvent in which a binder is dissolved to the composition containing the coated drug-containing material and kneading the composition to obtain a wet powder.
Including a molding step of compression molding the wet powder.
The coating base in the coating step is one or more selected from the group consisting of the methacrylic acid copolymer LD, ethyl cellulose and the aminoalkyl methacrylate copolymer E.
The amount of the coating base in the coating step is 30% by mass or more with respect to the drug-containing substance.
A method for producing a wet tablet, wherein the concentration of the organic solvent in the water-containing organic solvent in the wet powder preparation step is 30% by mass or less.
<2> The method for producing a wet tablet according to <1>, wherein the coating base is at least one of a methacrylic acid copolymer LD and ethyl cellulose.
<3> The method for producing a wet tablet according to any one of <1> to <2>, wherein the organic solvent in the water-containing organic solvent is ethanol.
<4> The wet tablet according to any one of <1> to <3>, wherein the amount of the coating base in the coating step is 30% by mass or more and 70% by mass or less with respect to the drug-containing substance. It is a manufacturing method.
<5> Production of the wet tablet according to any one of <1> to <4>, wherein the concentration of the organic solvent in the hydrous organic solvent in the wet powder preparation step is 1% by mass or more and 10% by mass or less. The method.
<6> The method for producing a wet tablet according to any one of <1> to <5> above, wherein the amount of the coated drug-containing substance in the wet tablet is 1.0% by mass to 50.0% by mass. Is.
<7> A method for improving the quality of wet tablets.
A coating step of coating a drug-containing substance with a coating base to obtain a coated drug-containing substance, and
A wet powder preparation step of adding a water-containing organic solvent in which a binder is dissolved to the composition containing the coated drug-containing material and kneading the composition to obtain a wet powder.
Including a molding step of compression molding the wet powder.
The coating base in the coating step is one or more selected from the group consisting of the methacrylic acid copolymer LD, ethyl cellulose and the aminoalkyl methacrylate copolymer E.
The amount of the coating base in the coating step is 30% by mass or more with respect to the drug-containing substance.
The concentration of the organic solvent in the water-containing organic solvent in the wet powder preparation step is 30% by mass or less.
The quality improvement is characterized in that the bitterness of the wet tablet is reduced and the disintegrated product does not become a gel and the oral disintegration time is 60 seconds or less. The method.
<8> The method according to <7>, wherein the coating base is at least one of a methacrylic acid copolymer LD and ethyl cellulose.
<9> The method according to any one of <7> to <8>, wherein the organic solvent in the water-containing organic solvent is ethanol.
<10> The method according to any one of <7> to <9>, wherein the amount of the coating base in the coating step is 30% by mass or more and 70% by mass or less with respect to the drug-containing substance.
<11> The method according to any one of <7> to <10>, wherein the concentration of the organic solvent in the water-containing organic solvent in the wet powder preparation step is 1% by mass or more and 10% by mass or less.
<12> The method according to any one of <7> to <11>, wherein the amount of the coated drug-containing substance in the wet tablet is 1.0% by mass to 50.0% by mass.

According to the present invention, the above-mentioned problems in the prior art can be solved, the above-mentioned object can be achieved, and bitterness is reduced while maintaining the orally disintegrating property required for an orally disintegrating tablet without spoiling the appearance. It is possible to provide a method for producing a wet tablet capable of producing a wet tablet and a method for improving the quality of the wet tablet.

(Manufacturing method of wet tablets)
The method for producing a wet tablet of the present invention includes at least a coating step, a wet powder preparation step, and a molding step, and further includes other steps as necessary.

<Coating process>
The coating step is a step of coating the drug-containing material with a coating base to obtain a coated drug-containing material.

-Drug-containing substances-
The drug-containing substance contains at least a drug having a bitter taste, and further contains other components as required.

--Drugs with bitter taste--
The drug having a bitter taste is not particularly limited and may be appropriately selected depending on the intended purpose. For example, amlogipin besilate, galantamine hydrobromide, memantin hydrochloride, donepezil hydrochloride, fexofenadine hydrochloride Examples include salts, levosetilidine hydrochloride, lamertheon, zorpidem tartrate and the like. These may be used alone or in combination of two or more.
As the drug having a bitter taste, a drug produced by a known method may be used, or a commercially available product may be used.

The content of the drug in the drug-containing substance is not particularly limited and may be appropriately selected depending on the intended purpose. The drug-containing substance may consist only of the drug.

－－Other ingredients －－
The other components in the drug-containing substance are not particularly limited as long as the effects of the present invention are not impaired, and additives usually used in the pharmaceutical field can be appropriately selected depending on the purpose, for example, shaping. Examples thereof include agents, fluidizing agents, binders, surfactants, plasticizers, disintegrants, lubricants, flavoring agents, fragrances, pH adjusters and the like. These may be used alone or in combination of two or more.

The excipient is not particularly limited and may be appropriately selected depending on the intended purpose. For example, mannitol (hereinafter, may be referred to as “D-mannitol”) or lactose (anhydrous may be used). It may be a hydrate), xylitol, sorbitol, cornstarch, sucrose, erythritol, talc, purified gelatin, hydroxypropyl starch, calcium silicate and the like. These may be used alone or in combination of two or more.

The fluidizing agent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include light anhydrous silicic acid, talc, hydrous silicon dioxide, magnesium aluminometasilicate, magnesium hydroxide and the like. .. These may be used alone or in combination of two or more.

The binder is not particularly limited and may be appropriately selected depending on the intended purpose. For example, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, hydroxypropyl cellulose, hypromellose, hydroxy Examples thereof include sodium propylmethyl cellulose, sodium starch glycolate, and hydroxyethyl cellulose. These may be used alone or in combination of two or more.

The surfactant is not particularly limited and may be appropriately selected depending on the intended purpose. For example, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 60, sodium lauryl sulfate, sucrose fatty acid ester, glycerin, macro. Gol, lauromacrogol, polysorbate, polyethylene glycol, triethyl citrate and the like can be mentioned. These may be used alone or in combination of two or more.

The plasticizer is not particularly limited and may be appropriately selected depending on the intended purpose. For example, triethyl citrate, glycerin fatty acid ester, sucrose fatty acid ester, talc, triacetin, castor oil, propylene glycol, macrogol 400. , Macrogol 600, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 20000, macrogol 35000 and the like. These may be used alone or in combination of two or more.

The disintegrant is not particularly limited and may be appropriately selected depending on the intended purpose. For example, starch (corn starch or the like), crystalline cellulose, carmellose calcium, sodium starch glycolate, crospovidone, croscarmellose sodium. , Croscarmellose calcium and the like. These may be used alone or in combination of two or more.

The lubricant is not particularly limited and may be appropriately selected depending on the intended purpose. For example, magnesium stearate, calcium stearate, talc, hydrogenated oil, sala shimitsuro, carnauba wax, polyethylene glycol 6000, sodium stearyl fumarate. , Stearic acid and the like. These may be used alone or in combination of two or more.

The flavoring agent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include sucralose, aspartame, acesulfame potassium and thaumatin. These may be used alone or in combination of two or more.

The fragrance is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include l-menthol, vanillin and orange oil. These may be used alone or in combination of two or more.

The pH adjusting agent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include inorganic acids, inorganic bases, acidic amino acids, basic amino acids and amino sugars. These may be used alone or in combination of two or more.

As the other components in the drug-containing substance, those produced by a known method may be used, or commercially available products may be used.

The content of the other components in the drug-containing substance is not particularly limited and may be appropriately selected depending on the intended purpose.

The mode of the drug-containing substance is not particularly limited and may be appropriately selected depending on the intended purpose, and examples thereof include granules.

-Coating base-
The coating base is not particularly limited as long as it is one or more selected from the group consisting of the methacrylic acid copolymer LD, ethyl cellulose and the aminoalkyl methacrylate copolymer E, and can be appropriately selected depending on the intended purpose. These may be used alone or in combination of two or more.
Among these, at least one of methacrylic acid copolymer LD and ethyl cellulose is preferable in that it can achieve both oral disintegration property and suppression of bitterness at a high level.
As the coating base, those produced by a known method may be used, or commercially available products may be used.

The amount of the coating base used for the coating is not particularly limited as long as it is 30% by mass or more with respect to the drug-containing substance, and can be appropriately selected depending on the intended purpose, but is 30% by mass or more. 70% by mass or less is preferable, and 40% by mass or more and 60% by mass or less is more preferable. When it is within the above preferable range, it is advantageous in that the orally disintegrating property of the tablet is more excellent and the bitterness can be further reduced.

-Cover-
The coating method is not particularly limited, and a known method can be appropriately selected. For example, a liquid containing the coating base by charging the drug-containing substance into a fluidized bed granulator (hereinafter,). , May be referred to as "coating liquid").
The spraying conditions are not particularly limited and may be appropriately selected depending on the intended purpose.

The coating liquid contains the coating base and, if necessary, further contains other components.

The amount of the coating base in the coating liquid is not particularly limited and may be appropriately selected depending on the intended purpose.

The other components in the coating liquid are not particularly limited as long as the effects of the present invention are not impaired, and can be appropriately selected depending on the intended purpose. For example, the other components described in the above-mentioned items of drug-containing substances. The same as the above can be mentioned. These may be used alone or in combination of two or more.
As the other components in the coating liquid, those manufactured by a known method may be used, or commercially available products may be used.

The content of other components in the coating liquid is not particularly limited and may be appropriately selected depending on the intended purpose.

The solvent of the coating liquid is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include water and a water-containing organic solvent.
The organic solvent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include pharmaceutically acceptable water-soluble organic solvents such as ethanol, propanol and isopropanol. These may be used alone or in combination of two or more.

The median diameter of the coated drug-containing substance is not particularly limited and may be appropriately selected depending on the intended purpose, and examples thereof include 5 μm to 1,000 μm.

<Wet powder preparation process>
The wet powder preparation step is a step of adding a water-containing organic solvent in which a binder is dissolved to the composition containing the coated drug-containing material and kneading the mixture to obtain a wet powder.

-Composition containing coated drug-containing material-
The composition comprises at least a coated drug-containing material, and optionally further other components. The composition may consist of a coated drug-containing material.

--Coated drug content ---
The content of the coated drug-containing substance in the composition is not particularly limited and may be appropriately selected depending on the intended purpose, and examples thereof include 1.0% by mass to 50.0% by mass. ..

－－Other ingredients －－
The other components in the composition are not particularly limited as long as the effects of the present invention are not impaired, and can be appropriately selected depending on the intended purpose. For example, the other components described in the above-mentioned items of drug-containing substances. The same as the above can be mentioned. These may be used alone or in combination of two or more.
As the other components in the composition, those produced by a known method may be used, or commercially available products may be used.

The content of the other components in the composition is not particularly limited and may be appropriately selected depending on the intended purpose.

-Water-containing organic solvent-
The water-containing organic solvent in the wet powder preparation step is a kneading solvent.
The water-containing organic solvent contains at least a binder and, if necessary, other components.

－－Organic solvent －－
The organic solvent in the water-containing organic solvent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include pharmaceutically acceptable water-soluble organic solvents such as ethanol, propanol and isopropanol. These may be used alone or in combination of two or more.
Among these, ethanol is preferable because it has low toxicity to humans.

The concentration of the organic solvent in the water-containing organic solvent is not particularly limited as long as it is 30% by mass or less, and can be appropriately selected depending on the intended purpose, but is preferably 1% by mass or more and 10% by mass or less. When it is within the above preferable range, it is advantageous in that the orally disintegrating property of the tablet is more excellent and the bitterness can be further reduced.

－－Binder －－
The binder is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include the same binders described in the item of other components of the drug-containing substance described above. These may be used alone or in combination of two or more.
Among these, polyvinyl alcohol is preferable because it has low hygroscopicity.

The polyvinyl alcohol is a polymer obtained by saponifying polyvinyl acetate.
The average degree of polymerization and the degree of saponification of the polyvinyl alcohol can be appropriately adjusted by appropriately adjusting vinyl acetate as a raw material.

The average degree of polymerization of the polyvinyl alcohol is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 200 to 3,500, more preferably 300 to 2,200. The average degree of polymerization can be measured according to JIS K 6726.

The degree of saponification of the polyvinyl alcohol is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 65 mL or more, more preferably 78 mL or more. Among these, the saponification degree is more preferably 78 mL% to 96 mL% (partially saponified), 97 mL% or more (completely saponified), and particularly preferably 78 mL% to 96 mL (partially saponified). The degree of saponification can be measured according to JIS K 6726.

The content of the binder in the water-containing organic solvent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include 1.0% by mass to 30.0% by mass.

－－Other ingredients －－
The other components in the water-containing organic solvent are not particularly limited as long as the effects of the present invention are not impaired, and can be appropriately selected depending on the intended purpose. Examples include those similar to the ingredients. These may be used alone or in combination of two or more.
As the other components in the water-containing organic solvent, those produced by a known method may be used, or commercially available products may be used.

The content of the other components in the water-containing organic solvent is not particularly limited and may be appropriately selected depending on the intended purpose.

-Kneading-
The kneading method is not particularly limited, and a known method can be appropriately selected. Examples thereof include a method of adding the water-containing organic solvent to the wet powder and mixing the wet powder.
The apparatus used for the kneading is not particularly limited, and a known apparatus can be appropriately selected, and examples thereof include an apparatus such as a ribbon mixer and a high-speed stirring granulator.
The kneading conditions are not particularly limited and may be appropriately selected depending on the intended purpose.

The amount of the water-containing organic solvent used for the kneading is not particularly limited and may be appropriately selected depending on the intended purpose. For example, 5% by mass to 20% by mass with respect to the wet powder. Can be mentioned.

The wet powder may be used as it is in the molding step, or may be used in the molding step after wet granulation to obtain a granulated product.
The wet granulation method is not particularly limited, and a known method can be appropriately selected. For example, an extrusion granulation method using a cylindrical granulator, a pelleter, or the like, a speed mill, a power mill, or the like is used for crushing. Using a granulation method, a stirring granulation method using a minimizer, a power kneader, a speed mill, a mulmerizer, a vertical granulator, etc., a rolling granulation method that granulates mainly by rolling motion, a fluidized bed by spray drying. The layer granulation method and the like can be mentioned.

<Forming process>
The molding step is a step of compression molding the wet powder.
The molding step may include a process of filling the mortar with the wet powder and grinding it to a certain amount, or a process of drying the tablets after compression molding.

The apparatus used in the molding step is not particularly limited, and a known apparatus can be appropriately selected. For example, a universal material test apparatus (Autograph, manufactured by Shimadzu Corporation), JP-A-8-19589. Disclosure tablet manufacturing equipment, tablet manufacturing equipment disclosed in Japanese Patent Application Laid-Open No. 8-19588, rotary tableting machine, wet tableting tableting machine (EMT-18 and ETD-18, manufactured by Sankyo Seisakusho Co., Ltd.), etc. Equipment is mentioned.

The conditions such as the pressure at the time of filling and pressurizing in the molding are not particularly limited and may be appropriately selected depending on the intended purpose.

The drying method is not particularly limited, and a known device can be appropriately selected, and examples thereof include a method using a shelf-type dryer.
The drying conditions are not particularly limited and may be appropriately selected depending on the intended purpose.

<Other processes>
The other steps are not particularly limited as long as the effects of the present invention are not impaired, and can be appropriately selected depending on the intended purpose. Examples thereof include a drug-containing preparation step.

-Drug content preparation process-
The drug-containing preparation step is a step of preparing the above-mentioned drug-containing substance.
The method for preparing the drug-containing substance is not particularly limited and may be appropriately selected depending on the intended purpose. For example, the drug and the other components as needed are mixed, and the mixture is mixed with the above-mentioned mixture. Examples thereof include a method of spraying an aqueous solution containing a binder to granulate the granules.
The method and apparatus used for the mixing and granulation are not particularly limited, and known methods and apparatus can be appropriately selected.
The median diameter of the drug-containing substance is not particularly limited and may be appropriately selected depending on the intended purpose, and examples thereof include 10 μm to 500 μm.

The shape, structure, size, weight, and hardness of the wet tablet are not particularly limited and may be appropriately selected depending on the intended purpose.
The wet tablet can be suitably used as an orally disintegrating tablet.

The amount of the coated drug-containing substance in the wet tablet is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 1.0% by mass to 50.0% by mass. Within the above preferable range, it is advantageous in that the disintegration property of the wet tablet is more excellent.

According to the method for producing a wet tablet of the present invention, it is possible to produce a wet tablet with reduced bitterness while maintaining the orally disintegrating property required for an orally disintegrating tablet without impairing the appearance.

(How to improve the quality of wet tablets)
The method for improving the quality of a wet tablet of the present invention includes at least a coating step, a wet powder preparation step, and a molding step, and further includes other steps as necessary.

The quality improvement in the method for improving the quality of the wet tablet means that the bitterness of the wet tablet is reduced and that the disintegrated product does not become a gel and the oral disintegration time is 60 seconds or less. It means to be compatible.
The bitterness in the present invention refers to the bitterness that is felt at the time of disintegration and after disintegration in the oral cavity, which contains a tablet in the mouth.
The oral disintegration time in the present invention means the time from the inclusion of the tablet in the oral cavity to the complete disintegration.

<Coating process>
The coating step is the same as the coating step of the method for producing a wet tablet of the present invention described above, and the preferred embodiment is also the same.

<Wet powder preparation process>
The wet powder preparation step is the same as the wet powder preparation step of the method for producing a wet tablet of the present invention described above, and the preferred embodiment is also the same.

<Forming process>
The molding step is the same as the molding step of the method for producing a wet tablet of the present invention described above.

<Other processes>
The other steps are not particularly limited as long as the effects of the present invention are not impaired, and can be appropriately selected depending on the intended purpose. Similar steps and the like can be mentioned.

According to the method for improving the quality of wet tablets of the present invention, the bitterness of wet tablets can be reduced, and the disintegrant does not become a gel and the oral disintegration time is 60 seconds or less. It can be compatible. Also, the appearance of the wet tablet is not impaired.

Hereinafter, the present invention will be described in more detail based on the test examples, but the present invention is not limited to these test examples.

(Test Example 1)
Amlodipine besilate, which has a bitter taste, was used as a model drug.

<Manufacturing of wet tablets-1- (i)>
-Drug content preparation process-
Amlodipine besilate (Kyongbo Pharmaceutical Co., Ltd.) 500 g, D-mannitol (Mannit P, Mitsubishi Corporation Foodtech Co., Ltd.) 465 g, and light anhydrous silicic acid (Adsolider 101, Freund Sangyo Co., Ltd.) 5 g was put into a fluidized bed granulator (MP-01, manufactured by Paulec Co., Ltd.) and mixed.
Next, granules containing 50% by mass of amlodipine besilate (drug-containing composition) were granulated by spraying an aqueous solution prepared by dissolving 30 g of hypromellose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) in 270 g of water. Got

-Wet powder preparation process-
20.79 g of granules obtained in the drug-containing preparation step and 232.94 g of D-mannitol (Mannitol P, manufactured by Mitsubishi Corporation Food Tech Co., Ltd.) were mixed.
Next, 26 10% by mass ethanol aqueous solution in which 1.275 g of polyvinyl alcohol (Gosenol EG-03 (partially saponified polyvinyl alcohol; saponification degree 86.5 mL% to 89.0 mL%), manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) was dissolved was added. .775 g was added and kneaded to obtain a wet powder-1- (i).

-Forming process-
The wet powder-1- (i) has a diameter of 8.0 mm and a weight per tablet using a wet lock tableting machine (EMT-18 and ETD-18, manufactured by Sankyo Seisakusho Co., Ltd.). The tablets were beaten to 170 mg to obtain wet tablets-1- (i) (the amount of the coated drug-containing material was 0% by mass).

<Manufacturing of wet tablets-1- (ii)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-1- (i).

-Wet powder preparation process-
In the same manner, except that the 10% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved was replaced with a 30% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved in the wet powder preparation step for producing the wet tablet-1- (i). Wet powder-1- (ii) was obtained.

-Forming process-
Wet tablet-in the same manner except that the wet powder-1- (i) in the molding step of the production of the wet tablet-1- (i) was replaced with the wet powder-1- (ii). 1- (ii) (the amount of coated drug-containing material was 0% by mass) was obtained.

<Manufacturing of wet tablets-1- (iii)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-1- (i).

-Wet powder preparation process-
In the same manner, except that the 10% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved was replaced with a 60% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved in the wet powder preparation step for producing the wet tablet-1- (i). Wet powder-1- (iii) was obtained.

-Forming process-
Wet tablet-in the same manner except that the wet powder-1- (i) in the molding step of the production of the wet tablet-1- (i) was replaced with the wet powder-1- (iii). 1- (iii) (the amount of coated drug content was 0% by mass) was obtained.

<Manufacturing of wet tablets-2-A- (i)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-1- (i).

-Coating process-
200 g of granules obtained in the above-mentioned drug-containing preparation step was put into a fluidized bed granulator (MP-01, manufactured by Paulec Co., Ltd.), and the following coating liquid I was sprayed to coat the coated drug-containing composition (). Hereinafter, IA (which may be referred to as "coated granules") was obtained.
The end point of the coating was defined as the time when the amount of the methacrylic acid copolymer LD in the coating liquid I was 10% by mass with respect to the granules obtained in the drug-containing preparation step.
[Coating liquid I]
・ Methacrylic acid copolymer LD ・ ・ ・ 732g
(Polykid PA-30A, manufactured by Sanyo Chemical Industries, Ltd.)
・ Surfactant ・ ・ ・ 8.8g
(Polysorbate 80, manufactured by Wako Pure Chemical Industries, Ltd.)
・ Plasticizer ・ ・ ・ 21.6g
(Macrogol 6000, manufactured by Sanyo Chemical Industries, Ltd.)

-Wet powder preparation process-
22.87 g of the coated granules IA and 230.86 g of D-mannitol (Mannitol P, manufactured by Mitsubishi Corporation Food Tech Co., Ltd.) were mixed.
Next, 26 10% by mass ethanol aqueous solution in which 1.275 g of polyvinyl alcohol (Gosenol EG-03 (partially saponified polyvinyl alcohol; saponification degree 86.5 mL% to 89.0 mL%), manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) was dissolved was added. .775 g was added and kneaded to obtain a wet powder-2-A- (i).

-Forming process-
Wet powder-1- (i) in the molding step of manufacturing the wet tablet-1- (i) was replaced with the wet powder-2-A- (i) in the same manner. Tablets-2-A- (i) (the amount of coated drug content was 9.0% by mass) were obtained.

<Manufacturing of wet tablets-2-A- (ii)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-1- (i).

-Coating process-
Coated granules IA were obtained in the same manner as in the coating step for producing the wet tablet-2-A- (i).

-Wet powder preparation process-
The same applies except that the 10% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved was replaced with a 30% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved in the wet powder preparation step of the wet tablet-2-A- (i). Wet powder-2-A- (ii) was obtained.

-Forming process-
Wet powder-1- (i) in the molding step of manufacturing the wet tablet-1- (i) was replaced with the wet powder-2-A- (ii) in the same manner. Tablets-2-A- (ii) (the amount of coated drug content was 9.0% by mass) were obtained.

<Manufacturing of wet tablets-2-A- (iii)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-1- (i).

-Coating process-
Coated granules IA were obtained in the same manner as in the coating step for producing the wet tablet-2-A- (i).

-Wet powder preparation process-
The same applies except that the 10% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved was replaced with a 60% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved in the wet powder preparation step of the wet tablet-2-A- (i). Wet powder-2-A- (iii) was obtained.

-Forming process-
Wet powder-1- (i) in the molding step of manufacturing the wet tablet-1- (i) was replaced with the wet powder-2-A- (iii) in the same manner. Tablets-2-A- (iii) (the amount of coated drug content was 9.0% by mass) were obtained.

<Manufacturing of wet tablets-2-B- (i)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-1- (i).

-Coating process-
In the coating step of the production of the wet tablet-2-A- (i), the end point of the coating is the amount of the methacrylic acid copolymer LD in the coating liquid I with respect to the granules obtained in the drug-containing preparation step. Coated granules IB were obtained in the same manner except that the point at which the content was 10% by mass was changed to the time when the content was 30% by mass.

-Wet powder preparation process-
27.03 g of the coated granules IB and 226.70 g of D-mannitol (Mannitol P, manufactured by Mitsubishi Corporation Food Tech Co., Ltd.) were mixed.
Next, 26 10% by mass ethanol aqueous solution in which 1.275 g of polyvinyl alcohol (Gosenol EG-03 (partially saponified polyvinyl alcohol; saponification degree 86.5 mL% to 89.0 mL%), manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) was dissolved was added. .775 g was added and kneaded to obtain a wet powder-2-B- (i).

-Forming process-
Wet powder-1- (i) in the molding step of manufacturing the wet tablet-1- (i) was replaced with the wet powder-2-B- (i) in the same manner. Tablets-2-B- (i) (the amount of coated drug content was 10.6% by mass) were obtained.

<Manufacturing of wet tablets-2-B- (ii)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-1- (i).

-Coating process-
Coated granules IB were obtained in the same manner as in the coating step for producing the wet tablet-2-B- (i).

-Wet powder preparation process-
The same applies except that the 10% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved was replaced with a 30% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved in the wet powder preparation step of the wet tablet-2-B- (i). Wet powder-2-B- (ii) was obtained.

-Forming process-
Wet powder-1- (i) in the molding step of manufacturing the wet tablet-1- (i) was replaced with the wet powder-2-B- (ii) in the same manner. Tablets-2-B- (ii) (the amount of coated drug content was 10.6% by weight) was obtained.

<Manufacturing of wet tablets-2-B- (iii)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-1- (i).

-Coating process-
Coated granules IB were obtained in the same manner as in the coating step for producing the wet tablet-2-B- (i).

-Wet powder preparation process-
The same applies except that the 10% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved in the wet powder preparation step in the production of the wet tablet-2-B- (i) was replaced with a 60% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved. Wet powder-2-B- (iii) was obtained.

-Forming process-
Wet powder-1- (i) in the molding step of manufacturing the wet tablet-1- (i) was replaced with the wet powder-2-B- (iii) in the same manner. Tablets-2-B- (iii) (the amount of coated drug content was 10.6% by weight) were obtained.

<Manufacturing of wet tablets-2-C- (i)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-1- (i).

-Coating process-
In the coating step of the production of the wet tablet-2-A- (i), the end point of the coating is the amount of the methacrylic acid copolymer LD in the coating liquid I with respect to the granules obtained in the drug-containing preparation step. Coated granules IC were obtained in the same manner except that the point at which the content was 10% by mass was changed to the time when the content was 50% by mass.

-Wet powder preparation process-
31.19 g of the coated granules IC and 222.54 g of D-mannitol (Mannitol P, manufactured by Mitsubishi Corporation Food Tech Co., Ltd.) were mixed.
Next, 26 10% by mass ethanol aqueous solution in which 1.275 g of polyvinyl alcohol (Gosenol EG-03 (partially saponified polyvinyl alcohol; saponification degree 86.5 mL% to 89.0 mL%), manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) was dissolved was added. .775 g was added and kneaded to obtain a wet powder-2-C- (i).

-Forming process-
Wet powder-1- (i) in the molding step of manufacturing the wet tablet-1- (i) was replaced with the wet powder-2-C- (i) in the same manner. Tablets-2-C- (i) (the amount of coated drug content was 12.2% by mass) were obtained.

<Manufacturing of wet tablets-2-C- (ii)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-1- (i).

-Coating process-
Coated granules IC were obtained in the same manner as in the coating step for producing the wet tablet-2-C- (i).

-Wet powder preparation process-
The same applies except that the 10% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved was replaced with a 30% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved in the wet powder preparation step of the wet tablet-2-C- (i). Wet powder-2-C- (ii) was obtained.

-Forming process-
Wet powder-1- (i) in the molding step of manufacturing the wet tablet-1- (i) was replaced with the wet powder-2-C- (ii) in the same manner. Tablets-2-C- (ii) (the amount of coated drug content was 12.2% by weight) were obtained.

<Manufacturing of wet tablets-2-C- (iii)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-1- (i).

-Coating process-
Coated granules IC were obtained in the same manner as in the coating step for producing the wet tablet-2-C- (i).

-Wet powder preparation process-
The same applies except that the 10% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved was replaced with a 60% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved in the wet powder preparation step for producing the wet tablet-2-C- (i). Wet powder-2-C- (iii) was obtained.

-Forming process-
Wet powder-1- (i) in the molding step of manufacturing the wet tablet-1- (i) was replaced with the wet powder-2-C- (iii) in the same manner. Tablets-2-C- (iii) (the amount of coated drug content was 12.2% by weight) were obtained.

<Manufacturing of wet tablets-3-A- (i)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-1- (i).

-Coating process-
200 g of granules obtained in the above-mentioned drug-containing preparation step was put into a fluidized bed granulator (MP-01, manufactured by Paulec Co., Ltd.), and the following coating liquid II was sprayed to coat the coated drug-containing composition (). Hereinafter, II-A (which may be referred to as "coated granules") was obtained.
The end point of the coating was defined as the time when the amount of ethyl cellulose in the coating liquid II was 10% by mass with respect to the granules obtained in the drug-containing preparation step.
[Coating liquid II]
・ Ethyl cellulose ・ ・ ・ 208g
(Ethocel 7 Premium, manufactured by Japan Colorcon LLC)
・ Ethanol ・ ・ ・ 3,744g
・ Water ・ ・ ・ 416g

-Wet powder preparation process-
Wet powder-3-A- (I) was obtained.

-Forming process-
Wet powder-1- (i) in the molding step of manufacturing the wet tablet-1- (i) was replaced with the wet powder-3-A- (i) in the same manner. Tablets-3-A- (i) (the amount of coated drug content was 9.0% by mass) were obtained.

<Manufacturing of wet tablets-3-A- (ii)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-1- (i).

-Coating process-
Coated granules II-A were obtained in the same manner as in the coating step for producing the wet tablet-3-A- (i).

-Wet powder preparation process-
The same applies except that the 10% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved was replaced with a 30% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved in the wet powder preparation step of the wet tablet-3-A- (i). Wet powder-3-A- (ii) was obtained.

-Forming process-
Wet powder-1- (i) in the molding step of manufacturing the wet tablet-1- (i) was replaced with the wet powder-3-A- (ii) in the same manner. Tablets-3-A- (ii) (the amount of coated drug content was 9.0% by mass) were obtained.

<Manufacturing of wet tablets-3-A- (iii)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-1- (i).

-Coating process-
Coated granules II-A were obtained in the same manner as in the coating step for producing the wet tablet-3-A- (i).

-Wet powder preparation process-
The same applies except that the 10% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved was replaced with a 60% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved in the wet powder preparation step of the wet tablet-3-A- (i). Wet powder-3-A- (iii) was obtained.

-Forming process-
Wet powder-1- (i) in the molding step of manufacturing the wet tablet-1- (i) was replaced with the wet powder-3-A- (iii) in the same manner. Tablets-3-A- (iii) (the amount of coated drug content was 9.0% by mass) were obtained.

<Manufacturing of wet tablets-3-B- (i)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-1- (i).

-Coating process-
In the coating step of manufacturing the wet tablet-3-A- (i), the amount of ethyl cellulose in the coating liquid II at the end point of coating is 10% by mass with respect to the granules obtained in the drug-containing preparation step. Coated granules II-B were obtained in the same manner except that the point at the time of becoming 30% by mass was changed to the time of becoming 30% by mass.

-Wet powder preparation process-
Wet powder-3-B-in the same manner except that the coated granules IB in the wet powder preparation step of the production of the wet tablet-2-B- (i) were replaced with the coated granules II-B. (I) was obtained.

-Forming process-
Wet powder-1- (i) in the molding step of manufacturing the wet tablet-1- (i) was replaced with the wet powder-3-B- (i) in the same manner. Tablets-3-B- (i) (the amount of coated drug content was 10.6% by mass) were obtained.

<Manufacturing of wet tablets-3-B- (ii)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-1- (i).

-Coating process-
Coated granules II-B were obtained in the same manner as in the coating step for producing the wet tablet-3-B- (i).

-Wet powder preparation process-
The same applies except that the 10% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved was replaced with a 30% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved in the wet powder preparation step of the wet tablet-3-B- (i). Wet powder-3-B- (ii) was obtained.

-Forming process-
Wet powder-1- (i) in the molding step of manufacturing the wet tablet-1- (i) was replaced with the wet powder-3-B- (ii) in the same manner. Tablets-3-B- (ii) (the amount of coated drug content was 10.6% by weight) were obtained.

<Manufacturing of wet tablets-3-B- (iii)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-1- (i).

-Coating process-
Coated granules II-B were obtained in the same manner as in the coating step for producing the wet tablet-3-B- (i).

-Wet powder preparation process-
The same applies except that the 10% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved in the wet powder preparation step in the production of the wet tablet-3-B- (i) was replaced with a 60% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved. Wet powder-3-B- (iii) was obtained.

-Forming process-
Wet powder-1- (i) in the molding step of manufacturing the wet tablet-1- (i) was replaced with the wet powder-3-B- (iii) in the same manner. Tablets-3-B- (iii) (the amount of coated drug content was 10.6% by weight) were obtained.

<Manufacturing of wet tablets-3-C- (i)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-1- (i).

-Coating process-
In the coating step of manufacturing the wet tablet-3-A- (i), the amount of ethyl cellulose in the coating liquid II at the end point of coating is 10% by mass with respect to the granules obtained in the drug-containing preparation step. Coated granules II-C were obtained in the same manner except that the point at the time of becoming 50% by mass was changed to the time of becoming 50% by mass.

-Wet powder preparation process-
Wet powder-3-C-in the same manner except that the coated granules IC in the wet powder preparation step of the production of the wet tablet-2-C- (i) were replaced with the coated granules II-C. (I) was obtained.

-Forming process-
Wet powder-1- (i) in the molding step of manufacturing the wet tablet-1- (i) was replaced with the wet powder-3-C- (i) in the same manner. Tablets-3-C- (i) (the amount of coated drug content was 12.2% by mass) were obtained.

<Manufacturing of wet tablets-3-C- (ii)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-1- (i).

-Coating process-
Coated granules II-C were obtained in the same manner as in the coating step for producing the wet tablet-3-C- (i).

-Wet powder preparation process-
The same applies except that the 10% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved was replaced with a 30% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved in the wet powder preparation step for producing the wet tablet-3-C- (i). Wet powder-3-C- (ii) was obtained.

-Forming process-
Wet powder-1- (i) in the molding step of manufacturing the wet tablet-1- (i) was replaced with the wet powder-3-C- (ii) in the same manner. Tablets-3-C- (ii) (the amount of coated drug content was 12.2% by weight) were obtained.

<Manufacturing of wet tablets-3-C- (iii)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-1- (i).

-Coating process-
Coated granules II-C were obtained in the same manner as in the coating step for producing the wet tablet-3-C- (i).

-Wet powder preparation process-
The same applies except that the 10% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved in the wet powder preparation step in the production of the wet tablet-3-C- (i) was replaced with a 60% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved. Wet powder-3-C- (iii) was obtained.

-Forming process-
Wet powder-1- (i) in the molding step of manufacturing the wet tablet-1- (i) was replaced with the wet powder-3-C- (iii) in the same manner. Tablets-3-C- (iii) (the amount of coated drug content was 12.2% by weight) were obtained.

<Evaluation>
-Intraoral disintegration-
For each wet tablet obtained above, the time from the inclusion of the tablet in the oral cavity to the complete disintegration was measured, and the time was calculated. The results are shown in Table 1.

-Bitter taste test-
For each wet tablet obtained above, the tablet was contained in the mouth, and the bitterness felt at the time of disintegration and after disintegration in the oral cavity was evaluated according to the following criteria. The results are shown in Table 1.
・ － ・ ・ ・ I don't feel any bitterness.
・ ± ・ ・ ・ Slightly bitter taste.
・ ＋ ・ ・ ・ I feel a bitter taste.
・ ++ ・ ・ ・ I feel a strong bitter taste.

-exterior-
The appearance of each wet tablet obtained above was evaluated according to the following criteria. The results are shown in Table 1.
・ ○ ・ ・ ・ There is no problem with the appearance.
・ × ・ ・ ・ There is a line on the tablet.

表１中、「※１」は、崩壊物がややゲル状であったことを示し、「※２」は、崩壊物がゲル状であったことを示す。※１及び※２が付された錠剤は、崩壊性が不適であった。

In Table 1, "* 1" indicates that the disintegrated product was slightly gel-like, and "* 2" indicates that the disintegrated product was gel-like. The tablets with * 1 and * 2 were unsuitable for disintegration.

From the results in Table 1, the drug-containing material was coated with a coating base in an amount of 30% by mass or more, and the concentration of the organic solvent in the water-containing organic solvent in the wet powder preparation step was 30% by mass. The wet tablets manufactured as follows are excellent in quality because they can achieve both reduction of bitterness and oral disintegration property in which the disintegrated product does not become gel-like and the oral disintegration time is 60 seconds or less. It was confirmed that a wet tablet was obtained. In addition, the appearance of these wet tablets was not impaired.

(Test Example 2)
As a model drug, memantine hydrochloride having a bitter taste was used for examination.

<Manufacturing of wet tablets-4>
-Drug content preparation process-
500 g of memantine hydrochloride (manufactured by DNP Fine Chemical Utsunomiya Co., Ltd.) and 5 g of light anhydrous silicic acid (manufactured by Adsolider 101, Freund Sangyo Co., Ltd.) were put into a fluidized bed granulator (MP-01, manufactured by Paulec Co., Ltd.). Mixed.
Next, an aqueous solution prepared by dissolving 25 g of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda Corporation) in 475 g of water was sprayed to granulate, and granules containing 100 g of memantine hydrochloride in 106 g (drug-containing composition). ) Was obtained.

-Coating process-
400 g of granules obtained in the above-mentioned drug-containing preparation step was put into a fluidized bed granulator (MP-01, manufactured by Paulec Co., Ltd.), and the following coating liquid III was sprayed to coat the coated drug-containing composition (). Hereinafter, (sometimes referred to as “coated granules”) III was obtained.
The end point of the coating was defined as the time when the amount of ethyl cellulose in the coating liquid III was 50% by mass with respect to the granules obtained in the drug-containing preparation step.
[Coating liquid III]
・ Ethyl cellulose ・ ・ ・ 200g
(Ethocel 7 Premium, manufactured by Japan Colorcon LLC)
・ Ethanol ・ ・ ・ 1,620g
・ Water ・ ・ ・ 180g

-Wet powder preparation process-
31.8 g of the coated granule III, 114.0 g of D-mannitol (Mannit P, manufactured by Mitsubishi Corporation Food Tech Co., Ltd.) and 3.0 g of sucralose (Saneigen FFI Co., Ltd.) were mixed.
Next, 1.2 g of polyvinyl alcohol (Gosenol EG-03 (partially saponified polyvinyl alcohol; saponification degree 86.5 mL% to 89.0 mL%), manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) and strawberry oil (manufactured by Ogawa Fragrance Co., Ltd.) 16.35 g of a 10 mass% ethanol aqueous solution in which 0.15 g was dissolved was added and kneaded to obtain a wet powder-4.

-Forming process-
Using a wet tableting machine (EMT-18 and ETD-18, manufactured by Sankyo Seisakusho Co., Ltd.), the wet powder-4 has a diameter of 8.5 mm and a weight of 150 mg per tablet. Wet tablets-4 (the amount of coated drug content was 21.2% by weight) was obtained.

<Manufacturing of wet tablets-5>
-Drug content preparation process-
500 g of memantine hydrochloride (manufactured by DNP Fine Chemical Utsunomiya Co., Ltd.) and 5 g of light anhydrous silicic acid (manufactured by Adsolider 101, Freund Sangyo Co., Ltd.) were put into a fluidized bed granulator (MP-01, manufactured by Paulec Co., Ltd.). Mixed.
Next, an aqueous solution prepared by dissolving 25 g of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda Corporation) in 475 g of water was sprayed to granulate, and granules containing 100 g of memantine hydrochloride in 106 g (drug-containing composition). ) Was obtained.

-Wet powder preparation process-
21.2 g of the drug-containing composition, 124.6 g of D-mannitol (Mannit P, manufactured by Mitsubishi Corporation Food Tech Co., Ltd.) and 3.0 g of sucralose (Saneigen FFI Co., Ltd.) were mixed. ..
Next, 1.2 g of polyvinyl alcohol (Gosenol EG-03 (partially saponified polyvinyl alcohol; saponification degree 86.5 mL% to 89.0 mL%), manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) and strawberry oil (manufactured by Ogawa Fragrance Co., Ltd.) 16.35 g of a 10 mass% ethanol aqueous solution in which 0.15 g was dissolved was added and kneaded to obtain a wet powder-5.

-Forming process-
The wet powder-5 is tableted using an autograph (manufactured by Shimadzu Corporation) so that the diameter is 8.5 mm and the weight per tablet is 150 mg, and the wet tablet-5 (coated). The amount of the drug-containing substance was 0% by mass).

<Evaluation>
Each of the wet tablets obtained above was evaluated for oral disintegration, bitterness, and appearance in the same manner as in Test Example 1. The results are shown in Table 2.

From the results in Table 2, even when different drugs were used, the drug-containing material was coated with a coating base in an amount of 30% by mass or more, and the drug-containing organic solvent in the wet powder preparation step was used. Wet tablets-4 produced with an organic solvent concentration of 30% by mass or less have reduced bitterness, do not become a gel-like disintegrant, and have an orally disintegrating property in which the disintegration time in the oral cavity is 60 seconds or less. It was confirmed that a wet tablet with excellent quality can be obtained. In addition, the appearance of these wet tablets was not impaired.

(Test Example 3)
<Manufacturing of wet tablets 6>
-Drug content preparation process-
250 g of memantin hydrochloride (manufactured by DNP Fine Chemical Utsunomiya Co., Ltd.) and 2.5 g of light anhydrous silicic acid (Aerosil 200, manufactured by Nippon Aerosil Co., Ltd.) are mixed with a high-speed stirring granulator (NMG-5 type, manufactured by Nara Machinery Co., Ltd.). ) And mixed.
Then, an aqueous solution prepared by dissolving 7.5 g of hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Corporation) in 37.5 g of water was added to granulate the granules. After crushing with a crusher (Komil, manufactured by Paulek Co., Ltd., screen diameter 1.58 mm), it is dried using a fluidized bed dryer (MP-01, manufactured by Paulek Co., Ltd.), and further crushed (Komil, Co., Ltd.). Granules (drug-containing composition) containing 100 g of memantine hydrochloride in 104 g were obtained by sizing with Paulek's screen diameter 0.81 mm).

-Coating process-
200 g of granules obtained in the above-mentioned drug-containing preparation step was put into a fluidized bed granulator (MP-01, manufactured by Paulec Co., Ltd.), and the following coating liquid IV was sprayed to cover the drug-containing composition (! Hereinafter, IV (sometimes referred to as “coated granules”) was obtained.
The end point of the coating was defined as the time when the amount of ethyl cellulose in the coating liquid IV was 50% by mass with respect to the granules obtained in the drug-containing preparation step.
[Coating liquid IV]
・ Ethyl cellulose ・ ・ ・ 100g
(ETHOCEL Standard 7 Premium, manufactured by Japan Colorcon LLC)
・ Ethanol ・ ・ ・ 810g
・ Water ・ ・ ・ 90g

-Wet powder preparation process-
High-speed stirring of 92.4 g of the coated granule IV, D-mannitol (Mannit P, manufactured by Mitsubishi Corporation Food Tech Co., Ltd.) 462.69 g, and 11.4 g of sucralose (Saneigen FFI Co., Ltd.). Mixing was performed using a grain device (NMG-5 type, manufactured by Nara Machinery Co., Ltd.).
Next, polyvinyl alcohol (Gosenol EG-03 (partially saponified polyvinyl alcohol; saponification degree 86.5 mL% to 89.0 mL%), manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) 2.85 g and strawberry oil (manufactured by Ogawa Fragrance Co., Ltd.) 60.42 g of a 10 mass% ethanol aqueous solution in which 0.57 g was dissolved was added and kneaded to obtain a wet powder-6.

-Forming process-
Using a wet tableting machine (EMT-18 and ETD-18, manufactured by Sankyo Seisakusho Co., Ltd.), the wet powder-6 has a diameter of 8.5 mm and a weight of 190 mg per tablet. Wet tablets-6 (the amount of coated drug content was 20.8% by weight) was obtained.

<Evaluation>
As a result of evaluating the oral disintegration property, bitterness, and appearance of the wet tablets obtained above in the same manner as in Test Example 1, the oral disintegration time of the wet tablets-6 was 15 seconds, and the bitterness was evaluated. The result was ±, and the evaluation result of the appearance was ○.

(Test Example 4)
<Manufacturing of wet tablets-7- (i)>
-Drug content preparation process-
Amlodipine besilate (Kyongbo Pharmaceutical Co., Ltd.) 500 g, D-mannitol (Mannit P, Mitsubishi Corporation Foodtech Co., Ltd.) 465 g, and light anhydrous silicic acid (Adsolider 101, Freund Sangyo Co., Ltd.) 5 g was put into a fluidized bed granulator (MP-01, manufactured by Paulec Co., Ltd.) and mixed.
Next, granules containing 50% by mass of amlodipine besilate (drug-containing composition) were granulated by spraying an aqueous solution prepared by dissolving 30 g of hypromellose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) in 270 g of water. Got

-Coating process-
200 g of granules obtained in the above-mentioned drug-containing preparation step was put into a fluidized bed granulator (MP-01, manufactured by Paulec Co., Ltd.), and the following coating liquid V was sprayed to coat the coated drug-containing composition (). Hereinafter, V- (i), which may be referred to as "coated granules", was obtained.
The end point of the coating was defined as the time when the amount of the aminoalkyl methacrylate copolymer E in the coating liquid V was 30% by mass with respect to the granules obtained in the drug-containing preparation step.
[Coating liquid V]
・ Aminoalkyl methacrylate copolymer E ・ ・ ・ 114.2 g
(Eudragit EPO, made by Evonik)
・ Sodium lauryl sulfate ・ ・ ・ 11.4g
(Made by Wako Pure Chemical Industries, Ltd.)
・ Stearic acid ・ ・ ・ 17.2g
(Made by AVANTOR)
・ Talc ・ ・ ・ 57.2g
(Talkan Hayashi, Hayashi Kasei Co., Ltd.)
・ Water ・ ・ ・ 1,134g

-Wet powder preparation process-
27.03 g of the coated granules V- (i) and 226.70 g of D-mannitol (Mannitol P, manufactured by Mitsubishi Corporation Food Tech Co., Ltd.) were mixed.
Next, 26 10% by mass ethanol aqueous solution in which 1.275 g of polyvinyl alcohol (Gosenol EG-03 (partially saponified polyvinyl alcohol; saponification degree 86.5 mL% to 89.0 mL%), manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) was dissolved was added. .775 g was added and kneaded to obtain a wet powder-7- (i).

-Forming process-
Using a wet tableting machine (EMT-18 and ETD-18, manufactured by Sankyo Seisakusho Co., Ltd.), the wet powder-7- (i) has a diameter of 8.0 mm and a weight per tablet. The tablets were beaten to 170 mg to obtain wet tablets-7- (i) (the amount of the coated drug-containing material was 10.6% by mass).

<Manufacturing of wet tablets-7- (ii)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-7- (i).

-Coating process-
In the coating step of manufacturing the wet tablet-7- (i), the amount of the aminoalkyl methacrylate copolymer E in the coating liquid V at the end point of the coating is 30 with respect to the granules obtained in the drug-containing preparation step. Coated granules V- (ii) were obtained in the same manner except that the point at which the content was 50% by mass was changed to the time when the content was 50% by mass.

-Wet powder preparation process-
31.19 g of the coated granule V- (ii) and 222.54 g of D-mannitol (Mannitol P, manufactured by Mitsubishi Corporation Food Tech Co., Ltd.) were mixed.
Next, 26 10% by mass ethanol aqueous solution in which 1.275 g of polyvinyl alcohol (Gosenol EG-03 (partially saponified polyvinyl alcohol; saponification degree 86.5 mL% to 89.0 mL%), manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) was dissolved was added. .775 g was added and kneaded to obtain a wet powder-7- (ii).

-Forming process-
Wet tablet-in the same manner except that the wet powder-7- (i) in the molding step of the production of the wet tablet-7- (i) was replaced with the wet powder-7- (ii). 7- (ii) (the amount of coated drug content was 12.2% by mass) was obtained.

<Evaluation>
As a result of evaluating the orally disintegrating property, bitterness, and appearance of the wet tablets-7- (i) and (ii) obtained above in the same manner as in Test Example 1, the wet tablets-7- (i). The oral disintegration time is 12 seconds, the bitterness evaluation result is-, the appearance evaluation result is ○, and the wet tablet-7- (ii) has an oral disintegration time of 21 seconds and the bitterness evaluation result. -, The evaluation result of the appearance was ○.

(Test Example 5)
<Manufacturing of wet tablets-8-A- (i)>
-Drug content preparation process-
Amlodipine besilate (Kyongbo Pharmaceutical Co., Ltd.) 500 g, D-mannitol (Mannit P, Mitsubishi Corporation Foodtech Co., Ltd.) 465 g, and light anhydrous silicic acid (Adsolider 101, Freund Sangyo Co., Ltd.) 5 g was put into a fluidized bed granulator (MP-01, manufactured by Paulec Co., Ltd.) and mixed.
Next, granules containing 50% by mass of amlodipine besilate (drug-containing composition) were granulated by spraying an aqueous solution prepared by dissolving 30 g of hypromellose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) in 270 g of water. Got

-Coating process-
200 g of granules obtained in the above-mentioned drug-containing preparation step was put into a fluidized bed granulator (MP-01, manufactured by Paulec Co., Ltd.), and the following coating liquid VI was sprayed to coat the coated drug-containing composition (). Hereafter, VI-A (which may be referred to as "coated granules") was obtained.
The end point of the coating was defined as the time when the amount of the ammonioalkyl methacrylate copolymer RS in the coating liquid VI was 10% by mass with respect to the granules obtained in the drug-containing preparation step.
[Coating liquid VI]
・ Ammonioalkyl methacrylate copolymer RS ・ ・ ・ 129.1 g
(Eudragit RL30D, made by Evonik)
・ Carmellose sodium ・ ・ ・ 14.4g
(Cerogen PR-S, manufactured by Daiichi Kogyo Co., Ltd.)
・ Polysorbate 80 ・ ・ ・ 28.7g
(Made by Junsei Chemical Co., Ltd.)
・ Light anhydrous silicic acid ・ ・ ・ 28.7g
(Adslider 101, manufactured by Freund Sangyo Co., Ltd.)
・ Water ・ ・ ・ 502g

-Wet powder preparation process-
22.87 g of the coated granule VI-A and 230.86 g of D-mannitol (Mannitol P, manufactured by Mitsubishi Corporation Food Tech Co., Ltd.) were mixed.
Next, 26 10% by mass ethanol aqueous solution in which 1.275 g of polyvinyl alcohol (Gosenol EG-03 (partially saponified polyvinyl alcohol; saponification degree 86.5 mL% to 89.0 mL%), manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) was dissolved was added. .775 g was added and kneaded to obtain a wet powder-8-A- (i).

-Forming process-
Using a wet tableting machine (EMT-18 and ETD-18, manufactured by Sankyo Seisakusho Co., Ltd.), the wet powder-8-A- (i) has a diameter of 8.0 mm per tablet. The tablets were tableted to a weight of 170 mg to obtain wet tablets-8-A- (i) (the amount of the coated drug-containing material was 9.0% by mass).

<Manufacturing of wet tablets-8-A- (ii)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-8-A- (i).

-Coating process-
Coated granules VI-A were obtained in the same manner as in the coating step for producing the wet tablet-8-A- (i).

-Wet powder preparation process-
The same applies except that the 10% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved was replaced with a 60% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved in the wet powder preparation step of the wet tablet-8-A- (i). Wet powder-8-A- (ii) was obtained.

-Forming process-
The same applies except that the wet powder-8-A- (i) in the molding step of the production of the wet tablet-8-A- (i) is replaced with the wet powder-8-A- (ii). Wet tablets-8-A- (ii) (the amount of coated drug-containing material was 9.0% by mass) was obtained.

<Manufacturing of wet tablets-8-B- (i)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-8-A- (i).

-Coating process-
In the coating step of the production of the wet tablet-8-A- (i), the end point of the coating is the amount of the ammonioalkyl methacrylate copolymer RS in the coating liquid VI with respect to the granules obtained in the drug-containing preparation step. The coated granules VI-B were obtained in the same manner except that the point at which the content was 10% by mass was changed to the time when the content was 30% by mass.

-Wet powder preparation process-
27.03 g of the coated granule VI-B and 226.70 g of D-mannitol (Mannitol P, manufactured by Mitsubishi Corporation Food Tech Co., Ltd.) were mixed.
Next, 26 10% by mass ethanol aqueous solution in which 1.275 g of polyvinyl alcohol (Gosenol EG-03 (partially saponified polyvinyl alcohol; saponification degree 86.5 mL% to 89.0 mL%), manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) was dissolved was added. .775 g was added and kneaded to obtain a wet powder-8-B- (i).

-Forming process-
The same applies except that the wet powder-8-A- (i) in the molding step of the production of the wet tablet-8-A- (i) is replaced with the wet powder-8-B- (i). Wet tablets-8-B- (i) (the amount of coated drug content was 10.6% by mass) were obtained.

<Manufacturing of wet tablets-8-B- (ii)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-8-A- (i).

-Coating process-
Coated granules VI-B were obtained in the same manner as in the coating step for producing the wet tablet-8-B- (i).

-Wet powder preparation process-
The same applies except that the 10% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved in the wet powder preparation step in the production of the wet tablet-8-B- (i) was replaced with a 60% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved. Wet powder-8-B- (ii) was obtained.

-Forming process-
The same applies except that the wet powder-8-A- (i) in the molding step of the production of the wet tablet-8-A- (i) is replaced with the wet powder-8-B- (ii). Wet tablets-8-B- (ii) (the amount of coated drug content was 10.6% by mass) were obtained.

<Manufacturing of wet tablets-8-C- (i)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-8-A- (i).

-Coating process-
In the coating step of the production of the wet tablet-8-A- (i), the end point of the coating is the amount of the ammonioalkyl methacrylate copolymer RS in the coating liquid VI with respect to the granules obtained in the drug-containing preparation step. The coated granules VI-C were obtained in the same manner except that the point at which the content was 10% by mass was changed to the time when the content was 50% by mass.

-Wet powder preparation process-
31.19 g of the coated granule VI-C and 222.54 g of D-mannitol (Mannitol P, manufactured by Mitsubishi Corporation Food Tech Co., Ltd.) were mixed.
Next, 26 10% by mass ethanol aqueous solution in which 1.275 g of polyvinyl alcohol (Gosenol EG-03 (partially saponified polyvinyl alcohol; saponification degree 86.5 mL% to 89.0 mL%), manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) was dissolved was added. .775 g was added and kneaded to obtain a wet powder-8-C- (i).

-Forming process-
The same applies except that the wet powder-8-A- (i) in the molding step of the production of the wet tablet-8-A- (i) is replaced with the wet powder-8-C- (i). Wet tablets-8-C- (i) (the amount of coated drug-containing material was 12.2% by mass) were obtained.

<Manufacturing of wet tablets-8-C- (ii)>
-Drug content preparation process-
Granules containing 50% by mass of amlodipine besilate were obtained in the same manner as in the drug-containing preparation step for producing the wet tablet-8-A- (i).

-Coating process-
Coated granules VI-C were obtained in the same manner as in the coating step for producing the wet tablet-8-C- (i).

-Wet powder preparation process-
The same applies except that the 10% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved was replaced with a 60% by mass ethanol aqueous solution in which polyvinyl alcohol was dissolved in the wet powder preparation step of the wet tablet-8-C- (i). Wet powder-8-C- (ii) was obtained.

-Forming process-
The same applies except that the wet powder-8-A- (i) in the molding step of the production of the wet tablet-8-A- (i) is replaced with the wet powder-8-C- (ii). Wet tablets-8-C- (ii) (the amount of coated drug-containing material was 12.2% by mass) was obtained.

<Evaluation>
Each of the wet tablets obtained above was evaluated for oral disintegration, bitterness, and appearance in the same manner as in Test Example 1. The results are shown in Table 3.

From the results of Test Examples 1 to 5, at least one of methacrylic acid copolymer LD, ethyl cellulose and aminoalkyl methacrylate copolymer E was used as the coating base, and the amount of the coating base was 30% by mass or more with respect to the drug-containing material. In a wet tablet produced by coating a drug-containing substance with a substance and making the concentration of the organic solvent in the hydrous organic solvent in the wet powder preparation step 30% by mass or less, the bitterness is reduced and the disintegrated product does not become gel-like. Moreover, it was confirmed that the wet tablet having excellent quality can be obtained by achieving both the orally disintegrating property in which the orally disintegrating time is 60 seconds or less. In addition, the appearance of these wet tablets was not impaired.

Claims (12)

A coating step of coating a drug-containing substance with a coating base to obtain a coated drug-containing substance, and
A wet powder preparation step of adding a water-containing organic solvent in which a binder is dissolved to the composition containing the coated drug-containing material and kneading the composition to obtain a wet powder.
Including a molding step of compression molding the wet powder.
The coating base in the coating step is one or more selected from the group consisting of the methacrylic acid copolymer LD, ethyl cellulose and the aminoalkyl methacrylate copolymer E.
The amount of the coating base in the coating step is 30% by mass or more with respect to the drug-containing substance.
A method for producing a wet tablet, wherein the concentration of the organic solvent in the water-containing organic solvent in the wet powder preparation step is 30% by mass or less. The method for producing a wet tablet according to claim 1, wherein the coating base is at least one of a methacrylic acid copolymer LD and ethyl cellulose. The method for producing a wet tablet according to any one of claims 1 to 2, wherein the organic solvent in the water-containing organic solvent is ethanol. The method for producing a wet tablet according to any one of claims 1 to 3, wherein the amount of the coating base in the coating step is 30% by mass or more and 70% by mass or less with respect to the drug-containing substance. The method for producing a wet tablet according to any one of claims 1 to 4, wherein the concentration of the organic solvent in the hydrous organic solvent in the wet powder preparation step is 1% by mass or more and 10% by mass or less. The method for producing a wet tablet according to any one of claims 1 to 5, wherein the amount of the coated drug-containing substance in the wet tablet is 1.0% by mass to 50.0% by mass. A method for improving the quality of wet tablets
A coating step of coating a drug-containing substance with a coating base to obtain a coated drug-containing substance, and
A wet powder preparation step of adding a water-containing organic solvent in which a binder is dissolved to the composition containing the coated drug-containing material and kneading the composition to obtain a wet powder.
Including a molding step of compression molding the wet powder.
The coating base in the coating step is one or more selected from the group consisting of the methacrylic acid copolymer LD, ethyl cellulose and the aminoalkyl methacrylate copolymer E.
The amount of the coating base in the coating step is 30% by mass or more with respect to the drug-containing substance.
The concentration of the organic solvent in the water-containing organic solvent in the wet powder preparation step is 30% by mass or less.
The quality improvement is characterized in that the bitterness of the wet tablet is reduced and the disintegrated product does not become a gel and the oral disintegration time is 60 seconds or less. Method. The method according to claim 7, wherein the coating base is at least one of a methacrylic acid copolymer LD and ethyl cellulose. The method according to any one of claims 7 to 8, wherein the organic solvent in the water-containing organic solvent is ethanol. The method according to any one of claims 7 to 9, wherein the amount of the coating base in the coating step is 30% by mass or more and 70% by mass or less with respect to the drug-containing substance. The method according to any one of claims 7 to 10, wherein the concentration of the organic solvent in the hydrous organic solvent in the wet powder preparation step is 1% by mass or more and 10% by mass or less. The method according to any one of claims 7 to 11, wherein the amount of the coated drug-containing substance in the wet tablet is 1.0% by mass to 50.0% by mass.