JPH0995439A - Production of solid preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To easily obtain a solid preparation without causing the mutual fusing of the granules on a thermal treatment. SOLUTION: This method for producing the solid preparation comprises compounding a solid medicinal agent, a wax and a binder as essential components, granulating the composition, and subsequently thermally treating the granules with a fluidized layer device. The wax is selected from paraffins having melting points of 40-90 deg.C, beewaxes, higher alcohols, higher fatty acids, higher fatty acid esters, glycerol fatty acid esters, and polyethylene glycols, and is compounded in an amount of >=20 pts.wt. per 100 pts.wt. of the solid preparation. The binder is selected from cellulose derivatives, methacrylic acid copolymers, polyvinylacetal diethylaminoacetate, pullulan, gum arabic, gelatin, polyvinyl pyrrolidone, and polyvinyl alcohol, and is compounded in an amount of >=1 pt.wt. per 100 pts.wt. of the solid preparation. The preparation masking the bitter taste and controlling the elusion is obtained. The wax treatment smoothens the surfaces of the solid preparation, and enables to obtain a sufficient coating effect by a small coating amount.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a solid preparation using waxes and the like.

[0002]

2. Description of the Related Art Conventionally, solid preparations such as tablets, granules, fine granules, and capsules are generally coated with a film or sugar for the purpose of protecting drug components, masking bitterness, controlling elution, or cosmetic appearance. It is being appreciated. Further, the drug substance may be made into a solid preparation through a special process such as mixing and pulverization and microencapsulation in order to mask the bitterness or improve the solubility of the poorly tolerant drug and control the dissolution.

On the other hand, Japanese Patent Application Laid-Open No. 1-287021 discloses that solid preparations such as uncoated granules, fine granules and drug substance are heat treated by using waxes as a coating agent. It is disclosed that a more effective masking effect can be obtained as compared with the coating using the water-soluble cellulose ether or the gastric / enteric base. That is,
It has been known to process a small amount of wax of about 0.1 to 0.2% for polishing coated tablets and the like,
This invention heats solid drugs such as uncoated granules, fine granules and drug substance together with 2 to 20% by weight of waxes to obtain a conventional water-soluble cellulose ether or gastric solution. It is disclosed that a more effective masking effect can be obtained as compared with coating using an enteric base.

[0004]

However, the drug substance, granules, and fine granules have smaller particles than tablets and the like.
Since the surface area is remarkably increased, the coating method similar to that for tablets often causes great difficulty. That is, fine particles including granules and fine granules have a remarkably large particle surface area in inverse proportion to the particle diameter. Need time. Further, when a gastric or enteric base is used, if the coating amount is increased to enhance the effect of coating, there are problems such as delayed drug release and poor dosing. Further, when the particles are small, it is not possible to completely prevent granulation by coating using a conventional aqueous solution or organic solvent solution.

Further, in the method disclosed in Japanese Patent Application Laid-Open No. 1-287021, a delicate temperature control is required at the time of heat treatment for a drug having an extremely remarkable bitterness, a drug requiring strict elution control, etc. It has been found that it is difficult to control the particle size of the obtained treated product. As a result of earnest efforts to solve these problems, the present inventor has found that the problems can be solved by the means described below, and completed the present invention.

[0006]

The present invention is a method for producing a solid preparation, which comprises granulating a solid drug, a wax and a binder as essential components and then heat-treating the mixture using a fluidized bed apparatus.

The waxes in the present invention include paraffins, beeswax, higher alcohols, higher fatty acids,
Higher fatty acid esters, glycerin fatty acid esters,
One or more waxes selected from polyethylene glycols, specifically, paraffins such as paraffin and petrolatum, beeswax such as beeswax and bleached beeswax, and higher alcohols such as cetyl alcohol and stearyl alcohol. , Higher fatty acids such as stearic acid, higher fatty acid esters such as carnauba wax and rice wax, glycerin fatty acid esters such as beef tallow, hardened soybean oil and hardened castor oil, PEG-6
Polyethylene glycols such as 000, PEG-20000, Lubriwax-101, 102 (hydrogenated vegetable oil), Polishing wax-101 (mixture of carnauba wax and paraffin), Precirol (glycerin-mono,
Di, tri mixed palmitate) and the like. These may be used alone or as a mixture of two or more thereof.

These waxes have a melting point of 40 to 40.
90 ° C. is preferable. With waxes having a melting point of less than 40 ° C., particles may fuse together under normal storage conditions, and with waxes having a melting point of more than 90 ° C., it takes a high temperature to melt and spread on the particle surface, This is not preferable because the decomposition of the drug becomes a concern. However, even if the melting point of a single wax is not in the range of 40 to 90 ° C., it is within the scope of the present invention as long as it shows a melting point in the range of 40 to 90 ° C. by combining two or more kinds. . The shape and particle size of the waxes are not particularly limited, and in order to perform a heat treatment using a granulation operation and a fluidized bed,
The particles need not be significantly larger than the particles to be coated, and the shape need not be extremely irregular, but even if they have an unfavorable shape, the properties are improved by crushing and sizing if necessary. Can be used.

The binder in the present invention is one or more selected from cellulose derivatives, copolymers of methacrylic acid, polyvinyl acetal diethylaminoacetate, pullulan, gum arabic, gelatin, polyvinylpyrrolidone and polyvinyl alcohol. A binder, and specific examples thereof include hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose phthalate,
Hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose derivatives such as ethyl cellulose, methyl methacrylate / butyl methacrylate / diethyl methacrylate /
Aminoethyl copolymer (Eudragit E), methacrylic acid-ethyl acrylate copolymer (Eudragit L 30 D-55, Eudragit L 100-55), methacrylic acid-methyl acrylate copolymer (Eudragit L 100), etc. Acrylic acid copolymers, polyvinyl acetal diethylaminoacetate (AE
A), pullulan, gum arabic, gelatin, polyvinylpyrrolidone, polyvinyl alcohol and the like,
You may use these as a mixture of 2 or more types.

Further, in the present invention, the solid drug usually means a drug substance, but a formulated drug such as powder, fine granule, granule or pill may be used. In the present invention, the mixing ratio of the waxes to the solid drug is 20 parts by weight or more with respect to 100 parts by weight of the solid drug. Further, the mixing ratio of the binder to the solid drug is 1 part by weight or more of the binder with respect to 100 parts by weight of the solid drug.

In the present invention, the term "granulation" refers to a drug having a desired particle size by rolling granulation, stirring granulation, extrusion granulation or fluidized bed granulation (including a stirring type fluidized bed granulation method). This means obtaining particles, and the granulation method or the machine used is not particularly limited. The heat treatment using the fluidized bed apparatus in the present invention means that the above-mentioned granulated granules and the like are heated in the fluidized bed to a temperature not lower than the melting point of the waxes to be used and fluidized. Further, usually, after the heat treatment, it is cooled while flowing. In the present invention, when a fluidized bed apparatus is used at the time of granulation, it is most preferable to use the apparatus because heat treatment after granulation can be consistently produced using the same apparatus.

[0012]

According to the present invention, a wax-treated product of fine powder particles such as drug substance, powder, fine particles and granules can be easily obtained without fusion of particles during heat treatment. Can be done. Therefore, it becomes possible to easily manufacture the above-mentioned drug with bitterness masking and dissolution control.
Further, since the surface of the treatment chemicals obtained by the present invention is smoothed by the wax treatment, when a coating layer such as a coating is further required, a sufficient coating effect can be obtained with a small coating amount.

[0013]

The present invention will be described below in more detail with reference to examples, but the present invention is not limited to these examples. In addition,
In the examples, parts and% mean parts by weight and% by weight, respectively. Example 1 <Preparation of Granulated Body> 100 parts of cimetidine (manufactured by Ichikawa Chemical Laboratory Co., Ltd.), hydrogenated oil (lovely wax 102H, manufactured by Freund Sangyo Co., Ltd., product name) 100 parts, hydrous silicon dioxide (Sylysia, 20 parts of Fuji Davison Co., Ltd., trade name) were mixed using a stirrer mixer, and 30 parts of hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd., trade name) was added to this powder mixture with water. Fluidized bed granulation dryer (FLO-
1. Granulation using Freund Industrial Co., Ltd., trade name,
Dried. <Wax Treatment> 250 g of this granulated product was subsequently heat-treated using a fluidized bed granulation drying device. The operating conditions are a flowing air temperature of 95 ° C, until the exhaust temperature reaches 45 ° C,
Heated and fluidized

Comparative Example 1 <Wax Treatment> 100 parts of cimetidine, 100 parts of hardened oil (lovely wax 102H), and 20 parts of hydrous silicon dioxide (Sylysia) were mixed using a stirrer mixer, and 230 g of the powder mixture was flowed. Heat treatment was performed using a layer granulation dryer. The operating conditions were a flowing air temperature of 95 ° C., and a heating and flowing treatment was performed until the exhaust temperature reached 45 ° C. <Result 1> The wax-coated chemicals obtained in Example 1 and Comparative Example 1 were observed with a microscope. In Example 1, there was almost no difference in particle size between the granulated product and the wax-treated product, but in Comparative Example 1, the powder after heat treatment had a significantly large particle size.

Example 2 <Preparation of granules> 100 parts of ticlopidine hydrochloride (manufactured by WIC Co., Ltd.), stearic acid (manufactured by Kao Corporation) 1
50 parts and 20 parts of hydrous silicon dioxide (Sylysia) were mixed using a stirring mixer, and the powder mixture was dissolved in 30 parts of hydroxypropylmethyl cellulose (TC5-RW, trade name of Shin-Etsu Chemical Co., Ltd.) in water. While adding the aqueous binder solution, the mixture was granulated and dried using a fluidized bed granulation dryer. <Wax Treatment> 250 g of this granulated product was subsequently heat-treated using a fluidized bed granulation drying device. The operating conditions were a flowing air temperature of 95 ° C., and a heating and flowing treatment was performed until the exhaust temperature reached 45 ° C.

Comparative Example 2 <Wax Treatment> 100 parts of ticlopidine hydrochloride, 150 parts of stearic acid, and 20 parts of hydrous silicon dioxide (Sylysia) were mixed using a stirrer mixer, and 270 g of the powder mixture.
Was heat-treated using a fluidized bed granulation dryer. The operating conditions were a flowing air temperature of 95 ° C., and a heating and flowing treatment was performed until the exhaust temperature reached 45 ° C. <Result 2> The wax-coated chemicals obtained in Example 2 and Comparative Example 2 were observed with a microscope. In Example 2, there was almost no difference in particle size between the granulated product and the wax-treated product, but in Comparative Example 2, the powder after heat treatment had a significantly large particle size.

Example 3 <Preparation of Granulated Body> 100 parts of trimeptin maleate (manufactured by Sumika Finechem Co., Ltd.) and 20 parts of hydrogenated oil (Lovely Wax 102H) were mixed using a stirrer mixer, and the powder was obtained. The body mixture was granulated and dried using a fluidized bed granulation dryer while adding an aqueous binder solution in which 20 parts of methyl cellulose (Metroze, manufactured by Shin-Etsu Chemical Co., Ltd.) was added to water. <Wax Treatment> 250 g of the above-mentioned granulated material was subsequently heat-treated using a fluidized bed granulation drying device. The operating conditions are a flowing air temperature of 95 ° C, until the exhaust temperature reaches 45 ° C,
A heat fluidization process was performed.

Comparative Example 3 <Wax Treatment> 100 parts of trimeptin maleate and 20 parts of hardened oil (lovely wax 102H) were mixed using a stirrer mixer, and 240 g of the powder mixture was used in a fluidized bed granulation drying device. Heat treatment was performed. The operating conditions were a flowing air temperature of 95 ° C., and a heating and flowing treatment was performed until the exhaust temperature reached 45 ° C. <Result 3> The wax-coated chemicals obtained in Example 3 and Comparative Example 3 were observed under a microscope. In Example 3, there was almost no difference in particle size between the granulated product and the wax-treated product, but in Comparative Example 3, the powder after heat treatment had a significantly large particle size.

Example 4 <Preparation of Granulated Body> 100 parts of ticlopidine hydrochloride (manufactured by YIC Co., Ltd.), hardened oil (lovely wax 102)
H) 60 parts, Macrogol 6000 (NOF Corporation)
Made, trade name) 40 parts, hydrous silicon dioxide (Sylysia)
20 parts were mixed using a stirrer mixer, and the powder mixture was granulated using a fluidized bed granulation dryer while adding a binder aqueous solution in which 30 parts of hydroxypropyl cellulose (HPC-L) was dissolved in water. Granules, dried. <Wax Treatment> 250 g of the above-mentioned granules were subsequently heat-treated using a fluidized bed granulation dryer. The operating conditions are a flowing air temperature of 95 ° C, until the exhaust temperature reaches 45 ° C,
A heat fluidization process was performed.

Comparative Example 4 <Wax treatment> 100 parts of ticlopidine hydrochloride, 60 parts of hydrogenated oil (lovely wax 102H), macrogol 6
000 40 parts, hydrous silicon dioxide (Sylysia) 20
Parts were mixed using a stirrer mixer, and the powder mixture 220
g was heat-treated using a fluidized bed granulation dryer. The operating conditions were a flowing air temperature of 95 ° C., and a heating and flowing treatment was performed until the exhaust temperature reached 45 ° C. <Result 4> The wax-coated chemicals obtained in Example 4 and Comparative Example 4 were microscopically observed. In Example 4, there was almost no difference in particle size between the granulated product and the wax-treated product, but in Comparative Example 4, the powder after heat treatment had a significantly large particle size.

Example 5 <Preparation of Granulated Body> 100 parts of ticlopidine hydrochloride (manufactured by WIC Co., Ltd.), hardened oil (lovely wax 102)
H) 100 parts and hydrous silicon dioxide (Sylysia) 20 parts were mixed using a stirrer mixer, and the powder mixture was added with a binder aqueous solution obtained by dissolving 30 parts of hydroxypropyl cellulose (HPC-L) in water. Meanwhile, granulation and drying were performed using a fluidized bed granulating and drying device, and a portion of JP-sieve No. 30 to No. 150 was sieved to obtain a fine granule. <Wax Treatment> 250 g of the above-mentioned fine granules were subsequently heat-treated using a fluidized bed granulation dryer. The operating conditions were a flowing air temperature of 95 ° C., and a heating and flowing treatment was performed until the exhaust temperature reached 45 ° C.

Comparative Example 5 <Wax Treatment> 100 parts of ticlopidine hydrochloride, 100 parts of hardened oil (lovely wax 102H), and 20 parts of hydrous silicon dioxide (Sylysia) were mixed using a stirrer mixer to obtain 220 g of the powder mixture. Heat treatment was performed using a fluidized bed granulation dryer. The operating conditions are flowing air temperature 95 ℃,
The heating and fluidizing treatment was performed until the exhaust temperature reached 45 ° C. <Result 5> The wax-coated chemicals obtained in Example 5 and Comparative Example 5 were observed with a microscope. In Example 5, when the heat treatment was not performed, there was almost no difference in particle size from the wax-treated product, but in Comparative Example 5, the powder after heat treatment had a significantly large particle size.

[0023]

[Brief description of drawings]

FIG. 1 is a drawing-substitute photograph showing a grain structure. FIG. 1a is a diagram showing a mixed powder, a granulated powder, and a heat-treated product (present invention) according to the first embodiment. FIG. 1b shows the mixed powder and the heat-treated product according to Comparative Example 1.

FIG. 2 is a drawing-substituting photograph showing a grain structure. FIG. 2a is a diagram showing a mixed powder, a granulated powder, and a heat-treated product (present invention) according to the second embodiment. FIG. 2b shows the mixed powder and the heat-treated product according to Comparative Example 2.

FIG. 3 is a drawing-substitute photograph showing a grain structure. FIG. 3a is a diagram showing a mixed powder, a granulated powder, and a heat-treated product (present invention) according to the third embodiment. FIG. 3b shows the mixed powder and the heat-treated product according to Comparative Example 3.

FIG. 4 is a drawing-substituting photograph showing a grain structure. FIG. 4a is a diagram showing a mixed powder, a granulated powder, and a heat-treated product (present invention) according to Example 4. FIG. 4b shows the mixed powder and the heat-treated product according to Comparative Example 4.

FIG. 5 is a drawing-substitute photograph showing a grain structure. FIG. 5a is a diagram showing a mixed powder, a granulated powder, and a heat-treated product (present invention) according to the fifth embodiment. FIG. 5b shows the mixed powder and the heat-treated product according to Comparative Example 5.

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Claims (6)

[Claims] 1. A method for producing a solid preparation, which comprises heat-treating using a fluidized bed apparatus after granulating a solid drug, a wax and a binder as essential components. 2. The wax is one or more waxes selected from paraffins, beeswax, higher alcohols, higher fatty acids, higher fatty acid esters, glycerin fatty acid esters, and polyethylene glycols. The method for producing a solid drug according to claim 1. 3. The binder is one or more binders selected from cellulose derivatives, copolymers of methacrylic acid, polyvinyl acetal diethylaminoacetate, pullulan, gum arabic, gelatin, polyvinylpyrrolidone and polyvinyl alcohol. The method for producing a solid drug according to claim 1. 4. The method for producing a solid drug according to claim 1, wherein the wax is a wax having a melting point of 40 to 90 ° C. 5. The method for producing a solid preparation according to claim 1, wherein 20 parts by weight or more of waxes are mixed with 100 parts by weight of the solid drug. 6. The binder is blended in an amount of 1 part by weight or more with respect to 100 parts by weight of the solid drug.
Method for producing solid preparation described