JP2005272347A - Method for producing solid preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for industrially advantageously producing a solid preparation that sustainably releasing a medicament. <P>SOLUTION: The method for producing the solid preparation comprises the following three consecutive steps: The step 1 comprises mixing and agitating together the medicament, a saccharide, a cellulose derivative and a lubricant, and concurrently, adding a mixed liquid of a methacrylic acid copolymer L, triethyl citrate and water to the system to carrying out a granulation. The step 2 comprises forming a fluidized bed of the resultant granulated product and adding to the fluidized bed a mixed liquid of a methacrylic acid copolymer L, triethyl citrate, glycerol monostearate, polysorbate-80 and water to coat the granulated product with a 1st coating film. The step 3 comprises forming a fluidized bed of the resultant coated granulated product and adding to the fluidized bed a mixed liquid of ethyl cellulose, glycerol monostearate and water to coat the coated granulated product with a 2nd coating film. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

The present invention relates to a method for producing a solid preparation that continuously releases a drug.

Various sustained-release preparations that release a drug continuously have been proposed. Among them, a method for controlling the release of a drug by coating a small particle core containing the drug with a water-soluble or enteric base material has been known for a long time, and various improvements and devices have been added until recently. It has been.
JP-A-7-330606

In addition, a formulation that releases a drug continuously without applying a continuous film has also been proposed. For example, each unit preparation is dissolved in one or more selected from acrylic acid polymers, copolymers, and cellulose derivatives in a mixture of a physiologically active substance and crystalline cellulose in a weight ratio of 50% or more. A sustained-release composite unit preparation comprising a granular material obtained by granulating with a control agent is disclosed.
However, when manufacturing a sustained-release preparation industrially by this method, it is difficult to manage the preparation conditions for making the drug release pattern constant.
Japanese Examined Patent Publication No. 7-72129

  An object of the present invention is to provide a method for industrially producing a solid preparation that continuously releases a drug.

  The present invention includes a step of granulating by adding a mixed solution of methacrylic acid copolymer L, triethyl citrate and water while mixing and stirring a drug, a saccharide, a cellulose derivative and a lubricant, and the granulated product obtained in the step A coating layer obtained by adding a mixed solution of methacrylic acid copolymer L, triethyl citrate, glyceryl monostearate, polysorbate-80 and water to the first film, and the coating obtained in the previous step The present invention relates to a method for producing a solid preparation comprising a step of forming a fluidized bed of a post-granulated product, and adding a mixed solution of ethyl cellulose, glyceryl monostearate and water to coat a second film.

  In the present invention, by using sugar and a cellulose derivative as excipients and using ethyl cellulose and glyceryl monostearate as a base material for the second film, the elution time of the drug in a thin film, more precisely, coating with the first film The elution time of the granulated product can be effectively extended. Moreover, by using enteric methacrylic acid copolymer L as the base material of the first film, the drug is released in the intestinal tract and efficiently absorbed.

The drug applied to the present invention is not particularly limited, but includes a drug having a long-lasting effect, for example, an α ₁ -blocker such as tamsulosin hydrochloride, a Ca antagonist such as nicardipine hydrochloride, and the like.

  Examples of the saccharide used in the present invention include lactose, corn starch, potato starch, sucrose, sucrose, and glucose. Among them, lactose is preferable. The amount of saccharide used is preferably 30 to 50% of the total weight of the preparation. Examples of the cellulose derivative include crystalline cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and the like. Among these, crystalline cellulose is preferable. The amount of cellulose used varies depending on the type, but is generally preferably in the range of 30 to 50% of the total weight of the preparation. For example, in the case of crystalline cellulose, about 30 to 40% is preferable. The lubricant used in the granulation step is not particularly limited, and examples thereof include talc and magnesium stearate.

In the present invention, the step of granulating the drug and the powder composition comprising the substrate and the step of coating the granulated product with the first film substrate and the second film substrate are not particularly difficult, and are known methods. According to. Moreover, the usage-amount of each base material (solid component) can adjust the release | release time of a drug, for example by adjusting suitably within the range of 1-20% of the formulation total weight.
The coated granulated product produced as described above may be filled into a capsule to form a capsule, or may be compressed into a tablet.

(1) Granulation Eudragit L30-55 (methacrylic acid copolymer L water dispersion sold by Higuchi Shokai) 396 g (solid content 119 g) and triethyl citrate 10 g were added to 860 ml of water and sufficiently stirred to prepare a uniform dispersion. .
Next, 3 g of tamsulosin hydrochloride, 1085 g of lactose, 840 g of crystalline cellulose, and 57 g of talc were put into a high-speed agitation granulator, granulated by adding 1266 g of the previously prepared dispersion, granulated after drying.

(2) Coating of the first film Eudragit L30D-55 (methacrylic acid copolymer L aqueous dispersion sold by Higuchi Shokai) (solid content 180 g), triethyl citrate 20.5 g, polysorbate 80 1.5 g and glyceryl monostearate 4 g Was added to 400 ml of water and sufficiently stirred to prepare a uniform dispersion.
Next, 2114 g of the granulated product produced in the above (1) was put into a fluidized bed granulator, spray-coated with 1026 g of the previously prepared dispersion, and dried.

(3) Coating of the second film Aqua coat (ethylcellulose aqueous dispersion sold by Asahi Kasei Co., Ltd.) 350 g (solid content 105 g) and glyceryl monostearate 35 g were added to 315 ml of water and sufficiently stirred to prepare a uniform liquid.
Next, 2320 g of the first film coating granulated product produced in the above (2) was put into a fluidized bed granulator, spray-coated with 700 g of the previously prepared dispersion, and dried.

(4) Capsule filling The No. 4 hard capsule was filled with the second film-coated granulated product produced in (3) above (filling amount of 164 mg of the second film-coated granulated product per capsule, 0.2 mg of tamsulosin hydrochloride content) ).

[Comparative Example 1] The granulated product produced as described in Example 1 (1) was filled into No. 4 hard capsules (filled amount of granulated product per capsule: 141 mg, tamsulosin hydrochloride content: 0.2 mg) .

[Comparative Example 2] Granules produced as described in Example 1 (1) and (2) were filled into No. 4 hard capsules (filling amount of first film coating granulated product per capsule 155 mg) , Tamsulosin hydrochloride content 0.2 mg).

[Comparative Example 3] A granulated product produced as described in Example 1 (1) was coated with a continuous film by the method described in Example (3) (same substrate, amount used and operation), After drying, the granulated product was filled into No. 4 hard capsules (filling amount of the second film coating granulated product per capsule 150 mg, tamsulosin hydrochloride content 0.2 mg).

[Test Example 1] Each capsule of Example 1, Comparative Example 1, Comparative Example 2, and Comparative Example 3 in accordance with the General Test Method / Dissolution Test Method Second Method (Paddle Method) described in the 14th revised Japanese Pharmacopoeia About the agent, the elution of tamsulosin with respect to each of the first liquid (pH 1.2) and the second liquid (pH 6.8) was examined. As a result (FIGS. 1 and 2), it was confirmed that the capsule of Example 1 sustained elution of tamsulosin in the second liquid. From this, the sustained release of the drug in the intestinal tract is estimated for the solid preparation produced by the method of the present invention.

  According to the present invention, since a specially difficult operation is not required for drug persistence, the sustained-release preparation can be produced industrially.

The graph which shows the elution behavior of the granulated material with which each capsule of Example 1, the comparative example 1, the comparative example 2, and the comparative example 3 in the 1st liquid was filled. The graph which shows the elution behavior of the granulated material with which each capsule of Example 1, the comparative example 1, the comparative example 2, and the comparative example 3 in the 2nd liquid was filled.

Claims (1)

  While mixing and stirring the drug, saccharide, cellulose derivative and lubricant, adding a mixture of methacrylic acid copolymer L, triethyl citrate and water and granulating the fluidized bed of the granulated product obtained in the previous step Forming and coating a first film by adding a mixture of methacrylic acid copolymer L, triethyl citrate, glyceryl monostearate, polysorbate-80 and water to this, and a granulated product after coating obtained in the previous step A solid preparation comprising a step of coating a second film by adding a mixed liquid of ethyl cellulose, glyceryl monostearate and water to the fluidized bed.

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