JP2013043834A - Elution improving solid preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a solid preparation, having an improved elution property by a method which is simple in formulating operation for a physiologically active substance having ultrahigh water solubility, forming an adhesive gel layer on the particle surface by contact with water, and delaying disintegration and elution.SOLUTION: There is provided the solid preparation having the improved elution property of the physiologically active substance by including the physiologically active substance extremely readily soluble in water and a water-soluble saccharide or a sugar alcohol.

Description

  The present invention is a preparation containing a physiologically active substance that has extremely high water solubility, forms a sticky gel layer on the particle surface upon contact with water, and disintegrates and dissolves slowly, and its dissolution rate is improved. Relates to a solid formulation.

  Drugs that are extremely soluble in water often exhibit strong tackiness when dissolved, and their properties can greatly affect the disintegration properties when tableted. For example, imatinib (generic name of Japanese pharmaceuticals) or a pharmaceutically acceptable salt thereof, which is very soluble in water, is a gel that adheres to each other due to the adhesion of particles by dissolving the surface of the particles when contacted with water. A film is formed. Because of this property, a large amount of disintegrant is required to ensure dissolution of the tablet.

  As a specific example of the prior art, Patent Document 1 uses lactate, crystalline cellulose, crospovidone using β-form crystals that are highly fluid, less hygroscopic, easy to process, and thermodynamically stable at 140 ° C. or lower. And the like, and a method for producing a tablet by direct compression is disclosed. In Patent Document 2, crospovidone having high disintegration is blended in an amount of 10 to 35% based on the total amount of the tablet, and further, microcrystalline cellulose having a high water absorption is blended, and a method for producing a high drug-filled tablet by wet granulation method is disclosed. It is disclosed. However, when a large amount of highly water-absorbing additives such as crospovidone or microcrystalline cellulose is blended, the tablet surface may become rough when stored in a non-packed state for a long time, and the tablet hardness may be significantly reduced. Therefore, it is insufficient to guarantee the storage stability in the distribution process and storage at the dispensing pharmacy. In Patent Document 3, a composition containing a surface stabilizer such as HPMC, HPC, PVP, etc., using nanoparticulate imatinib mesylate having a particle size of less than 2 μm in order to solve the fluctuation in absorbency during feeding / fasting Is disclosed. Further, Patent Document 4 describes a pharmaceutical formulation that does not transfer to α form and β form using crystal forms of V form and X form different from β form. However, these production methods are not fully satisfactory with respect to changes in tablet properties and stability during long-term storage, and it has been necessary to solve these problems and establish a production method suitable for industrialization.

Japanese Patent No. 3276359 JP 2010-31019 A Special table 2008-542397 gazette Special table 2010-540465 gazette

  An object of the present invention is to dissolve a bioactive substance that has extremely high water solubility and forms a sticky gel layer on the particle surface by contact with water, and that disintegrates and dissolves slowly, by a simple method in formulation operation. Is to provide an improved solid preparation.

  In order to improve the decrease in tablet hardness, imatinib or a pharmaceutically acceptable salt thereof was used to reduce the blending amount of disintegrant and the like to produce tablets. When the dissolution test of the obtained tablet was performed, the tablet gradually swelled but did not disintegrate instantaneously, and therefore it took a long time for the drug to dissolve. This is because imatinib or its pharmaceutically acceptable salt present in the water-absorbed part dissolves and at the same time forms a gel-like film due to its strong adhesiveness, which inhibits the penetration of water into the tablet and releases the drug. It was considered delayed. Based on this finding, the inventors have conducted various studies. As a result, imatinib or a pharmaceutically acceptable salt tablet containing a water-soluble saccharide or sugar alcohol does not cause the above phenomenon. It was found that the dissolution property was ensured, and further improvements were made to complete the present invention.

That is, according to the present invention, the following inventions (1) to (5) can be provided.
(1) A solid preparation with improved dissolution of a physiologically active substance, characterized by containing a physiologically active substance that is extremely soluble in water and a water-soluble saccharide or sugar alcohol.
(2) The solid preparation according to (1), wherein the physiologically active substance is imatinib or a pharmaceutically acceptable salt thereof.
(3) The solid preparation according to (1) or (2), which is an additive capable of dissolving 100 mg or more of water-soluble saccharide or sugar alcohol with respect to 1 g of water.
(4) The solid preparation according to (1) or (3), wherein the water-soluble saccharide or sugar alcohol is contained in an amount of 10 to 50% by weight based on the total weight of the tablet.
(5) The solid preparation according to (1) to (4), which is a film-coated tablet.

  According to the present invention, a water-absorbing additive is not blended in the production of a physiologically active substance that is extremely water-soluble and forms a sticky gel layer on the particle surface upon contact with water and delays disintegration and elution. Thus, it is possible to suppress the gelation of the surface of the physiologically active substance particle and improve the dissolution property by a simple method in terms of formulation operation.

  The water-soluble saccharide or sugar alcohol in the present invention is lactose, trehalose, D-mannitol, sorbitol, xylitol, maltitol, erythritol, reduced palatinose, sucrose, sucrose, glucose, powdered sugar, dextrin, powdered reduced maltose starch syrup, citrus Any acid, sodium citrate, sodium chloride, sodium hydroxide, or the like that dissolves in water can be used, and each can be used alone or in combination. can do. Examples of the binder used in the present invention include hydroxypropyl cellulose, hypromellose, povidone, polyethylene glycol, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, and polyvinyl alcohol graft copolymer. The binder used is mentioned. In addition, as disintegrants, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, crospovidone, partially pregelatinized starch, croscarmellose sodium, etc. The disintegrant used is mentioned. The tablet of the present invention may be provided with a film coating film for the purpose of protecting the exposure of the drug under a normal environment. As a coating agent, hypromellose, titanium oxide, talc, polyethylene glycol and the like are generally used. Coating agents, and colorants may be used for the purpose of discrimination.

Example 1
239 g of imatinib mesylate and 160 g of D-mannitol were put into a fluidized bed granulator (manufactured by Paulek, Inc .: MP-01 type), and a solution obtained by dissolving 6 g of hydroxypropyl cellulose in 114 g of purified water was sprayed and granulated. 202.5 g of the obtained granulated product was taken, 10 g of crospovidone and 1 g of magnesium stearate were blended and tableted to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Imatinib mesylate 119.5
D-mannitol 80.0
Hydroxypropyl cellulose 3.0
Crospovidone 10.0
Magnesium stearate 1.0

Example 2
239 g of imatinib mesylate and 100 g of reduced palatinose were put into a fluidized bed granulator (manufactured by Paulek, Inc .: MP-01 type), and a solution obtained by dissolving 6 g of hypromellose in 114 g of purified water was sprayed and granulated. 172.5 g of the obtained granulated product was taken, 10 g of low-substituted hydroxypropylcellulose and 1 g of magnesium stearate were blended and tableted to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Imatinib mesylate 119.5
Reduced palatinose 50.0
Hypromellose 3.0
Low-substituted hydroxypropylcellulose 6.0
Magnesium stearate 1.0

Example 3
239 g of imatinib mesylate and 240 g of trehalose were put into a fluidized bed granulator (manufactured by Paulek, Inc .: MP-01 type), and a solution obtained by dissolving 6 g of hypromellose in 114 g of purified water was sprayed and granulated. 242.5 g of the obtained granulated product was taken, mixed with 10 g of carmellose calcium and 1 g of magnesium stearate, and tableted to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Imatinib mesylate 119.5
Trehalose 120.0
Hypromellose 3.0
Carmellose calcium 10.0
Magnesium stearate 1.0

Comparative Example 1
239 g of imatinib mesylate was charged into a fluidized bed granulator (manufactured by Paulec Co., Ltd .: MP-01 type), and a solution obtained by dissolving 6 g of hydroxypropylcellulose in 114 g of purified water was sprayed and granulated. 122.5 g of the resulting granulated product was taken, 10 g of low-substituted hydroxypropyl cellulose and 1 g of magnesium stearate were blended and tableted to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Imatinib mesylate 119.5
Hydroxypropyl cellulose 3.0
Low-substituted hydroxypropylcellulose 10.0
Magnesium stearate 1.0

Test example 1
For the tablets obtained in Examples 1 to 3 and Comparative Example 1, the dissolution rate of imatinib was measured by a dissolution test (test solution water, paddle rotation speed 50 rpm), and the results shown in Table 1 were obtained.

From the result of Table 1, it turned out that the tablet of Examples 1-3 which concerns on this invention can improve the elution rate of imatinib very effectively compared with the tablet of the comparative example 1.

Formulation by blending water-soluble saccharides or sugar alcohols in the production of bioactive substances with extremely high water-solubility, forming a sticky gel layer on the particle surface when contacted with water, and disintegration and elution being delayed By a method that is simple in terms of operation, gelation of the surface of the physiologically active substance particle can be suppressed, and a solid preparation with improved dissolution can be provided.

Claims (5)

  A solid preparation with improved dissolution of a physiologically active substance, characterized by containing a physiologically active substance that is extremely soluble in water and a water-soluble saccharide or sugar alcohol.   The solid preparation according to claim 1, wherein the physiologically active substance is imatinib or a pharmaceutically acceptable salt thereof.   The solid preparation according to claim 1 or 2, wherein the water-soluble saccharide or sugar alcohol is an additive capable of dissolving 100 mg or more with respect to 1 g of water.   The solid preparation according to claim 1 or 3, wherein the water-soluble saccharide or sugar alcohol is contained in an amount of 20 to 50% by weight based on the total weight of the tablet. It is a film coating tablet, The solid formulation of Claims 1-4.