JP2007191419A - Pimobendan preparation for oral administration - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pimobendan preparation for oral administration which excels in dissolution properties and can obtain high blood concentration. <P>SOLUTION: The pimobendan preparation for oral administration comprises (A) pimobendan, (B) fumaric acid, and (C) polyoxyethylene (105) polyoxypropylene (5) glycol, and its manufacturing method is disclosed. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a preparation for oral administration of pimobendan having excellent dissolution properties and a method for producing the same.

Pimobendan [(±) -4,5-dihydro-6- [2- (p-methoxyphenyl) -5-benzimidazolyl] -5-methyl-3 (2H) -pyridazinone] enhances myocardial Ca ²⁺ sensitivity Since it has a PDE-III activity inhibitory action, it has a positive inotropic action and a vasodilatory action, and is widely used as a therapeutic agent for acute heart failure or chronic heart failure. However, in developing a drug product, this compound is extremely difficult to dissolve in water, particularly in the pH range near neutrality, so that there is a problem that the dissolution from the drug product is poor and sufficient blood concentration cannot be obtained. there were.

  In general, as a method for improving the dissolution property of a poorly water-soluble drug, (a) a method of obtaining fine drug particles by a pulverization method, a spray drying method, or the like (see Patent Document 1), and (b) heating a drug and a polymer compound A method of obtaining a solid solution by dissolution (see Patent Document 2), (c) a method of dissolving a drug and a polymer compound in an organic solvent and then distilling off the solvent to obtain a solid dispersion (see Patent Document 3), (d ) A method of blending an acidic substance or an alkaline substance with a drug whose pH depends on pH (see Patent Document 4), (e) A method of increasing the solubility of a drug by blending a surfactant (Patent Document 5, 6) and the like are known.

  However, the method (a) requires special equipment and complicated steps in production, and although the method (b) is simple, the applicable drug is a stable drug even when heated and melted with a polymer. It is limited and cannot be applied to drugs in general, and the method (c) uses an organic solvent, which may cause problems in terms of environmental protection, worker safety, residual solvent, and the drug can easily be used as an organic solvent. It cannot be applied when forming Japanese products. Also, many of the surfactants having solubilizing properties used for the method (e) are liquid or semi-solid. These types of solubilizers are generally utilized for filling hard and soft gelatin capsules and for use in solutions for intravenous and oral administration.

As a method for improving the dissolution property of pimobendan, Patent Document 4 of the method (d) discloses a method of adding citric acid to pimobendan. However, since this method requires a large amount of citric acid, the resulting preparation has high hygroscopicity and lacks storage stability. In addition, citric acid has poor compression moldability and fluidity, so it cannot be made into a tablet containing a sufficient amount of citric acid to bring out the dissolution property of pimobendan, and the dosage form of a commercial preparation is limited to capsules. ing. Therefore, an oral administration formulation of pimobendan that has sufficient dissolution properties and can be tableted and is not limited to a specific dosage form has been desired.
Japanese Patent Application Laid-Open No. 7-075616 Japanese Patent Laid-Open No. 9-208459 Japanese Patent Publication No. 3-028404 Japanese Patent No. 2608183 International Publication No. 95/01785 Pamphlet JP 2000-7484 A

  An object of the present invention is to provide an oral administration preparation of pimobendan which is excellent in dissolution and can obtain a high blood concentration.

  As a result of various investigations on pimobendan orally administered preparations that improve the poor solubility of pimobendan and show excellent dissolution properties particularly in the pH range near neutrality, the present inventors have found that pimobendan contains fumaric acid and polyoxyethylene (105). It has been found that by containing polyoxypropylene (5) glycol, it is possible to obtain a pimobendan oral administration preparation with excellent dissolution properties. And as a result of further examination, if pimobendan, fumaric acid and polyoxyethylene (105) polyoxypropylene (5) glycol are granulated by a wet granulation method, if this is tableted, particularly excellent dissolution properties are exhibited. As a result, the present invention has been completed.

That is, the present invention provides a pimobendan oral administration preparation comprising (A) pimobendan, (B) fumaric acid, and (C) polyoxyethylene (105) polyoxypropylene (5) glycol. is there.
Further, the present invention is characterized in that (A) pimobendan, (B) fumaric acid, and (C) polyoxyethylene (105) polyoxypropylene (5) glycol are mixed and then tableted by a direct tableting method. A method for producing a pimobendan oral administration preparation is provided.
Further, the present invention granulates a mixture containing (A) pimobendan, (B) fumaric acid, and (C) polyoxyethylene (105) polyoxypropylene (5) glycol, and then strikes the granulated product. The present invention provides a method for producing a preparation for oral administration of pimobendan characterized by being tableted.

  According to the present invention, a preparation containing pimobendan and having excellent dissolution properties can be obtained. Moreover, the formulation of this invention is not limited to a capsule, It can formulate various dosage forms, such as a tablet. Furthermore, the preparation of the present invention is excellent in storage stability.

(A) Pimobendan used in the present invention can be produced, for example, according to the method described in Japanese Patent Publication No. 63-24996. The obtained powdered pimobendan can be used as it is for the production of the medicament of the present invention. Moreover, you may grind | pulverize using a ball mill etc., and may use it as a granule by methods, such as a dry granulation method.
The amount of pimobendan is an amount that exhibits a desired medicinal effect, and is usually 0.1 to 20% by mass, preferably 0.5 to 10% by mass, and further 1 to 3% by mass with respect to the total mass of the preparation. It is a range.

  As fumaric acid used in the present invention, those usually used as an antioxidant and a colorant for liquids, or an acid component for effervescent tablets can be used, and are not particularly limited.

The content of fumaric acid in the preparation of the present invention is preferably 0.35 to 15 times in terms of mass ratio with respect to pimobendan, and more preferably 0.5 to 15 times from the viewpoint of dissolution and compression moldability. The range is 15 times, particularly preferably 0.5 to 10 times.
In the preparation of the present invention, organic acids other than fumaric acid, for example, succinic acid, tartaric acid, malic acid, ascorbic acid, aspartic acid and the like can be appropriately blended. However, the total amount of fumaric acid and other organic acids is preferably 20 parts by mass or less with respect to 1 part by mass of pimobendan from the viewpoints of elution and compression moldability.

  The polyoxyethylene (105) polyoxypropylene (5) glycol used in the present invention is mainly used for applications such as a plasticizer, and as a commercial product, PEP-101 (manufactured by Freund Sangyo Co., Ltd.), etc. Is mentioned.

  The content of polyoxyethylene (105) polyoxypropylene (5) glycol in the preparation of the present invention is 0.1 to 10 times in terms of mass ratio with respect to pimobendan from the viewpoint of dissolution and compression moldability. It is particularly preferable that the range is 2 to 6 times.

  The preparation of the present invention quickly elutes pimobendan in the pH range near neutrality, as shown in Examples below.

  Examples of the preparation of the present invention include tablets, powders, fine granules, granules, capsules and the like, and tablets are particularly preferable. These preparations can be produced by known methods.

In the present invention, when producing a tablet, even if it is produced by a direct tableting method, it may be a tablet after granulation using a dry granulation method, a wet granulation method, etc., but from the viewpoint of dissolution properties, It is preferable to form a tablet after granulation, and it is particularly preferable to granulate by a wet granulation method and then to tablet the granulated product into a tablet.
In the case of producing tablets by the direct tableting method, as a tableting machine, those usually used such as a rotary tableting machine and a single-shot tableting machine can be used. Moreover, when using a lubricant, an external lubricant type tableting machine may be used. When tableting after granulation by wet granulation method, extrusion granulation method using cylindrical granulator, spherical granulator, pelleter, etc .; crushing granulation method using speed mill, power mill, etc .; rolling After a granulated product is produced by a granulation method, agitation granulation method, a fluidized bed granulation method, etc., dried and sized, the obtained granulated product can be compressed by a tableting machine to form a tablet. The particle diameter of the granulated product is preferably 45 μm to 850 μm, particularly preferably 100 μm to 500 μm.
The shape of the tablet obtained in the present invention may be a round tablet or various irregular tablets having a surface shape such as an oval, an oval, or a quadrangle. The tablet may be a split tablet with a score line, and may be coated with sugar coating, film coating or the like.

  In order to prepare pharmaceutical preparations of such various dosage forms, other pharmaceutically acceptable excipients, disintegrants, binders, lubricants, fragrances, colorants, sweeteners, coating agents, etc. The carrier to be added can be added as desired. For example, excipients such as lactose, sucrose, mannitol, xylitol, erythritol, sorbitol, maltitol, calcium citrate, calcium phosphate, crystalline cellulose, magnesium metasilicate aluminate; corn starch, potato starch, sodium carboxymethyl starch, partial alpha Disintegrating agents such as modified starch, carmellose calcium, carmellose, low-substituted hydroxypropylcellulose, crosslinked carmellose sodium, crosslinked polyvinylpyrrolidone; hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, dextrin, pregelatinized starch, etc. Binder: magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, Lubricants such as hydrous silicon dioxide; phospholipid, glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, sucrose fatty acid ester , Surfactants such as sodium lauryl sulfate, polyoxyethylene polyoxypropylene glycol; fragrances such as orange oil, fennel oil, cinnamon oil, clove oil, turpentine oil, peppermint oil, eucalyptus oil; edible red No. 2, No. 3, Edible yellow No. 4, No. 5, Edible green No. 3, Edible blue No. 1, No. 2, these aluminum lakes, ferric oxides, yellow ferric oxides, etc .; sweeteners such as saccharin, aspartame; cyclodextrins, Arginine, lysine, trisamino Solubilizing agents such as sorbitan; hydroxypropylmethylcellulose, coating agents such as amino acrylic copolymer E and the like.

  The dosage of the preparation of the present invention varies depending on the body weight, age, sex, symptoms, etc. of the patient, but as pimobendan, usually 0.5 to 10 mg per day, preferably 1.25 to 5 mg is used for adults. It is preferable to administer divided doses.

EXAMPLES Next, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these at all.
(material)
Pimobendan used was prepared according to the method described in Japanese Patent Publication No. 63-24996. The following other raw materials were used.
Polyoxyethylene (105) Polyoxypropylene (5) Glycol: PEP-101, Freund Sangyo Co., Ltd.
Polyethylene glycol (macrogol) 400: Wako Pure Chemical Industries, Ltd.
Sodium lauryl sulfate: NIKKOL, Nikko Chemicals Corporation
Sucrose fatty acid ester: Ryoto sugar ester S-1170F, Mitsubishi Chemical Corporation
Glycerol monostearate: Riken Vitamin Co., Ltd.
Polysorbate 80: NOABLE ESO-8520, NOF Corporation
Alginic acid, fumaric acid, succinic acid, tartaric acid, citric acid: Wako Pure Chemical Industries, Ltd.

Examples 1-3 and Comparative Examples 1-3
Each component shown in Table 1 (excluding the lubricant) is mixed in a mortar, and further mixed with a lubricant to obtain a tableting powder, using a single-type tableting machine (manufactured by Kikusui Seisakusho). Then, the compression force was adjusted so that the tablet hardness was about 7 kgf or more, and a tablet having a diameter of 8.5 mm and a mass of 250 mg was obtained. The organic acid and the surfactant used were sieved with a 200 mesh (75 μm aperture) sieve.

Examples 4-6 and Comparative Examples 4-10
After mixing lactose and carmellose in a mortar, a binding solution prepared by dissolving or dispersing pimobendan, surfactant, organic acid and light silicic anhydride in ethanol is added, and a high-speed stirring granulator (Fukae Powtech Co., Ltd.) Granulated by the company). After granulation, it is dried using a shelf dryer (manufactured by Tabai Co., Ltd.), and 500
The particle size was adjusted using a sieve having an opening of μm to obtain pimobendan granules. This granule was mixed with crystalline cellulose, low-substituted hydroxypropylcellulose, light anhydrous silicic acid, and magnesium stearate, and then tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.), diameter 8 mm, mass 220 mg of the tablet having the composition shown in Table 2 was obtained.

Test Example 1 Dissolution test The tablets obtained in Examples 1 to 6 and Comparative Examples 1 to 10 were subjected to a dissolution test. The dissolution test was conducted in accordance with the 14th revised Japanese Pharmacopoeia General Test Method and Dissolution Test Method 2 (Paddle Method). Each tablet was put into 900 mL of a test liquid (Japanese disintegration test second liquid), and a dissolution test was performed under the conditions of 37 ± 0.5 ° C. and paddle rotation speed 50 rpm. For each test sample, pimobendan eluted in the test solution after 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes was measured by a high performance liquid chromatograph (HPLC) method (measurement wavelength 250 nm), and each tablet The dissolution rate (%) relative to the content of pimobendan was calculated. The results are shown in Tables 1 and 2.
As a result, all of the preparations of Examples 1 to 6 were preparations containing organic acids other than fumaric acid (Comparative Examples 7 to 10) and surfactants other than polyoxyethylene (105) polyoxypropylene (5) glycol. Compared with the preparations containing (Comparative Examples 1 to 6), elution was very quick. In addition, since the preparations of Examples 4 to 6 show rapid elution particularly in 15 minutes, it is clear that tableting is preferable after granulation by the wet granulation method for the preparation of the present invention. became.

Test Example 2 Storage Stability Test The preparation of Example 4 was stored in an aerated state for 1 month at a temperature of 60 ° C. and a relative humidity of 75%, and then the dissolution test of Test Example 1 was performed. As a result, the formulation of Example 4 did not change in appearance or content of pimobendan, which is a medicinal ingredient, and the dissolution rate of pimobendan was 85% or more at 15 minutes after the start of the test in the dissolution test, showing almost no change. There wasn't.

Example 7
Macrogol 6000 (manufactured by NOF Corporation) and hydroxypropylmethylcellulose 2910 (TC-5MW, Shin-Etsu Chemical Co., Ltd.) are dissolved in water, and then titanium oxide, yellow ferric oxide and light anhydrous silicic acid are dispersed. The coating liquid was adjusted so that the ratio of the solid component at the time of drying was as shown in Table 3 below. This coating solution was sprayed onto the tablet obtained in Example 4 using a film coating apparatus (manufactured by POWREC) and then dried at an intake air temperature of 45 ° C. to obtain a film coating agent having a weight of 230 mg.

Test example 3
About the formulation of Example 7, when the dissolution test was implemented like Test Example 1, the rapid dissolution property was shown similarly to the tablet of Examples 1-6.

Claims (10)

  A preparation for oral administration of pimobendan, comprising (A) pimobendan, (B) fumaric acid, and (C) polyoxyethylene (105) polyoxypropylene (5) glycol.   The content of fumaric acid is 0.35 to 15 parts by mass with respect to 1 part by mass of pimobendan. However, the total amount of fumaric acid and organic acids other than fumaric acid is 20 parts by mass or less, and polyoxyethylene ( 105) The preparation for oral administration of pimobendan according to claim 1, wherein the content of polyoxypropylene (5) glycol is 0.1 to 10 parts by mass with respect to 1 part by mass of pimobendan.   The preparation for oral administration of pimobendan according to claim 1 or 2, which is a tablet.   It was obtained by directly compressing a mixture containing (A) pimobendan, (B) fumaric acid, and (C) polyoxyethylene (105) polyoxypropylene (5) glycol, or granulating the mixture. The pimobendan oral administration preparation according to claim 3, which is obtained by tableting the granulated product.   The content of fumaric acid is 0.35 to 15 parts by mass with respect to 1 part by mass of pimobendan. However, the total amount of fumaric acid and organic acids other than fumaric acid is 20 parts by mass or less, and polyoxyethylene ( 105) The pimobendan according to claim 3, which is obtained by directly tableting a mixture having a polyoxypropylene (5) glycol content of 0.1 to 10 parts by mass with respect to 1 part by mass of pimobendan. Oral administration formulation.   The content of fumaric acid is 0.35 to 15 parts by mass with respect to 1 part by mass of pimobendan. However, the total amount of fumaric acid and organic acids other than fumaric acid is 20 parts by mass or less, and polyoxyethylene ( 105) It is obtained by tableting a granulated product obtained by granulating a mixture having a polyoxypropylene (5) glycol content of 0.1 to 10 parts by mass with respect to 1 part by mass of pimobendan. The preparation for oral administration of pimobendan according to claim 3, wherein the preparation is orally administered.   (A) Pimobendan, (B) fumaric acid, and (C) polyoxyethylene (105) polyoxypropylene (5) glycol are mixed, and then tableted by the direct tableting method, orally administered pimobendan Manufacturing method.   The content of fumaric acid is 0.35 to 15 parts by mass with respect to 1 part by mass of pimobendan. However, the total amount of fumaric acid and organic acids other than fumaric acid is 20 parts by mass or less, and polyoxyethylene ( 105) The method for producing an orally administered pimobendan preparation according to claim 7, wherein the content of the polyoxypropylene (5) glycol is 0.1 to 10 parts by mass with respect to 1 part by mass of pimobendan.   It is characterized by granulating a mixture containing (A) pimobendan, (B) fumaric acid, and (C) polyoxyethylene (105) polyoxypropylene (5) glycol, and then tableting the granulated product. A method for producing an oral dosage form of pimobendan.   The content of fumaric acid is 0.35 to 15 parts by mass with respect to 1 part by mass of pimobendan. However, the total amount of fumaric acid and organic acids other than fumaric acid is 20 parts by mass or less, and polyoxyethylene ( 105) The method for producing a preparation for oral administration of pimobendan according to claim 9, wherein the content of polyoxypropylene (5) glycol is 0.1 to 10 parts by mass with respect to 1 part by mass of pimobendan.