JP4572293B2 - Pimobendan oral dosage formulation - Google Patents

Description

  The present invention relates to a preparation for oral administration of pimobendan having excellent dissolution properties.

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 prophylactic and therapeutic drug 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 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 mixed with an organic solvent. It cannot be applied when forming Japanese products. In addition, 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 property and provides a high blood concentration.

  As a result of various investigations on pimobendan oral administration 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 and polyoxyethylene (105) polyoxypropylene ( 5) It was found that by containing glycol, a pimobendan oral administration preparation excellent in dissolution property can be obtained, and the present invention has been completed.

  That is, the present invention provides a pimobendan oral administration preparation characterized by containing pimobendan and polyoxyethylene (105) polyoxypropylene (5) glycol.

  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.

The 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.
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.

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 the polyoxyethylene (105) polyoxypropylene (5) glycol is preferably 1 to 10 times, particularly preferably 2 to 6 times the mass ratio of pimobendan.

In addition to the above compounds, an organic acid can be further added to the preparation of the present invention. Examples of such an organic acid include fumaric acid, succinic acid, alginic acid, tartaric acid, malic acid, ascorbic acid, aspartic acid and the like, and alginic acid, fumaric acid and succinic acid are particularly preferable. These organic acids can be used alone or in combination of two or more.
The content of the organic acid is preferably 1 to 20 times, particularly preferably 3 to 12 times the mass ratio of pimobendan.

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

Examples of the preparation for oral administration of the present invention include tablets, powders, fine granules, granules, capsules and the like. These preparations can be produced by known methods.
When a tablet is produced, it may be produced by a direct tableting method or may be granulated by using a dry granulation method or the like and then formed into a tablet. Further, it may be coated with sugar coating, film coating or the like. In the case of a film-coated tablet, polyoxyethylene (105) polyoxypropylene (5) glycol may be included in the coating component.
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. 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 can be a split tablet with a score line.

  In addition, in order to prepare such oral dosage forms of various dosage forms, other pharmacological agents such as excipients, disintegrants, binders, lubricants, fragrances, coloring agents, sweetening agents, coating agents, etc. Acceptable carriers 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; perfumes such as orange oil, fennel oil, cinnamon oil, clove oil, turpentine oil, mint oil, eucalyptus oil; food red 2, 3, food yellow 4, 5, food Green No. 3, Edible Blue No. 1, No. 2, these aluminum lakes, iron sesquioxide, yellow sesquioxide, etc .; sweeteners such as saccharin, aspartame; cyclodextrins, arginine, lysine, trisaminomethane, etc. Solubilizing agents; coating agents such as hydroxypropylmethylcellulose, aminoalkyl methacrylate copolymer E and the like.

  The dose of the oral preparation of the present invention varies depending on the patient's body weight, age, sex, symptom and the like, but as pimobendan, usually 0.5 to 10 mg per day, preferably 1.25 to 5 mg is 1 for adults. It is preferable to administer in two 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 surfactants and organic acids were used.
Polyoxyethylene (105) Polyoxypropylene (5) Glycol: PEP-101, Freund Sangyo Co., Ltd.
Sodium lauryl sulfate: NIKKOL, Nippon Chemicals Co., Ltd.
Sucrose fatty acid ester: Ryoto sugar ester S-1170F: Mitsubishi Chemical Corporation
Glycerol monostearate: Riken Vitamin Co., Ltd.
Alginic acid, fumaric acid: Wako Pure Chemical Industries, Ltd.

Examples 1-4 and Comparative Examples 1-3
Each component shown in Table 1 is mixed and slid in a mortar to obtain a tableting powder, and using a single-type tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.), compression force so that the tablet hardness is about 7 kgf or more. Was adjusted to obtain a tablet having a diameter of 8.5 mm and a mass of 250 mg. The organic acid and surfactant used were sieved with a 200 mesh sieve.

Test Example 1 Dissolution Test The tablets obtained in Examples 1 to 4 and Comparative Examples 1 to 3 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, the pimobendan eluted in the test solution after 15 minutes and 60 minutes was measured by a high performance liquid chromatograph (HPLC) method (measurement wavelength 250 nm), and the dissolution rate (%) relative to the pimobendan content in each powder was determined. Calculated. The results are shown in Table 1.
As a result, compared with other surfactants such as sodium lauryl sulfate, sucrose fatty acid ester, glyceryl stearate, polyoxyethylene (105) polyoxypropylene (5) glycol has a remarkable effect of improving the elution rate of pimobendan. It has been found.

Claims (3)

Oral administration of pimobendan characterized by containing pimobendan , polyoxyethylene (105) polyoxypropylene (5) glycol , and fumaric acid, and the organic acid content is 3 to 12 times the mass of pimobendan. Formulation. The content of the polyoxyethylene (105) polyoxypropylene (5) glycol respect pimobendan 1 part by weight, pimobendan oral administration preparation according to claim 1, wherein 1 to 10 parts by weight. The preparation for oral administration of pimobendan according to claim 1 or 2, which is a tablet.