JP2006028130A - Pimopendan preparation for oral administration - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pimopendan preparation for oral administration having excellent dissolution property to give high concentration in blood. <P>SOLUTION: The pimopendan preparation for oral administration is produced by compounding a finely powdered composition obtained by mixing and pulverizing pimopendan and one or more bases selected from light anhydrous silicic acid, polyvinylpyrrolidone and D-mannitol. <P>COPYRIGHT: (C)2006,JPO&NCIPI

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 also has a PDE-III activity inhibitory action, it has a positive inotropic action and a vasodilatory action, and is widely used as a preventive 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.

  As a method for improving the dissolution property of pimobendan, a method of adding citric acid to pimobendan is known (see Patent Document 1). However, since this method requires a large amount of citric acid, the resulting preparation has high hygroscopicity and lacks storage stability. Moreover, since citric acid has poor compression moldability and fluidity, 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 is limited to capsules. 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.

  As a solubilization technique for poorly soluble drugs, a mixed pulverization method is known. This method promotes the amorphization of the drug and the dispersion of the amorphous drug in the base by physically mixing and co-grinding a poorly soluble drug and a suitable base. It improves the solubility of soluble drugs. Bases used for mixing and grinding include water-soluble polymers such as crystalline cellulose and polyvinylpyrrolidone; water-soluble substances such as sugars, sugar alcohols, and amino acids; surface activity such as deoxycholic acid, sodium lauryl sulfate, and sucrose fatty acid esters. Organic substances including agents: inorganic substances such as talc, titanium dioxide, zinc oxide, kaolin, zeolite, silicic anhydride, silica gel, calcium phosphate, calcium carbonate, etc. Selection is important.

Examples of combinations of poorly soluble drugs whose solubility is improved by mixing and grinding and bases are porous substances such as malotilate and magnesium aluminate metasilicate, light anhydrous silicic acid, and light synthetic aluminum silicate (see Patent Document 2), Planoprofen derivatives and hydroxypropyl cellulose (see Patent Document 3), water-soluble cellulose derivatives such as nilvadipine and hydroxypropylmethyl cellulose, low-substituted hydroxypropyl cellulose (see Patent Document 4), d-2- [4- (3- Methyl-2-thienyl) phenyl] propionic acid and aminoalkyl methacrylic acid copolymer (see Patent Document 5) have been reported. However, there has been no report on improving the solubility of pimobendan by the mixed pulverization method so far.
Japanese Patent No. 2608183 JP 59-16820 A Japanese Patent Laid-Open No. 02-268117 JP 05-262642 A Japanese Patent Laid-Open No. 08-291063

  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 studies 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 light silicic anhydride, polyvinylpyrrolidone and D- It was found that an oral administration preparation of pimobendan having excellent dissolution properties can be obtained by mixing and grinding one or more bases selected from mannitol.

  That is, the present invention is characterized by blending a finely powdered composition obtained by mixing and grinding pimobendan and one or more bases selected from light anhydrous silicic acid, polyvinylpyrrolidone and D-mannitol. The present invention provides a preparation for oral administration of pimobendan.

  According to the present invention, a preparation containing pimobendan and having excellent dissolution properties can be obtained. The dosage form of the preparation of the present invention is not limited to capsules, and various dosage forms such as tablets can be formulated.

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 weight of the preparation. It is a range.

  The base used in the present invention is one or more selected from light anhydrous silicic acid, polyvinyl pyrrolidone and D-mannitol.

  The light anhydrous silicic acid is preferably porous, more preferably one having an average particle diameter of 2 to 5 μm, an average pore diameter of 2 to 30 nm, and an average pore volume of 0.4 to 1.8 mg / mL. Particularly preferable are an average particle size of 3.0 to 4.1 μm, an average pore size of 17 to 21 nm, and an average pore volume of 1.25 to 1.60 mg / mL. Commercially available products include Adsolider PH101 (Freund Sangyo Co., Ltd.) and Sirisia 430 (Fuji Silysia Chemical Co., Ltd.). Here, the average particle diameter can be measured by a light scattering / diffraction method, and the average pore diameter and the average pore volume can be measured by a mercury intrusion method.

Polyvinylpyrrolidone is a linear polymer of 1-vinyl-2-pyrrolidone and is represented by (C ₆ H ₉ NO) _n . n is preferably 10,000 to 100,000, more preferably 20,000 to 50,000. Examples of commercially available products include Povidone K25 (“Collidon 30P” manufactured by BASF Takeda Vitamin Co., Ltd.), Povidone K30 (“Prasdon K-25” manufactured by ASP Japan Co., Ltd.), and the like.

  As D-mannitol, what was manufactured by spray drying is preferable. Such spray-dried D-mannitol has a mass median diameter of 75 to 300 μm, an angle of repose of 25 to 45 degrees, a loose density of 0.35 to 0.75 g / mL, and 0.45 to 0.85 g / mL. Those having a tap density are preferred, and those having a median particle size of 75-250 μm, an angle of repose of about 31 degrees, a loose density of 0.51 g / mL and a tap density of 0.60 g / mL are more preferred.

Here, the “mass median diameter” refers to the particle size when the total mass of particles larger than a certain particle size in the particle size distribution of the powder occupies 50% of the mass of the total powder. The particle size distribution can be measured by a screening method, a light scattering / diffraction method, a sedimentation method, an electrical resistance test method, or the like.
“Angle of repose” is the angle at which the side slope of the conical sediment formed on the horizontal plane forms when the powder is gently dropped and deposited from the funnel to the horizontal plane, and is defined in ISO 4324. It can be measured by the method.
“Loose density” and “tap density” both indicate the apparent density of the powder. “Loose density” is a value obtained by dividing the weight of a powder sample by adding the powder sample to a container of a certain volume, weighing the powder surface, and weighing it, and is defined in DIN EN ISO 60 It can be measured by the method. “Tap density” refers to the apparent density obtained by tapping a container a specified number of times in the stage of adding a powder sample into the container so that the powder is more densely packed in the container. DIN EN ISO787-11 It can be measured by the method defined in

  As such spray-dried D-mannitol, for example, it can be produced according to the method described in International Publication No. 97/39739 pamphlet, and as a commercial product, Partec M (manufactured by Merck Co., Ltd.), etc. Can be mentioned.

  The base is preferably added to the pimobendan in a mass ratio of 0.1 to 10 times and mixed and pulverized, more preferably 1 to 10 times, particularly preferably 1 to 5 times. Add and mix and grind.

  As a means for mixing and pulverizing, it can be performed manually using a mortar or the like, but for example, a pulverizer of a type that generates high collision energy such as a ball mill, a rotary mill, a high vibration mill, a roller mill, a planetary mill or the like is used. It may be mechanically pulverized. It is particularly preferable to use a ball mill as the pulverizer.

  Using such a pulverizing means, pimobendan and the base are mixed and pulverized for 1 to 100 hours, preferably 5 to 70 hours, so that the dissolution property is improved and the fine powder composition containing the base is improved. Can be obtained.

Furthermore, in the present invention, when mixing and grinding, an organic acid may be added in addition to the base and pimobendan. Such an organic acid is not particularly limited, but preferably includes fumaric acid, succinic acid, alginic acid, tartaric acid, malic acid, ascorbic acid or aspartic acid, and fumaric acid or succinic acid is particularly preferable. These organic acids can be used alone or in combination of two or more.
The amount of the organic acid added at the time of mixing and pulverization is preferably 0.1 to 10 times, particularly preferably 1 to 10 times in terms of mass ratio with respect to pimobendan.

The pimobendan-containing fine powder composition thus obtained can be used for the production of oral administration preparations such as 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 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 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 order to prepare pharmaceutical preparations of such various dosage forms, other pharmaceutically 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 hydrosilicon 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 and polyoxyethylene polyoxypropylene glycol; perfumes such as orange oil, fennel oil, cinnamon oil, clove oil, turpentine oil, mint 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 Tan, and the like.

  Moreover, you may add the organic acid which can be added at the time of mixing and grinding | pulverization in the process of formulation. As the organic acid, the organic acid can be used, but fumaric acid, succinic acid, and alginic acid are particularly preferable. These organic acids can be used alone or in combination of two or more. When added in the formulation step, the amount of the organic acid is in the range of 0.1 to 50 times, particularly preferably 1 to 20 times in terms of mass ratio with respect to pimobendan.

  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 mixed grinding base was used.
Light anhydrous silicic acid: Silicia 430, Fuji Silysia Chemical Povidone K30: Kollidon K30P, BASF Takeda Vitamin Co., Ltd. Povidone K25: Plasdon K-25, IS Japan Co., Ltd. D-mannitol: Partec M-200, Merck Hydroxypropylmethylcellulose (HPMC) ) 2280: SB4, Shin-Etsu Chemical HPMC 2910: TC-5EW, Shin-Etsu Chemical Alpha-modified starch: Matsunoline SM, Matsutani Chemical Synthetic aluminum silicate: Kyowa Chemical Industry Magnesium aluminate metasilicate: Neoaluminum S, Tomita Pharmaceutical Porous calcium phosphate: Fujicalin SG , Fuji Chemical Industry Polyethylene glycol (PEG) 6000: Nippon Oil & Fats Fumaric acid: Wako Pure Chemical Industries (equipment)
For the mixing and pulverization, a ball mill apparatus AV type manufactured by Asahi Rika Seisakusho was used, and a combination of 100 alumina 10φ balls in a magnetic pot having an inner diameter of 90φ was used.

Reference example 1
1 g of pimobendan was pulverized at about 88 rpm for 10 hours using a ball mill (AV type manufactured by Asahi Rika Seisakusho Co., Ltd.) to obtain a pulverized powder.

Examples 1-7 and Comparative Examples 1-8
Each component was mixed with 500 mg of pimobendan at the blending ratios and pulverization conditions shown in Tables 1 and 2, and pulverized using a ball mill to obtain mixed pulverized powders.

Example 8
To 2.5 g of pimobendan, 7.5 g of povidone K25 (“Prasudon K-25” manufactured by ASP Japan Co., Ltd.) was added and pulverized at about 100 rpm for 20 hours using a ball mill. 25.0 g of acid was added and pulverized at about 100 rpm for 10 hours to obtain a mixed pulverized powder.

Test Example 1 Dissolution Test 14th revision of each mixed pulverized powder obtained in Reference Examples, Examples 1-8 and Comparative Examples 1-8 (equivalent to 5.0 mg of pimobendan) and 9.0 mg of sodium lauryl sulfate (SLS) A Japanese Pharmacopoeia No. 2 capsule (HPMC capsule SIZE2 OP. White 8, manufactured by Shionogi Qualicaps) was filled and subjected to a dissolution test. The dissolution test was performed according to the 14th revised Japanese Pharmacopoeia General Test Method and Dissolution Test Method Method 2 (Paddle Method) using water as the test solution. Each capsule was put into 900 mL of a test solution (water), and an elution test was performed at 37 ± 0.5 ° C. under a paddle rotation speed of 50 rpm.
For each test sample, pimobendan eluted in the test solution after 15 minutes was measured by a high performance liquid chromatograph (HPLC) method (measurement wavelength 250 nm), and the elution rate (%) relative to the pimobendan content in each powder was calculated. . Moreover, the improvement rate with respect to the elution of the reference example was calculated. The results are shown in Table 3.

  It can be seen that the mixed pulverized powders of Examples 1 to 4 have significantly increased elution after 15 minutes with respect to water as compared with the powder of the reference example obtained by ball milling with pimobendan alone. On the other hand, it is clear that Comparative Examples 1 to 8 all worsen the dissolution rather than improve the dissolution compared to the reference example, and that the effects of the invention can be obtained only with the mixed pulverized powder of the present invention. became.

Example 9
83.4 mg of the mixed pulverized powder obtained in Example 1, lactose (“Dilacto's S” manufactured by Freund Sangyo Co., Ltd.) 2586.6 mg, partially pregelatinized starch (PCS) (manufactured by Asahi Kasei Kogyo Co., Ltd.) 150.0 mg, SLS 150.0 mg and talc 15.0 mg were mixed in a stoppered Meyer. A tableting powder obtained by further adding 15.0 mg of magnesium stearate to this mixed powder and then mixing it was tableted using a universal compression tester (manufactured by Shimadzu Corporation), and a tablet containing 2.5 mg of pimobendan. (1 tablet: 180 mg) was obtained.

Example 10
The mixed pulverized powder 83.4 mg obtained in Example 1, lactose 2286.6 mg, PCS 150.0 mg, SLS 450.0 mg, and talc 15.0 mg were mixed in a stoppered Meyer. 15.0 mg of magnesium stearate was further added to the mixed powder and mixed, and the resulting tableted powder was tableted using a universal compression tester to obtain a tablet containing 2.5 mg of pimobendan (1 tablet: 180 mg). .

Example 11
Mixed pulverized powder 166.8 mg obtained in Example 5, lactose 2334.9 mg, PCS 333.3 mg, polyoxyethylene (105) polyoxypropylene (5) glycol ("PEP-101" manufactured by Freund Sangyo Co., Ltd.) 150.0 mg was mixed in a stoppered Meyer. 15.0 mg of magnesium stearate was further added to the mixed powder and mixed, and the resulting tableted powder was tableted using a universal compression tester to obtain a tablet containing 2.5 mg of pimobendan (1 tablet: 180 mg). .

Example 12
166.8 mg of the mixed pulverized powder obtained in Example 5, lactose 2334.9 mg, PCS 333.3 mg, and SLS 150.0 mg were mixed in a stoppered Meyer. 15.0 mg of magnesium stearate was further added to the mixed powder and mixed, and the resulting tableted powder was tableted using a universal compression tester to obtain a tablet containing 2.5 mg of pimobendan (1 tablet: 180 mg). .

Example 13
666.6 mg of the mixed pulverized powder obtained in Example 6, 1868.4 mg of lactose, 300.0 mg of carmellose calcium, and 150.0 mg of polyoxyethylene (105) polyoxypropylene (5) glycol were mixed in a stoppered Meyer. . 15.0 mg of magnesium stearate was further added to the mixed powder and mixed, and the resulting tableted powder was tableted using a universal compression tester to obtain a tablet containing 2.5 mg of pimobendan (1 tablet: 180 mg). .

Example 14
The mixed pulverized powder 166.8 mg obtained in Example 2, lactose 2503.2 mg, PCS 150.0 mg, SLS 150.0 mg, and talc 15.0 mg were mixed in a stoppered Meyer. 15.0 mg of magnesium stearate was further added to the mixed powder and mixed, and the resulting tableted powder was tableted using a universal compression tester to obtain a tablet containing 2.5 mg of pimobendan (1 tablet: 180 mg). .

Example 15
PCS 600 mg and polysorbate 80 (“NOFABLE ESO-8520” manufactured by Nippon Oil & Fats Co., Ltd.) 45.0 mg were mixed in the mortar, and the polysorbate 80 was absorbed in the PCS, and then obtained in Example 2 in this mortar. Further, 166.8 mg of the mixed pulverized powder and 2173.2 mg of lactose were added and further mixed. This mixture was further mixed with 15.0 mg of magnesium stearate, and the resulting tableting powder was tableted using a single-punch tableting machine (No. 4-B type manufactured by Kikusui Seisakusho Co., Ltd.), and pimobendan. A tablet containing 2.5 mg (1 tablet: 180 mg) was obtained.

Example 16
The mixed pulverized powder obtained in Example 7 was mixed with 1112.0 mg, lactose 15566.0 mg, PCS 2222.0 mg, and SLS 1000.0 mg in a mortar. To this mixed powder, 100.0 mg of magnesium stearate was further added and mixed, and the resulting tableted powder was tableted using a universal compression tester to obtain tablets containing 2.5 mg of pimobendan (1 tablet: 180 mg). .

Example 17
Pulverized powder 3890.0 mg obtained in Example 8, lactose 13010.0 mg, carmellose calcium (ECG-505; manufactured by Gotoku Pharmaceutical Co., Ltd.) 2000.0 mg, polyoxyethylene (105) polyoxypropylene (5) 1000.0 mg of glycol was mixed in a mortar. To this mixed powder, 100.0 mg of magnesium stearate was further added and mixed, and the resulting tableted powder was tableted using a universal compression tester to obtain tablets containing 2.5 mg of pimobendan (1 tablet: 180 mg). .

Example 18
250.2 mg of the mixed pulverized powder obtained in Example 4, 2419.8 mg of lactose, 150.0 mg of PCS, 150.0 mg of SLS, and 15.0 mg of talc were mixed in a mortar. 15.0 mg of magnesium stearate was further added to the mixed powder and mixed, and the resulting tableted powder was tableted using a universal compression tester to obtain a tablet containing 2.5 mg of pimobendan (1 tablet: 180 mg). .

Test example 2
The tablets obtained in Examples 9 to 18 were subjected to a dissolution test in the same manner as in Test Example 1. The dissolution test was conducted according to the JP General Test Method and the dissolution test method 2 (paddle method). Each tablet was put into 900 mL of a test liquid (water), 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 15 minutes was measured by a high performance liquid chromatograph (HPLC) method using a column (measurement wavelength 250 nm), and the dissolution rate relative to the pimobendan content in each tablet was calculated. did. Moreover, the improvement rate with respect to the elution of the reference example was calculated. The results are shown in Table 4.

  When the mixed pulverized product of the present invention was produced as a tablet, it was shown that pimobendan was dissolved well.

Claims (4)

  An agent for oral administration of pimobendan, comprising a fine powder composition obtained by mixing and pulverizing pimobendan and one or more bases selected from light anhydrous silicic acid, polyvinylpyrrolidone and D-mannitol.   The preparation for oral administration of pimobendan according to claim 1, wherein the mixing ratio of pimobendan and the base is 1: 0.1-10.   The preparation for oral administration of pimobendan according to claim 1 or 2, wherein an organic acid is further added when mixing and grinding pimobendan and a base.   The preparation for oral administration of pimobendan according to any one of claims 1 to 3, which is a tablet.