Oral film formulation containing pimobendan

Abstract

To provide an oral film formulation with enhanced dissolution of pimobendan.SOLUTION: An oral film formulation comprises pimobendan, an acid selected from phosphoric acid, citric acid, fumaric acid, and amino acid hydrochlorides, and a film-forming material, wherein the molar ratio (acid / pimobendan) of the acid to pimobendan is 0.3 to 5.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an oral film preparation containing pimobendan.

Background Art

[0002] Pimobendan has an effect of enhancing the Ca 2+ sensitivity of troponin C in the myocardium and an inhibitory effect on phosphodiesterase III (PDEIII) activity, and is used as a therapeutic agent for acute heart failure and chronic heart failure due to its effect of improving the pumping function of the heart and vasodilatory effect. Pimobendan is a drug clinically used not only in humans but also in dogs, and in dogs it is used for the treatment of chronic heart failure, mitral valve insufficiency, and cardiomyopathy. When pimobendan is used in dogs, not only improvement of symptoms but also an effect of extending the survival period has been reported.

[0003] On the other hand, the crystal structure of pimobendan has strong intermolecular interactions. Therefore, pimobendan is known to be a poorly soluble drug with low solubility in water and organic solvents, and its solubility is affected by pH, being low near neutrality and high under acidic conditions in a pH 1.2 buffer solution (Non-Patent Document 1). Pimobendan preparations with low elution properties due to the poor solubility of pimobendan are known to have low oral absorbability (Patent Document 1), and in the dissolution test specifications for pimobendan capsules of 1.25 mg and 2.5 mg, the dissolution rate at 15 minutes is defined to be 75% or more (dissolution test by the paddle method using water as the test solution) (Non-Patent Document 1).

[0004] For these reasons, the development of a formulation that can achieve high elution properties particularly near neutrality where solubility is low without being affected by pH fluctuations has become an issue in the oral solid formulation of pimobendan. As methods for overcoming this issue, conventionally, 1) mixing 5 parts by weight or more of citric acid with 1 part by weight of pimobendan to form a hard capsule preparation (Patent Document 1), 2) spraying an aqueous solution of pimobendan and a binder onto a solid support containing anhydrous citric acid and a flavor to form a solid preparation (Patent Document 2), 3) formulating by containing fumaric acid and polyoxyethylene (105) polyoxypropylene (5) glycol (Patent Document 3), 4) mixing and pulverizing pimobendan with a base selected from light anhydrous silicic acid, polyvinylpyrrolidone, and D-mannitol to form a fine powder composition (Patent Document 4), 5) microspherizing pimobendan by spray congealing to form a particle form coated with a carrier matrix (Patent Document 5), etc. have been reported.

[0005] However, an oral film formulation containing pimobendan with improved elution properties and solubility of pimobendan has not been known so far.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Non-Patent Documents

[0007]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0008] The present invention relates to providing an oral film preparation with improved elution property of pimobendan.

Means for Solving the Problems

[0009] As a result of various studies on film preparations containing pimobendan as an active ingredient, the present inventors have found that a film preparation produced using pimobendan and a specific acid has excellent elution property of pimobendan in water without using a large amount of acid.

[0010] That is, the present invention relates to the following 1) to 5). 1) An oral film preparation containing pimobendan, an acid selected from phosphoric acid, citric acid, fumaric acid, and amino acid hydrochloride, and a film-forming material, wherein the molar ratio of the acid to pimobendan (acid / pimobendan) is 0.3 to 5. 2) The oral film preparation according to 1), wherein the film-forming material is hydroxypropyl cellulose and / or hydroxypropyl methylcellulose. 3) The oral film preparation according to 1) or 2), wherein the molar ratio of the acid to pimobendan is 1 to 3. 4) The oral film preparation according to any one of 1) to 3), wherein the acid is phosphoric acid. 5) A method for producing the oral film preparation according to 1), which includes a step of adding either the acid or the film-forming material to pimobendan in an aqueous ethanol solution, mixing and stirring, and then adding the other and mixing and stirring.

Effects of the Invention

[0011] According to the present invention, an oral film formulation with improved elution properties of pimobendan can be provided. Since this formulation has a low acid content, it can have less sour taste and higher palatability, and in addition, it can be made thin and small, so it can be easily accepted by animals such as dogs.

Brief Description of the Drawings

[0012]

Figure 1

Modes for Carrying Out the Invention

[0013] In the present invention, "pimobendan" refers to a compound that is (±)-4,5-dihydro-6-[2-(p-methoxyphenyl)-5-benzimidazolyl]-5-methyl-3(2H)-pyridazinone, and can be produced, for example, according to the method described in Japanese Patent Publication No. 63-24996.

[0014] In the film formulation of the present invention, pimobendan is present in a state where it is mixed with an acid selected from phosphoric acid, citric acid, fumaric acid, and amino acid hydrochloride at a molar ratio (acid / pimobendan) of 0.3 to 5. The acid is one or more selected from phosphoric acid, citric acid, fumaric acid, and amino acid hydrochloride, and two or more kinds may be used, but it is preferable to use phosphoric acid. Examples of the amino acid hydrochloride include glycine hydrochloride, alanine hydrochloride, glutamic acid hydrochloride, aspartic acid hydrochloride, etc., and L-glutamic acid hydrochloride is preferable. Such an acid is blended with pimobendan in a molar ratio in the range of 0.3 to 5, but from the viewpoint of the elution properties of pimobendan, 0.5 or more is preferable, and 1 or more is more preferable.

[0015] The content of pimobendan in the film formulation of the present invention is preferably 1% by mass or more, more preferably 2% by mass or more, still more preferably 3% by mass or more, and preferably 15% by mass or less, more preferably 10% by mass or less, still more preferably 5% by mass or less, based on the film formulation.

[0016] The content of the acid in the oral film preparation of the present invention is appropriately determined according to the content of pimobendan, but is preferably 0.5% by mass or more, more preferably 1% by mass or more, still more preferably 1.5% by mass or more, and preferably 15% by mass or less, more preferably 12% by mass or less, still more preferably 9% by mass or less, based on the film preparation.

[0017] As the film-forming material used in the oral film preparation of the present invention, a polymer having the property of dissolving or becoming a viscous liquid when contacted with water, or swelling to form a hydrogel, and having the property of forming a film in a dry state is used. For example, alginic acid such as sodium alginate or its salts, pectin, pullulan, carrageenan, xanthan gum, tragacanth gum, starch, collagen, gelatin, galactomannan, glycoprotein, proteoglycan, glucosaminoglycan, polyvinyl alcohol, water-soluble cellulose derivatives, and the like can be mentioned.

[0018] Examples of the water-soluble cellulose derivatives include methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose or their salts. These film-forming materials can be used alone or in combination of two or more. As the film-forming material used in the present invention, water-soluble cellulose derivatives are preferred, among which hydroxypropylcellulose and hydroxypropylmethylcellulose are preferred, and more preferably a combination of hydroxypropylcellulose and hydroxypropylmethylcellulose. For example, it is preferable to combine 0.1 to 10 parts by mass of hydroxypropylmethylcellulose with 1 part by mass of hydroxypropylcellulose.

[0019] As the hydroxypropylcellulose, those having a kinematic viscosity (Japanese Pharmacopoeia, Fifteenth Revision) of the 2% aqueous solution at 20°C of 2.0 to 2.9 mPa·s are preferred. As the hydroxypropylmethylcellulose, those having the same viscosity of 5.2 to 7.0 mPa·s are preferred, and the substitution rates of the methoxy group and the hydroxypropoxy group are preferably 28.0 to 30.0% and 7.0 to 12.0%, respectively. Hydroxypropylcellulose and hydroxypropylmethylcellulose may be produced by known methods or commercially available products may be used. Examples of commercially available products of hydroxypropylcellulose include HPC-SSL, HPC-SL (above, Nippon Soda Co., Ltd.), etc., and examples of commercially available products of hydroxypropylmethylcellulose include TC-5 (registered trademark) (Shin-Etsu Chemical Co., Ltd.), etc.

[0020] The content of the above film-forming material in the oral film preparation of the present invention is preferably 40% by mass or more, more preferably 50% by mass or more, still more preferably 60% by mass or more, and preferably 99% by mass or less, more preferably 98% by mass or less, still more preferably 95% by mass or less, based on the film preparation, from the viewpoints of the elution property of pimobendan and the maintenance of the stability of the film preparation.

[0021] The oral film preparation of the present invention may contain a plasticizer, a flavoring agent, a perfume, a coloring agent, etc. within a range not impairing the effects of the present invention.

[0022] Examples of the plasticizer include glycerin, diglycerin, triglycerin, polyglycerin, sorbitol, maltitol, xylitol, polyethylene glycol, propylene glycol, butylene glycol, hexylene glycol, pentylene glycol, polyoxyethylene polyoxypropylene glycol, acetyl ethanolamine, reduced maltose syrup, etc.

[0023] Examples of flavoring agents include sucralose, acesulfame potassium, thaumatin, sucrose, saccharin, aspartame, alanine, glycine, glutamic acid and its salts, aspartic acid and its salts, inosinic acid and its salts, various extracts (beef, chicken, pork, fish, yogurt, milk, lemon, orange, chocolate, yeast, etc.), dried yeast, and the like.

[0024] Examples of flavoring agents include fragrances (vanilla, mint, menthol, yogurt, milk, lemon, orange, chocolate, sweet potato, butter), various extracts (beef, chicken, pork, fish, yogurt, milk, lemon, orange, chocolate, yeast, etc.), dried yeast, and the like.

[0025] Examples of coloring agents include titanium oxide, tar dyes, various iron oxides, and the like.

[0026] The oral film preparation of the present invention can have a thickness of, for example, 20 μm to 150 μm, preferably 40 μm to 80 μm, and can be in a form molded into a rectangle of 0.5 cm × 1 cm to 3 cm × 4 cm or a circle with a diameter of 1 cm to 4 cm. By adopting such a form, its flexibility and physical strength can be maintained, and discomfort in the oral cavity and difficulty in taking can be avoided.

[0027] The oral film preparation of the present invention can be produced by adding either the acid or the film-forming material to pimobendan in an aqueous ethanol solution, mixing and stirring, and then adding the other and mixing and stirring. Specifically, for example, it is produced by the following steps 1) to 4). 1) Adding either the acid or the film-forming material to pimobendan in an aqueous ethanol solution of 10 to 50% by volume and mixing and stirring (first step). 2) Then, adding the other of the acid or the film-forming material that was not selected in the first step, mixing and stirring to obtain a casting solution in which pimobendan and the acid are homogeneously dispersed (second step). 3) Cast the obtained casting solution in a predetermined amount onto a release film made of polyethylene terephthalate, polypropylene, or the like, and then dry it to distill off the solvent (third step). 4) After drying, peel it off from the release film and cut it into a predetermined size (fourth step).

[0028] In the first step, the ethanol concentration of the aqueous ethanol solution used is preferably 5 to 50% by volume, more preferably 20 to 40% by volume. Also, stirring is preferably performed using a stirring and mixing device such as a homomixer or a magnetic stirrer. When adding an acid and mixing and stirring, it is carried out at room temperature to 50 °C for 0.5 to 4 hours, preferably 1 to 3 hours, until the mixture becomes visually creamy. When adding a film-forming material and mixing and stirring, it is carried out at room temperature to 50 °C for 1 to 5 hours, preferably 1 to 4 hours. After stirring only pimobendan at room temperature to 50 °C for 1 to 5 hours, preferably 1 to 4 hours, until the particles are finer than at the start of stirring, add the film-forming material and stir at room temperature to 50 °C for 1 to 5 hours, preferably 1 to 4 hours.

[0029] Stirring in the second step is preferably carried out using a stirring and mixing device such as a homomixer or a magnetic stirrer at room temperature to 50 °C for 1 to 8 hours, preferably 2 to 7 hours. Drying in the third step is preferably carried out using a forced-air dryer at 20 to 80 °C for 0.05 to 2 hours, preferably 0.1 to 1 hour.

[0030] It is suggested that in the film preparation thus produced, pimobendan exists in a form different from the crystal form of the raw material powder (Figure 1), and the oral film preparation containing pimobendan has excellent elution properties of pimobendan in water.

Examples

[0031] Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited thereto.

[0032] Examples 1-5, Comparative Examples 1-5 (1) Preparation of pimobendan-containing film preparations Pimobendan films with the compositions shown in Table 1 were prepared by the following method. Pimobendan (25.0 mg) and an acid (25.0 mg) were weighed into a glass vial with a capacity of 6 mL. Then, ethanol (485.5 mg) and water (967.0 mg) were added, a magnetic stir bar was placed, and the vial was capped. It was stirred using a magnetic stirrer at room temperature for 2 hours. Hydroxypropylcellulose NISSO HPC-SSL (Nippon Soda Co., Ltd.) (144.5 mg) and hydroxypropylmethylcellulose TC-5 (registered trademark) R (Shin-Etsu Chemical Co., Ltd.) (289.0 mg) were added to the resulting mixture, the vial was capped, and it was stirred using a magnetic stirrer at room temperature for 3 hours. In both stirrings, the stirring was carried out while confirming that the contents were well mixed to obtain a uniform preparation solution. Approximately 100 mg of the obtained preparation solution was cast and spread on a 2.5×2.5 cm plastic tray and dried by blowing air at 40°C for 1 hour to produce a film. Also, a film preparation produced in the same manner without adding an acid was used as a control (Comparative Example 1).

[0033] (2) Measurement of dissolution rate The film obtained in (1) was peeled off from the plastic tray, weighed to obtain the total amount shown in Table 1, and a dissolution test was performed to measure the dissolution rate at 15 minutes in distilled water. The results are shown together with Table 1.

[0034] The dissolution test was carried out by the paddle method (900 mL of distilled water, paddle rotation speed 50 rpm, 37.0 ± 0.5°C). Quantification was performed by HPLC, and the analysis conditions were as follows. Column: Inertsil ODS-3, 4.6×150 mm, 5 μm Developing solvent: CH 3 CN / Solution A 1 / 4 Solution A: 1.56 g of sodium dihydrogen phosphate dihydrate was dissolved in 800 mL of water, phosphoric acid was added to adjust the pH to 2.2, and then water was added to make 1000 mL. Detection: 268 nm Flow rate: Adjusted so that the retention time of pimobendan is 7 min Development time: 10 min Temperature: 25 °C Injection volume: 50 μL Pimobendan standard solution: 0.0014 mg / mL (methanol / water = 1 / 1)

[0035] (3) X-ray analysis Powder X-ray analysis of the raw material pimobendan powder and the film preparation of Example 3 was performed (scanning angle 3 - 30° (2θ)). The results are shown in Figure 1.

[0036] (4) Results When 1 part by mass of an acid was used with respect to 1 part by mass of pimobendan, high elution was shown with fumaric acid, citric acid monohydrate, phosphoric acid, glycine hydrochloride, and L-glutamic acid hydrochloride. On the other hand, acetic acid, DL-lactic acid, DL-malic acid, and L-glutamic acid showed an elution rate equivalent to that of Comparative Example 1 without using an acid (Table 1). In addition, the film preparation of Example 3 showed a broad diffraction pattern different from that of the raw material pimobendan powder (Figure 1).

[0037]

Table 1

[0038] Examples 6 - 14, Comparative Examples 6 - 10 (1) Production of pimobendan-containing film preparation Pimobendan films having the compositions shown in Table 2 were prepared by the following method. Pimobendan (25.0 mg) and an acid (20-fold amount of the amount shown in Table 2) were weighed into a glass vial with a capacity of 6 mL, and then ethanol (485.5 mg) and water (967.0 mg) were added, and a film was prepared in the same manner as in Examples 1 - 5.

[0039] (2) Measurement of elution rate The film obtained in (1) was peeled off from the plastic tray, weighed for the total amount shown in Table 2, and an elution test was performed in the same manner as above, and the elution rate at 15 minutes in distilled water was measured. The results are shown together with Table 2.

[0040] (3) Results When the amounts of citric acid monohydrate, phosphoric acid, and L-glutamic acid hydrochloride were used at a molar ratio of 1 or more with respect to pimobendan, high elution was shown (Table 2).

[0041] [Table 2] Example 15 (1) Preparation of pimobendan-containing film preparation A pimobendan film having the composition shown in Table 3 was prepared by the following method. Pimobendan (25.0 mg) was weighed into a 6 mL glass vial, then ethanol (485.5 mg) and water (967.0 mg) were added, a magnetic stir bar was placed, the vial was capped, and stirred at room temperature for 2 hours using a magnetic stirrer. It was visually confirmed that the pimobendan particles were finer than at the start of stirring. To the resulting mixture, hydroxypropylcellulose NISSO HPC-SSL (Nippon Soda Co., Ltd.) (144.5 mg) and hydroxypropylmethylcellulose TC-5 (registered trademark) R (Shin-Etsu Chemical Co., Ltd.) (289.0 mg) were added, the vial was capped, and stirred at room temperature for 1 hour using a magnetic stirrer. Phosphoric acid (88%) (12.5 mg) was added and stirred at room temperature for 6 hours using a magnetic stirrer. All stirrings were carried out while confirming that the contents were well mixed to obtain a uniform preparation solution. Approximately 100 mg of the obtained preparation solution was cast and spread on a 2.5 × 2.5 cm plastic tray, and dried by blowing air at 40°C for 1 hour to prepare a film.

[0042] (2) Measurement of dissolution rate The film obtained in (1) was peeled off from the plastic tray, weighed to the total amount shown in Table 3, and a dissolution test was carried out in the same manner as above, and the dissolution rate at 15 minutes in distilled water was measured. The results are shown together with Table 3.

[0043] (3) Results The film agent of Example 15 produced by the process of stirring pimobendan in an aqueous ethanol solution, adding a film-forming material, mixing and stirring, and then adding an acid and mixing and stirring showed a high dissolution rate (Table 3).

[0044]

Table 3

[0045] Example 16 (1) Production of pimobendan-containing film preparation A pimobendan film having the composition shown in Table 4 was prepared by the following method. Pimobendan (100.0 mg), phosphoric acid (88%) (60.0 mg), and concentrated glycerin (386.0 mg) were weighed into a 20 mL glass vial, then ethanol (2820.0 mg) and water (5696.0 mg) were added, a magnetic stir bar was placed in, the cap was put on, and it was stirred at room temperature using a magnetic stirrer for 2 hours. It was visually confirmed that the mixture had become creamy compared to when stirring started. Sucralose (80.0 mg), sanet (80.0 mg), somatine (8.0 mg), L-alanine (80.0 mg), and yeast extract (320.0 mg) were added to the obtained mixture and stirred at room temperature for 30 minutes. Then hydroxypropylcellulose NISSO HPC-SSL (Nippon Soda Co., Ltd.) (578.0 mg) and hydroxypropylmethylcellulose TC-5 (registered trademark) R (Shin-Etsu Chemical Co., Ltd.) (1156.0 mg) were added, the cap was put on, and it was stirred at room temperature for 3 hours. Each stirring was carried out while confirming that the contents were well mixed to obtain a uniform preparation liquid. The obtained preparation liquid was coated on a Pyren (registered trademark) film-OT (Toyobo product name P2161) at a thickness of 400 μm, spread, and dried by blowing air at 40°C for 1 hour to prepare a film.

[0046]

Table 4

[0047] (2) Measurement of dissolution rate After storing the film obtained in (1) by the method described in Table 5, the total amount shown in Table 4 was weighed, an elution test was conducted in the same manner as described above, and the elution rate at 15 minutes in distilled water was measured. The results are shown in Table 5.

[0048] (3) Results When a plasticizer, a flavoring agent, and a perfume were added to the film components, high elution properties were shown. Also, the elution rate did not change significantly depending on the storage conditions, and stable high elution properties were shown (Table 5).

[0049]

Table 5

Claims

1. An oral film preparation containing pimobendan, an acid selected from phosphoric acid, citric acid, fumaric acid, and amino acid hydrochloride, and a film-forming material, wherein the molar ratio of the acid to pimobendan (acid / pimobendan) is 0.3 to 5.

2. The oral film preparation according to claim 1, wherein the film-forming material is hydroxypropyl cellulose and / or hydroxypropyl methylcellulose.

3. The oral film preparation according to claim 1 or 2, wherein the molar ratio of the acid to pimobendan is 1 to 3.

4. The oral film preparation according to any one of claims 1 to 3, wherein the acid is phosphoric acid.

5. A method for producing the oral film preparation according to claim 1, comprising the step of adding and mixing and stirring either the acid or the film-forming material to pimobendan in an aqueous ethanol solution, and then adding and mixing and stirring the other one.

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