Oral film formulation containing pimobendan

Abstract

Provided is an oral film preparation having improved dissolution properties of pimobendan. [Solution] The oral film preparation contains pimobendan, an acid selected from phosphoric acid, citric acid, fumaric acid and an amino acid hydrochloride, and a film-forming material, and the molar ratio of pimobendan to the acid (acid / pimobendan) is 0.3 to 5.

Description

[Technical field]

[0001] The present invention relates to an oral film formulation containing pimobendan. [Background technology]

[0002] Pimobendan inhibits Ca2+ binding to cardiac troponin C. 2+ It has a sensitivity enhancing effect and a phosphodiesterase III (PDEIII) activity inhibitory effect, and is used as a drug for acute and chronic heart failure due to its effect of improving the pumping function of the heart and dilating blood vessels. Pimobendan is a drug that is used clinically not only in humans but also in dogs, and in dogs it is used to treat chronic heart failure, mitral regurgitation, and cardiomyopathy. When pimobendan is used in dogs, it has been reported that it not only improves symptoms but also extends survival time.

[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, with low solubility near neutral and high solubility under acidic conditions such as pH 1.2 buffer solution (Non-Patent Document 1). It is known that pimobendan preparations with low dissolution due to the poor solubility of pimobendan have low oral absorbability (Patent Document 1), and the dissolution test standard for pimobendan capsules 1.25 mg and 2.5 mg specifies that the dissolution rate in 15 minutes is 75% or more (dissolution test by paddle method using water as the test liquid) (Non-Patent Document 1).

[0004] For these reasons, the development of a formulation that is not affected by pH fluctuations and can achieve high dissolution, especially at near neutral pH where solubility is low, is an issue in the preparation of oral solid formulations of pimobendan. As methods for overcoming this issue, the following have been reported: 1) mixing 5 parts by weight or more of citric acid with 1 part by weight of pimobendan to prepare a hard capsule (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 prepare a solid formulation (Patent Document 2); 3) formulating the formulation by containing fumaric acid and polyoxyethylene (105) polyoxypropylene (5) glycol (Patent Document 3); 4) mixing and grinding pimobendan with a base selected from light anhydrous silicic acid, polyvinylpyrrolidone, and D-mannitol to prepare a fine powder composition (Patent Document 4); 5) forming pimobendan into microspheres by spray coagulation method to prepare a particle form coated with a carrier matrix (Patent Document 5).

[0005] However, no oral film formulation containing pimobendan in which the dissolution and solubility of pimobendan are improved has been known so far. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Patent No. 2608183 [Patent Document 2] Special Publication No. 2007-526269 [Patent Document 3] JP 2007-191419 A [Patent Document 4] JP 2006-028130 A [Patent Document 5] JP 2019-123737 A [Non-patent literature]

[0007] [Non-Patent Document 1] Latest Quality Information on Medical Drugs (Blue Book) 2021.12.03 2nd Edition Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention relates to an oral film preparation having improved dissolution properties of pimobendan. [Means for solving the problem]

[0009] The present inventors have conducted various studies on film preparations containing pimobendan as an active ingredient and have found that a film preparation produced using pimobendan and a specific acid has excellent dissolution properties 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 an amino acid hydrochloride, and a film-forming material, wherein the molar ratio of pimobendan to the acid (acid / pimobendan) is 0.3 to 5. 2) The oral film formulation according to 1), wherein the film-forming material is hydroxypropyl cellulose and / or hydroxypropyl methylcellulose. 3) The oral film formulation according to 1) or 2), wherein the molar ratio of acid to pimobendan is 1 to 3. 4) An oral film formulation according to any one of 1) to 3), wherein the acid is phosphoric acid. 5) A method for producing the oral film formulation of 1), comprising the steps 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 material and mixing and stirring. Effect of the Invention

[0011] According to the present invention, an oral film preparation with improved dissolution property of pimobendan can be provided. Since the preparation has a low acid content, it has a less sour taste and is highly palatable. In addition, since the preparation can be made thin and small, it is easily accepted by animals such as dogs. [Brief description of the drawings]

[0012] [Figure 1] 4 shows the results of powder X-ray analysis of pimobendan powder and the film formulation of Example 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] In the present invention, "pimobendan" refers to a compound which 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 JP-B-63-24996.

[0014] In the film preparation of the present invention, pimobendan is present in a mixed state with an acid selected from phosphoric acid, citric acid, fumaric acid and amino acid hydrochlorides 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 hydrochlorides, and two or more may be used, but it is preferable to use phosphoric acid. Amino acid hydrochlorides include glycine hydrochloride, alanine hydrochloride, and glutamic acid hydrochloride. salt , aspartic acid hydrochloride, etc., preferably L-glutamic acid hydrochloride. Such an acid is blended in a molar ratio of 0.3 to 5 relative to pimobendan, but from the viewpoint of the dissolution property of pimobendan, the molar ratio is preferably 0.5 or more, and more preferably 1 or more.

[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, even more preferably 3% by mass or more, and preferably 15% by mass or less, more preferably 10% by mass or less, even more preferably 5% by mass or less, relative to the film formulation.

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

[0017] The film-forming material used in the oral film preparation of the present invention is a polymer that has the property of dissolving or becoming a viscous liquid or of swelling to form a hydrogel upon contact with water and of forming a film in a dry state. Examples of the surfactant include alginic acid or a salt thereof such as sodium alginate, pectin, pullulan, carrageenan, xanthan gum, tragacanth gum, starch, collagen, gelatin, galactomannan, glycoprotein, proteoglycan, glycosaminoglycan, polyvinyl alcohol, and water-soluble cellulose derivatives.

[0018] Examples of water-soluble cellulose derivatives include methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and salts thereof. These film-forming materials can be used alone or in combination of two or more. The film-forming material used in the present invention is preferably a water-soluble cellulose derivative, and more preferably hydroxypropyl cellulose or hydroxypropyl methyl cellulose, and more preferably a combination of hydroxypropyl cellulose and hydroxypropyl methyl cellulose. For example, it is preferable to combine 0.1 to 10 parts by mass of hydroxypropyl methyl cellulose with 1 part by mass of hydroxypropyl cellulose.

[0019] Hydroxypropyl cellulose preferably has a viscosity (kinetic viscosity of a 2% aqueous solution at 20°C (Japanese Pharmacopoeia, 15th Edition)) of 2.0 to 2.9 mPa s, and hydroxypropyl methylcellulose preferably has a viscosity of 5.2 to 7.0 mPa s. The substitution rates of methoxy groups and hydroxypropoxy groups are preferably 28.0 to 30.0% and 7.0 to 12.0%, respectively. Hydroxypropyl cellulose and hydroxypropyl methylcellulose may be produced by known methods, or commercially available products may be used. Commercially available products of hydroxypropyl cellulose include, for example, HPC-SSL and HPC-SL (both from Nippon Soda Co., Ltd.), and commercially available products of hydroxypropyl methylcellulose include, for example, TC-5 (registered trademark) (Shin-Etsu Chemical Co., Ltd.).

[0020] The content of the above-mentioned film-forming material in the oral film formulation of the present invention is preferably 40% by mass or more, more preferably 50% by mass or more, even more preferably 60% by mass or more, and is preferably 99% by mass or less, more preferably 98% by mass or less, even more preferably 95% by mass or less, relative to the film formulation, from the viewpoints of the dissolution of pimobendan and maintaining the stability of the film formulation.

[0021] The oral film preparation of the present invention may contain a plasticizer, a flavoring agent, a fragrance, a colorant, etc., within the range that does not impair 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, acetylethanolamine, and reduced maltose syrup.

[0023] Examples of flavoring agents include sucralose, acesulfame potassium, thaumatin, white sugar, 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, etc.

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

[0025] Examples of colorants include titanium oxide, tar dyes, and various iron oxides.

[0026] The oral film preparation of the present invention may have a thickness of, for example, 20 μm to 150 μm, preferably 40 μm to 80 μm, and may be molded into a rectangle of 0.5 cm×1 cm to 3 cm×4 cm, or a circle of 1 cm to 4 cm in diameter. By making it into such a shape, its flexibility and physical strength can be maintained, and the occurrence of discomfort in the oral cavity and difficulty in taking the preparation 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 material and mixing and stirring. Specifically, for example, it is produced by the following steps 1) to 4). 1) Either the acid or the film-forming material is added to pimobendan in a 10 to 50 volume % aqueous ethanol solution, and the mixture is mixed and stirred (first step). 2) Next, the acid or the film-forming material that was not selected in the first step is added and mixed with stirring to obtain a casting solution in which pimobendan and the acid are uniformly dispersed (second step). 3) A predetermined amount of the obtained casting solution is cast onto a release film made of polyethylene terephthalate, polypropylene or the like, and then dried to remove the solvent (third step). 4) After drying, the film is removed and the film is cut to the specified size (fourth step).

[0028] In the first step, the ethanol concentration of the aqueous ethanol solution used is preferably 5 to 50% by volume, and more preferably 20 to 40% by volume. Stirring is preferably performed using a homomixer, magnet stirrer, or other stirring and mixing device, and when an acid is added and mixed and stirred, it is preferable to perform mixing and stirring at room temperature to 50° C. for 0.5 to 4 hours, preferably 1 to 3 hours, until the mixture becomes creamy when visually observed. When a film-forming material is added and mixed and stirred, it is preferable to stir at room temperature to 50° C. for 1 to 5 hours, preferably 1 to 4 hours, until only pimobendan particles become finer when visually observed than at the start of stirring, and then add the film-forming material and stir at room temperature to 50° C. for 1 to 5 hours, preferably 1 to 4 hours.

[0029] The 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. The drying in the third step is carried out using a blower dryer at 20 to 80° C. for 0.05 to 2 hours, preferably 0.1 to 1 hour.

[0030] It was suggested that in the thus produced film preparation, pimobendan exists in a crystalline form different from that of the raw material powder (Figure 1), and the pimobendan-containing oral film preparation exhibits excellent dissolution properties of pimobendan in water. EXAMPLES

[0031] The present invention will be described in more detail below based on examples, but the present invention is not limited to these examples.

[0032] Examples 1-5, Comparative Examples 1-5 (1) Manufacture of film formulations containing pimobendan Pimobendan films having the compositions shown in Table 1 were prepared in the following manner. Pimobendan (25.0 mg) and acid (25.0 mg) were weighed into a 6 mL glass vial, then ethanol (485.5 mg) and water (967.0 mg) were added, a magnetic stirrer was placed in the vial, the vial was capped, and the vial was stirred at room temperature for 2 hours using a magnetic stirrer. Hydroxypropyl cellulose NISSO HPC-SSL (Nippon Soda Co., Ltd.) (144.5 mg) and hydroxypropyl methylcellulose TC-5 (registered trademark) R (Shin-Etsu Chemical Co., Ltd.) (289.0 mg) were added to the resulting mixture, the vial was capped, and the vial was stirred at room temperature for 3 hours using a magnetic stirrer. In both cases, the contents were thoroughly mixed while stirring, and a homogeneous preparation was obtained. About 100 mg of the resulting preparation solution was cast and spread on a 2.5 x 2.5 cm plastic tray, and dried with air at 40°C for 1 hour to prepare a film. In addition, a film preparation produced in the same manner but without adding 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, and the total amount shown in Table 1 was measured. A dissolution test was then performed to measure the dissolution rate in distilled water for 15 minutes. The results are also shown in Table 1.

[0034] The dissolution test was performed by the paddle method (distilled water 900 mL, paddle rotation speed 50 rpm, 37.0 ± 0.5 ° C.). Quantitative analysis was performed by HPLC under the following analytical conditions. Column: Inertsil ODS-3, 4.6 x 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 water was added to make the total volume 1000 mL. Detection: 268nm Flow rate: Adjust so that the retention time of pimobendan is 7 min. Deployment time: 10 min Temperature: 25℃ Injection volume: 50μL Pimobendan standard solution: 0.0014 mg / mL (methanol / water = 1 / 1)

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

[0036] (4) Results When 1 part by mass of acid was used per part by mass of pimobendan, fumaric acid, citric acid monohydrate, phosphoric acid, glycine hydrochloride, and L-glutamic acid showed high dissolution rates, whereas acetic acid, DL-lactic acid, DL-malic acid, and L-glutamic acid showed dissolution rates equivalent to those of Comparative Example 1, which did not use acid (Table 1). Furthermore, 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) Manufacture of film formulations containing pimobendan Pimobendan films having the compositions shown in Table 2 were prepared in the following manner. Pimobendan (25.0 mg) and acid (20 times the amount shown in Table 2) were weighed into a 6 mL glass vial, and then ethanol (485.5 mg) and water (967.0 mg) were added to prepare a film in the same manner as in Examples 1-5.

[0039] (2) Measurement of dissolution rate The film obtained in (1) was peeled off from the plastic tray, and the total amount shown in Table 2 was measured. The dissolution test was carried out in the same manner as above, and the dissolution rate in distilled water for 15 minutes was measured. The results are also shown in Table 2.

[0040] (3) Results High dissolution was observed when the molar ratio of citric acid monohydrate, phosphoric acid, and L-glutamic acid to pimobendan was 1 or more (Table 2).

[0041] [Table 2] Example 15 (1) Manufacture of film formulations containing pimobendan Pimobendan films having the compositions shown in Table 3 were prepared in the following manner. 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 stirrer was placed in the vial, the vial was capped, and the vial was stirred at room temperature for 2 hours using a magnetic stirrer. It was visually confirmed that the pimobendan particles had become finer than when the stirring started. Hydroxypropyl cellulose NISSO HPC-SSL (Nippon Soda Co., Ltd.) (144.5 mg) and hydroxypropyl methylcellulose TC-5 (registered trademark) R (Shin-Etsu Chemical Co., Ltd.) (289.0 mg) were added to the resulting mixture, the vial was capped, and the vial was stirred at room temperature for 1 hour using a magnetic stirrer. Phosphoric acid (88%) (12.5 mg) was added and the vial was stirred at room temperature for 6 hours using a magnetic stirrer. In both cases, the contents were thoroughly mixed while stirring, and a homogeneous preparation was obtained. About 100 mg of the resulting preparation solution was cast and spread on a 2.5 x 2.5 cm plastic tray, and dried with 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, and the total amount shown in Table 3 was measured. The dissolution test was carried out in the same manner as above, and the dissolution rate in distilled water for 15 minutes was measured. The results are also shown in Table 3.

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

[0044] [Table 3]

[0045] Example 16 (1) Manufacture of film formulations containing pimobendan Pimobendan films having the compositions shown in Table 4 were prepared in the following manner. Pimobendan (100.0 mg), phosphoric acid (88%) (60.0 mg), and concentrated glycerin (386.0 mg) were weighed into a 20 mL glass vial, followed by the addition of ethanol (2820.0 mg) and water (5696.0 mg). A magnetic stirrer was placed in the vial, the vial was capped, and the mixture was stirred at room temperature for 2 hours using a magnetic stirrer. The mixture was visually confirmed to have become creamier than when the stirring started. Sucralose (80.0 mg), Sanet (80.0 mg), Thaumatin (8.0 mg), L-alanine (80.0 mg), and yeast extract (320.0 mg) were added to the resulting mixture, and the mixture was stirred at room temperature for 30 minutes. Hydroxypropyl cellulose NISSO HPC-SSL (Nippon Soda Co., Ltd.) (578.0 mg) and hydroxypropyl methylcellulose TC-5 (registered trademark) R (Shin-Etsu Chemical Co., Ltd.) (1156.0 mg) were then added, the vial was capped, and the mixture was stirred at room temperature for 3 hours. In each case, stirring was performed while checking that the contents were thoroughly mixed to obtain a homogeneous preparation liquid. The obtained preparation liquid was coated and spread on PYLENE (registered trademark) Film-OT (Toyobo product name P2161) to a thickness of 400 μm, and dried with air at 40° C. for 1 hour to prepare a film.

[0046] [Table 4]

[0047] (2) Measurement of dissolution rate The film obtained in (1) was stored according to the method shown in Table 5, and then the total amount shown in Table 4 was measured, and the dissolution test was carried out in the same manner as above to measure the dissolution rate in distilled water for 15 minutes. The results are shown in Table 5.

[0048] (3) Results High dissolution was observed when plasticizers, flavorings, and fragrances were added to the film components. Furthermore, the dissolution rate did not change significantly depending on the storage conditions, demonstrating stable high dissolution (Table 5).

[0049] [Table 5]

Claims

1. An oral film formulation comprising pimobendan, an acid selected from phosphoric acid, citric acid, fumaric acid, glycine hydrochloride and glutamic acid hydrochloride, and a film-forming material, wherein the molar ratio of pimobendan to the acid (acid / pimobendan) is 1-5.

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

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

4. The oral film formulation according to claim 1 or 2, wherein the acid is phosphoric acid.

5. 2. A method for producing the oral film formulation according to claim 1, comprising the steps 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.

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