JP2010064965A - Amlodipine-containing film preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a film preparation with improved stability of amlodipine or a salt thereof. <P>SOLUTION: The film preparation is equipped with a pair of outermost layers each comprising a coating layer and at least one drug layer disposed between the outermost layers, provided that the drug layer contains amlodipine and/or a salt thereof, polyvinyl pyrrolidone, glycerine and a film-forming agent. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a film preparation with improved stability of amlodipine or a salt thereof.

Amlodipine and its salt, which are dihydropyridine calcium antagonists, have excellent vasodilatory action and are used as therapeutic agents for hypertension and angina.
The dosage form of a formulation containing amlodipine or a salt thereof includes tablets, capsules, jellies, gummies, dry syrups, powders, fine granules, granules, chewables, orally disintegrating tablets, film-coated tablets Etc. are known (Patent Documents 1 to 7).

  In recent years, the average life expectancy has increased, and the proportion of those over the age of 65 in the Japanese population has reached 21%. Under such circumstances, there has been a demand for a dosage form that can be taken even by elderly people who need nursing and have difficulty swallowing. Among the above dosage forms, orally disintegrating tablets have excellent advantages such as fast disintegration in the oral cavity and easy swallowing, and can be taken without water, but for that purpose it is necessary to add many additives Therefore, a preparation that can be easily swallowed and can be easily produced has been desired.

A film preparation has been developed to meet such demands. The film preparation is a thin sheet preparation (Patent Document 8) composed of a base such as a cellulosic polymer, for example, and disintegrates in the oral cavity. Since the amount of the base is small while retaining the advantages of the tablet, it has the advantages of being faster than the orally disintegrating tablet and easy to swallow.
However, a film preparation containing amlodipine or a salt thereof is not yet known.

JP 2003-40775 A JP 2006-306754 A JP 2007-63263 A JP 2007-126407 A JP 2008-13489 A JP 2008-133231 A JP 2008-133232 A Japanese Patent No. 3460538

The inventors of the present invention prepared a film preparation containing amlodipine or a salt thereof by a conventional method. Surprisingly, the stability of amlodipine or a salt thereof was very poor in the film preparation, and it was difficult to supply it as a pharmaceutical product. I found a problem.
Therefore, the subject of this invention is providing the film formulation which improved the stability of amlodipine or its salt.

  As a result of intensive studies to solve the above problems, the present inventors have arranged a drug layer between a pair of outermost layers consisting of a coating layer, and combined a specific component with amlodipine or a salt thereof in the drug layer. It was found that the stability of amlodipine or a salt thereof was remarkably improved by the inclusion, and the present invention was completed.

  That is, the present invention comprises a pair of outermost layers comprising a coating layer and at least one drug layer sandwiched between the outermost layers, the drug layer being amlodipine or a salt thereof, polyvinylpyrrolidone, glycerin, and film formation It is intended to provide a film preparation characterized by containing an agent.

ADVANTAGE OF THE INVENTION According to this invention, the film formulation which improved the stability of amlodipine or its salt, especially thermal stability can be provided. In addition, the film preparation of the present invention dissolves rapidly only with moisture in the oral cavity (fast solubility), so it is easy to swallow and has excellent handling properties.
Therefore, it can be easily taken even by an elderly person who needs nursing and has difficulty in swallowing, and is extremely effective in treating hypertension and angina.

The film preparation of the present invention comprises a pair of outermost layers comprising a coating layer and at least one drug layer sandwiched between the outermost layers.
The drug layer contains amlodipine or a salt thereof, polyvinylpyrrolidone, glycerin, and a film forming agent, but the coating layer has an effect of improving the plasticity and moldability of the preparation, and is a disintegrant, taste masking agent. Those containing at least one selected from agents, sweeteners and colorants and a film forming agent are preferred.
In addition, the film preparation of the present invention may further include an intermediate layer for improving the pressure-bonding property or plasticity between the two drug layers and / or between the drug layer and the coating layer. The intermediate layer preferably contains at least one selected from a disintegrant and a plasticizer and a film forming agent.

Next, the components of the film preparation of the present invention will be described.
Amlodipine or a salt thereof used in the present invention can be obtained by a known production method. Amlodipine may be a single optically active substance or a racemate, but (S)-(-) and racemates are preferably used.
The salt of amlodipine is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include a salt with an organic acid or an inorganic acid. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids include citric acid, tartaric acid, ethanesulfonic acid, acetic acid, and maleic acid. And fumaric acid, lactic acid, gluconic acid, p-toluenesulfonic acid, methanesulfonic acid, succinic acid, salicylic acid, pyroglutamic acid, and besylic acid. These can be used alone or in combination of two or more. Especially, as a salt of amlodipine, a salt with besylic acid is particularly preferable.

Although content of amlodipine or its salt can be set suitably, it is preferable to contain 2.5-5 mg as amlodipine per 1 preparation for adults, for example. Further, the number of doses is preferably once a day. These can be appropriately increased or decreased according to symptoms.
The content of amlodipine or a salt thereof in the film preparation of the present invention is preferably 1 to 50% by mass, more preferably 2.5 to 40% by mass, and particularly preferably 5 to 30% by mass. In addition, the content of amlodipine or a salt thereof in the drug layer is preferably 5 to 90% by mass, more preferably 10 to 80% by mass, and particularly preferably 20 to 70% by mass.

  Polyvinylpyrrolidone (hereinafter sometimes referred to as PVP) used in the present invention is generally a linear polymer of 1-vinyl-2-pyrrolidone and has a molecular weight of about 40,000 to 360,000. However, as such PVP, commercially available products (for example, polyvinylpyrrolidone K-30, polyvinylpyrrolidone K-90 (Nippon Shokubai Co., Ltd.) and crease (Daiichi Kogyo Seiyaku Co., Ltd.) can be used. PVP is used as a stabilizer for amlodipine or a salt thereof in the drug layer.

  0.1-20 mass% is preferable, as for content of PVP in the film formulation of this invention, 0.5-10 mass% is further more preferable, and 1-5 mass% is especially preferable. Moreover, 0.1-40 mass% is preferable, as for content of PVP in a drug layer, 0.5-20 mass% is further more preferable, and 1-10 mass% is especially preferable.

  As the glycerin used in the present invention, glycerin having a concentration of 84 to 87% is preferable, and concentrated glycerin having a concentration of 98% or more is particularly preferable. As such concentrated glycerin, commercially available products (for example, Japanese Pharmacopoeia Concentrated Glycerin (Kao Co., Ltd.), Japanese Pharmacopoeia Concentrated Glycerin (Sakamoto Pharmaceutical Co., Ltd.) can be used. Among them, it is used as a stabilizer for amlodipine or a salt thereof.

  The content of glycerin in the film preparation of the present invention is preferably 0.1 to 20% by mass, more preferably 0.5 to 10% by mass, and particularly preferably 1 to 5% by mass. In addition, the content of glycerin in the drug layer is preferably 0.5 to 50% by mass, more preferably 1 to 30% by mass, and particularly preferably 5 to 15% by mass.

  The film forming agent in the present invention means a component having a property of forming a film when the aqueous solution and / or the alcohol-containing aqueous solution is dried, and is particularly limited as long as it has such a film forming ability. For example, hydroxypropylcellulose (HPC), hypromellose (hydroxypropylmethylcellulose, HPMC), pullulan, hydroxyethylcellulose, carboxymethylcellulose / sodium, carboxymethylcellulose / calcium, carboxymethylcellulose / potassium, carboxymethylcellulose, sodium alginate, etc. 1 type or 2 types or more selected from these can be used. In particular, from the viewpoint of the stability of amlodipine and salts thereof, it is preferable to use hydroxypropylcellulose and hypromellose, and hydroxypropylcellulose is particularly preferably used for the drug layer and the intermediate layer, and hypromellose is particularly preferably used for the coating layer.

  Here, hydroxypropylcellulose means hydroxypropyl ether of cellulose, and is a commercially available product (for example, Celny SSL, Celnie SL, Celnie L, Celnie M, Celnie H (Nippon Soda Co., Ltd.), L-HPC (Low Substitution degree hydroxypropyl cellulose, Shin-Etsu Chemical Co., Ltd., etc.) The substitution degree in hydroxypropyl cellulose is not particularly limited, and the substitution degree is preset when etherifying cellulose. In the present invention, those containing 50 to 80%, more preferably 53.4 to 77.5% of hydroxypropoxy groups are preferred. Is not particularly limited, but, for example, 2% by mass aqueous solution at 20 ° C. In the case where hydroxypropylcellulose is used in the drug layer and the intermediate layer, the drug layer is more preferable than the intermediate layer. It is preferable to use hydroxypropylcellulose having a high viscosity.

  Hypromellose means a cellulose ester in which a 2-hydroxypropyl group is introduced into methylcellulose, and commercially available products (for example, TC-5, SB-4, Metrows (Shin-Etsu Chemical Co., Ltd., etc.)) can be used. The degree of substitution in hypromellose is not particularly limited, and a desired degree of substitution can be obtained by preliminarily setting the degree of substitution when etherifying methylcellulose. It is preferable that the propoxy group contains 4 to 12%, further 7 to 12%, methoxyl group 19 to 30%, and further 28 to 30%, although the viscosity of hypromellose is not particularly limited. A kinematic viscosity (15th revised Japanese Pharmacopoeia) of a 2% by mass aqueous solution at ℃ is 3.0 to 15.0 mPa · s. Masui.

The content of the film forming agent in the film preparation of the present invention is preferably 0.5 to 75% by mass, more preferably 1 to 70% by mass, and particularly preferably 2 to 65% by mass.
Moreover, 5-90 mass% is preferable, as for content of the film formation agent in a drug layer, 10-80 mass% is more preferable, and 20-70 mass% is especially preferable.
Furthermore, the content of the film forming agent in the coating layer is preferably 30 to 90% by mass, more preferably 40 to 80% by mass, and particularly preferably 50 to 70% by mass.
Furthermore, the content of the film forming agent in the intermediate layer is preferably 30 to 95% by mass, more preferably 40 to 90% by mass, and particularly preferably 50 to 85% by mass.

  In addition to the above components, one or more commonly used pharmaceutical additives can be used in the drug layer of the film preparation of the present invention as necessary. Examples of the pharmaceutical additive include, but are not limited to, a disintegrant, a colorant, a corrigent, a sweetener, and a plasticizer described below. In addition, the content of these in the drug layer can be appropriately set within a range that does not impair the object of the present invention.

Examples of the disintegrant used in the present invention include carmellose and its salt, starch, sucrose fatty acid ester, gelatin, sodium hydrogen carbonate, dextrin, dehydroacetic acid and its salt, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene poly Examples thereof include oxypropylene glycol, maltitol, trehalose and the like, and one or a combination of two or more selected from these is preferable. Of these, maltitol and trehalose are particularly preferable.
The content of the disintegrant in the film preparation of the present invention is preferably 1 to 30% by mass, particularly preferably 5 to 25% by mass.
Further, the content of the disintegrant in the coating layer is preferably 5 to 60% by mass, particularly preferably 10 to 50% by mass.
Furthermore, the content of the disintegrant in the intermediate layer is preferably 1 to 60% by mass, particularly preferably 10 to 50% by mass.

Examples of the corrigent used in the present invention include sour agents such as menthol, ascorbic acid, tartaric acid, citric acid, malic acid, and salts thereof, and one or a combination of two or more selected from these. preferable. Of these, menthol is particularly preferable.
The content of the corrigent in the film preparation of the present invention is preferably 0.05 to 1% by mass, particularly preferably 0.1 to 0.5% by mass.
Further, the content of the corrigent in the coating layer is preferably 0.1 to 5% by mass, particularly preferably 1.0 to 2.0% by mass.

Examples of the sweetener used in the present invention include aspartame, stevia, sucralose, glycyrrhizic acid or a salt thereof (for example, alkali metal salt), thaumatin, acesulfame potassium, saccharin or a salt thereof (for example, an alkali metal salt), and the like. One or a combination of two or more selected from these is preferred. Among them, glycyrrhizic acid salt, saccharin salt and sucralose are particularly preferable.
The content of the sweetener in the film preparation of the present invention is preferably 0.1 to 10% by mass, particularly preferably 0.5 to 5% by mass.
Further, the content of the sweetening agent in the coating layer is preferably 0.1 to 40% by mass, particularly preferably 1.0 to 20% by mass.

Examples of the colorant used in the present invention include yellow ferric oxide, brown iron oxide, caramel, black iron oxide, titanium oxide, ferric oxide, tar dye, aluminum lake dye, copper chlorophyllin sodium, and the like. One or a combination of two or more selected from the above is preferred. Of these, titanium oxide and iron sesquioxide are particularly preferable.
The content of the colorant in the film preparation of the present invention is preferably 0.01 to 10% by mass, particularly 0.05 to 5% by mass.
In addition, the content of the colorant in the coating layer is preferably 0.1 to 20% by mass, particularly preferably 0.2 to 15% by mass.

Examples of the plasticizer used in the present invention include sesame oil, sorbitol, castor oil, propylene glycol, polysorbate 80 (polyoxyethylene (20) sorbitan oleate), polyethylene glycol [for example, Macrogol 400 (of oxyethylene units). Polymerization degree n is 7 to 9, the same applies hereinafter, macrogol 600 (n is 11 to 13), macrogol 1500 (a mixture of n is 5 to 6 and n is 28 to 36), macrogol 4000 (N is 59 to 84), macrogol 6000 (n is 165 to 210)] and the like, and one or a combination of two or more selected from these is preferable. Among these, polyethylene glycol, particularly Macrogol 400 is preferable.
0.1-20 mass% is preferable, as for content of the plasticizer in the film formulation of this invention, 0.5-15 mass% is still more preferable, and 1-10 mass% is especially preferable.
Further, the content of the plasticizer in the intermediate layer is preferably 0.1 to 50% by mass, particularly preferably 0.1 to 30% by mass.

The film preparation of the present invention has a three-layer structure in which a coating layer, a drug layer, and a coating layer are sequentially laminated. When the same kind of layers are laminated adjacent to each other, they adhere to each other. In order to perform the same function as a unit, the present invention handles substantially one layer. In addition, the thickness of the whole film preparation is preferably 50 to 200 μm, particularly preferably 70 to 180 μm. In that case, the thickness of the drug layer is preferably 10 to 50 μm, particularly preferably 20 to 40 μm, and the thickness of the coating layer is preferably 10 to 50 μm, particularly preferably 20 to 50 μm. Thereby, it is possible to dissolve quickly in the oral cavity. In addition, the size of the film preparation of the present invention is not particularly limited as long as it is easy to take, but for example, it is preferably about 1 to ⁵ cm ² , and the shape is also easy to take. There is no particular limitation as long as it is a material, and for example, a square, a circle, an ellipse, or the like can be appropriately selected.

The film preparation of this invention can be suitably manufactured by a conventional or well-known method. For example, it is manufactured by laminating a first coating layer on a release film such as PET (polyethylene terephthalate), then laminating a drug layer, and then laminating a second coating layer on the drug layer. Can do. In addition, an intermediate product in which a first coating layer is laminated on a release film and a drug layer is further laminated, and an intermediate product in which a second coating layer is further laminated on the release film and a drug layer is further laminated. It is also possible to produce by manufacturing and then bonding and pressing so that both drug layers face each other.
Further, when an intermediate layer is provided between two drug layers or between a drug layer and a coating layer, it can be produced by the same method as described above. The coating layer, intermediate layer, drug layer, intermediate layer, and second coating layer are sequentially laminated, or two intermediate products in which the coating layer, intermediate layer, and drug layer are sequentially laminated on the release film are prepared. The two drug layers can be manufactured by being bonded and pressure-bonded so as to face each other.
In addition, the film forming agent in a 1st coating layer and a 2nd coating layer may be the same, and may differ.

  EXAMPLES Hereinafter, although an Example etc. demonstrate this invention further more concretely, this invention is not limited to the following Example.

[Example 1]
30 parts by mass of purified water, 3.47 parts by mass of amlodipine besylate (2.5 parts by mass as amlodipine), 6.95 parts by mass of hydroxypropylcellulose (HPC-SL, Nippon Soda Co., Ltd.), polyvinylpyrrolidone (PVP- K90, 1.0 parts by mass of Nippon Shokubai Co., Ltd. and 1.08 parts by mass of concentrated glycerin (Pharmacopeia concentrated glycerin, Kao Corporation) were added and dissolved by stirring to obtain a drug layer solution.
Further, in a purified water / anhydrous ethanol (15 parts by mass / 15 parts by mass) mixed solvent, hypromellose (TC-5R, Shin-Etsu Chemical Co., Ltd.) 5.35 parts by mass, trehalose 2.0 parts by mass, saccharin sodium 0.3 Mass parts, 1.25 parts by mass of dipotassium glycyrrhizinate, 0.10 parts by mass of L-menthol and 0.04 parts by mass of iron sesquioxide were added and dissolved by stirring to obtain a coating layer solution.
Furthermore, 5.2 parts by mass of hydroxypropylcellulose (HPC-SSL, Nippon Soda Co., Ltd.), 3.0 parts by mass of maltitol, and 1.8 parts by mass of Macrogol 400 are added to 20 parts by mass of purified water and dissolved by stirring. Thus, an intermediate layer 1 solution was obtained.
First, the coating layer solution was spread on a polyester release film and dried to form a coating layer, and then the drug layer solution was spread on the coating layer and dried to laminate the drug layer. Next, the intermediate layer 1 solution was spread on the drug layer and dried to obtain a three-layer structure of coating layer / drug layer / intermediate layer 1.
Two sets of this three-layer structure were prepared, and thermocompression bonded with a laminating machine so that the intermediate layers of the two three-layer structures were opposed to each other, and coating layer / drug layer / intermediate layer 1 / drug layer / coating layer 5 A layer structure was obtained. This five-layer structure was cut into 20 × 14 mm to obtain a film preparation having a thickness of about 100 μm.

[Example 2]
A film preparation having a thickness of about 100 μm in the same manner as in Example 1 except that the amount of amlodipine besylate in the drug layer solution of Example 1 was changed to 6.93 parts by mass (5.0 parts by mass as amlodipine). Got.

[Example 3]
In the same manner as in Example 1, a drug layer and intermediate layer 1 solution was obtained. Also, 1.25 parts by mass of dipotassium glycyrrhizinate in the coating layer solution of Example 1 was changed to 0.42 parts by mass of sucralose to obtain a coating layer solution. Furthermore, 1.6 parts by mass of hydroxypropylcellulose (HPC-SSL, Nippon Soda Co., Ltd.) and 0.4 parts by mass of Macrogol 400 were added to 2 parts by mass of purified water and dissolved by stirring to obtain an intermediate layer 2 solution. It was.
First, the coating layer solution was spread on a polyester release film and dried to form a coating layer, and then the intermediate layer 1 solution was spread on the coating layer and dried to laminate the intermediate layer 1. Next, the drug layer solution was spread on the intermediate layer 1 and dried to obtain a three-layer structure of coating layer / intermediate layer 1 / drug layer.
Two sets of this three-layer structure were prepared, and the intermediate layer 2 solution was spread on the drug layer of one of the three-layer structures and dried to form four layers of coating layer / intermediate layer 1 / drug layer / intermediate layer 2 A structure was obtained.
Next, the resulting 3-layer structure drug layer and the 4-layer structure intermediate layer 2 were thermocompression bonded by a laminating machine so that the coating layer / intermediate layer 1 / drug layer / intermediate layer 2 / drug layer / A seven-layer structure of intermediate layer 1 / coating layer was obtained. This seven-layer structure was cut into 20 × 14 mm to obtain a film preparation having a thickness of about 100 μm.

[Example 4]
A drug layer solution was obtained in the same manner as Example 1. Further, a coating layer solution was obtained in the same manner as in Example 3. Further, an intermediate layer 1 solution was obtained in the same manner except that the solvent of the intermediate layer 1 solution of Example 1 was changed to purified water / absolute ethanol (13.5 parts by mass / 6.5 parts by mass).
First, the coating layer solution is spread on a polyester release film and dried to form a coating layer, and then the intermediate layer 1 solution is spread on the coating layer and dried to form a laminate of the intermediate layer 1. Got the body.
Two sets of the two-layer structure are prepared, and the drug layer solution is spread on the intermediate layer 1 of one of the two-layer structures and dried to obtain a three-layer structure of coating layer / intermediate layer 3 / drug layer. It was.
Next, the obtained intermediate layer 1 of the two-layer structure and the drug layer of the three-layer structure are thermocompression-bonded with a laminating machine so that the coating layer / intermediate layer 1 / drug layer / intermediate layer 1 / coating layer A five-layer structure was obtained. This five-layer structure was cut into 20 × 14 mm to obtain a film preparation having a thickness of about 100 μm.

[Reference Example 1]
A film preparation having a thickness of about 100 μm was obtained in the same manner as in Example 1 except that polyvinylpyrrolidone and concentrated glycerin were not blended in the drug layer solution of Example 1.

[Reference Example 2]
A film preparation having a thickness of about 100 μm was obtained in the same manner as in Example 1 except that concentrated glycerin was not blended in the drug layer solution of Example 1.

[Test example] Stability test For the film preparations of Examples 1 to 4 and Reference Examples 1 to 2, the residual ratio of amlodipine after storage at 50 ° C for 0.5 months and 1 month was measured. The residual ratio was calculated by measuring the amlodipine content in the preparation by the HPLC method, and calculating the ratio to the content immediately after production.

  Table 1 shows the compositions of the film preparations obtained in Examples and Reference Examples, and the results of stability tests. In Table 1, a sample stored at 50 ° C. for 0.5 month is expressed as “50 ° C.-0.5M”, and a sample stored at 50 ° C. for 1 month is expressed as “50 ° C.-1M”.

As is apparent from Table 1, the film preparations (Examples 1 to 4) of the present invention in which polyvinylpyrrolidone, concentrated glycerin and a film forming agent were blended in a drug layer containing amlodipine besylate were stored at 50 ° C. for 1 month. Even after the test, the residual rate of amlodipine was high.
On the other hand, it was confirmed that in the film preparations of Reference Examples 1 and 2 in which the drug layer does not contain polyvinylpyrrolidone and / or concentrated glycerin, the residual ratio of amlodipine decreases with time.
Therefore, it has been found that the stability of amlodipine is significantly improved by blending polyvinylpyrrolidone and concentrated glycerin into a drug layer containing amlodipine.
Further, when the film preparation of the present invention (Example 1) was taken without water, it was confirmed that immediate effect was expected since it was dissolved in the oral cavity within 30 seconds.

Claims (3)

A pair of outermost layers comprising a coating layer, and at least one drug layer sandwiched between the outermost layers,
A film preparation, wherein the drug layer contains amlodipine or a salt thereof, polyvinylpyrrolidone, glycerin, and a film forming agent.   The film preparation according to claim 1, wherein the film forming agent is hydroxypropylcellulose and / or hypromellose.   The film formulation according to claim 1 or 2, further comprising an intermediate layer between the two drug layers and / or between the drug layer and the coating layer.