Capsule preparation

Abstract

To provide capsule formulations with suppressed insolubilization of a capsule coating film, in capsule formulations containing polyphenol.SOLUTION: In order to solve the above problems, provided is a capsule formulation characterized by that a capsule content contains (A) polyphenol, the capsule content or a capsule coating film contains (B) an organic acid, the (B) organic acid contains one or more selected from tartaric acid, fumaric acid, malic acid, and lactic acid, the mass ratio (A / B) of the content of (A) polyphenol to the content of (B) organic acid in the capsule formulation is 8 or less. This makes it possible to provide a capsule formulation with suppressed insolubilization of the capsule coating film, in capsule formulations containing polyphenol.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a capsule preparation in which insolubilization of the capsule film is suppressed. More specifically, the present invention relates to a capsule preparation in which insolubilization of the capsule film is suppressed when the capsule content contains polyphenols.

Background Art

[0002] Conventionally, various capsule preparations have been used in dosage forms such as drugs. Examples of these capsule preparations include soft capsule preparations (soft capsules) and hard capsule preparations (hard capsules). Soft capsule preparations are used for the purpose of encapsulating a liquid content such as a concentrated solution, suspension, or oily substance containing a drug and administering it to a living body. Hard capsule preparations are used for the purpose of encapsulating powders, granules, etc. and administering them to a living body.

[0003] These capsule preparations usually dissolve the capsule, i.e., the film, in the living body, and the capsule content containing the active ingredient is released to exert its effect. However, insolubilization of the film may occur due to the interaction between the film components, particularly gelatin, and specific components contained in the capsule content, resulting in a delay in the disintegration of the capsule preparation.

[0004] In response to such problems, for example, Patent Document 1 discloses a soft capsule film portion containing gelatin, a plasticizer, and water. When adjusting the soft capsule content, the content components contain 1 to 60% by weight of polyphenols, 1 to 20% by weight of a surfactant, and 1 to 20% by weight of an antioxidant. A technique for a soft capsule is disclosed.

[0005] Further, Patent Document 2 discloses a technique for a capsule preparation in which the capsule content uniformly contains lecithin and citric acid or phytic acid.

Prior Art Documents

Patent Documents

[0006] Patent Document 1 Japanese Patent Application Laid-Open No. 2011-79786 Patent Document 2 Japanese Patent Application Laid-Open No. 2012-51945 Summary of the Invention Problems to be Solved by the Invention

[0007] The above-described conventional technologies aim to suppress the insolubilization of the capsule film, but sufficient effects of suppressing the insolubilization of the film have not been obtained with these technologies.

[0008] An object of the present invention is to provide a capsule preparation in which the insolubilization of the capsule film is suppressed in a capsule preparation containing polyphenols. Means for Solving the Problems

[0009] The present inventor has found that in a capsule preparation in which the content filled in the capsule (capsule content) contains polyphenols, the insolubilization of the capsule film can be suppressed by containing a specific organic acid in the capsule content and / or the capsule film, and has completed the present invention.

[0010] That is, the present invention provides the following capsule preparation. [1] The capsule content contains (A) polyphenols, the capsule content and / or the capsule film contains (B) an organic acid, the (B) organic acid contains one or more selected from tartaric acid, fumaric acid, malic acid, and lactic acid, A capsule preparation, characterized in that the mass ratio (A / B) of the content of (A) polyphenols to the content of (B) organic acid in the capsule preparation is 8 or less. According to the capsule preparation of the present invention, it is possible to provide a capsule preparation in which the insolubilization of the capsule film is suppressed in a capsule preparation containing polyphenols. [2] The capsule preparation according to [1], wherein the capsule content contains (B) an organic acid, and the content of the (B) organic acid in the capsule content is 0.25% by mass or more and 15% by mass or less. According to this feature, insolubilization of the capsule film can be further suppressed. [3] The capsule preparation according to [1] or [2], wherein the (A) polyphenol contains at least one selected from anthocyanin, flavonoid or its glycoside. According to this feature, the effect of suppressing insolubilization of the capsule film of the present invention can be further exerted. [4] The capsule preparation according to any one of [1] to [3], wherein the capsule preparation is a soft capsule preparation. According to this feature, insolubilization of the capsule film can be further suppressed.

Effects of the Invention

[0011] According to the present invention, in a capsule preparation containing polyphenol, a capsule preparation in which insolubilization of the capsule film is suppressed can be provided.

Modes for Carrying Out the Invention

[0012] [Capsule Preparation] In the capsule preparation of the present invention, the capsule content contains (A) polyphenol, the capsule content or the capsule film contains (B) an organic acid, the (B) organic acid contains at least one selected from tartaric acid, fumaric acid, malic acid, and lactic acid, and the mass ratio (A / B) of the content of (A) polyphenol to the content of (B) organic acid in the capsule preparation is 8 or less.

[0013] The capsule preparation of the present invention is such that the insolubilization of the capsule film that occurs when the capsule content contains polyphenols is suppressed by containing a specific organic acid in a specific ratio with respect to the polyphenols. As a result, the delay in the disintegration of the capsule preparation and the formation of an insoluble film are suppressed. For this reason, the capsule preparation can be easily dissolved in the living body after ingestion and can easily release the capsule content.

[0014] The capsule preparation of the present invention is mainly composed of a film and a capsule content, but may include other components. The active ingredient is mainly contained in the capsule content. Examples of the capsule preparation referred to in the present invention include soft capsule preparations and hard capsule preparations. A soft capsule preparation mainly refers to a preparation in which a liquid capsule content is encapsulated and molded with a capsule film such as gelatin. A hard capsule preparation mainly refers to a preparation in which a powdery or granular capsule content is enclosed in a cylindrical capsule (capsule film). The capsule preparation of the present invention is preferably a soft capsule preparation.

[0015] The capsule preparation of the present invention contains (B) an organic acid, and (B) the organic acid is characterized by containing one or more selected from specific organic acids, namely tartaric acid, fumaric acid, malic acid, and lactic acid. It is preferable that (B) the organic acid is one or more selected from tartaric acid, fumaric acid, malic acid, and lactic acid, and it is more preferable that (B) the organic acid is tartaric acid. The organic acid is contained in the capsule content and the film of the capsule preparation, and from the viewpoints of the effect of suppressing insolubilization and production efficiency and the physical properties of the film, it is preferably contained in the capsule content.

[0016] In the capsule preparation of the present invention, the mass ratio (A / B) of the content of (A) polyphenols to the content of (B) organic acid is 8 or less. The upper limit value is preferably 5 or less. The lower limit value is preferably 0.1 or more. By setting the value of (A / B) within the above range, the insolubilization of the capsule film can be more effectively suppressed.

[0017] The disintegration time of the capsule preparation of the present invention is, for example, 120 minutes or less. As the upper limit value, it is preferably 80 minutes or less, more preferably 40 minutes or less. As the lower limit value, it is preferably 1 minute or more, more preferably 2 minutes or more. By setting the disintegration time of the capsule within the above range, the capsule contents can be appropriately released when ingested into the body. In the present invention, the disintegration time is the time determined by the disintegration test under the conditions specified in the Japanese Pharmacopoeia.

[0018] [Capsule membrane] The capsule preparation of the present invention has a capsule membrane. The composition of the capsule membrane is appropriately set according to the use and composition, but is roughly classified into whether it is a soft capsule preparation or a hard capsule preparation.

[0019] The components of the capsule membrane of the soft capsule preparation include, for example, a polymer component, a humectant, and the like. The polymer component is not particularly limited, and examples include gelatin, starch, carrageenan, and the like. Among these, gelatin is preferable from the viewpoint that the effect of suppressing insolubilization of the present invention is more exerted. The content of gelatin in the capsule membrane is, for example, 1% by mass or more and 95% by mass or less. As the lower limit value, it is preferably 5% by mass or more, and as the upper limit value, it is 90% by mass or less. The humectant is not particularly limited, and examples include saccharides such as glucose, alcohols such as glycerin, and sugar alcohols such as sorbitol. The blending ratio of each component in the capsule membrane of the soft capsule preparation is not particularly limited and can be appropriately set. The capsule membrane of the soft capsule preparation is formed by filling the capsule contents into a sheet produced from the above components of the capsule membrane and performing pressure bonding molding or the like.

[0020] The components of the capsule film of the hard capsule preparation include, for example, polymer components. Specifically, they include gelatin, pullulan, agar, carrageenan, starch, starch degradation products, alginic acid, HPMC (hydroxypropyl methylcellulose), polyvinyl alcohol (PVA), starch derivatives, gellan gum, and the like. Among these, gelatin is preferred from the viewpoint of more effectively exhibiting the insolubilization inhibitory effect of the present invention. The content of gelatin in the capsule film is, for example, 1% by mass or more and 95% by mass or less. The lower limit is preferably 5% by mass or more, and the upper limit is 90% by mass or less. The blending ratio of each component in the capsule film of the hard capsule preparation is not particularly limited and can be set as appropriate. The capsule film of the hard capsule preparation is usually used by molding the above components of the capsule film into the shape of a cylindrical body and a cap. As the capsule film of the hard capsule preparation used in the present invention, commercially available products may be used.

[0021] In the capsule preparation of the present invention, when an organic acid is contained in the capsule film, the content in the capsule film is not particularly limited, but is, for example, 0.1% by mass or more. From the viewpoint of suppressing insolubilization, the lower limit is preferably 0.25% by mass or more, and more preferably 0.5% by mass or more.

[0022] [Capsule contents] <(A) Polyphenol> The capsule preparation of the present invention is characterized by containing polyphenols as the capsule content. Polyphenols are compounds or their glycosides having two or more phenolic hydroxyl groups in the same molecule, and are components contained in most plants. The polyphenols used in the capsule preparation of the present invention are not particularly limited, and examples include anthocyanins, isoflavones, flavonols, flavanones, flavanols, flavones, catechins, tannins, flavonoids, chlorogenic acid, phenylcarboxylic acid, ellagic acid, lignans, curcumin, coumarin, or their glycosides. Among these, it is preferable to contain one or more selected from anthocyanins, picnogenol, flavonoids or their glycosides, more preferably to contain one or more selected from flavonoids, anthocyanins or their glycosides, and particularly preferably to contain anthocyanins or their glycosides. As the anthocyanins or their glycosides, it is possible to use, for example, bilberry extracts having a particularly high content.

[0023] The content of polyphenols in the capsule content is not particularly limited, but is, for example, 0.1% by mass or more and 60% by mass or less. The lower limit is preferably 0.5% by mass or more, more preferably 1.5% by mass or more. The upper limit is preferably 40% by mass or less, more preferably 20% by mass or less. By setting the content of polyphenols within the above range, a sufficient amount of polyphenols can be formulated, and the effect of suppressing insolubilization is further exerted.

[0024] <(B) Organic acid> The capsule formulation of the present invention contains an organic acid, and the organic acid contains one or more selected from tartaric acid, fumaric acid, malic acid, and lactic acid. (B) It is preferable that the organic acid is one or more selected from tartaric acid, fumaric acid, malic acid, and lactic acid, and (B) it is more preferable that the organic acid is tartaric acid. As described above, the organic acid is contained in the capsule contents and the capsule film of the capsule formulation, and from the viewpoints of the suppression effect of insolubilization and production efficiency and the physical properties of the film, it is preferably contained in the capsule contents. When the above-mentioned organic acid is contained in the capsule contents, the content of the organic acid in the capsule contents is not particularly limited, but for example, it is 0.1% by mass or more. The lower limit is preferably 0.25% by mass or more, more preferably 2.0% by mass or more, and still more preferably 5% by mass or more from the viewpoint of the suppression effect of insolubilization. The upper limit is preferably 20% by mass or less, more preferably 15% by mass or less from the viewpoint of production suitability.

[0025] [Other components] The capsule formulation of the present invention may contain components other than polyphenols and organic acids as the capsule contents. The other components vary depending on whether it is a soft capsule formulation or a hard capsule formulation, or depending on the use and formulation of the capsule formulation. In the case of a soft capsule formulation, although not particularly limited, for example, a dispersant, a diluent oil, a surfactant, a sweetener, a fragrance, a coloring agent, a preservative, an active ingredient, etc. can be mentioned. In the case of a hard capsule formulation, although not particularly limited, an excipient, a lubricant, a fluidizing agent, a surfactant, a sweetener, a fragrance, a coloring agent, a preservative, etc. can be mentioned.

[0026] [Diluent oil] The capsule formulation of the present invention may contain a diluent oil. Diluent oils are generally used to dilute the capsule contents of soft capsule formulations. Examples of diluent oils include oils rich in saturated fatty acids such as coconut oil, palm oil, palm kernel oil, grape seed oil, and medium-chain fatty acid triglycerides (MCT), and oils rich in unsaturated fatty acids such as soybean oil, sesame oil, perilla oil, peanut oil, rice bran oil (rice oil, rice germ oil), wheat germ oil, corn oil, rapeseed oil, cottonseed oil, pumpkin seed oil, olive oil, guava seed oil, date palm seed oil, grape seed oil, camellia seed oil, sunflower oil, and safflower oil. These diluent oils can be used in any combination of one or more at any blending amount as appropriate. The blending amount of the diluent oil in the capsule contents of the capsule formulation of the present invention is not particularly limited, but is, for example, 0.1% by mass or more and 20% by mass or less. The lower limit is preferably 0.5% by mass or more. The upper limit is preferably 10% by mass or less.

[0027] <Dispersant> The capsule formulation of the present invention may contain a dispersant. By including a dispersant, separation of the capsule contents is prevented and storage stability is improved. Examples of dispersants include beeswax, glycerin fatty acid esters, polyglyceryl condensed ricinoleate, sucrose fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, hydrogenated rapeseed oil, hydrogenated safflower oil, hydrogenated palm oil, sitosterol, stigmasterol, campesterol, brassicasterol, cocoa butter powder, carnauba wax, rice wax, candelilla wax, paraffin, and the like. Among these, beeswax is preferred. These dispersants can be used in any combination of one or more as appropriate. The content of the dispersant is not particularly limited, but is, for example, 0.1% by mass or more and 30% by mass or less. The lower limit is preferably 1% by mass or more. On the other hand, the upper limit is preferably 10% by mass or less.

[0028] Examples of excipients include, for example, crystalline cellulose, lactose, sucrose, glucose, D-mannitol, powdered reduced maltose syrup, maltitol, xylitol, erythritol, D-sorbitol, maltose, starch and starch derivatives, aspartame, glycyrrhizic acid and its salts, saccharin and its salts, stevia and its salts, sucralose, acesulfame potassium, calcium hydrogen phosphate, hydroxypropylmethylcellulose, polyvinylpyrrolidone, methylcellulose, dextrin, starch and starch derivatives, guar gum, gum arabic, tragacanth, alginic acid and its salts, pullulan, carrageenan, gelatin, agar, carboxyvinyl polymer, sodium carboxymethylcellulose, starch, sodium carboxymethyl starch, sodium carboxymethylcellulose, low-substituted hydroxypropyl cellulose, etc. These excipients can be used in any combination of one or more at any blending amount as appropriate.

[0029] Examples of lubricants include, for example, calcium stearate, magnesium stearate, talc, hydrogenated vegetable oil, etc. Among them, calcium stearate is preferred. These lubricants can be used in any combination of one or more at any blending amount as appropriate. Examples of fluidizing agents include, for example, fine silicon dioxide, etc.

Examples

[0030] Examples are shown below to further explain the present invention, but the present invention is not limited to these examples in any way. The blending amounts in the examples are shown in mass% unless otherwise specified.

[0031] (1) Test 1: Selection of the component for suppressing insolubilization of the capsule film By the following method, the capsule film and the capsule contents of the soft capsule preparations of each example shown in Tables 1 and 2 were prepared, and the effect of suppressing insolubilization of the capsule film of various test components (organic acids, organic acid salts, vitamin E, lecithin) was evaluated.

[0032] (Preparation of the capsule film) A film sheet with a thickness of 0.8 mm made of gelatin, glycerin, and water was cut into squares of about 1.5 cm × 1.5 cm and dried at room temperature until the moisture content reached about 8%. This was used in this test as the capsule film of the soft capsule preparation.

[0033] (Preparation of Capsule Contents) As shown in Tables 1 and 2, as the capsule contents of the soft capsule preparation, medium-chain fatty acid triglyceride (MCT) (「Coconutard MT」: manufactured by Kao Corporation), which is a diluent oil, and / or beeswax was added to olive oil, heated and dissolved, and this solution was allowed to cool at room temperature. Then, polyphenol (bilberry extract: 「Bilberry Extract ET」 (anthocyanin content about 36%), manufactured by Indena Japan Co., Ltd.) and the test component were added to this solution, and uniformly mixed with a homomixer. This solution was used as the capsule contents.

[0034] (Disintegration Test 1 of Capsule Film) 20 g of the solution of the capsule contents was collected in a cream bottle, the cut capsule film was put into it, and after sealing, it was stored at 60 °C for 7 days. After that, the capsule film was taken out, and a disintegration test was performed on this capsule film under the conditions specified in the Japanese Pharmacopoeia. The disintegration test solution was prepared using water at 37 °C, and the time when the capsule film disintegrated was measured. If it did not disintegrate within 120 minutes from the start of the test, it was regarded as 「×: insoluble」.

[0035]

Table 1

[0036]

Table 2

[0037] As shown in Table 1, in Examples 1 to 4 containing specific organic acids, namely tartaric acid, fumaric acid, malic acid, and lactic acid, it was confirmed that the insolubilization of the capsule film by polyphenol was suppressed as compared with Comparative Examples 1 to 12 and Comparative Examples 14 to 20 that did not contain the specific organic acids. Moreover, in Comparative Example 13 which does not contain polyphenols, capsule insolubilization was not observed.

[0038] (2) Test 2: Test on the ratio of polyphenols to organic acids The capsule contents of soft capsules having the compositions shown in Tables 3 to 5 were prepared in the same procedure as the preparation of the capsule contents in Test 1. In the tables, "rice bran oil" (manufactured by Oriza Oil Co., Ltd.) was used as the dilution oil. Then, using the capsule film manufactured in the same manner as in Test 1, the solubility of the capsule film was evaluated according to the following procedure.

[0039] (Disintegration test of capsule film 2) 20 g of the solution of the capsule contents was collected in a cream bottle, the cut capsule film was put therein, and after sealing, it was stored at 60 °C for 7 days. Thereafter, the capsule film was taken out, and the disintegration test was performed on this capsule film under the conditions specified in the Japanese Pharmacopoeia. The disintegration test solution was prepared using water at 37 °C, and the time when the capsule film dissolved was measured. The test was carried out for 120 minutes, and if it did not disintegrate within 120 minutes, it was regarded as "insoluble". In addition, the state of the capsule film was visually evaluated using the following criteria. The test was performed with n = 3, and the dissolution time showed the average value. (Evaluation of appearance) ◎: Film dissolves in less than 40 minutes. ○: Film dissolves in 40 minutes or more and less than 80 minutes. △: Film dissolves in 80 minutes or more and less than 120 minutes. ×: Film is insoluble even after 120 minutes have passed.

[0040] [Table 3]

[0041] [Table 4]

[0042] [Table 5]

[0043] As a result of the tests, it was confirmed that in the examples where the mass ratio (A / B) of the content of (A) polyphenol to the content of (B) organic acid was 8 or less, the insolubilization of the capsule film by the polyphenol was suppressed. Also, it was confirmed that it is preferable that A / B is 5 or less.

[0044] (3) Test 3: Tests on other polyphenols The capsule contents of the soft capsules having the composition shown in Table 6 were prepared in the same procedure as the preparation of the capsule contents in Test 1. In the table, ginkgo leaf extract was "Ginkgo leaf extract C" (flavonol glycoside content of about 24%, manufactured by Maruzen Pharmaceutical Co., Ltd.), and the diluent oil was "rice bran oil" (manufactured by Oriza Oil Co., Ltd.). Then, using the capsule film manufactured in the same manner as in Test 1, the solubility of the capsule film was evaluated according to the following procedure.

[0045] (Disintegration test of capsule film 3) 20 g of the solution of the capsule contents was collected in a cream bottle, and the cut capsule film was put therein. After sealing, it was stored at 60°C for 14 days. Thereafter, the capsule film was taken out, and a disintegration test was conducted on this capsule film under the conditions specified in the Japanese Pharmacopoeia. The disintegration test solution was prepared using water at 37°C, and the time when the capsule film dissolved was measured. The test was conducted for 120 minutes, and if it did not disintegrate within 120 minutes, it was regarded as "insoluble". Also, the state of the capsule film was visually evaluated using the following criteria. The test was conducted with n = 3, and the dissolution time represents the average. (Evaluation of appearance) ◎: Film dissolves in less than 40 minutes. ○: Film dissolves in 40 minutes or more and less than 80 minutes. △: Film dissolves in 80 minutes or more and less than 120 minutes. ×: Film remains insoluble even after 120 minutes have passed.

[0046]

Table 6

[0047] As a result of the tests, even when flavonoid glycosides were used as polyphenols, in Example 15 containing specific organic acids, it was confirmed that the insolubilization of the capsule film by the polyphenols was suppressed as compared with Comparative Example 30 not containing the specific organic acids.

[0048] (4) Test 4: Production of soft capsules The capsule contents of the soft capsules of Formulation 1 and Formulation 2 shown in Table 7 were prepared in the same procedure as the preparation of the capsule contents of Test 1. In the table, the diluent oil was "rice bran oil" (manufactured by Oriza Oil Co., Ltd.), and beeswax was used as the dispersant. Then, 200 mg per capsule of this capsule content was filled into capsules by a conventional method using a soft capsule molding machine with the capsule film prepared in Test 1 to obtain a soft capsule preparation. Then, the obtained soft capsule preparation was tested for disintegration after storage by the procedure shown in the disintegration test of the following capsule preparation.

[0049]

Table 7

[0050] (Disintegration test of capsule preparation) The disintegration of the manufactured soft capsule preparation was tested before and after the accelerated test. The accelerated test was carried out by sealing the soft capsule preparation in an aluminum pouch and storing it under the conditions of Accelerated Test 3 (40 °C, 9 weeks), and then the soft capsule preparation was taken out and used for the test. The disintegration test was carried out according to the conditions specified in the disintegration test method of the Japanese Pharmacopoeia, and the disintegration test solution was water at 37 °C. The time when the capsule preparation disintegrated was measured. The test was carried out with n = 3, and the disintegration time showed the average.

[0051]

Table 8

[0052] From these results, it was confirmed that in the capsule preparation of the present invention, insolubilization of the capsule film is suppressed.

Industrial Applicability

[0053] In the capsule preparation of the present invention, insolubilization of the capsule film by polyphenols is suppressed, and it can be used for capsule preparations such as soft capsule preparations and hard capsule preparations. The capsule preparation and powder composition of the present invention can be utilized in various fields such as pharmaceuticals, quasi-drugs, veterinary products, foods, and supplements.

Claims

1. The capsule contents contain (A) polyphenol and (B) organic acid, wherein the (B) organic acid contains one or more selected from fumaric acid and lactic acid, the capsule film contains gelatin, and a soft capsule preparation, characterized in that the mass ratio (A / B) of the content of (A) polyphenol to the content of (B) organic acid in the capsule preparation is 8 or less.

2. The capsule contents contain (B) organic acid, and the soft capsule preparation according to claim 1, characterized in that the content of the (B) organic acid in the capsule contents is 0.25% by mass or more and 15% by mass or less.

3. The soft capsule preparation according to claim 1 or 2, characterized in that the (A) polyphenol contains one or more selected from at least anthocyanin, flavonoid or its glycoside.

4. The capsule contents contain (A) polyphenol and (B) organic acid, wherein the (B) organic acid contains one or more selected from tartaric acid, fumaric acid, malic acid and lactic acid, the capsule film contains gelatin, and a method for suppressing insolubilization of a capsule film in a soft capsule preparation, characterized in that the mass ratio (A / B) of the content of (A) polyphenol to the content of (B) organic acid in the capsule preparation is 8 or less.

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