JP6944358B2 - Soft capsule disintegration delay inhibitor, soft capsule disintegration delay suppression method - Google Patents

Description

The present invention relates to a polyphenol-containing soft capsule preparation that suppresses disintegration delay.

Gelatin and carrageenan-derived plant polysaccharides are generally used as the film base for soft capsules.
Gelatin reversibly changes into a sol-gel due to temperature changes, has excellent film-forming ability and high mechanical strength of the formed film, easily disintegrates or dissolves in the body, and has nutritional value in itself. It has many advantages as a film base, such as being easily absorbed into the body, and is the most popular as a soft capsule.
However, gelatin soft capsules harden over time and become less disintegrating. Further, when the inclusions of the capsule contain polyphenols such as anthocyanin, catechin, and flavone compound, the curing of the capsule is further promoted. As a result, it causes a delay in the disintegration time in the stomach, and in extreme cases, the capsule may not disintegrate in the stomach.

Various techniques have been proposed to prevent delayed disintegration of gelatin soft capsules containing polyphenols and vitamin C in their contents.
Generally, various substances are added to gelatin constituting a soft capsule. For example, addition of citric acid (Patent Document 1), formulation of polyglutamic acid (Patent Document 2), formulation of inositol 6-phosphoric acid (Patent Document 3), formulation of low molecular weight gelatin (Patent Document 4), glycerin and reduced water candy. There are formulations (Patent Document 5) and the like.

In addition, a method has been proposed in which a specific substance is added to the contents contained in the capsule instead of the capsule film to suppress the delay in disintegration of the soft capsule. In this case, it is blended to suppress the curing action of the soft capsule of the contained substance.
Patent Document 6 describes that a medium-chain fatty acid triglyceride, a dipeptide sweetener, and menthol are blended to suppress hardening of soft capsules.
Patent Document 7 describes that in a soft capsule containing a polyphenol, curing of the soft capsule can be suppressed by further adding a reducing sugar to the content.
Patent Document 8 describes that curing of soft capsules can be suppressed by adding equol to an inclusion containing any of anthocyanins, proanthocyanidins, and procyanidins.
Patent Document 9 describes that when the inclusions contain polyphenols, the hardening of soft capsules can be suppressed by adding lecithin as a surfactant and vitamin E as an antioxidant together with the polyphenols in the contents. ing.

On the other hand, in recent years, oleuropein, which is a polyphenol compound contained in olive leaves and olive oil, and hydroxytyrosol, which is a metabolite thereof, have been attracting attention. This compound has a strong antioxidative action (Patent Document 10), and has attracted attention because it has an action of promoting bone formation (Patent Document 11), preventing fatty liver (Patent Document 12), and the like.

JP-A-59-39834 Japanese Unexamined Patent Publication No. 2005-139152 Japanese Patent No. 3790258 Japanese Unexamined Patent Publication No. 2011-136927 Japanese Unexamined Patent Publication No. 2017-100966 Japanese Unexamined Patent Publication No. 2015-193579 Japanese Unexamined Patent Publication No. 2010-90063 Japanese Unexamined Patent Publication No. 2016-69335 Japanese Unexamined Patent Publication No. 2011-77986 Japanese Unexamined Patent Publication No. 2016-79127 JP-A-2009-227616 Japanese Unexamined Patent Publication No. 2009-263257

The present inventor is conducting research and development of a soft capsule preparation containing a polyphenol compound derived from olive as one component of the content. In the process of researching soft capsule formulations, we faced the problem of hardening and delaying disintegration of gelatin soft capsule films containing contents containing olive-derived polyphenol compounds.
An object of the present invention is to provide a gelatin soft capsule preparation in which the delay in disintegration of a gelatin soft capsule film due to a content containing an olive-derived polyphenol compound is suppressed.

The main configuration of the present invention is as follows.
(1) A soft capsule preparation in which an olive-derived polyphenol and ampelopsin or catechin are encapsulated in a capsule film containing gelatin as a main component.
(2) The soft capsule preparation according to (1), wherein ampelopsin is derived from a wisteria tea extract.
(3) The soft capsule preparation according to (1) or (2), wherein the olive-derived polyphenol is hydroxytyrosol and / or oleuropein.

INDUSTRIAL APPLICABILITY The present invention provides a soft capsule preparation in which the content contains an olive-derived polyphenol compound and the curing of the film is suppressed. This formulation is a soft capsule formulation with suppressed delay in disintegration time.

It is a schematic diagram which shows the test method for evaluating the effect of this invention.

It is a soft capsule preparation in which the content is coated with a soft film, and the soft capsule film portion contains gelatin and is characterized by containing at least an olive-derived polyphenol compound and ampelopsin or catechin as content components. It is a soft capsule preparation.

Ampelopsin is a polyphenol compound extracted from a plant called wisteria tea. Wisteria tea is a plant belonging to the genus Ampelopsis in the family Grapes, and its Chinese name is Akito snake grape. The scientific name is Ampelopsis grossedentata. It is mainly distributed in provinces and autonomous regions such as Guangxi, Guangxi, Yunnan, Guizhou, Hunan, Hubei, Jiangxi, and Fujian in China. People from the Zhuang and Yao tribes in provinces and autonomous regions such as Guangxi and Hunan in China regularly use beverages made from these stems and leaves, which are also used for colds and sore throats. Ampelopsin has been identified as the active body of the therapeutic and antibacterial effects of Fujicha's liver disease.

Ampelopsin is represented by the following chemical formula 1.

AMPelopsin, for example, Fujicha (Ampelopsis grossedentata), DaiKano snake grape (Ampelopsis megalophylla), Guangdong snake grapes (Ampelopsiscantoniensis), from Kenponashi (Hoveniadulcis), Onoeyanagi (Salixsachalinensis), Yorehamatsu (Pinuscontorta), Erythrophleumafricanum and wig (Cercidiphyllumjaponicum) It can be isolated and purified from selected plant extracts. Among these, wisteria tea is preferable.

Specifically, ampelopsin can be obtained from Ampelopsis planta, which is a plant belonging to the genus Ampelopsis, as follows.
That is, the extract obtained by extracting the branches and leaves of dried wisteria tea with hydrous ethanol is concentrated, subjected to column chromatography using, for example, a porous resin (DIAION HP-20), and eluted with 80% by volume hydrous methanol. Amperopsin is obtained in the picture. This can be further purified by reverse phase silica gel column chromatography or recrystallization. The purified ampelopsin is also sold as a reagent, and this can also be used.

To obtain ampelopsin from wisteria tea, perform the following operations.
Using crushed dried wisteria tea leaves or stems or powder as an extraction raw material, it is put into water or a hydrophilic organic solvent or a mixed solvent thereof, and extracted using an arbitrary device at room temperature or a temperature below the boiling point of the solvent. Can be obtained by

Examples of the organic solvent used for extraction include lower alcohols having 1 to 5 carbon atoms such as methanol, ethanol, propyl alcohol and isopropyl alcohol; lower aliphatic ketones such as acetone and methyl ethyl ketone; 1,3-butylene glycol, propylene glycol and iso. Examples thereof include polyhydric alcohols having 2 to 5 carbon atoms such as propylene glycol and glycerin.
Further, a mixed solvent of these hydrophilic organic solvents and water can be used. When a mixed solvent of water and a hydrophilic organic solvent is used, the amount of lower alcohol is 30 to 90 parts by mass with respect to 10 parts by mass of water, and the amount of lower aliphatic ketone is 10 parts by mass of water. On the other hand, it is preferable to add 10 to 40 parts by mass, and in the case of polyhydric alcohol, 10 to 90 parts by mass with respect to 10 parts by mass of water.

A dried and crushed product of wisteria tea is put into a treatment tank filled with an extraction solvent, and allowed to stand for 30 minutes to 2 hours with occasional stirring as necessary to elute soluble components, and then filtered to form a solid product. Is removed, the extraction solvent is distilled off from this extract, and the extract is dried to obtain an extract. The amount of the extraction solvent is preferably 5 to 15 times the amount (mass ratio) of the extraction raw material, and the extraction conditions are usually about 1 to 4 hours at 50 to 95 ° C. when water is used as the extraction solvent. Is. When a mixed solvent of water and ethanol is used as the extraction solvent, it is usually about 30 minutes to 4 hours at 40 to 80 ° C.

When the extraction solvent is distilled off from the obtained extract, a paste-like concentrate is obtained. Further drying gives a solid extract. In the present invention, as long as the content of ampelopsin is 10% by mass or more, preferably 20% by mass or more, the above extract or a concentrated solution thereof may be used. These may be used after being purified by a method such as activated carbon treatment, adsorption resin treatment, ion exchange resin, or liquid-liquid countercurrent distribution.
Therefore, an extract extracted from the above-mentioned wisteria tea and having an increased concentration of ampelopsin can also be used as the composition of the present invention.

The content of ampelopsin in the composition can be analyzed by a known analytical method such as HPLC. The outline of the quantification method is as follows.
-Preparation of sample solution Approximately 20 mg of sample (extract) is precisely weighed, distilled water is added, and sonication is performed to dissolve the sample (extract) to make exactly 50 mL. Accurately dilute 2 mL of this solution to 50 mL to make a sample solution.
・ Preparation of standard solution and preparation of calibration curve
Weigh 2.00 mg of a standard product (manufactured by Ampelopsin SIGMA-ALDRICH), add an appropriate amount of 100% acetonitrile and sonicate to dissolve it, and then add acetonitrile to make exactly 25 mL, and add 80 μg / mL of ampelopsin standard stock solution. Prepare. This standard stock solution is diluted exactly 5-fold with distilled water to prepare a 16 μg / mL ampelopsin standard solution. The injection volume to HPLC is 10, 20, 40 μL, and a calibration curve is prepared based on the peak of ampelopsin.
-HPLC measurement conditions Set the conditions in Table 1 below.

Generally, when the contents of a gelatin-containing soft capsule contain polyphenols, it is known that the reaction between the polyphenols in the contents and the gelatin molecules derived from the soft capsule film causes a delay in capsule disintegration. However, unlike other polyphenols, ampelopsin suppresses the delay in disintegration of soft capsule preparations due to polyphenol compounds and plant extracts containing polyphenols.
The mechanism of this capsule disintegration delay is unclear.
The ampelopsin in the present invention may be purified or extracted from the above-mentioned wisteria tea. Ampelopsin extracted from wisteria tea can be used in the present invention as long as it contains 10% by mass or more of ampelopsin.

The contents of the soft capsule preparation of the present invention include ampelopsin and olive-derived polyphenols as essential constituents. As for the other components, any component can be blended as long as it does not adversely affect the disintegration of the gelatin soft capsule film.

The catechin used in the present invention is botanically the genus Camellia of the Theaceae family.
Tea leaves belonging to sinensis) can be extracted and refined from sencha, roasted tea, kabusecha, gyokuro, etc., which are classified as non-fermented teas depending on the production method.

Generally, the catechins of green tea extract are catechin, galocatechin, catechin gallate, galocatechin gallate, epicatechin, epigallocatechin, epicatechin gallate and epigallocatechin gallate, and the component ratio is plant. It is also affected by the type, variety, and production area of the catechin. In addition, products in which a specific component ratio is industrially increased by a process such as refining are also commercially available.
It was also found as a new finding that catechin alone cures gelatin soft capsules and delays disintegration, but surprisingly suppresses the disintegration delay of gelatin soft capsules due to polyphenols derived from olive leaves or olive extracts. Therefore, by blending catechin, it becomes possible to produce a soft capsule containing polyphenol derived from olive leaf or olive extract, which suppresses the delay of disintegration of a completely new composition.

As the content of the soft capsule preparation of the present invention, ampelopsin or catechin and olive-derived polyphenol are essential constituents. As for the other components, any component can be blended as long as it does not adversely affect the disintegration of the gelatin soft capsule film.

The olive-derived polyphenol in the present invention refers to a plant-derived component having a plurality of phenolic hydroxy groups (hydroxy groups bonded to aromatic rings such as benzene ring and naphthalene ring) in the molecule, and is mainly oleuropein and its metabolites. There is a hydroxytyrosol.
Oleuropein is a compound represented by the following chemical formula 2.

The oleuropein content can be measured by a known HPLC method. In particular. Using an agricultural and marine product functional component separation measuring device (manufactured by JASCO Corporation), using X-PressPak V-C18 (2.0 x 50 mm 2 μm) as a column, eluting with a gradient using 2% acetic acid and methanol. Measure (see Gianfrancesco Montedoro, Maurizio Servili, Maura Baldioli, and Enrico Miniati: J.Agric.Food Chem, 40,1577-1580 (1992)).

Hydroxytyrosol is a compound represented by the following chemical formula 3.

The content of hydroxytyrosol can also be measured by a known HPLC method in the same manner as oleuropein.

The olive-derived polyphenol in the present invention may be purified or extracted from olive leaves or olive fruits. The olive extract can be used in the present invention as long as it mainly contains oleuropein and hydroxytyrosol, which is a metabolite thereof, in an amount of 10% by mass or more.

In the present invention, when ampelopsin is blended as the soft capsule content liquid, 0.1 to 5% by mass, preferably 0.3 to 3% by mass of ampelopsin is blended to suppress the delay in disintegration of the soft capsule due to olive-derived polyphenols. can do.
When catechin is blended as the soft capsule content liquid, catechin is blended in an amount of 0.1 to 10% by mass, preferably 1 to 7% by mass, particularly preferably 2 to 5% by mass, so that the soft capsule is made of olive-derived polyphenol. It is possible to suppress the decay delay of.

The present invention will be described below with reference to test examples.
1. 1. Test 1
(1) Test method Fig. 1 shows the outline of the test method. Hereinafter, description will be given with reference to this figure.

1) Preparation of soft capsule film After adding 35 g of gelatin to a mixture of 60 g of water and 15 g of glycerin, the mixture was allowed to stand at room temperature until the gelatin swelled. Then, it was heated and dissolved until gelatin was dissolved to obtain a gelatin solution. After defoaming the solution, 8 g was poured into a petri dish having a diameter of 90 mm to form a film. The coating was dried at room temperature until the water content reached about 9%.
Then, it was peeled off from a petri dish and cut into a square of 13 mm × 13 mm, which was used as a soft capsule film in this test (flow on the right side of the figure).

2) Preparation of soft capsule content solution Beeswax was added to medium-chain fatty acid triglyceride (“Coconade MT”: manufactured by Kao Corporation) as the content solution of the soft capsule, and the solution was allowed to cool at room temperature. Then, ampelopsin and a polyphenol compound or a polyphenol-containing plant extract were added to this solution, and the mixture was uniformly mixed with a homomixer. This was used as the soft capsule content liquid (flow on the left side of the figure).
As ampelopsin, a commercially available wisteria tea extract (product containing 32% by mass of ampelopsin: manufactured by Maruzen Pharmaceuticals Co., Ltd.) was used.

3) Disintegration test of soft capsule film 10 g of the content liquid was collected in a screw bottle, a cut gelatin sheet was placed therein, and the mixture was stored at 50 ° C. for 1 week after sealing.
Then, the gelatin sheet was taken out, and the gelatin sheet was subjected to a disintegration test under the conditions specified in the Japanese Pharmacopoeia. The disintegration test solution was carried out using water at 37 ° C., and the time during which the gelatin sheet disintegrated was measured.

(2) Results The composition and disintegration test results of the soft capsule content liquid using hydroxytyrosol-containing olive leaf extract (containing 20% or more of "Olaris" hydroxytyrosol: manufactured by Mitsubishi Chemical Foods Co., Ltd.) as the soft capsule content are as follows. It is shown in Table 2 of.

As shown in Table 2, the olive leaf extract (hydroxytyrosol) significantly prolonged the disintegration time of the soft capsule film (Test Example 2). On the other hand, Test Example 1 containing 0.54% by mass of ampelopsin had a slightly longer disintegration time than the blank. On the other hand, Test Example 3 suppressed the prolongation of the disintegration time due to the olive leaf extract.

2. Exam 2
The interaction between the olive leaf extract and various polyphenol compounds on the soft capsule disintegration time was investigated.
(1) Test method 1) Preparation of soft capsule film In the same manner as in Test Example 1, after adding 35 g of gelatin to a mixture of 60 g of water and 15 g of glycerin, the mixture was allowed to stand at room temperature until the gelatin swelled. Then, it was heated and dissolved until gelatin was dissolved to obtain a gelatin solution. After defoaming the solution, 8 g was poured into a petri dish having a diameter of 90 mm to form a film. The coating was dried at room temperature until the water content reached about 9%.
Then, it was peeled off from a petri dish and cut into a square of 13 mm × 13 mm, which was used as a soft capsule film in this test (flow on the right side of the figure).

2) Preparation of soft capsule content solution A content solution having the composition shown in Table 3 was prepared. The following polyphenols were used as the compounded polyphenols.
Fujicha extract (containing 66% by mass of ampelopsin: manufactured by Maruzen Pharmaceutical Co., Ltd.), Fujicha high-concentration extract (containing 87% by mass of amperopsin: manufactured by Maruzen Pharmaceutical Co., Ltd.), green tea extract ("Sanphenon 30S-OP" total polyphenol Contains 30% or more, contains 20% or more of catechin: manufactured by Taiyo Kagaku Co., Ltd.), catechin (containing 90% or more of "Sanphenon EGCG-OP" EGCg: manufactured by Taiyo Kagaku Co., Ltd.), olive leaf extract ("Olaris" hydroxytyrosol 20) % Or more content: Mitsubishi Chemical Foods Co., Ltd.), Bilberry ("Bilberry dry extract ET" anthocyanin 36% or more content: Indena Co., Ltd.) Made by Chemical Co., Ltd.).
As the content of the soft capsule, beeswax was added to the medium-chain fatty acid triglyceride (“Coconade MT”: manufactured by Kao Corporation), and the solution was allowed to cool at room temperature. Then, ampelopsin and a polyphenol compound or a polyphenol-containing plant extract were added to this solution, and the mixture was uniformly mixed with a homomixer. This was used as the soft capsule content liquid (flow on the left side of the figure).

3) Disintegration test of soft capsule film 10 g of the content liquid was collected in a screw bottle, a cut gelatin sheet was placed therein, and the mixture was stored at 50 ° C. for 2 weeks after sealing.
Then, the gelatin sheet was taken out, and the gelatin sheet was subjected to a disintegration test by a disintegration tester. The disintegration test solution was carried out using water at 37 ° C., and the time during which the gelatin sheet disintegrated was measured.

(2) Results The test results are shown in Table 3 below.

Ampelopsin (Test Examples 5 and 6, Test Examples 11 to 13) all suppressed the disintegration and prolongation of soft capsules by olive leaf extract (hydroxytyrosol). Test Example 7 (green tea extract) and Test Example 8 (catechin) also suppressed the disintegration and extension of soft capsules by the olive leaf extract (hydroxytyrosol). However, Test Examples 9 and 10 (blueberries, ginkgo biloba) showed no effect.
Further, from Test Examples 7 and 8, it was found that the catechin concentration in the content liquid required for suppressing the delay in disintegration time was about 0.2 to 0.5% by mass.

3. 3. Test 3
The effect of low concentrations of ampelopsin or catechin on the disintegration time was investigated.
(1) Test method 1) Preparation of soft capsule film In the same manner as in Test Example 1, after adding 35 g of gelatin to a mixture of 60 g of water and 15 g of glycerin, the mixture was allowed to stand at room temperature until the gelatin swelled. Then, it was heated and dissolved until gelatin was dissolved to obtain a gelatin solution. After defoaming the solution, 8 g was poured into a petri dish having a diameter of 90 mm to form a film. The coating was dried at room temperature until the water content reached about 9%.
Then, it was peeled off from a petri dish and cut into a square of 13 mm × 13 mm, which was used as a soft capsule film in this test (flow on the right side of the figure).

2) Preparation of soft capsule content solution A content solution having the composition shown in Table 4 was prepared. As ampelopsin and catechin, wisteria tea extract (containing 66% by mass of ampelopsin: manufactured by Maruzen Pharmaceuticals Co., Ltd.), green tea extract ("Sanphenon 30S-OP" containing 30% or more of total polyphenols, containing 20% or more of catechins: Taiyo Kagaku Co., Ltd. (Manufactured by the company), catechin (containing 90% or more of "Sanphenon EGCG-OP" EGCg: manufactured by Taiyo Kagaku Co., Ltd.), olive leaf extract (containing 20% or more of "Oralis" hydroxytyrosole: manufactured by Mitsubishi Chemical Foods Co., Ltd.) ..
As the content of the soft capsule, beeswax was added to the medium-chain fatty acid triglyceride (“Coconade MT”: manufactured by Kao Corporation), and the solution was allowed to cool at room temperature. Then, ampelopsin and a polyphenol compound or a polyphenol-containing plant extract were added to this solution, and the mixture was uniformly mixed with a homomixer. This was used as the soft capsule content liquid (flow on the left side of the figure).

3) Disintegration test of soft capsule film 10 g of the content liquid was collected in a screw bottle, a cut gelatin sheet was placed therein, and the mixture was stored at 50 ° C. for 7 days after sealing.
Then, the gelatin sheet was taken out, and the gelatin sheet was subjected to a disintegration test by a disintegration tester. The disintegration test solution was carried out in water at 37 ° C., and the time during which the gelatin sheet disintegrated was measured.

(2) Results The test results are shown in Table 4 below.

From the above results, it was confirmed that the addition of 0.3% or more of ampelopsin and 0.08% or more of catechin was effective in suppressing the delay in the disintegration of the gelatin film by the olive leaf extract (Olaris).

4. Test 4 (disintegration test when applied to soft capsule formulation)
(1) Test method Capsules were filled with a manufacturing machine in order to confirm whether the same results could be obtained even with capsules. The film was prepared according to a general formulation, and the content liquid was prepared according to the formulation shown in Table 5 below. The disintegration time after storing the capsules at 50 ° C. for 10 days was measured. The disintegration test was carried out under the same conditions as in Test 1 above.

(2) Results The results of the disintegration test are shown in Table 6 below. The disintegration time is the average value of the results of testing 6 capsules.

It was confirmed that the soft capsule formulation of the example clearly suppressed the delayed occurrence of disintegration with respect to the control.

Claims (3)

A soft capsule disintegration delay inhibitor containing 0.1 to 10% by mass of ampelopsin or catechin with respect to the content containing olive-derived hydroxytyrosol and / or oleuropein in a capsule film containing gelatin as a main component. The soft capsule disintegration delay inhibitor according to claim 1, wherein ampelopsin is derived from a wisteria tea extract. A method of suppressing the delay in disintegration of the gelatin soft capsule film caused by the contents containing hydroxytyrosol derived from olive and / or oleuropein.
A method for suppressing delay in disintegration of soft capsules, which comprises 0.1 to 10% by mass of ampelopsin or catechin as the contents of the capsule.

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