JP2019099482A - Polyphenols-containing soft capsule formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a gelatin soft capsule preparation which suppresses a delay in disintegration of a gelatin soft capsule film by a content containing an olive-derived polyphenol compound. SOLUTION: A soft capsule preparation containing olive-derived polyphenol and ampelopsin or catechin in a capsule film containing gelatin as a main component. [Selection diagram] Fig. 1

Description

  TECHNICAL FIELD The present invention relates to a polyphenol-containing soft capsule preparation with suppressed disintegration delay.

Gelatin and plant polysaccharides derived from carrageenan are generally used as a film base of soft capsules.
Gelatin has a sol-gel change reversibly with temperature change, excellent film forming ability and high mechanical strength of the formed film, easy disintegration or dissolution in the body, and itself has a nutritional value. It has many advantages as a film base, such as being easy to be absorbed into the body, and is most widely used as a soft capsule.
However, gelatine soft capsules harden with the passage of time and the disintegration property decreases. When the inclusions of the capsule contain polyphenols such as anthocyanins, catechins, and flavone compounds, hardening of the capsule is further accelerated. The result is a delay in disintegration time in the stomach, and in extreme cases the capsule may not collapse in the stomach.

Various techniques have been proposed to prevent the disintegration delay of gelatin soft capsules containing polyphenols and vitamin C in their contents.
In general, various substances are added to gelatin which constitutes a soft capsule. For example, addition of citric acid (patent document 1), blending of polyglutamic acid (patent document 2), blending of inositol hexaphosphate (patent document 3), blending of low molecular weight gelatin (patent document 4), glycerin and reduced starch syrup There is a formulation (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 hardening effect of the soft capsule of the substance to be contained.
Patent Document 6 describes that medium-chain fatty acid triglyceride, a dipeptide sweetener, and menthol are blended to suppress the hardening of the soft capsule.
Patent Document 7 describes that in a soft capsule containing a polyphenol, curing of the soft capsule can be suppressed by further blending a reducing sugar into the content.
Patent Document 8 describes that hardening of the soft capsule can be suppressed by adding equol to an inclusion containing any of anthocyanin, proanthocyanidin and procyanidin.
Patent Document 9 describes that when the inclusion contains polyphenols, hardening of the soft capsule can be suppressed by blending lecithin as a surfactant and vitamin E as an antioxidant together with the polyphenols in the contents. ing.

  On the other hand, attention has recently been focused on oleuropein, which is a polyphenol compound contained in olive leaves and olive oil, and hydroxytyrosol, which is a metabolite thereof. This compound has a strong antioxidative effect (Patent Document 10) and attracts attention for its action of promoting bone formation (Patent Document 11), preventing fatty liver (Patent Document 12), and the like.

JP-A-59-39834 JP, 2005-139152, A Patent No. 3790258 gazette JP 2011-136927 A Unexamined-Japanese-Patent No. 2017-100966 JP, 2015-193579, A JP, 2010-90063, A JP, 2016-69335, A JP, 2011-79786, A JP, 2016-79127, A JP, 2009-227616, A JP, 2009-263257, A

The present inventor has been researching and developing a soft capsule preparation containing a polyphenol compound derived from olive as one component of the contents. In the course of conducting research on soft capsule formulations, we encountered the problem of hardening and disintegration delay 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 disintegration delay of the gelatin soft capsule film due to the content containing the olive-derived polyphenol compound is suppressed.

The main components of the present invention are as follows.
(1) A soft capsule formulation comprising an olive-derived polyphenol and an amperpsin or catechin in a capsule shell mainly composed of gelatin.
(2) The soft capsule preparation according to (1), wherein the amperopsin is derived from a wisteria tea extract.
(3) The soft capsule formulation according to (1) or (2), wherein the olive-derived polyphenol is hydroxytyrosol and / or oleuropein.

  According to the present invention, there is provided a soft capsule formulation in which curing of a film is suppressed, which contains an olive-derived polyphenol compound in its content. This formulation is a soft capsule formulation in which the delay in disintegration time is suppressed.

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

  A soft capsule preparation comprising a content coated with a soft film, wherein the soft capsule film portion contains gelatin and is characterized in that it contains at least an olive-derived polyphenol compound and an amperpsin or catechin as content components. Soft capsule formulation.

  Amperopsin is a polyphenol compound extracted from a plant called wisteria tea. Wisteria tea is a plant of the family Vitis cerebella, and its Chinese name is called a toothed snake. The scientific name is Ampelopsis grossedentata. Mainly distributed in provinces and autonomous regions such as Guangxi, Guangdong, Yunnan, Guizhou, Hunan, Hubei, Jiangxi, Fujian etc. of China. People from Zhejiang and Hunan tribes and tribes of China's Guangxi and Hunan regularly use beverages made from stems and leaves and are used for colds and sore throats. Amperopsin has been identified as the active substance of the therapeutic action and antibacterial action of the liver disease exhibited by Fujicha.

  Amperopsin is represented by the following chemical formula 1.

  Amperopsin is exemplified by, for example, fuji tea (Ampellosis grossedentata), great corpse snake (Apperopsis megalophylla), guangdong snake moth (Ampelopsiscantoniensis), hempenashi (Hovenia dulcis), salve snail (Salixsachalinensis), yorehamata (Pinuscontorta), Erithiolucilium It can be isolated and purified from extracts of selected plants. Among these, Fuji tea is preferable.

Specifically, Ampelopsin can be obtained as follows from an Ampelopsis genus plant, Fuji tea (Ampelopsis grossedentata).
That is, the extract obtained by extracting the dried leaves of the dried Fuji tea with water-containing ethanol is concentrated, for example, subjected to column chromatography using a porous resin (DIAION HP-20), and the fraction eluted with 80% by volume water-containing methanol Amperopsin is obtained in the drawing. This can be further purified by reverse phase silica gel column chromatography or recrystallization. Purified amperopsin is also sold as a reagent, and it can also be used.

The following operations are performed to obtain Amperopsin from Fujicha.
A ground product or a powder of dried wisteria tea leaves or stems is used as an extraction raw material, placed in water, a hydrophilic organic solvent or a mixed solvent thereof, and extracted using any device at room temperature to a temperature equal to or lower than the boiling point of the solvent. It 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.
In addition, a mixed solvent of these hydrophilic organic solvents and water can be used. In the case of using a mixed solvent of water and a hydrophilic organic solvent, in the case of lower alcohol, 30 to 90 parts by mass with respect to 10 parts by mass of water, and in the case of lower aliphatic ketone, 10 parts by mass of water On the other hand, it is preferable to add 10 to 40 parts by mass, and 10 to 90 parts by mass with respect to 10 parts by mass of water in the case of polyhydric alcohol.

The dried and ground product of Fujicha is put into a treatment tank filled with the extraction solvent, and the mixture is allowed to stand for 30 minutes to 2 hours with occasional stirring while being dissolved to dissolve soluble components, followed by filtration. The extract is obtained by removing the extract, distilling off the extractive solvent from the extract and drying. The amount of extraction solvent is preferably 5 to 15 times (mass ratio) of the extraction raw material, and the extraction conditions are usually 50 to 95 ° C. for about 1 to 4 hours when water is used as the extraction solvent. It is. Moreover, when using the mixed solvent of water and ethanol as an extraction solvent, it is about 30 minutes-about 4 hours normally at 40-80 degreeC.

The extractive solvent is distilled off from the obtained extract to obtain a paste-like concentrate. Further drying gives a solid extract. In the present invention, when the content of Amperopsin is 10% by mass or more, preferably 20% by mass or more, it may be in the state of the above-mentioned extract or its concentrate. These may be used after being purified by methods such as activated carbon treatment, adsorption resin treatment, ion exchange resin, liquid-liquid countercurrent distribution, and the like.
Therefore, the 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 determination method is as follows.
Preparation of sample solution Weigh accurately about 20 mg of sample (extract), add distilled water and sonicate to dissolve to make exactly 50 mL. Dilute 2 mL of this solution exactly to 50 mL to make a sample solution.
・ Preparation of standard solution and preparation of calibration curve
Weigh accurately 2.00 mg of a standard product (manufactured by Dihydromyricetin SIGMA-ALDRICH), add an appropriate amount of 100% acetonitrile, sonicate and dissolve, add acetonitrile to make exactly 25 mL, and add 80 μg / mL of amperpsin standard stock solution Prepare. This standard stock solution is diluted 5-fold exactly with distilled water to prepare a 16 μg / mL ampelopsin standard solution. The injection volume to HPLC is made into 10, 20, 40 microliters, and a standard curve is created based on the peak of amperpsin.
-HPLC measurement conditions Set the conditions of Table 1 below.

In general, when the gelatin-containing soft capsule content contains polyphenols, it is known that the reaction between the polyphenols in the content and the gelatin molecules derived from the soft capsule shell causes a delay in capsule disintegration. However, unlike other polyphenols, Amperopsin inhibits the delay in disintegration of soft capsule preparations by polyphenol compounds and plant extracts containing polyphenols.
The mechanism of this capsule disintegration delay is not clear.
Amperopsin in the present invention may be purified or may be extracted from the above-mentioned Fuji tea. Amperopsin extracted from wisteria tea can be used in the present invention as long as it contains 10% by mass or more as ampelopsin.

  As the contents of the soft capsule preparation of the present invention, amperopsin and olive-derived polyphenols are essential components. With regard to the other components, any component may 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 botanically is the camellia genus Camellia (Camellia)
Tea leaves belonging to S. sinensis can be extracted and refined from sencha, roasted tea, covered tea, gyokuro, etc. which are classified as unfermented tea depending on the difference in the production method.

Generally, the catechin of green tea extract is eight types in total including catechin, gallocatechin, catechin gallate, gallocatechin gallate, epicatechin, epigallocatechin, epicatechin gallate and epigallocatechin gallate, but the component ratio is It is also influenced by the type and variety of In addition, products in which the ratio of specific components is increased industrially by a process such as purification are also commercially available.
In addition, catechin alone hardens the gelatin soft capsule and delays disintegration, but surprisingly, it has been found as a new finding that the delay of disintegration of the gelatin soft capsule due to olive leaf or polyphenol derived from olive extract is suppressed. Therefore, the incorporation of catechin makes it possible to produce a soft capsule containing olive leaf or polyphenol derived from olive extract, which has a completely new composition with reduced disintegration delay.

  As the contents of the soft capsule preparation of the present invention, amperopsin or catechin and olive-derived polyphenols are essential components. With regard to the other components, any component may 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 is 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 It is 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. Elution was performed with a gradient using 2% acetic acid and methanol using X-PressPak V-C18 (2.0 × 50 mm 2 μm) as a column using an agricultural and marine product functional component separation and measurement apparatus (manufactured by JASCO Corporation). 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.

  Similar to oleuropein, the content of hydroxytyrosol can also be measured by a known HPLC method.

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

In the present invention, when amperpsin is blended as the soft capsule content liquid, the disintegrating delay of the soft capsule by the polyphenol derived from olive is suppressed by blending amperpsin in 0.1 to 5% by mass, preferably 0.3 to 3% by mass. can do.
In addition, when catechin is blended as a soft capsule content liquid, a soft capsule based on olive-derived polyphenol is blended by blending 0.1 to 10% by mass, preferably 1 to 7% by mass, and particularly preferably 2 to 5% by mass of catechin. Collapse delay can be suppressed.

Test examples are shown below to illustrate the present invention.
1. Examination 1
(1) Test method FIG. 1 shows an outline of the test method. A description will be given below along this figure.

1) Preparation of Soft Capsule Film After adding 35 g of gelatin to a mixture of 15 g of glycerin and 60 g of water, it was left at room temperature until the gelatin swelled. Thereafter, the mixture was heated and dissolved until gelatin was dissolved to obtain a gelatin solution. After degassing the solution, 8 g was poured into a petri dish of φ 90 mm to form a film. The film was allowed to dry at room temperature until the moisture value was about 9%.
Thereafter, the petri dish was peeled off and cut into a 13 mm × 13 mm square, 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 Liquid As a content liquid of soft capsule, beeswax was added to medium chain fatty acid triglyceride ("COCONAD MT": manufactured by Kao Corporation), dissolved by heating, and this solution was allowed to cool at room temperature. Then, to this solution, an amperpsin and a polyphenol compound or polyphenol-containing plant extract were added and uniformly mixed with a homomixer. This was used as the soft capsule content liquid (flow on the left side of the figure).
In addition, a commercially available extract of Fuji tea (containing 32% by mass of Amperopsin: manufactured by Maruzen Pharmaceutical Co., Ltd.) was used as amperopsin.

3) Disintegration Test of Soft Capsule Film 10 g of the content liquid was collected in a screw bottle, and the cut gelatin sheet was put into this, and sealed after sealing to store at 50 ° C. for 1 week.
Thereafter, the gelatin sheet was taken out, and the disintegration test was carried out on the gelatin sheet under the conditions specified in the Japanese Pharmacopoeia. The disintegration test solution was carried out using water at 37 ° C., and the time when the gelatin sheet collapsed was measured.

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

  As shown in Table 2, olive leaf extract (hydroxytyrosol) significantly prolonged the disintegration time of the soft capsule coat (Test Example 2). On the other hand, in the test example 1 containing 0.54% by mass of ampelopsin, the disintegration time was slightly extended compared to the blank. On the other hand, Test Example 3 suppressed the prolongation of the disintegration time by the olive leaf extract.

2. Examination 2
We examined the interaction of olive leaf extract and the influence of various polyphenol compounds on soft capsule disintegration time.
(1) Test Method 1) Preparation of Soft Capsule Film In the same manner as in Test Example 1, 35 g of gelatin was added to a mixture of 15 g of glycerin and 60 g of water, and left at room temperature until the gelatin swelled. Thereafter, the mixture was heated and dissolved until gelatin was dissolved to obtain a gelatin solution. After degassing the solution, 8 g was poured into a petri dish of φ 90 mm to form a film. The film was allowed to dry at room temperature until the moisture value was about 9%.
Thereafter, the petri dish was peeled off and cut into a 13 mm × 13 mm square, 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 Liquid The content liquid of the composition shown in Table 3 was prepared. The following polyphenols were used as blended polyphenols.
Fuji tea extract (Amprospin 66% by mass: made by Maruzen Pharmaceutical Co., Ltd.), Fuji tea high concentration extract (Ampelopsin 87% by mass: contained by Maruzen Pharmaceutical Co., Ltd.), green tea extract ("Sanphenon 30S-OP" total polyphenol 30% or more, catechin 20% or more: contained by Taiyo Kagaku Co., Ltd., catechin (“Sanphenon EGCG-OP” EGCg 90% or more contained: Made by Taiyo Chemical Co., Ltd.), olive leaf extract (“Oralis”) hydroxytyrosol 20 % Or more: Mitsubishi Chemical Foods Co., Ltd. made, Bilberry ("Billberry dried extract ET" anthocyanin contained 36% or more: Indena company made), Ginkgo biloba ("Ginkgo biloba extract F" flavone glycoside 24% or more contained: Tama raw Chemical Co., Ltd.).
As a content liquid of the soft capsule, beeswax was added to medium-chain fatty acid triglyceride ("COCONAD MT": manufactured by Kao Corporation), dissolved by heating, and this solution was allowed to cool at room temperature. Then, to this solution, an amperpsin and a polyphenol compound or polyphenol-containing plant extract were added and 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, and the cut gelatin sheet was put into it, and after sealing, it was stored at 50 ° C. for 2 weeks.
Thereafter, the gelatin sheet was taken out, and the disintegration test was performed on the gelatin sheet by a disintegration tester. The disintegration test solution was carried out using water at 37 ° C., and the time when the gelatin sheet collapsed was measured.

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

Amperopsin (Test Examples 5 and 6, Test Examples 11 to 13) suppressed the disintegration and extension of the soft capsule by the olive leaf extract (hydroxytyrosol). Test Example 7 (green tea extract) and Test Example 8 (catechin) also inhibited the disintegration and extension of the soft capsule by the olive leaf extract (hydroxytyrosol). However, Test Examples 9 and 10 (bilberry, ginkgo biloba) showed no effect.
Further, from Test Examples 7 and 8, it was found that the concentration of catechin in the content solution necessary for delay time suppression was about 0.2 to 0.5 mass%.

3. Examination 3
We examined the effect of low concentration of Amperopsin or catechin on the decay time.
(1) Test Method 1) Preparation of Soft Capsule Film In the same manner as in Test Example 1, 35 g of gelatin was added to a mixture of 15 g of glycerin and 60 g of water, and left at room temperature until the gelatin swelled. Thereafter, the mixture was heated and dissolved until gelatin was dissolved to obtain a gelatin solution. After degassing the solution, 8 g was poured into a petri dish of φ 90 mm to form a film. The film was allowed to dry at room temperature until the moisture value was about 9%.
Thereafter, the petri dish was peeled off and cut into a 13 mm × 13 mm square, 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 Liquid The content liquid of the composition shown in Table 4 was prepared. In addition, as an Amperopsin and a catechin, Fuji tea extract (Aperopsin 66 mass% content: made by Maruzen Pharmaceutical Co., Ltd. product), a green tea extract ("Sanphenon 30S-OP" total polyphenols content 30% or more, a catechin content 20% or more content: Made by company, catechin ("Sanphenon EGCG-OP" containing at least 90% EGCg: made by Taiyo Kagaku Co., Ltd.), olive leaf extract (containing at least 20% "Oralis" hydroxytyrosol: made by Mitsubishi Chemical Foods Co., Ltd.) .
As a content liquid of the soft capsule, beeswax was added to medium-chain fatty acid triglyceride ("COCONAD MT": manufactured by Kao Corporation), dissolved by heating, and this solution was allowed to cool at room temperature. Then, to this solution, an amperpsin and a polyphenol compound or polyphenol-containing plant extract were added and 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, and the cut gelatin sheet was put into it, and after closing, it was stored at 50 ° C. for 7 days.
Thereafter, 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 with water at 37 ° C., and the time when the gelatin sheet collapsed was measured.

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

  From the above results, it has been confirmed that addition of 0.3% or more of Amperopsin and 0.08% or more of catechin is effective for suppressing the disintegration delay of the gelatin film by olive leaf extract (olaris).

4. Test 4 (Disintegration test when applied to soft capsule formulation)
(1) Test method In order to confirm whether similar results can be obtained even in the actual capsule, capsule filling was performed in a manufacturing machine. The film was prepared according to a general formulation, and the content liquid was implemented according to the formulation of Table 5 below. The disintegration time after storing the capsules at 50 ° C. for 10 days was measured. The disintegration test was conducted under the same conditions as in the above-mentioned test 1.

(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 has been confirmed that the soft capsule preparation of the example clearly suppresses the delayed onset of disintegration with respect to the control.

Claims (3)

  A soft capsule formulation in which olive-derived polyphenol and amperpsin or catechin are encapsulated in a capsule shell mainly composed of gelatin.   The soft capsule preparation according to claim 1, wherein the amperopsin is derived from a wisteria tea extract. The soft capsule formulation according to claim 1 or 2, wherein the olive-derived polyphenol is hydroxytyrosol and / or oleuropein.