JPS625891B2 - - Google Patents

Description

[Detailed Description of the Invention] [A] Purpose of the Invention [Field of Industrial Application] The present invention is directed to the use of yellow cypress bark, which is extracted (eluted) using a fatty acid ester, from the bark of the yellow cypress tree as a raw material. Ingredients for pharmaceutical or cosmetic use,
For use in external skin preparations. Furthermore, by using the residue of yellow oak after elution with fatty acid ester as a raw material, we obtained an aqueous extract that contains a high amount of berberine and has very little sludge formation, and uses this as a topical skin preparation. to be used for On the other hand, when using the well-known method of extracting berberine from Aspergillus or obtaining a water-soluble extract, a degreasing operation is adopted using an organic solvent such as n-hexane, ether, or benzole, and this substance is removed and used effectively. Although this has not been done yet, it is also concerned with recovering and dissolving it in fatty acid ester and using it in external preparations for the skin. By the way, when we say external skin preparations,
Refers to cosmetics, pharmaceuticals, and quasi-drugs for the skin or hair that are used in forms other than oral administration or injection, as defined by Japan's Pharmaceutical Affairs Law.

[Conventional technology]

Yellow oak is known as Chinese medicine or folk medicine.
It is one of the representative herbal medicines. Japan Bureau (JP) also has
It is listed. For use on the skin (external preparations), berberine, which is known as the main ingredient, has antibacterial effects, and has been used in powders and water-based extracts (paste extracts, etc.) in ointments and bandages since ancient times, as well as in tinctures. There are applications such as agents. From this,
Of course, there are also cosmetics made with yellow oak powder,
Attempts have been made to use aqueous extracts.

Recent publications that apply the above-mentioned anti-inflammatory and antibacterial effects of yellow oak to skin preparations include (1) and the published patents (2) to (9) listed below. There is a public notice.

(1) Fragrance Journal (magazine) special issue
No. 1, 45-46 1979 (2) Published Patent Publication 1979-23918 (3) 〃 1982-125019 (4) 〃 1981-40609 (5) 〃 1982-53404 (6) 〃 1982- 185210 (7) 〃 1984-140014 (8) 〃 1982-1406 (9) 〃 1972-88411 Among the above publications, (6) uses the word “Oren”, but (1) Huanglian has already been used in skin care products and cosmetics along with Huangbai, and the main ingredient is berberine, so they are listed as being in the same category.

[Problem that the invention seeks to solve]

To explain the history of the development of the present invention, the initial research theme was how to obtain a higher yield of berberine contained in Aspergillus or an aqueous extract containing berberine. It was about. In other words, in order to obtain berberine or an extract with a high content of berberine, according to the conventional method, the lipids in Aspergillus orientalis are removed using an organic solvent such as benzol, ether, or n-hexane, and then the crude extract is prepared. The methods used have been to obtain and purify it, or to extract it directly using a water-soluble organic solvent (ethanol, methanol, etc.).

According to these conventional methods, the disadvantages are:
A large amount of sludge or precipitate is generated in the crude extract, and in order to remove it, it is necessary to filter it many times using a filter aid, etc., and as a result, the final product is However, the content of berberine is
It gets lower. Particularly when an aqueous extract contains a high amount of berberine, if it is dissolved in water, the occurrence of dregs increases over time. For this reason, although it can be incorporated into formulations such as salves, plasters, creams, emulsions, lotions, and powder formulations, it cannot be incorporated into aqueous transparent liquid products after formulation. In particular, due to the effects of other ingredients used in the formulation, the occurrence of sludge and precipitates increases.To prevent this, filter aids such as perline and diatomaceous earth are used. It's here.

In addition, no other example has been found to date of the use of an extract consisting mainly of fat-soluble components contained in Aspergillus orientalis for the skin of cosmetics or the like.

The original purpose of the present inventors was to improve the conventional method. As a first step to that end,
A water-soluble crude extract with a high content of berberine was prepared by a conventional method, and then the scum and precipitate generated over time were collected and analyzed for the main component of this causative substance.

As a result, ether, benzol,
A common oli-like substance is found in both the crude extract after defatting using n-hexane, etc., and the crude extract obtained without pretreatment using ethanol or methanol alone or in a mixture with water. Or, as a precipitate, the bitter substances oobacnon, limonene, and proteins, linoleic acid/sitosterol, and
Sterols and high-molecular phytin-like polysaccharides have been identified.

In the degreasing operation, if the above-mentioned solvent is used and this operation is insufficient, naturally, lipids will be formed as olivine. On the other hand, in the degreasing operation during pretreatment, even when the solvent is completely treated and removed using the above-mentioned solvent, sludge-like substances are generated, and most of them are protein-based. Furthermore, it was found that the oli-like matter and precipitate of the crude extract extracted using a water-soluble solvent such as ethanol or methanol contained a large amount of both lipids and proteins. Therefore, we would like to discuss a method for obtaining an aqueous extract with less sludge and sediment.
I decided to continue my research.

[Means and actions for solving problems]

The present inventors found that when analyzing the ooze and precipitates collected from the crude extract obtained by the conventional method described above, it was found that because these substances adhered to the skin,
When I tried to wipe it off, it felt very nice.
It was discovered that a smooth feeling can be obtained.

Therefore, the present inventors conducted research on extracting an aqueous extract or berberine at a high efficiency, and on the other hand, simultaneously collected oli-like substances or precipitates that were conventionally removed or discarded. We focused on research to apply this to external skin preparations.

As a result, each of the extracts obtained by the extraction methods shown in the Examples below can be used as a skin preparation, and the object of the present invention was achieved.

Example 1 To 1 part of Oriental oak, from various known fatty acid esters, for example, octyldodecyl myristate, neopentyl glycol-2-ethylhexanate (Cosmol 525 manufactured by Nisshin Oil Co., Ltd.), octyldodecyl oleate, isopropyl myristate, Any compound used in the formulation of cosmetics or external medicines, such as hexyl laurate, may be used, but it is preferable to select one compound with a boiling point of 80 to 100°C or higher, add 2 parts of it, 80-100
When digested at ℃ for about 2 hours with stirring,
This causes soluble components to migrate into the fatty acid ester used. Next, leave it to stand naturally and when it reaches room temperature, separate the fatty acid ester layer. still,
The residue obtained at this time is used for the aqueous extract in Example 2 or for the isolation of berberine in Example 3.

A centrifuge was used for fractionation in the above steps. Next, the aliquoted liquid was stored at -20°C.
After allowing it to stand overnight under freezing at ±5°C, it is returned to room temperature and then filtered to obtain the liquid. This liquid is hereinafter referred to as liquid A for convenience. This liquid A can be used as it is as a skin preparation for external use, or by being incorporated into the formulation of a skin preparation for external use.

Liquid A contains linoleic acid and sitosterol.
2.0-4.8%, other sterols 0.1-1.0%,
0.1-1.3% of bitter substances and bitter-tasting glycosides such as Oobacnon and limonene, and phytin-like polysaccharides,
Although protein was confirmed, berberine was found at zero or in very small amounts. In Example 1,
When obtaining Liquid A, a fatty acid ester was used, but instead of this, squalane, squalene, pristane, and other hydrocarbon oils and fats such as Pearleem No. 6 (manufactured by Nippon Oil & Fats) may be used. however,
When hydrocarbon oils and fats are used, if berberine or water-soluble extracts are subsequently obtained from the residue, dregs and precipitates will not occur if only smooth operations are performed as shown in Examples 2 and 3 below. As a result, a decrease in yield is observed.

Example 2 The residue obtained by centrifugation in the process of Example 1 contains about 1-5% fatty acid ester. To remove this, n-hexane,
The fatty acid ester in the residue is transferred using one of the ethers. This allows the fatty acid ester in the residue to be easily removed.
For 1 part of the residue after the above organic solvent treatment, 1 part of a polyol solvent such as butylene glycol or propylene glycol and water was added to 20 parts of a 1:1 mixture solution while stirring at 80 to 100°C. Digestion for hours or add a 1:1 mixture of ethanol and water to 1 part of the residue after the above-mentioned organic solvent treatment.
Digestion is carried out in 20 parts at 60-80° C. for 1 hour with stirring. After digestion, the mixture is left to stand until it reaches room temperature, and then the extract is separated using a centrifuge. The fractionated extract is allowed to stand overnight in a freezer at -20°C plus -5°C, then returned to room temperature and filtered to obtain a filtrate. This filtrate is hereinafter referred to as liquid B for convenience.

Liquid B can be used as it is as an external skin preparation, but it can also be used by adding an appropriate amount into the formulation of an external skin preparation.

When the B solution is concentrated to dryness under reduced pressure using an evaporator, 140 to 240 g of water-soluble extract is obtained per 1 kg of residue. It also contains 38-40g of berberine. Even when this dry solid product is diluted with water again, almost no sludge or precipitate is observed.

Example 3 The residue obtained in the process of Example 1 was preliminarily adsorbed into the residue using an organic solvent such as n-hexane or ether, as shown in Example 2. After removing the fatty acid ester, water was added at a ratio of 20 parts to 1 part of the residue after the organic solvent treatment, and the following operations were performed in accordance with Example 2 at a temperature of 80 to 100°C. Digestion is carried out for 1 hour under heating. After completing the digestion, separate the aqueous layer and leave it in a freezer at -20°C ± 5°C overnight. Next, after returning the temperature to room temperature again, the supernatant liquid is collected and concentrated to dryness using an evaporator.
240g is obtained. This dry matter contains 30 to 40g
Contains berberine. This dried product is hereinafter referred to as C extract for convenience.

Even when C extract is redissolved in water, almost no deposits or precipitates are observed, and it can be used not only for external preparations for the skin but also for internal preparations.
In addition, when blending into cosmetics etc., C extract,
It may be mixed with a liquid dissolved in advance at an appropriate concentration. Furthermore, it can be used for isolating berberine.

Example 4 One part of fine pieces or powder of Aspergillus orientalis is soaked with 3 to 5 parts of one of ether, n-hexane, or benzene while stirring. The components are mainly transferred to the organic solvent layer. At the same time, a portion of proteins, bitter substances, etc. are also transferred to the organic solvent layer. Therefore, after separating this organic solvent layer portion, the organic solvent is distilled off and concentrated using an evaporator to obtain a wax-like or paste-like material.
Hereinafter, this concentrate will be referred to as D oil and fat for convenience.

If D oil is used as it is as a skin preparation for external use, scum and deposits will be formed in the oil base used for the skin preparation. In particular, it increases in liquid oil. To prevent this, we used the same method used in Example 1, in which fatty acid ester was heated at 80 to 100°C, D fat was added, dissolved, and then filtered. It's not enough. In this method, for example, when added to olive oil, etc., sludge and precipitates are generated over time. Therefore, after separating the above-mentioned organic solvent layer, it was left to stand for a day and night in a freezer at -20°C ± 5°C, then returned to room temperature, and then filtered. I tried switching to a method of obtaining a wax-like or paste-like product by concentrating the liquid while distilling off the organic solvent using an evaporator. This concentrate is hereinafter referred to as D-1 fat for convenience.

D-1 oils and fats are used for external skin preparations (including cosmetics)
It is completely dissolved in all oil and fat bases used in
The occurrence of sludge and sediment is hardly observed.

However, in Example 4, it was shown that n-hexane, ether, and benzole were used as organic solvents.
- It is observed that more sludge and precipitates tend to migrate than when hexane or ether is used, so it is more advantageous to use n-hexane or ether from an operational point of view.

Example 5 The D-1 oil obtained in Example 4 above has a content of linoleic acid and sitosterol.
Contains 20-30% and other fatty acids derived from Aspergillus orientalis, and is used in external skin preparations (including cosmetics).
Considering its wide range of prescription uses, D-1 oil and fat further dissolved in the fatty acid ester employed in Example 1 has even higher stability. The dissolution conditions at that time include linoleic acid,
As a guideline, the sitosterol content should be adjusted to 2.0 to 4.8%.
This adjustment liquid is hereinafter referred to as D-1 liquid for convenience. D-
Part 1 provides a slippery feeling effect similar to that of Part A, and is particularly easy to add to liquid fats and oils.

In Examples 4 to 5, D oil and fat, D-1 oil and fat,
The basic operation of liquid D-1 is to carry out a treatment known as a degreasing process as a pretreatment operation from so-called yellow oak or yellow lotus when obtaining conventionally known berberine or a water-soluble extract containing berberine. This is based on the effective use of the degreasing substance components.

[C] Effect of the invention Liquid A obtained in Example 1 of the present invention or
An example of applying the D-1 oil obtained in Example 4 and the D-1 liquid prepared in Example 5 to a skin external preparation is as follows.
I can't find anything else. On the other hand, B obtained in Example 2
There are no other reports on the production of a water-soluble extract from Oriental oak using the liquid or the C extract obtained in Example-3, nor any examples of its use in external preparations for the skin.

In other words, extracts such as B liquid and C extract, which dissolve in water and do not form any deposits or precipitates over a long period of time, can be used as external skin preparations in the form of liquid products, such as lotions, etc. Easy to incorporate into water-based products. In particular, with conventional water-soluble extracts, when the liquid product contains a high amount of ethanol, scum and precipitation occur over time, and because of this, filtration and other procedures are required several times in the final process of the product. Previously, methods were used to remove the cage and sediment, but this is unnecessary. Of course, this will be shown in Examples 1 to 5. The final products are creams, emulsions, lotion-type skin products, hair care products,
It can be used by incorporating it into ointments, adhesive plasters, wiping papers, and cloths.

As can be understood from the extraction process, the yellow oak extract obtained by the method of Examples 1 to 3 has no waste, and in Examples 4 to 5, it was not wasted or removed. It is a great achievement that we were able to recover and effectively utilize the fat-soluble components that had been present in the plant, based on the results of Example 1.

There is no need to explain the medicinal effects of liquid B and extract C obtained in Examples 2 to 3, which are extracts containing berberine.
It exhibits anti-inflammatory, antibacterial, and water-retaining effects, but
Particularly in the case of liquid B, the water retention effect is enhanced. This is thought to be due to the fact that in addition to berberine, Liquid B contains flavonoid components and phenol compounds.

On the other hand, C extract can be used in the formulation of internal medicines and skin external medicines, but it can be used in advance with water, a mixture of water and ethanol in a ratio of 1:1, or
When converting to berberine content as the content of C extract in a mixture of water and polyol solvent, propylene glycol and butylene glycol at a ratio of 1:1, a solution adjusted to 0.14 to 0.24% is an aqueous type. It is easier to blend as a transparent liquid product.

Next, the liquid A obtained in Example 1, which does not contain berberine, mainly contains fat-soluble components such as linoleic acid and sitosterol in the fatty acid ester used in the step, and also contains bitter substances. However, the effects of this liquid A include good lubricious feeling on the skin,
It has the following effects.

After cutting off the hair on the back of the mouse, small incisions were made on both sides of the back using a scalpel on the epidermis treated with a depilatory agent, and Solution A was applied once a day to one side, while the other side was left unapplied. When observing the process leading to healing, it was found that the treated areas healed quickly, and at the same time, the length of cut hair also accelerated.

On the other hand, in the non-applied area, edema was observed around the cut area made by the scalpel, but in the applied area, there was little edema. This effect is due to the 20% of liquid A and B.
Observations can be made with the double diluted solution, the solution prepared by diluting the C extract diluted 20 times, D-1 oil, and D-1 solution. showed a tendency to be faster. Furthermore, the hair elongation rate was remarkable for solutions A and D-1.
Therefore, it can also be incorporated into hair growth agents. Substances that exhibit such a hair elongation (growth) promoting effect are thought to include bitter components such as octopus, linoleic acid, and sitosterol, but these are still unknown.

Example of combination prescription 1 The prescription prescribed by the Japanese pharmacies includes petrolatum, hydrophilic ointment,
In the water-absorbing ointment, add 0.3 to 10 of liquid A obtained in Example 1.
% or D-1 fat obtained in Example 4 0.3~
10% or D-1 liquid obtained in Example 5 0.3-10
% under heating to prepare ointments.

Formulation example 2 In accordance with known cream and emulsion formulations, add 0.1 to 10% of Part A or D-1 oil or fat or D-1 together with other fat bases under heating to prepare cream or emulsion. Manufacture.

Combination Prescription Example 3 In the formulation of a topical lubricant using known creams, emulsions, other emulsifiers, dispersants, and suspensions, together with Liquid A or D-1 oil or fat, or Liquid D-1,
A suitable amount of liquid B or extract C is added to prepare a skin preparation for external use. However, when using liquid B or extract C, the content of berberine in the product manufactured is as follows:
A good guideline is about 0.001% to 0.23%.

Formulation example 4 Add an appropriate amount of liquid B or extract C to the formulation of a lotion or a known aqueous external preparation containing ethanol to prepare a liquid product. At this time, for cosmetics, the amount of berberine in the product is 0.001~
One guideline for the content is about 0.01%, and for external medicines (including quasi-drugs), the content is about 0.001 to 0.23%.

Claims (1)

[Claims] 1. The boiling point of the fatty acid ester is
Add 2 parts of one type of food that is at a temperature of 80 to 100℃ or higher, and make 80
After digestion under heating at ~100℃, the fatty acid ester layer was collected, then left to stand still under freezing at around -20℃, and then filtered to obtain fatty acid esters of yellow oak. A skin external preparation characterized by containing a soluble ingredient. 2. The boiling point of the fatty acid ester for 1 part of yellow oak is
Add 2 parts of 1 type that has a temperature of 80 to 100℃ or higher, and
After digestion at 100°C, the fatty acid ester layer was separated and the remaining yellow oak residue was immersed in n-hexane or ether to remove the fatty acid ester remaining in the residue. The residue is separated into the solvent layer, and for each part of the separated residue, 20 parts of a mixture of water and propylene glycol or water and butylene glycol in a 1:1 mixing ratio are added. Add 80~
After digestion at 100℃, the liquid layer is collected, left to stand under freezing at around -20℃, filtered, and the liquid layer is concentrated under reduced pressure. , a skin external preparation characterized by containing a water-soluble component of Aspergillus orientalis. 3. After completely removing the solvent under reduced pressure from the eluted components transferred from Huangbai using n-hexane or ether, the boiling point is 80 to 100℃.
After adding the above fatty acid esters and dissolving them under heating at 80 to 100 degrees Celsius, they are left to stand still under freezing at around -20 degrees Celsius, and then filtered, and the linoleic acid/sitosterol in the filtrate is A skin external preparation characterized by containing a soluble component of fatty acid ester of Aspergillus orientalis, which is adjusted to contain 4.8%.