JPH0782131A - Hyaluronidase activity inhibitor and oil in water type cream base preparation - Google Patents

Abstract

PURPOSE:To obtain a hyaluronidase activity ihibitor and an oil in water type cream base preparation therefrom, containing chondroitin sulfuric acid or its salts having a potent hyaluronidase inhibiting activity and a surface active effect. CONSTITUTION:A hyaluronidase activity inhibitor having a high safety and a good stability, containing chondroitin sulfuric acid or its salts. An oil in water type cream base preparation is obtained by combining an oil component and a water component containing chondroitin sulfuric acid or its salts (a water component containing conchiolin is especially preferable), and by emulsifying them by using a microfluidizer. The substance obtained by emulsifying the preparation containing chondroitin sulfuric acid, shows very solid creamy state and is hard to be separated. Since no surfactantis used, it is safe to the skin. It keeps moistness and flexibility of the skin, contributes to the stability of hyaluronic acid, suppresses skin inflammation, and acts also suppressivelyto allergic symptoms.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a highly safe and highly stable hyaluronidase activity inhibitor and a cream base for pharmaceuticals such as cosmetics or external preparations for skin.

[0002]

2. Description of the Related Art When a cream, that is, an emulsion is prepared, it is usually emulsified by using a surfactant. However, the surfactant has a problem in safety for human body, and efforts are made to reduce the compounding amount as much as possible. Has been paid. For this reason, various studies have been conducted, but sufficient stability and sensory aspects such as feeling have not been obtained.

Therefore, as one measure, it has been attempted to utilize colloidal hydrous silicate to increase the yield value of the aqueous phase and stabilize the emulsion. Colloidal hydrous silicates have been conventionally used as thickeners or emulsification aids, but colloidal hydrous silicates also have problems in terms of functionality and stability within the scope of conventional techniques. It was

As one of the solutions to this problem, Japanese Unexamined Patent Publication No.
In 83909, it is proposed to use silicone oil.

Further, in Japanese Patent Application No. 3-221290,
Methods have been proposed for solving with fatty acid dextrins.

On the other hand, as a method for emulsifying cosmetics, external preparations for skin and the like, a rotary homogenizer has hitherto been generally used. Recently, a high pressure type homogenizer has appeared, and the emulsifying power has also increased. However, US Pat. No. 4,533,254
The microfluidizer described in No. 1 is particularly excellent. This emulsifying device emulsifies by emulsifying the emulsifying liquid under high pressure from a plurality of nozzles having flat orifices, and it is possible to form an emulsion without using an emulsifier such as a surfactant. It is something to do. However, even if it is used, the conventional emulsion-forming formulation has problems in separation and stability.

Chondroitin sulfate is a kind of mucopolysaccharide widely distributed in various connective tissues such as human and animal cartilage, bone, cornea, umbilical cord and skin together with protein collagen. N
-Acetylgalactosamine, uronic acid, sulfuric acid, and the like are contained in equimolar amounts, and various isomers are known depending on the binding position of the sulfate group, the type of uronic acid, and the like. Chondroitin sulfate is currently used as a drug for the treatment and prevention of arteriosclerosis, touch poison, neuralgia, arthritis or nephritis, and is used as a thickener and a texture improving agent in cosmetics, but it has a hyaluronidase activity inhibitory action. That is not known.

The method for producing chondroitin sulfate is to extract tissues such as calf nasal septal cartilage with dilute alkali at low temperature, or to decompose proteins with proteolytic enzymes and desalting them by dialysis, ion exchange method, gel filtration method and the like. Then, after freeze-drying or concentration under reduced pressure, ethanol is added in the presence of sodium acetate, or after dissolving in calcium acetate or sodium acetate buffer, ethanol is added to precipitate. Industrially, these methods of extraction, deproteinization, desalting and recovery are appropriately combined and produced.

[0009]

SUMMARY OF THE INVENTION The object of the present invention is to use an extract of an animal for which safety is guaranteed, rather than a synthetic drug for which safety is not guaranteed for a long period of time. The purpose is to find a hyaluronidase inhibitor that suppresses the activity of hyaluronidase, which decomposes hyaluronic acid, which keeps skin lubricity and flexibility and prevents aging, while sufficiently removing it. Another purpose is to apply it to the skin. In the production of a cream base which is sometimes required, it is to obtain an emulsion which is sufficiently satisfactory in terms of sensory aspects and has good stability without using a harmful surfactant.

[0010]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that chondroitin sulfate or its salt has a large effect of inhibiting the activity of hyaluronidase and a large surface activity. I found that.
As an emulsification method, a cream base obtained by using chondroitin sulfate or a salt thereof as an aqueous phase component and adding an oil drop component thereinto and emulsified with the microfluidizer described in the above-mentioned US Pat. No. 4,533,254 is suitable. Then, the present invention was completed.

That is, the present invention is as follows. (1) A hyaluronidase activity inhibitor containing chondroitin sulfate or a salt thereof.

(2) An oil-in-water cream base containing an oily component and an aqueous component containing chondroitin sulfate or a salt thereof and emulsified using a microfluidizer.

(3) An oil-in-water cream base containing an oily component, an aqueous component containing chondroitin sulfate or its salt, and conchiolin, and emulsified using a microfluidizer.

The amount of chondroitin sulfate (salt) as a hyaluronidase activity inhibitor is influenced by the components of the aqueous phase, and therefore varies depending on the formulation, and also depends on the type and grade of the chondroitin sulfate (salt).
The general range is 0.01 to 5.0 with respect to the aqueous phase.
% By weight.

As the emulsification method, a general homogenizer can be applied, but it has been found that stability and safety are particularly improved by emulsification using the microfluidizer described in US Pat. No. 4,533,254. When using a microfluidizer, it is preferable to perform the treatment at a treatment pressure of 700 kg / cm ² or more that exerts this function.

Raw materials other than chondroitin sulfate (salt) are:
Formulations can be made using common ingredients. Although all polyhydric alcohols can be used, glycerin is the most predominant. The oil phase is preferably 40% by weight or less.

Since chondroitin sulfate (salt) is commercially available in a purified state, it can be used. Also, the variety of chondroitin sulfate is usually Na salt or free acid form, but K, Mg, Fe salts and the like can also achieve the purpose.

This substance may be used as a raw material for other cosmetics such as liquid oils such as squalane and jojoba oil, solid oils such as beeswax and cetyl alcohol, various activators, moisturizers such as glycerin and 1,3 butylene glycol, and various agents. It can be added to prepare cosmetics in various dosage forms. For example, a lotion, a cream, a milky lotion, a pack, or the like may be used depending on the purpose.

Hyaluronidase is an enzyme widely distributed in the living body and also present in the skin. As its name implies, it decomposes hyaluronic acid. Hyaluronic acid is a linear polymer polysaccharide in which β-D-N-acetylglucosamine and β-D-glucuronic acid are alternately bonded, and is a glycosaminoglucan that widely exists in connective tissues of mammals along with chondroitin sulfate and the like. It is a kind.

As a function of hyaluronic acid in connective tissue, water is retained in the intercellular spaces, and a jelly-like matrix is formed in the tissue to retain cells, and the lubricity and flexibility of the skin are maintained. It is thought to prevent external force (mechanical damage) and bacterial infection. It is said that hyaluronic acid in the skin decreases with age, resulting in aging such as wrinkles and roughness.

Therefore, suppressing the activity of hyaluronidase that decomposes this is the stability of hyaluronic acid used in the preparation, the hyaluronic acid of the preparation after being applied to the skin, and the hyaluronic acid present in the skin. Is considered to contribute to the stability of. Hyaluronidase is also known as an inflammatory enzyme, and it is known that suppressing the activity suppresses inflammation and also suppresses allergies.

[0022]

According to the literature, chondroitin sulfates A and C are decomposed by Kou-maru hyaluronidase. Considering this together with the effects of the present invention, it is considered that the chondroitin sulfate preferentially reacts with hyaluronidase, whereby the decomposition of hyaluronic acid is delayed and suppressed.

[0023]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. (Example 1) Cream (wt%) A Squalane 10.0 Octyldodecyl myristate 10.0 Gelow 5.0 Beeswax 5.0 Silicon 0.5 B Purified water 56.1 Sodium chondroitin sulfate 0.2 Smecton SA 0. 5 Glycerin 10.0 Polyoxyethylene glycol (molecular weight 4000) 2.0 Methyl paraoxybenzoate 0.2 Hyaluronic acid Na 0.5 A and B are weighed and dissolved by heating. A and B were mixed with stirring, and the mixture was treated with Microfluidizer M-110Y at a treatment pressure of 1600 kg / cm.

Example 2 Cream (wt%) A Squalane 10.0 Octyldodecyl myristate 10.0 Beeswax 1.0 Batyl alcohol 3.5 Stearyl alcohol 2.5 Stearyl acid 0.5 Silicon 0.5 B Purification Water 48.8 Sodium chondroitin sulfate 0.5 2% aqueous crystalline cellulose solution 10.0 Glycerin 10.0 Polyoxyethylene glycol (molecular weight 6000) 1.0 Polyoxyethylene glycol (molecular weight 1540) 1.0 Methyl paraoxybenzoate 0 .2 Na 0.5 hyaluronate A and B are weighed and dissolved by heating. A and B were mixed with stirring, and the mixture was treated with Microfluidizer M-110Y at a treatment pressure of 1600 kg / cm.

Comparative Example 1 A product obtained by emulsifying Example 1 with a tabletop homomixer LR-1 (manufactured by Mizuho Industry Co., Ltd.).

(Comparative Example 2) A mixture of Example 1 with water instead of chondroitin sulfate.

(Comparative Example 3) A composition obtained by emulsifying the formulation of Example 2 with a tabletop homomixer LR-1 (manufactured by Mizuho Industry Co., Ltd.).

(Comparative Example 4) A mixture of Example 2 with water instead of chondroitin sulfate.

Table 1 shows the states of the creams of Examples 1 and 2 and Comparative Examples 1 to 4, the average particle size of oil droplets in water, the results of centrifugation and the results of long-term storage at 50 ° C. .

[Table 1]

(Hyaluronidase activity inhibition test) 0.4
6 g of a 0.1 M sodium hyaluronate (pH 6.0) phosphate buffer solution was weighed and allowed to stand in a constant temperature water bath at 37 ° C. for 5 minutes, and then 1.0 ml of an aqueous solution of sodium chondroitin sulfate sample having a specified concentration was added and stirred, 0.01% hyaluronidase (beef testicles manufactured by Sigma, type I-S)
1 ml of a 1 M (pH 6.0) phosphate buffer solution was added and immediately stirred, and 6 ml was placed in an Ostwald viscometer placed in a constant temperature water bath at 37 ° C. 1 minute later, 5 minutes later, 10 minutes later, 2
The viscosity was measured after 0 minutes and 40 minutes. As a control, pure water was added instead of the sample solution and the same measurement was performed. The results are shown in Table 2 as an index, with the viscosity after 1 minute being 100.

[0031]

[Table 2]

[0032]

[Effects of the Invention] The formulation containing the chondroitin sulfate of the present invention emulsified with a microfluidizer has a strong creamy form, an average particle size of 0.1 µm or less, is not separated even by centrifugation, and is at 50 ° C. It became a strong cream that does not separate even after storage for more than 3 months. It is safe for the skin because it does not contain a surfactant. Suppressing the activity of hyaluronidase, which decomposes hyaluronic acid, which keeps the skin lubricity and flexibility, and prevents external forces (mechanical disorders) and bacterial infection, helps to stabilize the stability of hyaluronic acid used in the formulation and , Contributes to the stability of hyaluronic acid in the preparation after application to the skin, and to the stability of hyaluronic acid in the preparation after application to the skin and hyaluronic acid present in the skin, suppresses skin inflammation, and allergies Work suppressively.

Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location A61K 31/725 ADA AED 9454-4C

Claims (3)

[Claims] 1. A hyaluronidase activity inhibitor containing chondroitin sulfate or a salt thereof. 2. An oil-in-water cream base comprising an oily component and an aqueous component containing chondroitin sulfate or a salt thereof and emulsified using a microfluidizer. 3. An oil-in-water cream base containing an oily component, an aqueous component containing chondroitin sulfate or a salt thereof, and conchiolin, and emulsified using a microfluidizer.