JP2006248953A - Wrinkle ameliorating agent and external composition for skin - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a wrinkle ameliorating agent having excellent ameliorating effect on wrinkles caused by photoageing. <P>SOLUTION: The wrinkle ameliorating agent comprises one or more kinds selected from bile acid and its pharmaceutically permissible salts, especially a cholic acid represented by chemical formula (1) (M is a hydrogen atom or a salt-forming cation) or its salt. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a wrinkle improving agent which has an excellent effect of improving wrinkles generated at an exposed site with aging, and has an effect of keeping the skin in a dermatological and cosmetically healthy state.

  Organs of all living organisms including humans are born and grow, then gradually decline with age, eventually stop functioning, and die when a certain part of the function is stopped. A state in which the function gradually declines is called aging. The skin is directly affected by the surrounding environment, and since it has an important function to maintain the environment inside the living body, it is unlikely that everything will stop functioning, but aging such as wrinkles, spots, dullness, tarmi, etc. This is an organ in which signs are easily manifested, and is particularly prominent in exposed areas exposed to sunlight.

  As skin aging progresses, defense against stimuli such as oxidative stress is weakened, causing the internal environment of the skin to be disturbed and further aging. In particular, since the exposed part is constantly exposed to strong oxidative stress caused by ultraviolet irradiation or the like, the progress of aging is remarkable. Such skin changes are called photoaging. In such skin, collagen, which is a constituent component of the majority of the dermis, decreases, and wrinkles deepen and become larger on the skin surface. No state.

  In the United States, retinoic acid is used as a prescription drug as a substance that has an improvement effect on wrinkles caused by the progress of photoaging, but it has not been approved in Japan because of its side effects and safety issues. . In addition, retinol (vitamin A), which is said to be converted into retinoic acid after being absorbed into the body and exert its effect, ascorbic acid (vitamin C) having an antioxidant and collagen synthesis promoting effect, and tocopherol having a strong antioxidant effect ( Vitamin E) and the like have been proposed as wrinkle-improving substances, but these have the disadvantage that a satisfactory effect cannot be obtained. In addition, antioxidants and anti-inflammatory agents used in pharmaceuticals, quasi-drugs, and cosmetics have not been able to obtain sufficient effects to improve wrinkles. In other words, none of the substances that have improved wrinkles so far have a sufficiently satisfactory effect and safety.

  Further, many conventional wrinkle improving agents are obtained by chemical synthesis, and there are many problems in terms of safety. On the other hand, natural substances that are less likely to cause safety problems are hardly known except vitamins, and those that are sufficiently effective have not been obtained. Furthermore, many natural wrinkle-improving agents such as retinol lack light stability, and even if they have an effect, there are substances that are difficult to be incorporated into the formulation, such as being rapidly degraded in the formulation. It was almost.

  Bile acids are tetracyclic steroids widely found in the bile of mammals, birds, etc., are produced from cholesterol, and are useful for digestion and absorption of lipids. Cholic acid is a known substance contained in bile acids (Non-patent Document 1). In addition, it is known that bile acids are also contained in a large amount in “oxen yellow” used as a Chinese medicine (Non-patent Document 2). Regarding bile acids and salts thereof, proposals as an oral hygiene enhancer (Patent Document 1), proposals of a topical skin preparation for improving tsunami (Patent Document 2), and proposals as a bactericidal cleaning agent (Patent Document 3) have been made. However, no study was made on the effect of improving wrinkles.

JP 10-45550 A JP-A-10-120579 JP 2000-198998 A Biochemistry Dictionary (2nd edition), Tokyo Chemical Doujin Tatsuo Karime, “Wakan Seiyaku”, p327, 1971, Yodogawa Shoten

  The object of the present invention is to improve wrinkles that are remarkably manifested in aging, especially in exposed areas, to keep skin healthy and cosmetically, and to improve wrinkles. Is to provide.

（但し、Ｍは水素原子又は塩形成が可能な陽イオンを表す。） As a result of intensive studies in view of the above, the present inventors have improved the wrinkle that appears prominently at the exposed site due to aging of bile acids, and the effect of keeping the skin healthy cosmetically. The present invention has been completed by confirming that it has excellent safety and stability. That is, the first invention of the present application resides in a wrinkle improving agent characterized by containing at least one selected from the group consisting of bile acids or physiologically acceptable salts thereof. In addition, the second invention of the present application is characterized in that the selected bile acid or one of the physiologically acceptable salts thereof is cholic acid represented by the following chemical formula (1) or a salt thereof, In the improver. Furthermore, a third invention of the present application resides in a composition for external use on the skin, which contains the above wrinkle improving agent.

(However, M represents a hydrogen atom or a cation capable of salt formation.)

  INDUSTRIAL APPLICABILITY The present invention can provide a wrinkle improving agent that is excellent in improving wrinkles that occur particularly in exposed areas with aging and that keeps the skin in a dermatological and cosmetically healthy state.

  The present invention is described in detail below. As mentioned above, bile acids are contained in bile, and cholic acid is one of the components known as bile acids. It is also known to be contained in cow yellow used as a traditional Chinese medicine. Therefore, the bile acid or its salt, cholic acid or salt used in the present invention can be extracted from bile or cow yellow by a known method. For example, organic solvents such as the above-mentioned herbal medicines, for example, lower alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol, butanol and hydrous lower alcohols, polyhydric alcohols such as 1,3-butylene glycol, etc. and hydrous polyhydric alcohols, Or it can extract with various organic solvents, such as acetone, ethyl acetate, hexane, or water. The extract can be purified by a known technique as necessary. Moreover, since refined products are marketed, you may utilize them.

The bile acid and cholic acid used in the present invention or salts thereof may be clathrate. Bile acids that have undergone secondary metabolism by bacteria or the like are also included in the bile acids of the present invention. Furthermore, various derivatives derived from bile acids can also be used as equivalent to bile acids. Examples of the range of the derivative include derivatives such as acylation, esterification and glycosylation, but are not limited thereto.

  Examples of physiologically acceptable salts of bile acids and cholic acids used in the present invention include alkali metal salts, alkaline earth metal salts, and organic ammonium salts. Examples of organic ammonium include methylammonium, dimethylammonium, trimethylammonium, ethylammonium, monoethanolammonium, diethanolammonium, triethanolammonium, monopropanolammonium, diisopropylammonium and the like.

  The bile acids or salts thereof, and cholic acid or salts thereof in the present invention have a wrinkle improving effect, and a preparation containing one or more selected from the group consisting of these exhibits a function as a wrinkle improving agent. . The blending amount of these active ingredients in the wrinkle improving agent of the present invention is preferably 0.001 to 20.0% by mass (hereinafter simply referred to as%), particularly preferably 0.00% based on the total amount of the wrinkle improving agent. 5 to 5.0%. If the blending amount is less than the lower limit, the intended effect of the present invention is not sufficient. On the other hand, blending in excess of the upper limit is not preferable because the effect corresponding to the increase is not improved.

  The wrinkle improving agent of the present invention can be blended not only in skin cosmetics but also in skin external compositions such as pharmaceuticals and bath agents. As the blending amount, it is preferable that the blending amount of bile acid, cholic acid, and salts thereof as the active ingredients is within the above range with reference to the composition for external use on the skin because the effect of improving wrinkles is excellent. Examples of the dosage form of the external composition for skin include lotions, emulsions, creams, packs and the like. In addition, in the composition for external use of the skin of the present invention, in addition to the wrinkle improving agent of the present invention, various commonly used components such as dyes, fragrances, preservatives, surfactants, pigments, antioxidants, etc. Can be appropriately blended within the range of achieving the object of the present invention.

  EXAMPLES Hereinafter, although an Example is given and this invention is explained in full detail, it is not limited to these. In addition, all% in an Example is the mass%.

Example 1 (Cholic acid formulation)
The effect of applying a wrinkle improving agent containing 1.0% of cholic acid to the skin was evaluated as an effect on the reduction of the dermis collagen content in photoaged skin. Cholic acid was a reagent (purity 98% or more) manufactured by Tokyo Chemical Industry Co., Ltd.

(Test method)
1. Test animals A group of 10 hairless mice aged 10 weeks at the start of the test was used.

2. 2. Method for evaluating the effect on dermal collagen reduction 2-1. Photoaging conditions Photoaging was induced by irradiating UVA and UVB once a day, 5 times a week for 8 weeks. Irradiation dose, UVA is increased with ^{20J / cm 2, 25J / cm} 2, 30J / cm 2, UVB is ^{20mJ / cm 2, 30mJ / cm} 2, 40mJ / cm 2, an irradiation amount for each 1 week, 3 After week, the maximum dose was irradiated.

2-2. Evaluation Method Dermal Collagen Amount: All skin layers were collected and polytron homogenizer (KINEMATI)
After crushing with CA), the collagen fraction was extracted and subjected to acid hydrolysis, and then the hydroxyproline content was quantified using an amino acid analyzer (manufactured by JASCO). The amount of hydroxyproline per cm ² was used as a relative indicator of the amount of dermal collagen.

3. Test procedure A sample containing 1.0% cholic acid was prepared using a 50% ethanol aqueous solution as a base (Example 1). On the other hand, a sample containing only the base was used as Comparative Example 1. 0.1 ml of the evaluation sample was applied to the back skin of a hairless mouse (diameter: about 2.5 cm) once a day at a frequency of 5 times a week from the fifth week after the start of UV irradiation to the fourth week after the end of irradiation. . After the final application, the mice were sacrificed, the skin was collected, and the dermis collagen content (hydroxyproline amount per 1 cm ² ) was measured.

4). Test result (Dermal collagen content measurement result)
――――――――――――――――――――――――――――――――――――
Group Hydroxyproline level (mean ± SE) Significant difference
(Μmol / cm ² ) (base)
――――――――――――――――――――――――――――――――――――
Example 1 (containing cholic acid) 8.07 ± 0.76 (p <0.01)
Comparative Example 1 (base only) 5.69 ± 0.28
――――――――――――――――――――――――――――――――――――

  The application group of Example 1 containing cholic acid showed a significantly higher collagen content (hydroxyproline amount) compared to Comparative Example 1 with only the base, whereas the amount of dermal collagen decreased by photoaging. The acid was shown to be effective.

  From the result of this test, it was shown that the cholic acid combination preparation of Example 1 is excellent in the effect as a wrinkle improving agent for improving wrinkles.

Example 2, Comparative Example 2 (skin lotion)
A skin lotion (Example 2) having the following composition was prepared according to a conventional method, and the wrinkle improvement effect was evaluated by using the sample as a sample by the following operation. In addition, the thing which does not mix | blend cholic acid of a component (7) was made into the comparative example 2. 10 healthy skin wrinkles (female, 40-70 years old) as subjects were determined for each of the skin lotions of Example 2 and Comparative Example 2 to the left or right, after face washing in the morning and after bathing in the evening 2 times a day for 2 months (60 days), about 0.2 ml each was applied to the wrinkles of the eye corners (about 4 cm ² , 2 × 2 cm centered around the eye corners). Then, after the final application, they were asked to answer a questionnaire regarding the condition of the skin (wrinkles) on the left and right eye corners.

(composition)
Ingredients Component Blending amount (%)
(1) Butylene glycol 30.0
(2) Monolauric acid 0.5
Polyoxyethylene (20) sorbitan
(3) Propylene glycol 20.0
(4) Glycerin 10.0
(5) Methylparaben 0.1
(6) Ethanol 7.0
(7) Cholic acid 1.0
(8) Purified water balance

  Based on the questionnaire results, the number of respondents who answered that the skin lotion of Example 2 is more effective than Comparative Example 2 for each item related to the skin (wrinkle) state is shown below.

―――――――――――――――――
Item Number of people
―――――――――――――――――
Wrinkles are less noticeable 6
The skin became soft 4
The skin got firmer 6
Shining on the skin 3
My skin became moist 3
―――――――――――――――――

  From this test result, it can be seen that the skin lotion of Example 2 clearly improved the wrinkles as compared with Comparative Example 2, and further improved the flexibility and color tone deteriorated by photoaging. Wrinkles formed on the human face appear as a result of repeated exposure to ultraviolet rays that do not cause inflammation repeatedly over a long period of time, and it is considered impossible to improve wrinkles with a simple anti-inflammatory action. In addition, skin abnormalities such as irritation and itching due to the skin lotion of the present invention were not observed.

Example 3 (skin cream)
A skin cream containing cholic acid having the following composition was prepared by a conventional method, and 20 healthy people (women, 50-55 years old) who listed wrinkles in the corner of the eye as a skin trouble in a preliminary questionnaire were used for over a week. A questionnaire survey was conducted.

(composition)
Ingredients Component Blending amount (%)
(1) Beeswax 2.0
(2) Stearic acid 5.0
(3) Stearyl alcohol 5.0
(4) Reduced lanolin 2.0
(5) Squalene 20.0
(6) Sorbitan monostearate 3.0
(7) Monostearic acid 3.0
Polyoxyethylene (20) sorbitan
(8) Propylene glycol 5.0
(9) Methylparaben 0.2
(10) Residual amount of purified water
(11) Sodium cholate 1.0
(12) Fragrance appropriate amount

  A questionnaire survey was conducted using the skin cream of Example 3. The results are shown below. In addition, the result was shown by the number of people who answered that they thought so after use compared to before use for each item.

―――――――――――――――――
Item Number of people
―――――――――――――――――
Wrinkles are less noticeable 15
Wrinkle size decreased 16
Number of wrinkles decreased 7
Increased wrinkles 0
―――――――――――――――――

  From this test result, the skin cream of Example 3 is almost all humans who feel that wrinkles are less noticeable than before use, and the factor is that the size of wrinkles is reduced rather than the number of wrinkles. It can be seen that wrinkles due to photoaging were improved. In addition, skin abnormalities such as irritation and itching with the skin cream of the present invention were not observed.

One or more kinds selected from bile acids or their salts, particularly wrinkle improving agents containing cholic acid or its salts, according to the invention of the present application, are applied to pharmaceuticals, bathing agents, etc. as skin external compositions in addition to skin cosmetics. In terms of dosage form, for example, lotions, emulsions, creams, packs and the like can be used, which is very useful from the viewpoint of skin beauty.

Claims (3)

A wrinkle improving agent comprising at least one selected from the group consisting of bile acids or physiologically acceptable salts thereof. The wrinkle improving agent according to claim 1, wherein one of the selected bile acids or physiologically acceptable salts thereof is cholic acid or a salt thereof represented by the following chemical formula (1).

(However, M represents a hydrogen atom or a cation capable of salt formation.) An external composition for skin, comprising the wrinkle improving agent according to claim 1 or 2.