JPH11255614A - Recovery promoter for skin barrier function - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject promoter capable of recovering a reduced skin barrier function in an extremely short time, capable of preventing epidermal growth disorder, etc., caused by reduction in the epidermal function of skin, by including cetraxate hydrochloride. SOLUTION: This promoter contains (A) cetraxale hydrochloride. The promoter for recovering the barrier function of skin contains (B) at least one histamine H1 antagonist. Further the promoter for recovering the barrier function of skin contains (C) at least one histamine H2 antagonist. Diphenhydramine hydrochloride, tripelennamine, promethazine, etc., may be cited as the component B and famotidine, cimetidine, nizatidine, etc., may be cited as the component C. The promoter can be formulated with an ointment, a cosmetic such as a cream a milky lotion, etc., or a medicine (quasi medicine), etc., and applied to the skin.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an agent for promoting the recovery of skin barrier function. More specifically, the present invention relates to a skin barrier function recovery promoter useful for promoting recovery of skin barrier function and preventing epidermal hyperplasia due to a decrease in skin epidermal function.

[0002]

2. Description of the Related Art It is known that in skin roughening symptoms seen in various skin diseases and the like, the loss of moisture from the skin is more active than in healthy skin. It has been considered that the increase in the so-called transepidermal water loss (TEWL) involves a decrease in components that are considered to have a function of retaining moisture and functioning as a barrier in the epidermis.

Therefore, NMF (Natural Moisturizi) has been conventionally used as an active ingredient having an effect of improving and preventing skin diseases and rough skin from the viewpoint of replenishing the skin with an intra-epidermal component having a moisture retaining function and a skin barrier function.
Amino acids as ng Factar), lipids as keratinocyte intercellular lipids, and other mucopolysaccharides such as hyaluronic acid or similar substances have been added to cosmetics and external preparations for skin because of their high safety.

[0004] Recently, it has been reported that a specific substance that activates the biosynthesis of an intraepidermal component that is responsible for the skin barrier function has an effect of improving skin roughness (Japanese Patent Laid-Open No. 9-2952). No.).

[0005]

However, although many studies have been made on substances having an effect of improving and preventing rough skin, studies on substances having an effect of improving or recovering the skin barrier function are not sufficient. Since the relationship between the effect of improving the barrier function and the effect of improving and preventing rough skin is not clear, a substance having the effect of improving and preventing rough skin does not necessarily have the effect of improving the skin barrier function.

[0006] On the other hand, it has been reported that when the skin barrier function is reduced, the epidermal function of the skin is reduced and abnormal epidermal proliferation is caused. In particular, in the case of elderly people, it takes a long time to recover the reduced skin barrier function, and a new skin barrier function that is effective to prevent epidermal hyperproliferative abnormalities due to a decrease in skin epidermal function with aging The development of a recovery accelerator was requested.

In view of the above circumstances, the present inventors have conducted extensive research on substances that act rapidly on the reduction of skin barrier function, that is, on changes in TEWL, and as a result, have found that cetraxate hydrochloride, histamine H1 antagonists and histamine H2
The present inventors have found a new finding that the antagonist can restore the damaged skin barrier function in a very short time, and have completed the present invention.

[0008] It is an object of the present invention to provide a novel skin barrier function recovery promoter capable of recovering a reduced skin barrier function in an extremely short time.

[0009]

That is, the present invention provides a skin barrier function recovery promoting agent comprising cetraxate hydrochloride.

[0010] The present invention also provides a skin barrier function recovery promoter comprising one or more histamine H1 antagonists.

Further, the present invention provides a skin barrier function recovery promoting agent comprising one or more histamine H2 antagonists.

The present invention also provides a skin external preparation for improving rough skin characterized by containing cetraxate hydrochloride.

The present invention further provides a skin external preparation for improving rough skin, which comprises one or more histamine H2 antagonists.

[0014]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The configuration of the present invention will be described below in detail.

The cetraxate hydrochloride, the histamine H1 antagonist and the histamine H2 antagonist used in the present invention are conventionally known substances as components for external preparations for skin or cosmetics, but have an effect of promoting the recovery of the skin barrier function. Is a novel effect first discovered by the present inventors.

In the present invention, promoting the recovery of the skin barrier function means that the value of the transepidermal water loss (TEWL) 1 hour after tape stripping of the skin is 0% and the value before the tape stripping is 100%, The value of TEWL at the measurement time showed a significant difference when compared with the state where nothing was applied, meaning that it had an effect of promoting the recovery rate of TEWL, and was determined by the method of Andrew et al. (J Invest Dermatol, 86 598, 1986), which is different from the so-called skin roughness improvement / prevention effect in which skin is treated with a Cotton ball impregnated with a 4% sodium dodecyl sulfate (SDS) aqueous solution to make a judgment.

The mechanism and the mechanism of action of the above substances for promoting the recovery of the skin barrier function are unknown at present, and the cetraxate hydrochloride, histamine H1 antagonist and histamine H2 antagonist of the present invention promote the recovery of the skin barrier function. Although it was found to have an effect, the similar substances gefarnate, lansoprazole, and pirenzepine hydrochloride did not show any effect of promoting the recovery of the skin barrier function.

Examples of the histamine H1 antagonist used in the present invention include diphenhydramine hydrochloride, tripelenamine, promethazine and chlorpheniramine, and examples of the histamine H2 antagonist include famotidine, cimetidine, nizatidine and roxatidine acetate hydrochloride. Can be

The skin barrier function recovery promoter of the present invention comprises:
For example, ointments, creams, emulsions, lotions, packs,
In cosmetics such as bath agents, pharmaceuticals, quasi-drugs,
Can be applied to skin. The mixing amount is not particularly limited, but is about 0.005 to 20.0% by weight based on the total amount of these bases.

[0020]

Next, the present invention will be described in more detail with reference to examples, but the technical scope of the present invention is not limited to these examples. The compounding amount is% by weight.

The effect of cetraxate hydrochloride, a histamine H1 antagonist and a histamine H2 antagonist on the promotion of the recovery of the skin barrier function was evaluated by the following method, and the results are shown in each figure.

"Skin Barrier Function Recovery Acceleration Effect Test" The effect of each sample on the process of restoring the skin barrier function, which was destroyed by tape stripping the skin to its original state, was evaluated using TEWL as an index. The method was evaluated. That is, using the inner part of the forearm of 10 male panels, each sample was applied one hour after tape stripping, and then TEWL was added to TEWAMETER over time.
It was measured with TM-200 (COURAGE + KHAZAKA). PEG30
0: ethanol: distilled water = 1: 3: 1 as a base, and a 5% by weight solution or suspension of the evaluation substance was used as a sample. The base was used as a control. Assuming that the TEWL value one hour after the tape stripping is 0% and the TEWL value before the tape stripping is 100%, the recovery rate is calculated from the TEWL value at each measurement time, and the TEWL recovery for each sample is compared with the control. The promotion effect was evaluated. The results are shown in each figure. In the graphs of the figures, open circles indicate evaluation samples, black circles indicate controls, the vertical axis indicates TEWL recovery rate (%), and the horizontal axis indicates time after tape stripping (hr).
Represents

As can be seen from the graphs in each figure, cetraxate hydrochloride, the histamine H1 antagonist diphenhydramine hydrochloride, tripelenamine, and the histamine H2 antagonist famotidine and cimetidine significantly accelerate the recovery of TEWL from a short time. Gefarnate, lansoprazole, and pirenzepine hydrochloride have no significant difference from the control, and have no effect of promoting the recovery of TEWL.

The effects of cetraxate hydrochloride and the histamine H2 antagonist famotidine and cimetidine on the improvement of rough skin were evaluated by the following test methods.

"Skin roughness improvement effect test" (1) Actual use test by visual judgment The skin roughness improvement effect by applying the outer skin of cetraxate hydrochloride and a histamine H2 antagonist was evaluated for winter female skin roughness and male razor defeat. did. That is,
Using the face of a panel of 60 women who suffer from rough skin in winter,
Of the lotions having the composition (% by weight) shown in “Table 1,” the example was applied to one of the left and right cheeks, and the comparative example was applied to the other cheek.
The composition was applied twice a day for two consecutive weeks, and the skin condition thereafter was visually determined. In addition, a lotion having the composition shown in Table 1 was similarly applied to 40 male panels who lost the razor immediately after shaving, and the effect on razor losing was determined. The results of evaluation based on the following criteria are shown in Table 2.

Judgment Criteria for Improvement Effect on Skin Roughness Significant effect: Those with disappeared symptoms. Effective: those with reduced symptoms. Somewhat effective: Somewhat weakened symptoms. Ineffective: No change in symptoms.

Judgment Criteria for Improvement Effect on Razor Loss Significant effect: Loss of razor loss. Effective: Razor loser weakened. Somewhat effective: Razor losing slightly weakened. Invalid: No change in razor loss.

Evaluation of improvement effect on rough skin and razor losing A: The proportion (effective rate) at which the subject shows remarkably effective, effective and slightly effective (effective rate) is 80% or more. ：: The proportion (effective rate) at which the test subject shows significant, effective and somewhat effective (effective rate) is 50% or more and less than 80%. Δ: The ratio (effective rate) at which the subject exhibited a remarkable effect, an effective effect, and a slightly effective effect was 30% or more and less than 50%. ×: The ratio (effective rate) at which the subject showed significant, effective, and somewhat effective was less than 30%. Invalid: No change in razor loss.

[0029]

[Table 1] ---------------------------------------------- -------------------------- Example Comparative example 1 2 3 4 1 --------------- -------------------------------------------------- ------- Cetraxate hydrochloride 3.0--1.0-Famotidine-3.0-1.0-Cimetidine--3.0 1.0-Glycerin 1.0 1.0 1.0 1.0 1.0 1,3-butylene glycol 4.0 4.0 4.0 4.0 4.0 Ethanol 7.0 7.0 7.0 7.0 7.0 Poly Oxyethylene (20 mol) Oleyl alcohol 0.5 0.5 0.5 0.5 0.5 Ion exchange water Residue Residue Residue Residue Residue ----------------------------- -------------------------------------------

[0030]

[Table 2] ---------------------------------------------- -------------------------- Example Comparative example 1 2 3 4 1 --------------- -------------------------------------------------- ------- Skin roughness improvement effect ◎ ◎ ◎ ◎ × Razor loss improvement effect ○ ○ ○ ◎ × -------------------------- ----------------------------------------------

As is clear from Table 2, the examples in which cetraxate hydrochloride and a histamine H2 antagonist were blended were as follows:
As compared with the comparative example, the present invention showed an excellent improvement effect on rough skin and razor loss.

(2) Test for Implementation by Replica Method The skin surface morphology of healthy female subjects (face) was replicated using a replica method with myristin resin and observed with a microscope (17 ×). Evaluation of skin roughness 1 and 2 based on criteria shown in Table 3 based on skin crest state and horny layer peeling state
Using the 20 persons (rough panel) determined to be, the lotion of the example and the comparative example shown in “Table 1”, the example on one of the right and left cheeks, and the comparative example on the other cheek.
It was applied twice a day for two consecutive weeks. Two weeks later, the skin condition was observed again according to the replica method described above, and evaluated according to the criteria shown in Table 3. The results are shown in Table 4.

[0033]

[Table 3] ---------------------------------------------- ------------------ Grading Grading criteria -------------------------- -------------------------------------- 1 Skin sulcus, disappearance of skin ridges, wide corners The layers are turned up. 2 Skin groove and skin ridges are unclear and horny layer is turned up. 3 Skin sulcus and skin ridge are recognized, but flat. 4 Skin grooves and ridges are clear. 5 Skin grooves and ridges are clear and well-organized. -------------------------------------------------- --------------

[0034]

[Table 4] ---------------------------------------------- --------------------- Replica evaluation Example 1 Example 2 Example 3 Example 4 Comparative example 1 ------------ -------------------------------------------------- ----- 100 000 521 2 1 1 1 1 0 7 3 2 1 2 0 8 8 4 11 13 10 10 11 0 5 6 5 7 9 9 0 --------------- -------------------------------------------------- -

As can be seen from Table 4, the examples in which cetraxate hydrochloride and the histamine H2 antagonist were blended exhibited a more remarkable skin roughness improving effect than the comparative examples.

The following are examples of the formulation of the skin barrier function recovery promoter of the present invention.

"Cream" (formulation)% by weight Stearic acid 5.0 Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glycerin monostearate 3.0 Propylene glycol 10.0 Famotidine 0.1 Caustic potassium 0.2 Bisulfite Sodium 0.01 Preservative Appropriate amount Fragrance Appropriate amount Ion-exchanged water Residue (Preparation method) Add propylene glycol and caustic potash to ion-exchanged water, dissolve, heat and maintain at 70 ° C (aqueous phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is gradually added to the water phase, and after the addition is completed, the temperature is maintained for a while to cause a reaction. Thereafter, the mixture is uniformly emulsified with a homomixer and cooled to 30 ° C. while stirring well.

“Cream” (prescription) wt% stearic acid 2.0 stearyl alcohol 7.0 hydrogenated lanolin 2.0 squalane 5.0 2-octyldodecyl alcohol 6.0 polyoxyethylene (25 mol) cetyl alcohol ether 3 0.0 Glycerin monostearate 2.0 Propylene glycol 5.0 Famotidine 0.2 Cetraxate hydrochloride 1.0 Sodium bisulfite 0.03 Ethyl paraben 0.3 Perfume Appropriate amount Ion exchange water Residue (Production method) Propylene glycol in ion exchange water And add
Heat and maintain at 70 ° C. (aqueous phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is added to the water phase, pre-emulsified, homogenized with a homomixer, and cooled to 30 ° C. with good stirring.

“Cream” (Formulation)% by weight Solid paraffin 5.0 Beeswax 10.0 Vaseline 15.0 Liquid paraffin 41.0 Glycerin monostearate 2.0 Polyoxyethylene (20 mol) Sorbitan monolaurate 2 0.0 Soap powder 0.1 Borax 0.2 Diphenhydramine hydrochloride 3.0 Sodium bisulfite 0.03 Ethyl paraben 0.3 Appropriate amount Ion-exchanged water Residue (Preparation method) Add diphenhydramine hydrochloride, soap powder, and borax to ion-exchanged water. Heat and maintain at 70 ° C. (aqueous phase).
The other components are mixed, melted by heating and kept at 70 ° C. (oil phase).
The oil phase is gradually added to the aqueous phase while stirring to carry out the reaction.
Thereafter, the mixture is uniformly emulsified with a homomixer and cooled to 30 ° C. while stirring well.

“Emulsion” (Formulation) Weight% Stearic acid 2.5 Cetyl alcohol 1.5 Vaseline 5.0 Liquid paraffin 10.0 Polyoxyethylene (10 mol) Monooleate 2.0 Polyethylene glycol 1500 3.0 Triethanolamine 1.0 Carboxyvinyl polymer 0.05 (Product name: Carbopol 941, BFGoodrich Chemical company) Famotidine 0.01 Sodium bisulfite 0.01 Ethyl paraben 0.3 Perfume Appropriate amount Ion exchange water Residue (Preparation method) Small amount The carboxyvinyl polymer is dissolved in ion-exchanged water (phase A). Polyethylene glycol 1500 and triethanolamine are added to the remaining ion-exchanged water, and the mixture is heated and dissolved and maintained at 70 ° C. (aqueous phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is added to the water phase, pre-emulsification is performed, phase A is added, and the mixture is uniformly emulsified with a homomixer. After the emulsification, the mixture is cooled to 30 ° C. while stirring well.

"Emulsion" (formulation) weight% microcrystalline wax 1.0 beeswax 2.0 lanolin 20.0 liquid paraffin 10.0 squalane 5.0 sorbitan sesquioleate 4.0 polyoxyethylene (20 mol) sorbitan Monooleic acid ester 1.0 Propylene glycol 7.0 Cetraxate hydrochloride 5.0 Famotidine 1.0 Sodium bisulfite 0.01 Ethyl paraben 0.3 Perfume Appropriate amount Ion-exchanged water Residue (Production method) Add propylene glycol to ion-exchanged water.
Heat and maintain at 70 ° C. (aqueous phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The aqueous phase is gradually added while stirring the oil phase, and after uniform emulsification with a homomixer,
Cool to 30 ° C with good stirring.

"Jelly" (prescription) wt% 95% ethyl alcohol 10.0 dipropylene glycol 15.0 polyoxyethylene (50 mol) oleyl alcohol ether 2.0 carboxyvinyl polymer 0.05 (trade name: Carbopol 940) BF Goodrich Chemical company) Caustic soda 0.15 Famotidine 0.1 Sodium bisulfite 0.01 Ethyl paraben 0.3 Perfume Appropriate amount Ion-exchanged water Residue (Preparation method) Carbopol 940 is uniformly dissolved in ion-exchanged water, and polyoxyethylene ( 50 mol) Oleyl alcohol ether is added to the aqueous phase. Next, after adding other components, the mixture is neutralized with caustic soda to increase the viscosity.

"Jelly" (Formulation) Weight% (A phase) 95% Ethyl alcohol 10.0 Polyoxyethylene (20 mol) Octyldodecanol 1.0 Pantothenyl ethyl ether 0.1 Methyl paraben 0.15 (B phase) Potassium hydroxide 0.1 (C phase) Glycerin 5.0 Dipropylene glycol 10.0 Sodium bisulfite 0.03 Diphenhydramine hydrochloride 3.0 Carboxyvinyl polymer 0.2 (Product name: Carbopol 940, BFGoodrich Chemical company) Ion Exchange water residue (Production method) Dissolve A phase and C phase uniformly, and add A to C phase
Add phases and solubilize. Next, after the phase B is added, filling is performed.

“Pack” (Formulation) Weight% (A phase) Dipropylene glycol 5.0 Polyoxyethylene (60 mol) Hardened castor oil 5.0 (Phase B) Olive oil 5.0 Tocopherol acetate 0.2 Ethyl paraben 0 0.2 Perfume 0.2 (Phase C) Diphenhydramine hydrochloride 0.3 Sodium bisulfite 0.03 Polyvinyl alcohol 13.0 (Saponification degree 90, Polymerization degree 2,000) Ethyl alcohol 7.0 Ion-exchanged water Residue (Production method) A Phase, phase B and phase C are uniformly dissolved,
Add phase B to phase and solubilize. Next, after adding the phase C to this, filling is performed.

"Solid foundation" (formulation)% by weight Talc 43.1 Kaolin 15.0 Sericite 10.0 Zinc white 7.0 Titanium dioxide 3.8 Yellow iron oxide 2.9 Black iron oxide 0.2 Squalane 8. 0 Isostearic acid 4.0 POE sorbitan monooleate 3.0 Isocetyl octoate 2.0 Famotidine 0.5 Preservatives Appropriate amount Flavors Appropriate amount (Production method) Thorough mixing of talc and black iron oxide powder components in a blender, and squalane Add the oily component of isocetyl octanoate, famotidine, preservatives, and fragrance, knead well, fill into a container, and mold.

"Emulsion type foundation" (Formulation) wt% (powder part) Titanium dioxide 9.3 Magnesium chloride 1.0 Sericite 5.4 Kaolin 3.0 Yellow iron oxide 0.8 Bengala 0.3 Black iron oxide 0.2 (oil phase) decamethylcyclopentasiloxane 11.5 liquid paraffin 4.5 polyoxyethylene-modified dimethylpolysiloxane 4.0 (aqueous phase) ion-exchanged water 50.0 1,3-butylene glycol 4.5 hydrochloric acid Diphenhydramine 1.5 Sorbitan sesquioleate 3.0 Preservatives Appropriate amount Flavors Appropriate amount (Preparation method) After heating and stirring the aqueous phase, a well-mixed and pulverized powder portion is added, followed by homomixer treatment. Further, the oil phase mixed by heating is added, and the mixture is treated with a homomixer. Then, a fragrance is added with stirring, and the mixture is cooled to room temperature.

[0047]

According to the present invention, it is possible to provide an excellent skin barrier function recovery promoter which can promote the recovery of skin barrier function.

[Brief description of the drawings]

FIG. 1 is a graph showing an evaluation of the effect of cetraxate hydrochloride on promoting the recovery of skin barrier function using TEWL as an index.

FIG. 2 is a graph showing the effect of diphenhydramine hydrochloride, a histamine H1 antagonist, on the promotion of skin barrier function recovery, evaluated using TEWL as an index.

FIG. 3 is a graph showing the effect of tripellenamine, a histamine H1 antagonist, on promoting the recovery of skin barrier function, evaluated using TEWL as an index.

FIG. 4 is a graph showing the effect of famotidine, a histamine H2 antagonist, on the promotion of skin barrier function recovery, evaluated using TEWL as an index.

FIG. 5 is a graph showing the effect of a histamine H2 antagonist on promoting the recovery of cimetidine skin barrier function using TEWL as an index.

FIG. 6 is a graph showing an evaluation of the effect of gefarnate on promoting the recovery of the skin barrier function using TEWL as an index.

FIG. 7 is a graph showing the effect of lansoprazole on promoting the recovery of the skin barrier function evaluated using TEWL as an index.

FIG. 8 is a graph showing the effect of pirenzepine hydrochloride on promoting the recovery of the skin barrier function using TEWL as an index.

Continuing from the front page (72) Inventor Junichi Koyama 2-12-1 Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa Prefecture Shiseido Second Research Center Co., Ltd.

Claims (5)

[Claims] 1. An agent for promoting the recovery of skin barrier function, comprising cetraxate hydrochloride. 2. A skin barrier function recovery promoter comprising one or more histamine H1 antagonists. 3. A skin barrier function recovery promoter comprising one or more histamine H2 antagonists. 4. An external preparation for improving rough skin, which comprises cetraxate hydrochloride. 5. An external preparation for improving skin roughness, which comprises one or more histamine H2 antagonists.