JPH10251293A - Dermal collagen fascicular normalizing agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a means for normalizing an abnormality in a dermal collagen fascicle caused by the formation of a crease, a fibrosis, a keloid, etc. SOLUTION: This dermal collagen fascicular normalizing agent comprises a steroid and its derivative and/or a physiologically permissible salt thereof. The dermal collagen fascicular normalizing agent is contained in a composition such as a cosmetic or a skin preparation for external use. Thereby, a means for normalizing an abnormality in a dermal collagen fascicle caused by the formation of a crease, a fibrosis, a keloid, etc., can be provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a dermal collagen fiber bundle normalizing agent and an external preparation for skin containing the same as an active ingredient.

[0002]

2. Description of the Related Art Wrinkles are an aging phenomenon that can be said to be a symbol of aging for human beings, and have many effects on their appearance. Therefore, wrinkles have been taken up as a problem to be solved for cosmetics and external medicine for skin for many years. However, there are various opinions on the mechanism by which wrinkles are formed, and it has not yet been clarified. Therefore, a method of suppressing the formation of wrinkles or returning the formed wrinkles to a state with less wrinkles has not yet been obtained. As with wrinkles, the mechanism of formation of keloids formed in fibroses, scars and burns is not known, and there is still no known method of suppressing their formation or treating these abnormalities. Had not been.

No study has been made on the relationship between the formation of wrinkles, fibroses and keloids and the state of the dermal collagen fiber bundle.

[0004] It has not been known at all that steroids represented by corticosteroids have an effect of normalizing abnormalities of dermal collagen fiber bundles caused by formation of wrinkles, fibroses, keloids and the like.

[0005]

DISCLOSURE OF THE INVENTION The present invention has been made under such circumstances, and it is an object of the present invention to provide means for normalizing abnormalities of dermal collagen fiber bundles caused by formation of wrinkles, fibroses, keloids and the like. Make it an issue.

[0006]

In view of such a situation,
The present inventors have conducted intensive studies for the formation mechanisms of wrinkles, fibroses, and keloids, and as a result, have found out that wrinkles generated by light irradiation among wrinkles are caused by abnormalities in dermal collagen fiber bundles. As a result of further studies, it has been found that abnormalities in the dermal collagen fiber bundles are also a mechanism during the formation of keloids that occur during healing of fibrosis, burns and wounds. As a result of further research for a drug that normalizes the abnormalities of the dermal collagen fiber bundle, the inventors have found such an effect on steroids typified by adrenocortical hormone and completed the invention. Hereinafter, the present invention will be described in detail focusing on embodiments.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION

(1) Relationship between formation of wrinkles and structure of dermal collagen fiber bundle Relationship between formation of wrinkles and structure of dermal collagen fiber bundle
This will be described using a mouse light irradiation model. From this experimental example, it is understood that the disorder of the structure of the dermal collagen fiber bundle is the mechanism of wrinkle formation by light irradiation. Similarly, the disorder of the structure of the dermal collagen fiber bundle has been observed in fibroses and keloids, suggesting that this is a mechanism.

<Experimental example> Examination of changes in skin condition in a photoaging model A hairless mouse (Skh: HR-1, female, 8 weeks old) is irradiated with ultraviolet rays B (Toshiba SE lamp, 60 mJ / cm ² ) every day. Then, skin and skin surface morphological replicas were collected 2, 5 and 10 weeks after the start of irradiation. For the collected skin, the collagen fiber bundle structure was observed by a scanning electron microscope using the NaOH method. FIG. 1 shows the skin surface morphology at 50 × magnification (A: non-irradiated control, B: irradiation 2 weeks, C: irradiation 5 weeks, D: irradiation 10 weeks), and FIG. 2 shows the dermal surface morphology at 50 × magnification (E : Non-irradiated control, F: 2 weeks of irradiation, G: 5 weeks of irradiation, H: 10 weeks of irradiation), FIG. 3 shows the structure of dermal collagen fiber bundle at 500 × magnification (I: non-irradiated control, J: 2 irradiated) Week, K: irradiation 5 weeks, L: irradiation 10 weeks), FIG. 4 shows the structure of the dermal collagen fiber bundle at 2500 × magnification (M: non-irradiation control, N: irradiation 2 weeks,
O: irradiation 5 weeks, P: irradiation 10 weeks). From these figures, when wrinkles are formed, grooves are also formed on the surface of the dermis so as to correspond to them, and the change in the morphology of the skin surface corresponds to the change in the morphology of the dermis surface. It can be seen that the change in the dermis surface reflects a change in the structure of the collagen fiber bundle in the dermis, that is, a decrease in the order of the fiber bundle such that the fiber bundle becomes less clear. Here, the microscope image of FIG. 4 was given a score based on the following criteria. That is, score 0: no fiber bundle structure was observed in the entire observation region, score 1: collapse of the fiber bundle structure or transition to an abnormal structure was observed in the majority region, and score 2: partial collapse of the fiber bundle structure or Degeneration is observed, but an almost normal structure is recognized as a whole. Score 3: This is a criterion that a normal fiber bundle structure is observed over the entire surface and collapse / degeneration is almost not observed. The result is shown in FIG. Regarding the structure of the skin surface, the shadow of wrinkles that could be irradiated with a xenon lamp at an incident angle of 20 degrees on the replica was quantified by image analysis to determine the amount of wrinkles generated. FIG. 6 shows the measurement results. The calculated coefficient of correlation between the amount of wrinkles and the average of the score values was 0.91, and there was a strong relationship between the formation of wrinkles and the disorder (order) of the dermal collagen fiber bundle. It can be seen that turbulence is the mechanism of wrinkle formation.

(2) The dermal collagen fiber bundle normalizing agent of the present invention The dermal collagen fiber bundle normalizing agent of the present invention comprises a steroid. As the dermal collagen fiber bundle normalizing agent of the present invention, corticosteroid hormones are particularly preferred, and fluorosinolone acetonide, flumethasone bivalate, fluocinonide, fluoromesolone, beclomethasone propionate, dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate, Fludroxycortide, betamethasone valerate, betamethasone dipropionate, triamcinolone acetonide, prednisolone, methylprednisolone, methylprednisolone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, diflucortron valerate, clobetasol propionate,
Amcinonide, halcinonide, hydrocortisone butyrate propionate are particularly preferred. These are already known substances and are already commercially available as commercial products. In the present invention, these steroids can be used as they are in a dosage form, but they can also be used as derivatives or salts. Examples of the derivative include aromatic or aliphatic esters or ethers, which may have a functional group, sulfonic acid esters, and phosphoric acid esters. Not limited,
For example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium and magnesium; basic amino acid salts such as lysine and arginine;
Examples thereof include primary, secondary, tertiary and quaternary ammonium salts.

(3) External preparation for skin of the present invention The external preparation for skin of the present invention is characterized by containing one or more selected from the above agents for normalizing dermal collagen fiber bundles. The preferred content of the dermal collagen fiber bundle normalizing agent in the skin external preparation of the present invention is 0.00001 to
10% by weight, more preferably 0.00005 to 5%.
% By weight, more preferably 0.0001 to 1% by weight.
It is. The external preparation for skin of the present invention may contain, in addition to the agent for normalizing dermal collagen fiber bundles, optional components usually used in external preparations for skin. Such optional components include, for example, hydrocarbons such as petrolatum and microcrystalline wax, esters such as jojoba oil and gay wax, triglycerides such as tallow, olive oil, higher alcohols such as cetanol and oleyl alcohol,
Fatty acids such as stearic acid and oleic acid, polyhydric alcohols such as glycerin and 1,3-butanediol, nonionic surfactants, anionic surfactants, cationic surfactants, amphoteric surfactants, ethanol, carbopol, etc. Thickeners, preservatives, ultraviolet absorbers, antioxidants, pigments, powders and the like. The topical skin preparation of the present invention is characterized by being suitably applied to diseases associated with abnormal dermal collagen fiber bundles. Diseases associated with abnormal dermal collagen fiber bundles include, for example, abnormal formation of wrinkles, fibrosis,
Preferable examples include keloid formation at the time of burn or wound healing. Above all, application to abnormal formation of wrinkles is preferable. Among abnormal formation of wrinkles, application to abnormal formation of wrinkles caused by long-term irradiation with light is particularly preferable. The external preparation for skin of the present invention can be used as a pharmaceutical or a cosmetic depending on the degree of normalizing action of the collagen fiber bundle. In order to reduce the effect, the content of the steroid to be contained may be reduced.
0001-0.0001% by weight, more preferably 0.00003-0.00007% by weight. In particular, when the composition is administered for wrinkle abnormal formation, it is preferable to administer the composition as a cosmetic having a small effect for a long period of time. The external preparation for skin of the present invention not only has a therapeutic effect of normalizing the abnormalities of the dermal collagen fiber bundles that have already occurred, but also has a preventive effect of preventing the abnormalities of the dermal collagen fiber bundles, and further worsens the abnormalities of the dermal collagen fiber bundles. It has a therapeutic prophylactic action to prevent The dosage form of the external preparation for skin of the present invention can be applied without any particular limitation as long as it is a dosage form usually used in external preparations for skin such as lotions, gel preparations, emulsions, creams, ointments and the like. These can be manufactured according to a generally known method.

[0011]

EXAMPLES The present invention will be described in detail below with reference to examples, but it goes without saying that the present invention is not limited only to these examples.

<Example 1> Using the above animal model example,
It was examined how changes in the deterioration of the skin such as wrinkles caused by light irradiation were changed by dexamethasone lotion, which is a skin external preparation of the present invention. Dexamethasone lotion was prepared by adding 99.95 parts by weight of ethanol to 0.05 parts by weight of dexamethasone (lotion preparation 1), sonicating and solubilizing. Using the above-mentioned light-irradiated hairless mouse (Skh: HR-1, female, 8 weeks old), one group contained 0.05% lotion 1 and the other group received only 0.05 ml of ethanol alone.
Administered daily for weeks. The skin of this animal was treated in the same manner as described above, and the morphology of the skin surface, the dermis surface, and the collagen fiber bundle structure were observed. FIG. 7 shows the skin surface morphology at 50 × magnification, FIG. 8 shows the dermis surface morphology at 50 × magnification, FIG. 9 shows the collagen fiber bundle structure at 500 × magnification, and FIG.
1 shows a 00x collagen fiber bundle structure. Regarding the core value, the ethanol administration group was 0.78, and the lotion preparation 1 administration group was 1.71. From this, the improvement value of the skin condition is calculated as 1.71 / 0.78 = 2.28. As can be seen from the scanning micrographs of the morphology of the skin surface, it can be seen that the administration of the lotion agent 1 has significantly improved.

<Examples 2 to 4> Creams were prepared according to the formulations shown in Table 1 below. That is, the mixture (b) was kneaded, diluted with the mixture (1), adjusted to a temperature of 80 ° C., and gradually heated to 80 ° C. and gradually added to emulsify the mixture, followed by stirring and cooling to obtain a cream. When this was evaluated according to the photoaging screening method described above, the improvement value of the dermal collagen fiber bundle structure was as shown in Table 1.
It became the value shown in. These creams were used for 20 months for a group of panelists suffering from wrinkles for 2 months, and the condition of wrinkles was investigated by a questionnaire. These results are also shown in Table 1. These results indicate that the external preparation for skin of the present invention is excellent in the effect of normalizing the collagen fiber bundle. In addition, the numerical value of a prescription represents a weight part.

[0014]

[Table 1]

<Examples 5 to 9> Ointments were prepared according to the formulation shown in Table 2 below. That is, the ingredients were kneaded with a kneader to obtain an ointment. All of these showed a normalizing effect on the dermal collagen fiber bundle in the light-irradiated hairless mouse model by electron microscopic observation.

[0016]

[Table 2]

[0017]

According to the present invention, it is possible to provide a means for normalizing abnormalities of the dermal collagen fiber bundle caused by the formation of wrinkles, fibroses, keloids and the like.

[Brief description of the drawings]

FIG. 1 is a diagram showing a change in skin surface morphology in a photoaging model.

FIG. 2 is a diagram showing a change in dermal surface morphology in a photoaging model.

FIG. 3 is a diagram showing a collagen fiber bundle structure in a photoaging model. (500 times)

FIG. 4 is a diagram showing a collagen fiber bundle structure in a photoaging model. (2500 times)

FIG. 5 is a diagram showing a wrinkle amount due to light irradiation.

FIG. 6 is a view showing a fiber bundle structure score by light irradiation.

FIG. 7 is a diagram showing changes in skin surface morphology during the healing process of wrinkles.

FIG. 8 is a diagram showing changes in the dermal surface morphology during the healing process of wrinkles.

FIG. 9 is a view showing a structural change of a collagen fiber bundle during a healing process of wrinkles. (500 times)

FIG. 10 is a view showing a structural change of a collagen fiber bundle in a healing process of wrinkles. (2500 times)

Claims (5)

[Claims] 1. A dermal collagen fiber bundle normalizing agent comprising a steroid and a derivative thereof and / or a physiologically acceptable salt thereof. 2. The steroid is a corticosteroid,
The dermal collagen fiber bundle normalizing agent according to claim 1. 3. The agent for normalizing dermal collagen fiber bundles according to claim 1, wherein the corticosteroid is any of the following a. (A) Fluorosinolone acetonide, flumethasone bivalate, fluocinonide, fluoromesolone, beclomethasone propionate, dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate, fludoxycortide, betamethasone valerate, betamethasone dipropionate, triamcinolone acetonide, Prednisolone, methylprednisolone, methylprednisolone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, diflucortron valerate, clobetasol propionate, amcinonide, halcinonide, hydrocortisone butyrate propionate 4. A disease associated with abnormal dermal collagen bundles, comprising one or more selected from the dermal collagen fiber bundle normalizing agents according to any one of claims 1 to 3 as an active ingredient. External preparation for skin. 5. The external preparation for skin according to claim 4, wherein the disease associated with dermal collagen fiber bundle abnormality is abnormal formation of wrinkles due to light, fibrosis or keloid.