JPH0853337A - Sebum suppressing agent - Google Patents

Abstract

PURPOSE:To obtain a sebum suppressing agent expressing mild effect on seborrheic diseases such as pimples and capable of effectively preventing seborrheic dandruff. CONSTITUTION:This sebum suppressing agent preferably comprises 0.0001-10wt.% of (A) a protease inhibitor, preferably tranexamic acid or its derivative or a salt thereof, 0.001-10wt.% of (B) a lipase inhibitor, e.g. tetracycline hydrochloride, an extract of Coptis japonica Makino and, if needed, 0.01-0.1wt.% of (C) an antimicrobial agent, e.g. benzalkonium chloride and triclosan. As the ingredient (A), in addition, a compound derived from animal or plant (e.g. soybean trypsin inhibitor), a compound derived from microorganisms (e.g. leupeptin) and the following compounds and their derivatives are cited: benzamidine, acetamide, guanidine, an w-amino acid (especially p-aminomethylbenzoic acid), guanidinobenzoic acid, lysine (its derivatives) and arginine (its derivatives).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a sebum inhibitor. Specifically, a sebum suppressor containing one or more protease inhibitors and one or more lipase inhibitors as active ingredients, and sebum containing one or more antibacterial agents as active ingredients. The present invention relates to an inhibitor, which is a therapeutic agent for skin diseases that exhibits a mild effect on seborrheic diseases such as acne caused by excessive secretion of sebum. or,
It can be used on the scalp to effectively prevent seborrheic dandruff.

[0002]

2. Description of the Related Art To date, no compound has been known that exhibits a specific effect on the suppression of sebum secretion and does not affect other organs. There is a sebum suppressor cyproterone acetate for oral administration, but oral administration often has more side effects than topical application. Also, because of its anti-androgenic properties, cyproterone acetate can only be used in women. Further, tetracycline, peony extract and the like, which have a lipase inhibitory action, cannot exhibit the lipase inhibitory effect due to the relationship with other compounding ingredients, and thus the expected effect is not always satisfactory.

[0003]

In view of the above situation, the present inventors have eagerly searched for a compound that specifically shows a sebum secretion inhibitory effect and does not affect other organs,
We have found that this object can be achieved by combining a protease inhibitor and a lipase inhibitor, and further by combining an antibacterial agent, and completed the present invention.

[0004]

Means for Solving the Problems That is, the present invention is a sebum inhibitor containing one or more protease inhibitors and one or more lipase inhibitors as active ingredients, and an antibacterial agent effective. It is a sebum inhibitor as a component. The configuration of the present invention will be described in detail below.

The protease inhibitor in the present invention is
It means all chemical substances capable of reversibly or irreversibly inhibiting the hydrolysis action of the protease or proteolytic enzyme. The main substances are listed below.

(1) Animal- or plant-derived compounds Preferred are bovine pancreatic basic trypsin inhibitor, aprotinin, soybean trypsin inhibitor, lima bean protease inhibitor, corn protease inhibitor and the like.

(2) Compounds derived from microorganisms Antipain and plasminostreptin are preferable, and leupeptin represented by the following general formula 1 is a generic name.

[0008]

Embedded image

(3) Benzamidine and its derivatives Preferably benzamidine, p-aminobenzamidine, m
-Aminobenzamidine, phenylguanidine, (2R,
4R) -4-methyl-1- [N ^2- (3-methyl-1,
2,3,4-tetrahydro-8-quinolinesulfonyl)
-L-arginyl] -2-piperidinecarboxylic acid monohydrate, dansylarginine N-
(3-ethyl-1,5-pentanesyl) amide and the like.

(4) Acetamide and Derivatives Thereof Preferably, acetamide, 2-phenylacetamide, cyclohexyl kaixamide and the like are mentioned.

(5) Guanidine and derivatives thereof Preferably, phenylguanidine, cyclohexylguanidine and the like are used.

(6) ω-Amino acids Preferably p-aminomethylbenzoic acid, 4-aminomethylbicyclo (2.2.2.) Octane-1-carboxylic acid, 5- [trans-4 (aminomethyl) cyclohexyl. ] Tetrazole, 3- [trans-4 (aminomethyl) cyclohexyl-2-oxopropionate, trans-4- (aminomethyl) cyclohexylglyoxal monohydrate, trans-4- (aminomethyl)
Examples include cyclohexane hydroxamic acid and substances having a carbon chain of n = 1 to 8 in the following general formula 2.

[0013]

Embedded image NH ₂ (CH ₂ ) _n COOH

Among these ω-amino acids, p-aminomethylbenzoic acid has a particularly excellent effect.

(7) Tranexamic Acid and Salts or Derivatives Thereof Preferably, tranexamic acid is preferred, and as the tranexamic acid carboxyl group-modified derivative, there is one represented by the general formula (3).

[0016]

[Chemical 3]

X is, for example, --NH ₂ , --NHCH ₂ CH _{2
CH 3, -NHCH 2 CH 2 CH} 2 CH 2 CH 2 CH 3, -N
_{HCH 2 CH 2 COOH, -NHCH 2} CH 2 CH 2 CH 2 C
H ₂ COOH, and the like. Further, salts of the tranexamic acid carboxyl group-modified derivative include those represented by the general formula 4.

[0018]

[Chemical 4]

Examples of X include those shown in Chemical formula 5.

[0020]

[Chemical 5]

The amino group-modified derivative of tranexamic acid is represented by the general formula (6).

[0022]

[Chemical 6]

Examples of X include those shown in Chemical formula 7 and the like.

[0024]

[Chemical 7]

As a derivative in which both the amino group and the carboxyl group of tranexamic acid are modified, there is a compound represented by the general formula (8).

[0026]

Embedded image

In this, X is a residue shown in Chemical formula 9,

[0028]

[Chemical 9]

Some examples are those in which Y is --NH--CH ₂ CH ₂ CH ₃ or --NH-(CH ₂ ) ₅ CH ₃ .

(8) Guanidinobenzoic acid and its derivatives Preferably p-nitrophenyl-p'-guanidinobenzoic acid, 3 ', 6'-bis (4-guanidinobenzoyloxy) -5- (N'-4- Carboxyphenyl) thioureido spiro [isobenzofuran-1 (3H), 9'-
(9H) xanthene] -3-one and the like.

(9) Lysine and derivatives thereof Preferably, there are compounds represented by the following general formula 10.

[0032]

[Chemical 10]

The present invention is not limited to these, but among these lysines and their derivatives, those in which R ₂ is —CH ₂ Cl are particularly preferable.

(10) Arginine and its derivatives Preferably, there are compounds represented by the following general formula 11 and the like.

[0035]

[Chemical 11]

Among the above-mentioned arginines and their derivatives, those in which R ₂ is —CH ₂ Cl are particularly preferable.

The lipase inhibitor in the present invention is
It means any substance capable of reversibly or irreversibly inhibiting the action of lipase, which is an enzyme that hydrolyzes glycerol ester to release fatty acid. The main substances are:
Ibuprofen piconol, tetracycline hydrochloride,
There are minocycline, doxytetracycline, clindamycin, erythromycin, lincomycin, nadicloxacin, chloramphenicol, and metal salts. , Herbs, hamamelis, birch and the like, or solvent-extracted extracts thereof.

As the antibacterial agent, hinokitiol,
Triclosan, trichlorocarbanilide, chlorhexidine hydrochloride, chlorhexidine gluconate, halocarban, chlorophenesin, benzethonium chloride, benzalkonium chloride, lysozyme chloride, alkyldiaminoethylglycine hydrochloride, isopropylmethylphenol,
Examples thereof include benzoic acid, Photosensitizer No. 201, thymol, hexachlorophen, berberine, thioxolone and derivatives thereof.

In the present invention, the amount of the protease inhibitor added to the sebum inhibitor composition is 0.0001 based on the total amount of the composition.
10% (% by weight, the same applies hereinafter) is preferable, and 0.001
-5% is more preferable. If it is less than 0.0001%, the effect of the present invention is not sufficient, and if it exceeds 10%, the solubility is poor, which is not preferable in terms of formulation and is also disadvantageous in terms of cost.

The amount of the lipase inhibitor used in combination is
The total amount of the composition is 0.001% or more and 10% or less, preferably 0.01% or more and 5% or less. If it is less than 0.001%, the effect of the present invention is not sufficient, and if it exceeds 10%, no further increase in effect is observed. For crude drugs such as peony, the whole composition as an extract (residue obtained by distilling off the extraction solvent) usually obtained by extraction treatment at 15 to 20 ° C. using powder or water or aqueous alcohol such as ethanol, or a mixture thereof. Generally, 0.005% or more is mixed therein. The upper limit of the blending amount is not particularly limited, but from the viewpoint of commercial value such as coloring, the blending amount of the crude drug and its extract is preferably about 10% or less in total as the dry residue.

The amount of the antibacterial agent used in combination is 0.001 to 1% with respect to the total amount of the composition, preferably 0.01 to 0.1.
%. If it is less than 0.001%, the effect of the present invention is not sufficient, and if it exceeds 1%, no further increase in effect is observed. In the sebum suppressor of the present invention, in addition to the compounds described above, vitamin A acid and its derivatives, salicylic acid, zinc and its compounds, lactic acid and other drugs and keratolytic agents, depending on the properties, oil, surfactant, Moisturizers such as water, ethanol and hyaluronic acid, thickeners, fragrances, dyes and the like can be appropriately added within a range that does not impair the effects of the present invention.
Properties of the sebum suppressor of the present invention include cream, lotion,
Any material such as an ointment that can be applied to the outer skin may be used.

[0042]

EXAMPLES Next, the effects of the present invention will be described in more detail with reference to clinical test examples. (Pharmaceutical agent used) A lotion-type sebum suppressor based on the formulation in Table 1 was used. The blending amount is% by weight.

(Target of use and observation period) 4 out of 120 men and women with acne vulgaris aged 15 to 30 years old (20 people per group)
Used for a week. At the time of use, the forehead part of the subject was divided into left and right, and one of Examples 1 to 5 was applied to the other, and the lotion having the formulation of Comparative Example 1 was applied to the other for 4 weeks in the morning and evening.

(Measurement of sebum) The total amount of sebum before use and after use for 4 weeks was measured by a gravimetric method [Ohok
awa H., et al., Anal Biochem, 95.351 358 (1979)]. The sebum reduction rate was calculated by the relative ratio of the following equation.

(Sensory evaluation) A questionnaire survey was carried out after the application, and when 15 or more people out of 20 felt no oiliness compared to before the application of lotion, A was 10 to 14 people. The case was determined as B, the case of 5 to 9 out of 20 was determined as C, and the case of less than 5 out of 20 was determined as D. Table 1
The results are shown in.

[0046]

[Table 1] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Example Example Comparative Example Comparative Example Comparative Example Comparative Example Example 1 2 12 2 3 4 ─────────────────────────────────── Tranexamic acid 1.0 1.0 1.0 − − − Peony extract 1.0 1.0 − 1.0 − − Benzalkonium chloride − 0.05 − − 0.05 − Glycerin 4.0 4.0 4.0 4.0 4.0 4.0 1,3-Butylene glycol 4.0 4.0 4.0 4.0 4.0 4.0 Ethanol 7.0 7.0 7.0 7.0 7.0 7.0 Polyoxyethylene oleyl alcohol 0.5 0.5 0.5 0.5 0.5 0.5 Methylparaben 0.05 0.05 0.05 0.05 0.05 0.05 Citric acid 0.01 0.01 0.01 0.01 0.01 0.01 Sodium citrate 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Fragrance 0.05 0.05 0.05 0.05 0.05 0.05 Purified water Residual Residual Residual Residual Residual ──── ───────────────────────── ──── Average sebum reduction rate (%) 14.6 15.1 5.2 5.0 1.1 0.2 Sensory evaluation A A B B C D ━━━━━━━━━━━━━━━━━━━━━━━━━━━ ━━━━━━━━━━ As a result, the lotion of Example 1 containing tranexamic acid and peony extract and the lotion of Example 2 containing tranexamic acid, peony extract and benzalkonium chloride were compared with each other. It was shown to be more effective than the example lotion.

Good sebum-suppressing effects were observed for all sebum-suppressing agents prepared on the basis of the compositions and production methods shown in the following Examples. Example 3 Toner lotion g Sorbitol (70%) 3.5 Glycerin 5.0 Purified water 70.0 Tranexamic acid propylamide 1.0 Oolene extract 1.5 Polyoxyethylene hydrogenated castor oil derivative 0.5 Hinokitiol 0.1 Ethanol 20 0.0 Fragrance Appropriate amount A lotion was produced by a conventional method.

Example 4 Cream g Beeswax 11.0 Paraffin wax 6.0 Lanolin 3.0 Isopropyl myristate 6.0 Squalane 8.0 Liquid paraffin 27.5 Tranexamic acid propylamide 5.0 Peony extract 1.5 Chlorinated benza Ruconium 0.05 Indomethacin 0.5 Polyoxyethylene sorbitan monostearate 1.5 Sorbitan monostearate 4.0 Preservative Appropriate amount Propylene glycol 2.0 Borax 1.0 Purified water 28.0 Cream by conventional method Was manufactured.

Example 5 Ointment g Solid paraffin 10.0 Beeswax 10.0 Squalane 10.0 Tranexamic acid n-hexyl ester hydrochloride 1.0 Peony extract 1.0 Trichlorocarbanilide 0.1 Resorcin 0. 1 Zinc white 0.5 Fragrance Suitable amount Vaseline 68.4 An ointment was produced by a conventional method.

Example 6 Hair Tonic g Ethanol 55.0 Nikkor HCO-60 1.0 Fragrance Suitable amount Tranexamic acid guanidide 0.3 Buttonpi extract 0.7 Halocarban 0.1 Purified water 42.0 Glycerin 1.0 color Hair Tonic was manufactured by a conventional method.

[0051]

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to obtain an excellent sebum suppressor which exhibits very good reversible local sebum suppression and does not affect other organs at all.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 7/00 W 7/06 31/155 9455-4C 31/16 9455-4C 31/19 ADE 9455 -4C 31/215 9455-4C 38/55 ADA

Claims (3)

[Claims] 1. A sebum suppressor comprising, as active ingredients, one or more protease inhibitors and one or more lipase inhibitors. 2. The sebum suppressor according to claim 1, which further contains one or more antibacterial agents as active ingredients. 3. The sebum inhibitor according to claim 1 or 2, wherein the protease inhibitor is tranexamic acid, a tranexamic acid derivative or a salt thereof.