JPH02275820A - External antifungal agent - Google Patents

Abstract

PURPOSE:To obtain an antifungal agent excellent in therapeutic efficacy with a little irritation to the applied site of skin and a favorable skin-penetrative property by containing a specified known antifungal agent and a lower hydroxyalkylamine. CONSTITUTION:The objective antifungal agent can be obtained by containing (A) 6,7-dihydro-9-fluoro-8-(4-hydroxy-1-piperidyl)-5-methyl-1-oxo-1H,5H-be nzo[i, j]quinolizine-5-carboxylic acid or its salt having strong antifungal effect on Gram-negative bacteria such as Pseudomonas aeruginosa and Escherichia coli as well as Grampositive bacteria such as Demodex bacillus and staphylococcus and (B) a compound of formula R<1>R<2>R<3>N (R<1> to R<3> are each H or hydroxy lower alkyl, but at least one of them being other than H), pref. di(beta- oxyethyl)amine, with a content of 0.01 to 20 (pref. 0.1 to 5)wt.%.

Description

[Detailed description of the invention] Industrial applications The present invention relates to external antibacterial agents.

Conventional techniques and their problems It is said that MM vulgaris develops due to increased sebaceous gland function in hair follicles, and then the condition worsens due to the proliferation of bacteria.The causative bacteria are mainly K. acnes and Staphylococcus epidermidis. Antibiotics such as tetracycline, erythromycin, and clindamycin have been used as conventional therapeutic agents.However, in recent years, problems such as an increase in bacteria resistant to these drugs and side effects due to long-term oral administration have become a problem.

Means for solving the problem 6. 7-dihydro-9-fluoro-8-(4hydroxy-1-piperidyl)-5-methyl-1-oxo-1H,
5H-benzo[i,j)quinolidine-2-carboxylic acid (hereinafter referred to as "compound A") exhibits strong antibacterial activity against Durham-positive bacteria such as Klebsiella acnes and Staphylococcus, as well as against Pseudomonas aeruginosa, Escherichia coli, etc. Strong antibacterial activity has been recognized against Durham-negative bacteria (Japanese Patent Application Laid-open No. 158652/1983).

Therefore, it is an object of the present invention to develop an excellent topical antibacterial agent for treating superficial purulent skin diseases such as acne vulgaris using the above-mentioned compound A or a salt thereof, which is a local therapy that reduces the side effects caused by systemic administration. is extremely significant.

In view of the current situation, the present inventor has conducted extensive research in order to develop a topical antibacterial agent that causes little irritation to the application site, has good skin permeability, and can exhibit excellent therapeutic effects. As a result, the following general formula (1), which has not been used as a transdermal absorption enhancer until now, is added to the above compound A or its salt.
It has been found that the intended object of the present invention can be achieved by incorporating a hydroxy lower alkylamine.

The present invention was completed based on this knowledge.

That is, the present invention contains Compound A or a salt thereof as an active ingredient, and further has the general formula % (1) [wherein R1, R2 and R3 each represent a hydrogen atom or a hydroxy lower alkyl group]. However, R1, R2 and R
3 cannot be a hydrogen atom at the same time. ] This relates to an external antibacterial agent characterized by containing a hydroxy lower alkylamine represented by the following.

Compound A incorporated as an active ingredient in the external antibacterial agent of the present invention may be a racemate or an optically active compound. Further, the salt of Compound A is not particularly limited as long as it is a pharmacologically acceptable salt commonly used in this field. Specific examples of such salts include potassium salts, sodium salts, barium salts, calcium salts, and the like.

The amount of Compound A or its salt to be incorporated into the external antibacterial agent of the present invention is not particularly limited and can be appropriately selected within a wide range, but is usually 0.01 to 20% by weight (
(hereinafter simply referred to as "%"), preferably 0.1 to 5%
It is best to mix the ingredients so that the amount is the same.

Further, as the hydroxy lower alkylamine of general formula (1), any conventionally known hydroxyl alkylamine can be used as long as it is included in the above general formula (1). Representative examples include β-oxyethylamine [monoethanolamine], di(β-
oxyethyl)amine [jetanolamine], tri
(β-oxyethyl)amine [triethanolamine]
, β-hydroxypropylamine [monoisopropanolamine], di(β-hydroxypropyl)amine [diisopropanolamine], tri(β-hydroxypropyl)amine [triisopropanolamine], (β
-oxyethyl)(β-hydroxypropyl)amine,
Di(β-oxyethyl)(β-hydroxypropyl)amine, (β-oxyethyl)-di(β-hydroxypropyl)amine, 4-hydroxybutylamine, di(4-
hydroxybutyl)amine, tri(4-hydroxybutyl)amine, 5-hydroxypentylamine, di(5-
hydroxypentyl)amine, tri(5-hydroxypentyl)amine, 6-hydroxybutylamine, di(
Examples include 6-hydroxyhexyl)amine and tri(6-hydroxyhexyl)amine. Among these, β-oxyethylamine, di(β-oxyethyl)amine and tri(β-oxyethyl)amine are preferred;
Particularly preferred is di(β-oxyethyl)amine. In the present invention, these amines may be used alone or in combination of two or more.

The level of the hydroxy lower alkylamine of the general formula (1) to be incorporated into the external antibacterial agent of the present invention is not particularly limited and can be appropriately selected from a wide range, but usually 0.01 ~20% or so, preferably 0.1~5%
It is best to mix the ingredients so that the amount is the same.

As the base used in the present invention, a wide range of oil-based bases and water-soluble bases conventionally known in this field can be used as long as they do not themselves exhibit medicinal efficacy. Peanut oil, sesame oil, soybean oil, corn oil, rapeseed oil, menjitsu oil, castor oil, camellia oil, coconut oil, olive oil, poppy oil, cacao butter, lanolin fat, beef tallow,
Oils and fats such as squalane and wool fat; Modified oils and fats by chemical changes such as hydrogenation; Vaseline,
Mineral oils such as paraffin and silicone oil; isopropyl myristate, n-butyl myristate, isoprobilurate, cetyl lysyllate, stearyl lysyllate,
Higher fatty acid esters, higher fatty alcohols and waxes such as diethyl sebacate, diisopropyl adipate, cetyl alcohol, stearyl alcohol, white beeswax, gay wax, zero wax; higher aliphatic acids such as stearic acid, oleic acid, palmitic acid; carbon Numbers 12-18
Examples include mixtures of mono-, di-, and triglycerides of natural saturated fatty acids. Among these, the various vegetable oils mentioned above and mixtures of the mono-, di-, and triglycerides mentioned above are particularly suitable. Specific examples of the water-soluble base include polyethylene glycol, propylene glycol, glycerogelatin, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyvinyl polymer, and polyvinyl alcohol. In the present invention, these bases may be used alone or in combination of two or more.

The topical antibacterial agent of the present invention contains conventional additives such as water, surfactants, gelling agents, preservatives, antioxidants, buffers, pH
Conditioners, wetting agents, preservatives, colorants, fragrances, and the like can be added as appropriate.

The form of the external antibacterial agent of the present invention is not particularly limited, but ointment, cream, lotion, milky lotion, and gel forms are preferred, and ointment and cream forms are particularly preferred. These forms can be prepared according to conventional methods.

Effects of the Invention The external antibacterial agent of the present invention causes almost no irritation to the application site, has good skin permeability, and can exhibit excellent therapeutic effects.

EXAMPLES Below, Examples, Control Examples, and Test Examples are given to further clarify the present invention.

Example 1 Component I White petrolatum 10.0g Light liquid paraffin 9.0g Stearyl alcohol 4.0g Cetanol
4.0g polyoxyethylene cetyl ether3.
0g Ingredients Compound A 1.0g Glycerin 10.0g β-oxyethylamine 0.1g Purified water
58.9g of the above component (1) was heated to about 80°C and melted.

Separately, component (1) is dissolved and mixed, heated to about 80°C, and then mixed with component (2) and cooled to obtain a cream-form external antibacterial agent.

Example 2 Ingredients ■ White petrolatum 10.0g Light liquid paraffin 9.0g Stearyl alcohol 4.0g Cetanol
4.0g polyoxyethylene cetyl ether3.
0g Ingredient ■ Compound A 1. Og10.0
g 0.1g 58.9g External glycerin di(β-oxyethyl)amine purified water in the form of cream An antibacterial agent is obtained in the same manner as in Example 1 above.

Example 3 Ingredients ■ White petrolatum 10゜Light liquid paraffin 9゜Stearyl alcohol
4゜Cetanol 4゜Polyoxyethylene cetyl ether 3゜Ingredient ■ Compound A Sodium hydroxide Glycerin Di(β-oxyethyl)amine Sodium edetate 0,5g 0.056g 10.0g 0,36g 0,1g 0g 0g 0g 0g 0g 58 .984g Externally purified water in cream form An antibacterial agent is obtained in the same manner as in Example 1 above.

Example 4 Component I White petrolatum 10° Light liquid paraffin 9° Stearyl alcohol
4゜Cetanol 4.Polyoxyethylene cetyl ether 3゜Component ■ Compound A Sodium hydroxide Glycerin Di(β-oxyethyl)amine Sodium edetate Purified water Same as in Example 1 above 1.0g 0.112g 10.0g 0 , 36g 0, 1g 58.428g An antibacterial agent for external use in cream form is obtained.

Example 5 Component I White petrolatum 10° Light liquid paraffin 9° Stearyl alcohol
4゜Cetanol 4゜Polyoxyethylene Cetyl Ether 3゜Ingredient ■ Compound A Propylene glycol di(β-oxyethyl)amine Purified water An antibacterial agent is obtained in the same manner as in Example 1 above.

Example 6 Component I White petrolatum 10.0g 5.0g 10.0g 1.2g 53.8g Outside cream form 0g 0g 0g 0g 0g Light liquid paraffin 9° Stearyl alcohol 4° Setanol
4゜Polyoxyethylene cetyl ether 3゜Ingredient ■ Compound A Gunocerin tri(β-oxyethyl) Purified water An antibacterial agent is obtained in the same manner as in Example 1 above.

Example 7 Component I White petrolatum 10° Light liquid paraffin 9° Stearyl alcohol
4゜cetanol 4゜polyoxyethylene cetyl ether 3゜60g 10.0g Amine 5.0g 54.0g Outside cream form 0g 0g 0g 0g 0g 0g 0g 0g g Ingredients Compound A Sodium hydroxide glycerin tri(β-oxyethyl) Purified water An antibacterial agent was obtained in the same manner as in Example 1 above.

Example 8 White petrolatum Light liquid paraffin Setanol Cholesterol Compound A Sodium hydroxide Sodium propylene glycol di(β-oxyethyl)amiedetate 1.0 g 0.112 g 10.0 g Amine 20. Og 38.888g Cream-form Gain 73, 54g 10.0g 5.0g 4.0g 1,0g O,112g 5.0g 0.2g O, 1g Purified water 1.048g Heat each of the above ingredients to approximately 80°C After dissolving and mixing, the mixture is cooled to obtain a topical antibacterial agent in the form of an ointment.

Example 9 White petrolatum 83, 54g liquid paraffin 10.0g cetanol
5.0g cholesterol
4.0g Compound A
1.0g propylene glycol 5.0g di(β-oxyethyl)amine 0.2g polyethylene glycol 1500 10. Og sodium edetate 0.1g purified water
L, 16g A topical antibacterial agent in the form of an ointment is obtained in the same manner as in Example 8 above.

Example 10 Compound A 1.0g Hydroxyvinyl polymer 1.0g Hydroxyethyl cellulose 1.0g Propylene glycol
5.0g polyoxyethylene sorbitan monoester 0.5g ethanol 36.0g di(β-oxyethyl)amine 1.0g purified water
54.5 g After the above components except di(β-oxyethyl)amine are mixed uniformly, di(β-oxyethyl)amine is added dropwise to obtain an external antibacterial agent in the form of a gel ointment.

Example 11 Component I White petrolatum 6.5g Light liquid paraffin 6.0g Stearyl alcohol 2.5g Cetanol
2.5g polyoxyethylene cetyl ether2.
0g Ingredients Compound A 1.0g Sodium hydroxide O, 112g Di(β-oxyethyl)amine 0.36g Purified water
79.028g of the above ingredients are heated to about 80°C and melted. Separately, component (1) is dissolved and mixed, heated to about 80° C., and then mixed with component I and cooled to obtain a topical antibacterial agent in the form of an emulsion.

Example 12 Component I White petrolatum 74.4g Paraffin 3.0g Stearic acid
1.0g oleyl alcohol
5.0g Ingredients Compound A 1.0g Sodium hydroxide 0.25g Tri(β-oxyethyl)amine 0.5g Sodium edetate
0.1g purified water 14,
Heat 75 g of component I above to about 80° C. to melt. Separately, component (1) is dissolved and mixed, heated to about 80° C., and then mixed with component I and cooled to obtain an antibacterial agent for external use in the form of an ointment.

Example 13 Compound A 1.0g Isopropyl alcohol 62.4g Propylene glycol 2.5g Tri(β-oxyethyl)amine 0.4g Sodium hydroxide 0.2
g Purified water appropriate amount total amount 100
rrIQ The above components are dissolved and mixed to obtain an antibacterial agent for external use in the form of a lotion.

Control Example 1 Component I White petrolatum 10.0g Light liquid paraffin 9.0g Stearyl alcohol 480g Cetanol
4.0g polyoxyethylene cetyl ether 3.0
g Ingredients ■ Di(β-oxyethyl)amine 0, 38g Glycerin 10.0g Sodium hydroxide
O, 112g hydrochloric acid
0.261g Sodium edetate
0.1g purified water 59.167
g Heat the above component I to about 80° C. to melt it. Separately, component (1) is dissolved and mixed, heated to about 80° C., and then mixed with component I and cooled to obtain a cream-form external preparation.

Control Example 2 Component I White petrolatum 10.0g Light liquid paraffin 9.0g Stearyl alcohol 4.0g Cetanol
4.0g polyoxyethylene cetyl ether 3.0
g component ■ Compound A 1. 0g glycerin 10.0g sodium edetate 0.1g purified water
58.9g An external antibacterial agent in cream form is obtained in the same manner as in Control Example 1 above.

Test Example 1 (Antibacterial Comparison Test) Using male ICR mice, 6 mice were in the − group, their back hair was shaved with electric clippers for anesthetization, and a burn wound was created by applying an electric trowel at approximately 100°C. P, ae under the skin of the burn wound
A bacterial solution of S. ruginosa ATCC10145 was inoculated.

Using the external preparations obtained in Example 3, Example 4 and Control Example 1, these test drugs were administered once a day at 0, 21119/
It was applied to mice continuously for 5 days, and the number of viable bacteria in the burn wound was measured over time. The results are shown in Table 1 below.

As is clear from Table 1 above, the external antibacterial agent of the present invention showed a significant decrease in the number of bacteria and exhibited extremely good therapeutic effects.

Test Example 2 (Skin permeability test) The abdominal skin of an ICR mouse with its hair removed was placed in a Franz diffusion cell, and 3 g each of the external antibacterial agents obtained in Examples 4, 6, and Control Example 2 were applied. The sample was placed accurately, and the amount of compound A in the release diffusion layer that had passed through the skin was measured over time using 10% of phosphate buffer (pH 7.5) as the diffusion solution. The results are shown in Table 2 below.

Table 2 From Table 2 above, The topical antibacterial agent of the present invention has excellent It showed skin permeability.

Test Example 3 (-Sub-Irritation Test) Using the external antibacterial agents obtained in Examples 3, 4, and 8 above, and using white petrolatum as a control, the skin-sub-irritation test was conducted in the following manner. We conducted an evaluation. That is, methods such as heavy use [early use, etc., skin.

25 (4), 622-633 (1983)), a human batch test was conducted 48 hours after application and
．． Macroscopic findings after 2 hours are based on Japanese standards [materials, etc.

Journal of the Japanese Dermatological Association, 80 (5), 301-314
(1970)] and compared the irritating properties. The results are shown in Table 3 below.

Table 3 From Table 3 above, the external antibacterial agent of the present invention showed extremely weak primary irritation.

(that's all)

Claims (1)

[Claims] (1) 6,7-dihydro-9-fluoro-8-(4-hydroxy-1-piperidyl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolidine-2-carboxylic acid or It contains a salt thereof as an active ingredient, and has the general formula R^1R^2R^3N [wherein R^1, R^2 and R^3 each represent a hydrogen atom or a hydroxy lower alkyl group. However, R^1, R
^2 and R^3 are never hydrogen atoms at the same time. ] An external antibacterial agent characterized by containing a hydroxy lower alkylamine represented by: