JP2863811B2 - Antifungal composition - Google Patents

Description

The present invention relates to an antifungal composition.

[Conventional technology and its problems]

BACKGROUND ART Conventionally, various antifungal agents have been used in the treatment of superficial mycosis such as ringworm, candida and scar, and deep mycosis such as Candida and coccidioides.

However, the conventionally used antifungal agents, for example, have a problem that, when used externally, itching and rashes occur; when taken internally, injections and the like cause side effects such as nausea and vomiting and abnormal liver function.

For this reason, development of a highly safe antifungal agent without side effects has been desired.

[Means for solving the problem]

Under such circumstances, the present inventors have conducted intensive studies for the purpose of reducing the side effects while maintaining the efficacy of the conventional antifungal agent, and as a result, obtained by enzymatic degradation of colistin, the antifungal action itself It has been found that the combined use of a cyclic peptide having no antibacterial activity and an antifungal substance enhances the antifungal activity and provides an excellent antimycotic composition, thereby completing the present invention.

That is, the present invention provides an antifungal composition comprising one or more peptides selected from colistin octapeptide, colistin nonapeptide and colistin decapeptide, and an antifungal substance. .

Examples of the antifungal substance used in the present invention include azole antifungal agents such as clotrimazole, miconazole, ketoconazole, terconazole, econazole, thioconazole, oxyconazole, bifonazole; polyene antifungals such as amphotericin B and nystatin; Fungal antibiotics and the like can be mentioned, and clotrimazole is particularly preferred.

The colistin octapeptide, colistin nonapeptide and colistin decapeptide used in the present invention are:
For example, Japanese Patent Publication No. 46-4178, CHIHARA, S. et al., Agri
c. Biol. Chem., 37 , 2445-2463 (1973). Of these, colistin nonapeptide is particularly preferred. These peptides can be used alone or in combination of two or more.

The compounding ratio of the antifungal substance and the peptide to the antifungal composition of the present invention is preferably from 1:10 to 1: 5000. In this range, the same effect can be obtained when the amount of the antifungal substance used is 1/2 to 1/67 of that when used alone.

The antifungal composition of the present invention includes, in addition to the above essential components, components used in ordinary antifungal compositions, for example, organic acids such as citric acid, benzoic acid, salicylic acid, and lactic acid;
Excipients such as sucrose, lactose, starch, crystalline cellulose, carboxymethylcellulose sodium salt and the like; oils such as ethanol, cetanol, soybean oil, orange oil, lanolin, cocoa butter and the like can be blended as required.

The antifungal composition of the present invention can be produced by a usual method, for example, creams, ointments, external preparations such as vaginal suppositories, tablets, powders, oral preparations such as syrups, and dosage forms such as injections. can do. Examples of oils used for preparing external preparations such as creams, ointments, suppositories and the like include ethanol, cetanol, glycerin, soybean oil, olive oil, witepsol, petrolatum, cocoa butter and the like. Examples of the emulsifier used in preparing the cream include polyoxyethylene glycol alkyl ether, alkyl sulfates, lecithin, pectin and the like. In preparing an injection, ethanol, propylene glycol,
Dissolution aids such as macrogol and sodium deoxycholate can also be used.

[Action]

The minimum growth inhibitory concentration against various fungi was measured when various antifungal agents were used in combination with colistin-derived peptides.

(1) Bmmon's modified sublobe loss (ESB) as medium
The drug at each concentration was added to a solution to which a colistin-derived peptide was added to 20 μg / ml and a solution to which no peptide was added, and mixed uniformly. Then, Saccharomyces cere
Visiae Society No. 6 or a 100-fold dilution of a liquid culture of Candida albicans IFO 1385 was inoculated, cultured at 37 ° C. for 72 hours, and the minimum inhibitory concentration was determined by a turbidity method. Table 1 shows the results.

As a colistin-derived peptide (CLNP), colistin obtained by enzymatic degradation according to the method described in Agric. Biol. Chem. 37 , 2455 to 2463 (1973) was used (the same applies hereinafter). Its composition was colistin octapeptide: colistin nonapeptide: colistin decapeptide = 1: 2: 1.

(2) In the same manner as (1) except that clotrimazole was used as a drug and the strains shown in Table 2 were used as test bacteria,
The minimum inhibitory concentration was determined. Table 2 shows the results.

(3) 0.2% of a liquid culture of Saccharomyces cerevisiae Association No. 6 or Candida albicans IFO 1385 as a test bacterium on the antifungal activity Sabouraud agar medium by pulp disk method.
Inoculated and flattened.

6 mm pulp impregnated with the drug is grounded on this plate,
After culturing at 24 ° C. for 24 hours, the inhibition circle was measured.

As is clear from Table 1, Table 2 and Table 3, the combined use of CLNP resulted in 2-67 more than the case where the drug was used alone.
A two-fold increase in activity was observed.

〔The invention's effect〕

The antifungal agent composition of the present invention, by using a combination of an antifungal substance and colistin nonapeptide, colistin octapeptide, colistin decapeptide, etc., the activity of the antifungal substance is increased, and the amount conventionally used is reduced. 1 / 2〜1 / 67
It is possible to reduce to. Therefore, since the dose of the drug is reduced, side effects can be reduced, and those used only as an external preparation such as an azole antifungal agent can be administered orally or as an injection. It has become possible. Furthermore, it is also effective in treating deep mycosis that is increasing due to opportunistic infections.

〔Example〕

 Example 1 Powder: A powder having the following composition was produced by a conventional method.

Nystatin 200,000 units (about 50 mg) CLNP 1000 mg Hydroxypropylcellulose 5 mg Lactose 300 mg Maize starch 145 mg Total 1500 mg Example 2 Injection: An injection having the following composition was produced by a conventional method.

Amphotericin B 1 mg CLNP 500 mg Sodium deococcholate 1 mg Water was added and dissolved to give a lyophilized product.

Dissolve the product in distilled water or 10 ml of 5% glucose injection, add to 500 ml of 5% glucose injection and inject intravenously.

Example 3 Cream: A cream having the following composition was produced by a conventional method.

Miconazole 2.5g CLNP 500g Methyl salicylate 10g Cetanol 50g Propylene glycol 50g Twin 80 20g Span 80 10g Methyl paraben 1g Refined water 356.5g Total 1000g Example 4 Vaginal suppository: Vaginal suppository of the following composition The preparation was manufactured by a conventional method.

Clotrimazole 0.005 g CLNP 0.4 g Macrogol 0.2 g Witepsol 1.395 g Total 2.0 g Example 5 Ointment An ointment having the following composition was produced by a conventional method.

Clotrimazole 1g CLNP 500g Methyl salicylate 10g White petrolatum 470g Liquid paraffin 19g Total 1000g

Continuation of front page (56) References JP-A-52-154521 (JP, A) JP-A-49-31688 (JP, A) JP-B-46-4178 (JP, B2) International Publication 89/5139 (WO, A1) International Publication No. 84/4249 (WO, A1) French Patent 2624018 (FR, A) French Patent 2624017 (FR, A) French Patent 2624016 (FR, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) A61K 45/00 A61K 37/02 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. An antifungal composition comprising one or more peptides selected from colistin octapeptide, colistin nonapeptide and colistin decapeptide, and an antifungal substance.