JPH02204413A - Antimycotic agent for external use - Google Patents

Abstract

PURPOSE:To obtain an external preparation having excellent skin-penetrability, capable of transferring the drug component to not only corneum but also cuticle and corium and exhibiting excellent remedying effect against profound mycosis as well as latent mycosis by compounding liposome including an antimycotic agent as a main drug component. CONSTITUTION:An antimycotic agent (e.g. imidazole derivative or antibiotic substance) is dissolved in a solvent (e.g. alcohol or polyhydric alcohol). Ultrasonic vibration is applied to a mixture of the above solution, a phospholipid and water to obtain a liposome containing the antimycotic agent included in the membrane or microsome of the phospholipid. The liposome is compounded as a main drug component. The amount of the antimycotic agent included in the liposome is 0.01-10wt.%, preferably 0.1-5wt.% and the amount of the phospholipid to be used in the formation of liposome is 0.1-10 pts. per. 1 pt. of the antimycotic agent.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to an antifungal external preparation. For more details,
This is an antifungal topical preparation that has superior safety by containing an antifungal agent in liposome form as the main ingredient.When administered topically to the skin, transdermal absorption is increased and the drug is retained in the epidermis and dermis of the skin.

[Conventional technology]

As antifungal external preparations, cream liquid preparations containing undecylenic acid, salicylic acid, iodine, tolnaftate, clotrimazole, siccanin, etc. are known.

[Problem that the invention seeks to solve]

When an antifungal topical preparation is administered transdermally, sufficient drug efficacy cannot be expected because the amount of drug absorbed is small due to the barrier function of the skin's stratum corneum. In fact, it is effective only for the superficial 8 lines, where the parasitic site of dermatophytes remains in the first layer of the stratum corneum, and is completely ineffective against the deep dermatophytes that invade the skin below the dermis. Therefore, although the surface of the skin appears to have healed, there is a problem in that it recurs with skin turnover and is difficult to heal, and no effective means have yet been found.

[Means to solve the problem]

In view of these circumstances, the inventors of the present invention have conducted extensive research and found that by forming antifungal agents into liposomes and blending them as the main ingredient, skin permeability is good and the drug is able to penetrate not only the stratum corneum, but also the epidermis. The present invention was completed after recognizing that it reaches the dermis and exerts an excellent therapeutic effect not only on superficial mycoses but also on deep mycoses. The present invention relates to an antifungal external preparation containing cellulose liposomes as the main ingredient.

Antifungal agents used in the present invention include imidazole derivatives, antibiotics, and the like. Imidazole derivatives include clotrimazole, miconazole, econazole, and ketoconazole.

Imidazole derivatives have the effect of directly inhibiting fungal cell membranes and inhibiting ergosterol synthesis.
Its antibacterial spectrum extends to almost all fungi and some bacteria such as staphylococci, and its antibacterial activity is strong, making it widely used. In addition, among antibiotics, siccanine and virolnidrine are listed, and others include tolnaftate, tricyclate, cycloviroxolamine, salicylic acid,
Examples include iodine, exalamide, and undecylenic acid.

The liposome of the present invention is obtained by applying ultrasound to three components: an antifungal agent dissolved in a solvent, a phospholipid, and water. This liposome is a spherical endoplasmic reticulum consisting of a single or multilayered phospholipid bilayer membrane, and the antifungal agent is incorporated into the phospholipid membrane or within the endoplasmic reticulum (inner vesicle).

Solvents that dissolve antifungal agents include alcohol, polyhydric alcohol, and the like. Alcohols include ethanol, propatool, isopropatool, etc.
Polyhydric alcohol is polyethylene glycol 300
, polyethylene glycol 400, polyethylene glycol 600, glycerin, 1,3-butylene glycol, propylene glycol, and the like. Other examples include isopropyl myristate, crotamiton, acetone, and methyl ethyl ketone.

In addition, there are other methods for creating liposomes, such as the Vortex mixer method, thin film mffff agent removal method, injection method, and French press melon reverse phase evaporation method, which can be selected as appropriate depending on the properties of the antifungal agent to prepare liposomes. Just mix it up. Furthermore, for the purpose of stabilizing the liposome, cholesterol, glucose, amino acids, higher alcohols, nonionic surfactants, ionic surfactants, etc. can be added.

The phospholipids used for liposome formation are soybean phospholipids,
These include egg yolk phospholipids, hydrogenated soybean phospholipids, hydrogenated egg yolk phospholipids, synthetic phospholipids, etc., and they can be used alone or in combination of two or more.

In the present invention, the antifungal agent contained in the liposome is added in a proportion of 0.01 to 10% by weight in consideration of pharmacological activity. Preferably 0°1~5! is added in a proportion of %. The phospholipid used for liposomalization is 0.0% against antifungal agents. Blend so that the concentration is 1 to 10 times the amount. If the concentration of antifungal agent is less than 0.01% by weight, no effect can be expected;
It is difficult to form liposomes with the above amount. In addition, phospholipids have a 0.0% resistance to antifungal agents. If the concentration is less than 1 times the amount, it is not possible to form all the antifungal agent into liposomes, and if the amount is 10 times or more, there are too many phospholipids and it is difficult to form them into liposomes.

The L D se of the antifungal agents for mice was all 1000 mg/kg or more.

〔Example〕

Next, the present invention will be further explained with reference to Examples, but the present invention is not limited thereto. The numbers in the formulations indicate weight %.

Example-1 Cream ■ Squalane 9. 0■Stearyl alcohol 0. 5■Yacyl alcohol 065■Polyoxyethylene (20) sorbitan monostearate
1.5■ Sorbitan monooleate
2.3■ Octyldodecyl myristate
8.5 ■ Vaseline 4
,0 ■ Purified water 33.8 ■
Crotamiton 5.0 [phase]
Polyethylene glycol 400 5.0 ■ Tolnaftate 3.0 @ Hydrogenated soybean phospholipid 9. 017.9 Total 100.0 Ingredient ■ [Phase] With ultrasonic stirring, ribbon component ■ Tolnaftate is added to component 00 to prepare -mu.

After heating and dissolving components (1) to (2) at 80°C, component (2) previously heated and dissolved at 80°C is added to emulsify and cooled to 30'C. Add the liposomes prepared with ingredients ① to ＠ to this and stir and mix to obtain a cream.

Example-2 Liquid ■Ethanol 5.0■
Purified water 53.5 ■ Ethanol 10.0 ■ Clotrimazole 1.0 ■ Hydrogenated soybean phospholipid 7,023.5 Total 100.0 Ingredient ■ clotrimazole dissolved in component ■, ingredient ■ Component (1) is added to the solution heated and dissolved at 70°C and stirred ultrasonically to prepare liposomes. Next, component (2) is added to obtain the liposome.

Example-3 Liquid ■Ethanol 10.0■
Glycerin 4.0■1,3
-Butylene glycol 3.0 ■Purified water
40.9 ■ Hydrogenated egg yolk phospholipid 3.5 ■ Cholesterol
0. 1■ Shitsukanin
0.5 ■ Isopropyl alcohol
14.024.0 Total 100.0 Ingredients (■) are dissolved in ether and placed in an eggplant-shaped flask.The ether is distilled off using an evaporator. Add component (■) to this and stir at 60°C. Next, dissolve component (■) and cool it to 30°C to prepare liposomes. Add the prepared liposome and stir to mix to obtain a liquid preparation.

Example-4 Cream ■ Squalane 7.0 ■ Octyldodecyl myristate 5.0 ■ White beeswax 3.0 ■ Liquid paraffin 2.0 ■ Glycerin
2.0 ■ Sorbitan monooleate 2.5 ■ Polyoxyethylene (15)
Cetyl ether 1.5 ■ Purified water 45. 0 ■ Hydrogenated egg yolk lecithin 6.0 [Phase] Polyoxyethylene (60) Hydrogenated castor oil
0. 5 ■ Miconazole
26023.5 Total 100.0 Ingredients ■ Miconazole, ■ [Phase] are dissolved in component @, and liposomes are prepared by applying ultrasound.

After heating and dissolving components (1) to (2) at 80°C, component (2), which had been previously heated and dissolved at 85°C, was added to emulsify and cooled to 30°C. Add the liposomes prepared with ingredients ① to ＠ to this and stir and mix to obtain a cream.

[Effects of the Invention] The effects of the present invention are that, by forming an antifungal agent into liposomes and blending them as the main agent, during topical treatment of the skin, the transdermal absorption of the main agent is increased, and it is stored in the surface and dermis of the skin, resulting in an excellent It is an antifungal topical preparation that exhibits medicinal efficacy.

Next, we will examine the effects of the present invention through animal experiments, concentration distribution tests, and
The results of clinical and culture tests are shown.

(Animal experiment) For the cream of Example-1 and the cream of Comparative Example-1 below, 20 guinea pigs each were treated with Tri, a dermatophyte, on the backs of 10×10 crrf of guinea pigs whose hair had been shaved two days earlier.
Suspension of chophyton Rubrum 0. 5m
1 was applied gently to infect the patient. This suspension is suitable for infection 24
A fungal suspension exhibiting an absorbance of 0.4 before time and Nervi
It was prepared by mixing na nutrient broth at a ratio of 2=1 and incubated at 28°C. For treatment, 1 g of the creams of Example-1 and Comparative Example-1 were administered to the infected site once a day for 7 days from the third day after infection, and changes in the condition of the infected site were visually observed. The results are shown in Table 1.

Comparative Example-1 Cream A cream was prepared in the same manner as in Example-1 by adding component (2) to the cream of Example-1 without forming it into liposomes.

From the results in Table ], it was found that the cream containing the antifungal agent tolnaftate in liposomes was effective against the dermatophyte Tri.
It shows good curative effects against ehophyton Rubrum I and 2, and is effective as an antifungal external preparation. Similar results were also obtained in Examples 2, 3, and 4.

Table 1 Animal experiment results (concentration distribution test) 14c for the liquid formulations of Example-2 and Comparative Example-2 below
Skin permeation PL using clotrimaseal labeled with
Regarding concentration distribution and percutaneous absorption, 0.5 ml was applied to 5 x 10 cnf on the shaved back of a rat, and 12
The concentration distribution after being allowed to act for a period of time was measured by autoradiography. The results are shown in Figure 2.

Comparative Example-2 Example-2J: Ingredient ■■ was dissolved in the lipolytic component ■, without forming liposomes, and blended as it was with the component ■■■.Example-2
Prepared in the same manner.

From the results in Table 42, the liquid formulation containing the antifungal agent clotrimazole in liposome has excellent transdermal absorption.It reaches the epidermis and dermis of the skin. It is also found to be effective in treating diseases. In addition, Example-1
, 3 and 4 also gave similar good results.

Space 9 below 2. Concentration distribution in tissues (clinical trial) For the clinical trial, volunteers were recruited, among whom were those who had albinism and were positive for the bacteria on speculum.
For 8 people, an appropriate amount of the solution of Example 3 and Comparative Example 3 below for foot whitening was administered to the infected area twice a day, and the observation period was set at 2 weeks. . Regarding side effects, as well as contact dermatitis, application
), the sensation of irritation, irritation, and itching were also described. The results are shown in Mugi 3 and 4.

Comparative Example-3 A liquid preparation was prepared in the same manner as in Example-3 by blending component (1) from the liquid preparation of Example-3 as it was without forming it into liposomes. Based on the results shown in Table 3.4, the antifungal agent siccanin was formed into liposomes and blended. The results show that it has an excellent curative effect on foot whitening and has few side effects. Further, Examples 1, 2, and 4 also showed good results.

Below margin table.

Effect judgment table.

Blank space below side effects (culture test) For the cream of Example 4 and the cream of Comparative Example 4 below, 1010 x 20' of the backs of 10 rabbits each, whose hair had been shaved one day earlier, were treated with Candidiasis candidum.
a. albicans at 1 to 3 x 10 per 1 m
2 ml of a solution containing 3 cells was applied and infected.

Treatment was carried out twice a day for 10 days starting from the second day after infection.
4 and Comparative Example-4 were administered to the infected area. After that, the skin was peeled off and a part of the epidermal tissue and dermal tissue was cultured to detect bacteria. The culture results were as follows:
Judgments were made on the 5th, 7th, 14th, and 28th days (culture days).

Table 5 shows the number of plots where Candida albicans was found.

Comparative Example-4 Cream A cream was prepared in the same manner as in Example-4 except that component (1) was added to the cream of Example-4 without forming it into liposomes.

From the results in Table 5, it can be seen that by blending the antifungal agent miconazole in the form of liposomes, less Cancita bacteria was detected in the skin and a good healing effect was exhibited. Also,
Similar results were obtained in Examples 1, 2, and 3.

table.

Culture test results

Claims (1)

[Claims] An antifungal external preparation characterized by containing liposomes containing an antifungal agent as the main ingredient.